Sample records for reward circuitry function
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Reward Circuitry Function in Autism during Face Anticipation and Outcomes
ERIC Educational Resources Information Center
Dichter, Gabriel S.; Richey, J. Anthony; Rittenberg, Alison M.; Sabatino, Antoinette; Bodfish, James W.
2012-01-01
The aim of this study was to investigate reward circuitry responses in autism during reward anticipation and outcomes for monetary and social rewards. During monetary anticipation, participants with autism spectrum disorders (ASDs) showed hypoactivation in right nucleus accumbens and hyperactivation in right hippocampus, whereas during monetary…
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Lighting up the brain's reward circuitry.
Lobo, Mary Kay
2012-07-01
The brain's reward circuit is critical for mediating natural reward behaviors including food, sex, and social interaction. Drugs of abuse take over this circuit and produce persistent molecular and cellular alterations in the brain regions and their neural circuitry that make up the reward pathway. Recent use of optogenetic technologies has provided novel insights into the functional and molecular role of the circuitry and cell subtypes within these circuits that constitute this pathway. This perspective will address the current and future use of light-activated proteins, including those involved in modulating neuronal activity, cellular signaling, and molecular properties in the neural circuitry mediating rewarding stimuli and maladaptive responses to drugs of abuse. © 2012 New York Academy of Sciences.
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Plasticity of reward neurocircuitry and the 'dark side' of drug addiction.
Koob, George F; Le Moal, Michel
2005-11-01
Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a 'dark side'--a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction.
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Reward from bugs to bipeds: a comparative approach to understanding how reward circuits function
Scaplen, Kristin M.; Kaun, Karla R.
2016-01-01
Abstract In a complex environment, animals learn from their responses to stimuli and events. Appropriate response to reward and punishment can promote survival, reproduction and increase evolutionary fitness. Interestingly, the neural processes underlying these responses are remarkably similar across phyla. In all species, dopamine is central to encoding reward and directing motivated behaviors, however, a comprehensive understanding of how circuits encode reward and direct motivated behaviors is still lacking. In part, this is a result of the sheer diversity of neurons, the heterogeneity of their responses and the complexity of neural circuits within which they are found. We argue that general features of reward circuitry are common across model organisms, and thus principles learned from invertebrate model organisms can inform research across species. In particular, we discuss circuit motifs that appear to be functionally equivalent from flies to primates. We argue that a comparative approach to studying and understanding reward circuit function provides a more comprehensive understanding of reward circuitry, and informs disorders that affect the brain’s reward circuitry. PMID:27328845
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Vythilingam, Meena; Nelson, Eric E.; Scaramozza, Matthew; Waldeck, Tracy; Hazlett, Gary; Southwick, Steven M.; Pine, Daniel S.; Drevets, Wayne; Charney, Dennis S.; Ernst, Monique
2008-01-01
Enhanced brain reward function could contribute to resilience to trauma. Reward circuitry in active duty, resilient special forces (SF) soldiers was evaluated using fMRI during a monetary incentive delay task. Findings in this group of resilient individuals revealed unique patterns of activation during expectation of reward in the subgenual prefrontal cortex and nucleus accumbens area; regions pivotal to reward processes. PMID:19243926
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Blum, Kenneth; Gardner, Eliot; Oscar-Berman, Marlene; Gold, Mark
2012-01-01
In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: "liking,"learning," and "wanting" [1]. That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or "wanting" hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily selfadministered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens (NAC), and they stimulate the functioning of brain reward circuitry (producing the "high" that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions.
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Reward Circuitry in Addiction.
Cooper, Sarah; Robison, A J; Mazei-Robison, Michelle S
2017-07-01
Understanding the brain circuitry that underlies reward is critical to improve treatment for many common health issues, including obesity, depression, and addiction. Here we focus on insights into the organization and function of reward circuitry and its synaptic and structural adaptations in response to cocaine exposure. While the importance of certain circuits, such as the mesocorticolimbic dopamine pathway, are well established in drug reward, recent studies using genetics-based tools have revealed functional changes throughout the reward circuitry that contribute to different facets of addiction, such as relapse and craving. The ability to observe and manipulate neuronal activity within specific cell types and circuits has led to new insight into not only the basic connections between brain regions, but also the molecular changes within these specific microcircuits, such as neurotrophic factor and GTPase signaling or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function, that underlie synaptic and structural plasticity evoked by drugs of abuse. Excitingly, these insights from preclinical rodent work are now being translated into the clinic, where transcranial magnetic simulation and deep brain stimulation therapies are being piloted in human cocaine dependence. Thus, this review seeks to summarize current understanding of the major brain regions implicated in drug-related behaviors and the molecular mechanisms that contribute to altered connectivity between these regions, with the postulation that increased knowledge of the plasticity within the drug reward circuit will lead to new and improved treatments for addiction.
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Dichter, Gabriel S; Damiano, Cara A; Allen, John A
2012-07-06
This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.
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2012-01-01
This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies. PMID:22958744
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Blum, Kenneth; Gardner, Eliot; Oscar-Berman, Marlene; Gold, Mark
2013-01-01
In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: “liking,” “learning,” and “wanting” [1]. That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or “wanting” hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily self-administered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens, and they stimulate the functioning of brain reward circuitry (producing the “high” that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions. PMID:22236117
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Castro, Daniel C.; Cole, Shannon L.; Berridge, Kent C.
2015-01-01
The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (“liking”) and motivational incentive salience (“wanting”) of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including “liking” and “wanting” for food rewards. PMID:26124708
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Reward system dysfunction in autism spectrum disorders
Schulte-Rüther, Martin; Nehrkorn, Barbara; Müller, Kristin; Fink, Gereon R.; Kamp-Becker, Inge; Herpertz-Dahlmann, Beate; Schultz, Robert T.; Konrad, Kerstin
2013-01-01
Although it has been suggested that social deficits of autism spectrum disorders (ASDs) are related to reward circuitry dysfunction, very little is known about the neural reward mechanisms in ASD. In the current functional magnetic resonance imaging study, we investigated brain activations in response to both social and monetary reward in a group of children with ASD, relative to matched controls. Participants with ASD showed the expected hypoactivation in the mesocorticolimbic circuitry in response to both reward types. In particular, diminished activation in the nucleus accumbens was observed when money, but not when social reward, was at stake, whereas the amygdala and anterior cingulate cortex were hypoactivated within the ASD group in response to both rewards. These data indicate that the reward circuitry is compromised in ASD in social as well as in non-social, i.e. monetary conditions, which likely contributes to atypical motivated behaviour. Taken together, with incentives used in this study sample, there is evidence for a general reward dysfunction in ASD. However, more ecologically valid social reward paradigms are needed to fully understand, whether there is any domain specificity to the reward deficit that appears evident in ASD, which would be most consistent with the ASD social phenotype. PMID:22419119
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Bradley, Kailyn A L; Case, Julia A C; Freed, Rachel D; Stern, Emily R; Gabbay, Vilma
2017-07-01
There has been growing interest under the Research Domain Criteria initiative to investigate behavioral constructs and their underlying neural circuitry. Abnormalities in reward processes are salient across psychiatric conditions and may precede future psychopathology in youth. However, the neural circuitry underlying such deficits has not been well defined. Therefore, in this pilot, we studied youth with diverse psychiatric symptoms and examined the neural underpinnings of reward anticipation, attainment, and positive prediction error (PPE, unexpected reward gain). Clinically, we focused on anhedonia, known to reflect deficits in reward function. Twenty-two psychotropic medication-free youth, 16 with psychiatric symptoms, exhibiting a full range of anhedonia, were scanned during the Reward Flanker Task. Anhedonia severity was quantified using the Snaith-Hamilton Pleasure Scale. Functional magnetic resonance imaging analyses were false discovery rate corrected for multiple comparisons. Anticipation activated a broad network, including the medial frontal cortex and ventral striatum, while attainment activated memory and emotion-related regions such as the hippocampus and parahippocampal gyrus, but not the ventral striatum. PPE activated a right-dominant fronto-temporo-parietal network. Anhedonia was only correlated with activation of the right angular gyrus during anticipation and the left precuneus during PPE at an uncorrected threshold. Findings are preliminary due to the small sample size. This pilot characterized the neural circuitry underlying different aspects of reward processing in youth with diverse psychiatric symptoms. These results highlight the complexity of the neural circuitry underlying reward anticipation, attainment, and PPE. Furthermore, this study underscores the importance of RDoC research in youth. Copyright © 2016 Elsevier B.V. All rights reserved.
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Dopamine homeostasis: brain functional connectivity in reward deficiency syndrome.
Febo, Marcelo; Blum, Kenneth; Badgaiyan, Rajendra D; Baron, David; Thanos, Panayotis K; Colon-Perez, Luis M; Demortrovics, Zsolt; Gold, Mark S
2017-01-01
Reward deficiency syndrome (RDS) was first proposed by Kenneth Blum in 1995 to provide a clinically relevant and predictive term for conditions involving deficits in mesocorticolimbic dopamine function. Genetic, molecular, and neuronal alterations in key components of this circuitry contribute to a reward deficit state that can drive drug-seeking, consumption, and relapse. Among the dysfunctions observed in RDS are dysregulated resting state networks, which recently have been assessed in detail in chronic drug users by, positron emission tomography, functional magnetic resonance imaging, and functional connectivity analysis. A growing number of studies are helping to determine the putative roles of dopamine and glutamatergic neurotransmission in the regulation of activity in resting state networks, particularly in brain reward circuitry affected in drug use disorders. Indeed, we hypothesize in the present review that loss of homeostasis of these systems may lead to 'unbalanced' functional networks that might be both cause and outcome of disrupted synaptic communication between cortical and subcortical systems essential for controlling reward, emotional control, sensation seeking, and chronic drug use.
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The Brain Reward Circuitry in Mood Disorders
Russo, Scott J.; Nestler, Eric J.
2013-01-01
Mood disorders are common and debilitating conditions characterized in part by profound deficits in reward-related behavioral domains. A recent literature has identified important structural and functional alterations within the brain’s reward circuitry —particularly in the ventral tegmental area to nucleus accumbens pathway — that are associated with symptoms such as anhedonia and aberrant reward-associated perception and memory. This review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression. We also discuss some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms. PMID:23942470
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Reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder.
Marsh, Rachel; Tau, Gregory Z; Wang, Zhishun; Huo, Yuankai; Liu, Ge; Hao, Xuejun; Packard, Mark G; Peterson, Bradley S; Simpson, H Blair
2015-04-01
The authors assessed the functioning of mesolimbic and striatal areas involved in reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder (OCD). Functional MRI blood-oxygen-level-dependent response was compared in 33 unmedicated adults with OCD and 33 healthy, age-matched comparison subjects during a reward-based learning task that required learning to use extramaze cues to navigate a virtual eight-arm radial maze to find hidden rewards. The groups were compared in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudorandomly to experimentally prevent learning. Both groups learned to navigate the maze to find hidden rewards, but group differences in neural activity during navigation and reward processing were detected in mesolimbic and striatal areas. During navigation, the OCD group, unlike the healthy comparison group, exhibited activation in the left posterior hippocampus. Unlike healthy subjects, participants in the OCD group did not show activation in the left ventral putamen and amygdala when anticipating rewards or in the left hippocampus, amygdala, and ventral putamen when receiving unexpected rewards (control condition). Signal in these regions decreased relative to baseline during unexpected reward receipt among those in the OCD group, and the degree of activation was inversely associated with doubt/checking symptoms. Participants in the OCD group displayed abnormal recruitment of mesolimbic and ventral striatal circuitry during reward-based spatial learning. Whereas healthy comparison subjects exhibited activation in this circuitry in response to the violation of reward expectations, unmedicated OCD participants did not and instead over-relied on the posterior hippocampus during learning. Thus, dopaminergic innervation of reward circuitry may be altered, and future study of anterior/posterior hippocampal dysfunction in OCD is warranted.
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Schreiter, S; Spengler, S; Willert, A; Mohnke, S; Herold, D; Erk, S; Romanczuk-Seiferth, N; Quinlivan, E; Hindi-Attar, C; Banzhaf, C; Wackerhagen, C; Romund, L; Garbusow, M; Stamm, T; Heinz, A; Walter, H; Bermpohl, F
2016-11-01
Bipolar disorder (BD), with the hallmark symptoms of elevated and depressed mood, is thought to be characterized by underlying alterations in reward-processing networks. However, to date the neural circuitry underlying abnormal responses during reward processing in BD remains largely unexplored. The aim of this study was to investigate whether euthymic BD is characterized by aberrant ventral striatal (VS) activation patterns and altered connectivity with the prefrontal cortex in response to monetary gains and losses. During functional magnetic resonance imaging 20 euthymic BD patients and 20 age-, gender- and intelligence quotient-matched healthy controls completed a monetary incentive delay paradigm, to examine neural processing of reward and loss anticipation. A priori defined regions of interest (ROIs) included the VS and the anterior prefrontal cortex (aPFC). Psychophysiological interactions (PPIs) between these ROIs were estimated and tested for group differences for reward and loss anticipation separately. BD participants, relative to healthy controls, displayed decreased activation selectively in the left and right VS during anticipation of reward, but not during loss anticipation. PPI analyses showed decreased functional connectivity between the left VS and aPFC in BD patients compared with healthy controls during reward anticipation. This is the first study showing decreased VS activity and aberrant connectivity in the reward-processing circuitry in euthymic, medicated BD patients during reward anticipation. Our findings contrast with research supporting a reward hypersensitivity model of BD, and add to the body of literature suggesting that blunted activation of reward processing circuits may be a vulnerability factor for mood disorders.
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Life stress in adolescence predicts early adult reward-related brain function and alcohol dependence
Shaw, Daniel S.; Sitnick, Stephanie L.; Musselman, Samuel C.; Forbes, Erika E.
2015-01-01
Stressful life events increase vulnerability to problematic alcohol use, and they may do this by disrupting reward-related neural circuitry. This is particularly relevant for adolescents because alcohol use rises sharply after mid-adolescence and alcohol abuse peaks at age 20. Adolescents also report more stressors compared with children, and neural reward circuitry may be especially vulnerable to stressors during adolescence because of prefrontal cortex remodeling. Using a large sample of male participants in a longitudinal functional magnetic resonance imaging study (N = 157), we evaluated whether cumulative stressful life events between the ages of 15 and 18 were associated with reward-related brain function and problematic alcohol use at age 20 years. Higher cumulative stressful life events during adolescence were associated with decreased response in the medial prefrontal cortex (mPFC) during monetary reward anticipation and following the receipt of monetary rewards. Stress-related decreases in mPFC response during reward anticipation and following rewarding outcomes were associated with the severity of alcohol dependence. Furthermore, mPFC response mediated the association between stressful life events and later symptoms of alcohol dependence. These data are consistent with neurobiological models of addiction that propose that stressors during adolescence increase risk for problematic alcohol use by disrupting reward circuit function. PMID:24795442
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Altered functioning of reward circuitry in youth offspring of parents with bipolar disorder.
Manelis, A; Ladouceur, C D; Graur, S; Monk, K; Bonar, L K; Hickey, M B; Dwojak, A C; Axelson, D; Goldstein, B I; Goldstein, T R; Bebko, G; Bertocci, M A; Gill, M K; Birmaher, B; Phillips, M L
2016-01-01
Offspring of parents with bipolar disorder (BD) (BO) are at higher risk of BD than offspring of parents with non-BD psychopathology (NBO), although both groups are at higher risk than offspring of psychiatrically healthy parents (HC) for other affective and psychiatric disorders. Abnormal functioning in reward circuitry has been demonstrated previously in individuals with BD. We aimed to determine whether activation and functional connectivity in this circuitry during risky decision-making differentiated BO, NBO and HC. BO (n = 29; mean age = 13.8 years; 14 female), NBO (n = 28; mean age = 13.9 years; 12 female) and HC (n = 23; mean age = 13.7 years; 11 female) were scanned while performing a number-guessing reward task. Of the participants, 11 BO and 12 NBO had current non-BD psychopathology; five BO and four NBO were taking psychotropic medications. A 3 (group) × 2 (conditions: win-control/loss-control) analysis of variance revealed a main effect of group on right frontal pole activation: BO showed significantly greater activation than HC. There was a significant main effect of group on functional connectivity between the bilateral ventral striatum and the right ventrolateral prefrontal cortex (Z > 3.09, cluster-p < 0.05): BO showed significantly greater negative functional connectivity than other participants. These between-group differences remained after removing youth with psychiatric disorders and psychotropic medications from analyses. This is the first study to demonstrate that reward circuitry activation and functional connectivity distinguish BO from NBO and HC. The fact that the pattern of findings remained when comparing healthy BO v. healthy NBO v. HC suggests that these neuroimaging measures may represent trait-level neurobiological markers conferring either risk for, or protection against, BD in youth.
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Jager, Gerry; Block, Robert I.; Luijten, Maartje; Ramsey, Nick F.
2013-01-01
Adolescents' risk-taking behavior has been linked to a maturational imbalance between reward (“go”) and inhibitory-control (“stop”) related brain circuitry. This may drive adolescent drug-taking, such as cannabis use. In this study we assessed the non-acute effects of adolescent cannabis use on reward-related brain function. We performed a two-site (United States and Netherlands; pooled data) functional magnetic resonance imaging (fMRI) study with a cross-sectional design. Twenty-one abstinent but frequent cannabis-using boys were compared with 24 non-using peers on reward-related brain function, using a monetary incentive delay task with fMRI. Focus was on anticipatory and response stages of reward and brain areas critically involved in reward processing like the striatum. Performance in users was normal. Region-of-interest analysis indicated striatal hyperactivity during anticipatory stages of reward in users. Intriguingly, this effect was most pronounced during non-rewarding events. Striatal hyperactivity in adolescent cannabis users may signify an overly sensitive motivational brain circuitry. Frequent cannabis use during adolescence may induce diminished ability to disengage the motivational circuit when no reward can be obtained. This could strengthen the search for reinforcements like drugs of abuse, even when facing the negative (non-rewarding) consequences. PMID:23909003
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Jager, Gerry; Block, Robert I; Luijten, Maartje; Ramsey, Nick F
2013-01-01
Adolescents' risk-taking behavior has been linked to a maturational imbalance between reward ("go") and inhibitory-control ("stop")-related brain circuitry. This may drive adolescent drug-taking, such as cannabis use. In this study, we assessed the non-acute effects of adolescent cannabis use on reward-related brain function. We performed a two-site (United States and Netherlands; pooled data) functional magnetic resonance imaging (fMRI) study with a cross-sectional design. Twenty-one abstinent but frequent cannabis-using boys were compared with 24 non-using peers on reward-related brain function, using a monetary incentive delay task with fMRI. Focus was on anticipatory and response stages of reward and brain areas critically involved in reward processing like the striatum. Performance in users was normal. Region-of-interest analysis indicated striatal hyperactivity during anticipatory stages of reward in users. Intriguingly, this effect was most pronounced during non-rewarding events. Striatal hyperactivity in adolescent cannabis users may signify an overly sensitive motivational brain circuitry. Frequent cannabis use during adolescence may induce diminished ability to disengage the motivational circuit when no reward can be obtained. This could strengthen the search for reinforcements like drugs of abuse, even when facing the negative (non-rewarding) consequences.
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Phillips, Mary L; Swartz, Holly A.
2014-01-01
Objective This critical review appraises neuroimaging findings in bipolar disorder in emotion processing, emotion regulation, and reward processing neural circuitry, to synthesize current knowledge of the neural underpinnings of bipolar disorder, and provide a neuroimaging research “roadmap” for future studies. Method We examined findings from all major studies in bipolar disorder that used fMRI, volumetric analyses, diffusion imaging, and resting state techniques, to inform current conceptual models of larger-scale neural circuitry abnormalities in bipolar disorder Results Bipolar disorder can be conceptualized in neural circuitry terms as parallel dysfunction in bilateral prefrontal cortical (especially ventrolateral prefrontal cortical)-hippocampal-amygdala emotion processing and emotion regulation neural circuitries, together with an “overactive” left-sided ventral striatal-ventrolateral and orbitofrontal cortical reward processing circuitry, that result in characteristic behavioral abnormalities associated with bipolar disorder: emotional lability, emotional dysregulation and heightened reward sensitivity. A potential structural basis for these functional abnormalities are gray matter decreases in prefrontal and temporal cortices, amygdala and hippocampus, and fractional anisotropy decreases in white matter tracts connecting prefrontal and subcortical regions. Conclusion Neuroimaging studies of bipolar disorder clearly demonstrate abnormalities in neural circuitries supporting emotion processing, emotion regulation and reward processing, although there are several limitations to these studies. Future neuroimaging research in bipolar disorder should include studies adopting dimensional approaches; larger studies examining neurodevelopmental trajectories in bipolar disorder and at-risk youth; multimodal neuroimaging studies using integrated systems approaches; and studies using pattern recognition approaches to provide clinically useful, individual-level data. Such studies will help identify clinically-relevant biomarkers to guide diagnosis and treatment decision-making for individuals with bipolar disorder. PMID:24626773
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Ikemoto, Satoshi; Bonci, Antonello
2013-01-01
In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. PMID:23664810
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Holsen, L M; Savage, C R; Martin, L E; Bruce, A S; Lepping, R J; Ko, E; Brooks, W M; Butler, M G; Zarcone, J R; Goldstein, J M
2012-05-01
The majority of research on obesity (OB) has focused primarily on clinical features (eating behavior, adiposity measures) or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions that are associated with appetite-regulatory hormones are also involved in the development and maintenance of OB. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic OB. Simple (non-PWS) OB represents an OB-control state. This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (that is, hypothalamus, amygdala) and prefrontal regions associated with cognitive control (that is, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) after eating. A total of 14 individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC and DLPFC. Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in the hypothalamus and hippocampus in response to food (vs non-food) images pre-meal. Post meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared with OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. In PWS, compared with OB per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple OB.
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Holsen, Laura M.; Savage, Cary R.; Martin, Laura E.; Bruce, Amanda S.; Lepping, Rebecca J.; Ko, Eunice; Brooks, William M.; Butler, Merlin G.; Zarcone, Jennifer R.; Goldstein, Jill M.
2011-01-01
Background The majority of research on obesity has focused primarily on clinical features (eating behavior, adiposity measures), or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions which are associated with appetite-regulatory hormones are also involved in the development and maintenance of obesity. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic obesity. Simple (non-PWS) obesity (OB) represents an obesity control state. Objective This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (i.e., hypothalamus, amygdala) and prefrontal regions associated with cognitive control [i.e., dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC)] after eating. Design and Participants Fourteen individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls (HWC) viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC, and DLPFC. Results Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in hypothalamus and hippocampus, in response to food (vs. non-food) images pre-meal. Post-meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared to OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. Conclusion In PWS compared with obesity per se, results suggest hyperactivations in subcortical reward circuitry and hypoactivations in cortical inhibitory regions after eating, which provides evidence of neural substrates associated with variable abnormal food motivation phenotypes in PWS and simple obesity. PMID:22024642
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Sweitzer, Maggie M; Donny, Eric C; Hariri, Ahmad R
2012-06-01
Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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Soehner, Adriane M; Bertocci, Michele A; Manelis, Anna; Bebko, Genna; Ladouceur, Cecile D; Graur, Simona; Monk, Kelly; Bonar, Lisa K; Hickey, Mary Beth; Axelson, David; Goldstein, Benjamin I; Goldstein, Tina R; Birmaher, Boris; Phillips, Mary L
2016-11-15
Altered reward circuitry function is observed in individuals with bipolar disorder (BD) and their unaffected offspring (OBP). While OBP are at elevated risk for BD, modifiable risk factors that may exacerbate neural vulnerabilities in OBP remain under-characterized. As sleep loss is strongly linked to mania in BD, this study tested associations between sleep duration, reward circuitry function, and mood dysregulation in OBP. Two groups of youth unaffected with BD (9-17yr) completed a number-guessing fMRI reward paradigm: 25 OBP and 21 age-sex-IQ-matched offspring of control parents with non-BD psychopathology (OCP), to differentiate risk for BD from risk for psychopathology more broadly. Regressions tested effects of group status, self-reported past-week sleep duration, and their interaction on neural activity and bilateral ventral striatum (VS) functional connectivity to win>control. Correlations with parent-reported mood dysregulation were assessed. Group effects were observed for right posterior insula activity (OCP>OBP) and VS-left posterior insula connectivity (OBP>OCP). Group ⁎ sleep duration interactions were observed for left dorsal anterior-mid-cingulate (daMCC) activity and VS-left anterior insula/ventrolateral prefrontal cortex (VLPFC) connectivity. Specifically, sleep duration and daMCC activity were positively related in OBP, but negatively related in OCP and sleep duration and VS-left anterior insula/VLPFC connectivity were negatively related in OBP, but positively in OCP. Additionally, increased VS-left posterior insula connectivity and VS-left anterior insula/VLPFC connectivity were associated with greater mood dysregulation in OBP only. Cross-sectional design and small sample size. Altered reward-related VS-insula connectivity could represent a neural pathway underpinning mood dysregulation in OBP, and may be modulated by shortened sleep duration. Copyright © 2016 Elsevier B.V. All rights reserved.
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Blum, Kenneth; Oscar-Berman, Marlene; Stuller, Elizabeth; Miller, David; Giordano, John; Morse, Siobhan; McCormick, Lee; Downs, William B; Waite, Roger L; Barh, Debmalya; Neal, Dennis; Braverman, Eric R; Lohmann, Raquel; Borsten, Joan; Hauser, Mary; Han, David; Liu, Yijun; Helman, Manya; Simpatico, Thomas
2013-01-01
In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the “Brain Reward Cascade” (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications. PMID:23926462
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Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism.
Hernandez, L M; Krasileva, K; Green, S A; Sherman, L E; Ponting, C; McCarron, R; Lowe, J K; Geschwind, D H; Bookheimer, S Y; Dapretto, M
2017-08-01
Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain's reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) - a hub of the reward network - focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.
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ERIC Educational Resources Information Center
Mattfeld, Aaron T.; Gluck, Mark A.; Stark, Craig E. L.
2011-01-01
The goal of the present study was to elucidate the role of the human striatum in learning via reward and punishment during an associative learning task. Previous studies have identified the striatum as a critical component in the neural circuitry of reward-related learning. It remains unclear, however, under what task conditions, and to what…
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Interactions between the nucleus accumbens and auditory cortices predict music reward value.
Salimpoor, Valorie N; van den Bosch, Iris; Kovacevic, Natasa; McIntosh, Anthony Randal; Dagher, Alain; Zatorre, Robert J
2013-04-12
We used functional magnetic resonance imaging to investigate neural processes when music gains reward value the first time it is heard. The degree of activity in the mesolimbic striatal regions, especially the nucleus accumbens, during music listening was the best predictor of the amount listeners were willing to spend on previously unheard music in an auction paradigm. Importantly, the auditory cortices, amygdala, and ventromedial prefrontal regions showed increased activity during listening conditions requiring valuation, but did not predict reward value, which was instead predicted by increasing functional connectivity of these regions with the nucleus accumbens as the reward value increased. Thus, aesthetic rewards arise from the interaction between mesolimbic reward circuitry and cortical networks involved in perceptual analysis and valuation.
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Hunger does not motivate reward in women remitted from anorexia nervosa
Wierenga, Christina E.; Bischoff-Grethe, Amanda; Melrose, A. James; Irvine, Zoe; Torres, Laura; Bailer, Ursula F.; Simmons, Alan; Fudge, Julie L.; McClure, Samuel M.; Ely, Alice; Kaye, Walter H.
2014-01-01
Background Hunger enhances sensitivity to reward, yet individuals with anorexia nervosa (AN) are not motivated to eat when starved. This study examined whether diminished response to reward could underlie food restriction in AN by investigating brain response to rewards during hunger and satiated states. Methods Using a delay discounting monetary decision task known to discriminate brain regions contributing to processing of immediate rewards and cognitive control important for decision making regarding future rewards, we compared 23 adults remitted from AN (to reduce the confounding effects of starvation [RAN]) to 17 healthy women (CW). Monetary rewards were used because the rewarding value of food may be confounded by anxiety in AN. Results Interactions of group (RAN, CW) × visit (hunger, satiety) revealed that, for CW, hunger significantly increased activation in reward salience circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during processing of immediate reward, whereas satiety increased activation in cognitive control circuitry (ventrolateral prefrontal cortex, insula) during decision-making. In contrast, brain response in reward and cognitive neurocircuitry did not differ during hunger and satiety in RAN. A main effect of group revealed elevated response in the middle frontal gyrus for RAN. Conclusions RAN failed to increase activation of reward valuation circuitry when hungry and showed elevated response in cognitive control circuitry independent of metabolic state. Decreased sensitivity to hunger’s motivational drive may explain AN individuals’ ability to restrict food when emaciated. Moreover, difficulties in valuating emotional salience may contribute to inabilities to appreciate the risks inherent in this deadly disorder. PMID:25481622
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Gold, Mark S; Badgaiyan, Rajendra D; Blum, Kenneth
2015-09-01
This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.
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Chester, David S; DeWall, C Nathan
2018-05-01
Alcohol use and abuse (e.g., binge drinking) are among the most reliable causes of aggressive behavior. Conversely, people with aggressive dispositions (e.g., intermittent explosive disorder) are at greater risk for subsequent substance abuse. Yet it remains unknown why aggression might promote subsequent alcohol use. Both aggressive acts and alcohol use are rewarding and linked to greater activity in neural reward circuitry. Through this shared instantiation of reward, aggression may then increase subsequent alcohol consumption. Supporting this mechanistic hypothesis, participants' aggressive behavior directed at someone who had recently rejected them, was associated with more subsequent beer consumption on an ad-lib drinking task. Using functional MRI, both aggressive behavior and beer consumption were associated with greater activity in the bilateral ventral striatum during acts of retaliatory aggression. These results imply that aggression is linked to subsequent alcohol abuse, and that a mechanism underlying this effect is likely to be the activation of the brain's reward circuitry during aggressive acts. © 2018 Wiley Periodicals, Inc.
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Hunger does not motivate reward in women remitted from anorexia nervosa.
Wierenga, Christina E; Bischoff-Grethe, Amanda; Melrose, A James; Irvine, Zoe; Torres, Laura; Bailer, Ursula F; Simmons, Alan; Fudge, Julie L; McClure, Samuel M; Ely, Alice; Kaye, Walter H
2015-04-01
Hunger enhances sensitivity to reward, yet individuals with anorexia nervosa (AN) are not motivated to eat when starved. This study investigated brain response to rewards during hunger and satiated states to examine whether diminished response to reward could underlie food restriction in AN. Using a delay discounting monetary decision task known to discriminate brain regions contributing to processing of immediate rewards and cognitive control important for decision making regarding future rewards, we compared 23 women remitted from AN (RAN group; to reduce the confounding effects of starvation) with 17 healthy comparison women (CW group). Monetary rewards were used because the rewarding value of food may be confounded by anxiety in AN. Interactions of Group (RAN, CW) × Visit (hunger, satiety) revealed that, for the CW group, hunger significantly increased activation in reward salience circuitry (ventral striatum, dorsal caudate, anterior cingulate cortex) during processing of immediate reward, whereas satiety increased activation in cognitive control circuitry (ventrolateral prefrontal cortex, insula) during decision making. In contrast, brain response in reward and cognitive neurocircuitry did not differ during hunger and satiety in the RAN group. A main effect of group revealed elevated response in the middle frontal gyrus for the RAN group compared with the CW group. Women remitted from AN failed to increase activation of reward valuation circuitry when hungry and showed elevated response in cognitive control circuitry independent of metabolic state. Decreased sensitivity to the motivational drive of hunger may explain the ability of individuals with AN to restrict food when emaciated. Difficulties in valuating emotional salience may contribute to inabilities to appreciate the risks inherent in this disorder. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Addiction and brain reward and antireward pathways.
Gardner, Eliot L
2011-01-01
Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly), and that they enhance the functioning of the reward circuitry of the brain (producing the 'high' that the drug user seeks). The core reward circuitry consists of an 'in-series' circuit linking the ventral tegmental area, nucleus accumbens and ventral pallidum via the medial forebrain bundle. Although originally believed to simply encode the set point of hedonic tone, these circuits are now believed to be functionally far more complex, also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. 'Hedonic dysregulation' within these circuits may lead to addiction. The 'second-stage' dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dop-aminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g. opiates), tolerance to the euphoric effects develops with chronic use. Postuse dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get high, but simply to get back to normal ('get straight'). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the 'bio-psycho-social' model of etiology holds very well for addiction. Addiction appears to correlate with a hypodopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are (a) reexposure to addictive drugs, (b) stress, and (c) reexposure to environmental cues (people, places, things) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves (a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter corticotrophin-releasing factor, and (b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. Copyright © 2011 S. Karger AG, Basel.
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Oxytocin modulates hemodynamic responses to monetary incentives in humans
Mickey, Brian J.; Heffernan, Joseph; Heisel, Curtis; Peciña, Marta; Hsu, David T.; Zubieta, Jon-Kar; Love, Tiffany M.
2016-01-01
Oxytocin is a neuropeptide widely recognized for its role in regulating social and reproductive behavior. Increasing evidence from animal models suggests that oxytocin also modulates reward circuitry in non-social contexts, but evidence in humans is lacking. Here we examined the effects of oxytocin administration on reward circuit function in 18 healthy men as they performed a monetary incentive task. The blood oxygenation level dependent (BOLD) signal was measured using functional magnetic resonance imaging in the context of a randomized, double-blind, placebo-controlled, crossover trial of intranasal oxytocin. We found that oxytocin increases the BOLD signal in the midbrain (substantia nigra and ventral tegmental area) during the late phase of the hemodynamic response to incentive stimuli. Oxytocin’s effects on midbrain responses correlated positively with its effects on positive emotional state. We did not detect an effect of oxytocin on responses in the nucleus accumbens. Whole-brain analyses revealed that oxytocin attenuated medial prefrontal cortical deactivation specifically during anticipation of loss. Our findings demonstrate that intranasal administration of oxytocin modulates human midbrain and medial prefrontal function during motivated behavior. These findings suggest that endogenous oxytocin is a neurochemical mediator of reward behaviors in humans – even in a non-social context – and that the oxytocinergic system is a potential target of pharmacotherapy for psychiatric disorders that involve dysfunction of reward circuitry. PMID:27614896
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Introduction: Addiction and Brain Reward and Anti-Reward Pathways
Gardner, Eliot L.
2013-01-01
Addictive drugs have in common that they are voluntarily self-administered by laboratory animals (usually avidly) and that they enhance the functioning of the reward circuitry of the brain (producing the “high” that the drug-user seeks). The core reward circuitry consists of an “in series” circuit linking the ventral tegmental area, nucleus accumbens, and ventral pallidum - via the medial forebrain bundle. Although originally believed to encode simply the set-point of hedonic tone, these circuits are now believed to be functionally far more complex - also encoding attention, expectancy of reward, disconfirmation of reward expectancy, and incentive motivation. “Hedonic dysregulation” within these circuits may lead to addiction. The “second-stage” dopaminergic component in this reward circuitry is the crucial addictive-drug-sensitive component. All addictive drugs have in common that they enhance (directly or indirectly or even transsynaptically) dopaminergic reward synaptic function in the nucleus accumbens. Drug self-administration is regulated by nucleus accumbens dopamine levels, and is done to keep nucleus accumbens dopamine within a specific elevated range (to maintain a desired hedonic level). For some classes of addictive drugs (e.g., opiates), tolerance to the euphoric effects develops with chronic use. Post-use dysphoria then comes to dominate reward circuit hedonic tone, and addicts no longer use drugs to get “high,” but simply to get back to normal (“get straight”). The brain circuits mediating the pleasurable effects of addictive drugs are anatomically, neurophysiologically, and neurochemically different from those mediating physical dependence, and from those mediating craving and relapse. There are important genetic variations in vulnerability to drug addiction, yet environmental factors such as stress and social defeat also alter brain-reward mechanisms in such a manner as to impart vulnerability to addiction. In short, the “bio-psycho-social” model of etiology holds very well for addiction. Addiction appears to correlate with a hypo-dopaminergic dysfunctional state within the reward circuitry of the brain. Neuroimaging studies in humans add credence to this hypothesis. Credible evidence also implicates serotonergic, opioid, endocannabinoid, GABAergic, and glutamatergic mechanisms in addiction. Critically, drug addiction progresses from occasional recreational use to impulsive use to habitual compulsive use. This correlates with a progression from reward-driven to habit-driven drug-seeking behavior. This behavioral progression correlates with a neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal striatal control over drug-seeking behavior. The three classical sets of craving and relapse triggers are a) re-exposure to addictive drugs, b) stress, and c) re-exposure to environmental cues (“people, places, things”) previously associated with drug-taking behavior. Drug-triggered relapse involves the nucleus accumbens and the neurotransmitter dopamine. Stress-triggered relapse involves a) the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the neurotransmitter CRF; and b) the lateral tegmental noradrenergic nuclei of the brain stem and the neurotransmitter norepinephrine. Cue-triggered relapse involves the basolateral nucleus of the amygdala, the hippocampus, and the neurotransmitter glutamate. Knowledge of the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of addictive drug action in the brain is currently producing a variety of strategies for pharmacotherapeutic treatment of drug addiction, some of which appear promising. PMID:21508625
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Patel, Krishna T; Stevens, Michael C; Meda, Shashwath A; Muska, Christine; Thomas, Andre D; Potenza, Marc N; Pearlson, Godfrey D
2013-10-01
Abnormal function in reward circuitry in cocaine addiction could predate drug use as a risk factor, follow drug use as a consequence of substance-induced alterations, or both. We used a functional magnetic resonance imaging monetary incentive delay task (MIDT) to investigate reward-loss neural response differences among 42 current cocaine users, 35 former cocaine users, and 47 healthy subjects who also completed psychological measures and tasks related to impulsivity and reward. We found various reward processing-related group differences in several MIDT phases. Across task phases we found a control > current user > former user activation pattern, except for loss outcome, where former compared with current cocaine users activated ventral tegmental area more robustly. We also found regional prefrontal activation differences during loss anticipation between cocaine-using groups. Both groups of cocaine users scored higher than control subjects on impulsivity, compulsivity and reward-punishment sensitivity factors. In addition, impulsivity-related factors correlated positively with activation in amygdala and negatively with anterior cingulate activation during loss anticipation. Compared with healthy subjects, both former and current users displayed abnormal brain activation patterns during MIDT performance. Both cocaine groups differed similarly from healthy subjects, but differences between former and current users were localized to the ventral tegmental area during loss outcome and to prefrontal regions during loss anticipation, suggesting that long-term cocaine abstinence does not normalize most reward circuit abnormalities. Elevated impulsivity-related factors that relate to loss processing in current and former users suggest that these tendencies and relationships may pre-exist cocaine addiction. © 2013 Society of Biological Psychiatry.
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The importance of context: When relative relief renders pain pleasant
Leknes, Siri; Berna, Chantal; Lee, Michael C.; Snyder, Gregory D.; Biele, Guido; Tracey, Irene
2013-01-01
Context can influence the experience of any event. For instance, the thought that “it could be worse” can improve feelings towards a present misfortune. In this study we measured hedonic feelings, skin conductance, and brain activation patterns in 16 healthy volunteers who experienced moderate pain in two different contexts. In the “relative relief context,” moderate pain represented the best outcome, since the alternative outcome was intense pain. However, in the control context, moderate pain represented the worst outcome and elicited negative hedonic feelings. The context manipulation resulted in a “hedonic flip,” such that moderate pain elicited positive hedonics in the relative relief context. Somewhat surprisingly, moderate pain was even rated as pleasant in this context, despite being reported as painful in the control context. This “hedonic flip” was corroborated by physiological and functional neuroimaging data. When moderate pain was perceived as pleasant, skin conductance and activity in insula and dorsal anterior cingulate were significantly attenuated relative to the control moderate stimulus. “Pleasant pain” also increased activity in reward and valuation circuitry, including the medial orbitofrontal and ventromedial prefrontal cortices. Furthermore, the change in outcome hedonics correlated with activity in the periacqueductal grey (PAG) of the descending pain modulatory system (DPMS). The context manipulation also significantly increased functional connectivity between reward circuitry and the PAG, consistent with a functional change of the DPMS due to the altered motivational state. The findings of this study point to a role for brainstem and reward circuitry in a context-induced “hedonic flip” of pain. PMID:23352758
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Badgaiyan, Rajendra D.; Thanos, Panayotis K.; Kulkarni, Praveen; Giordano, John; Baron, David; Gold, Mark S.
2017-01-01
Dopaminergic reward dysfunction in addictive behaviors is well supported in the literature. There is evidence that alterations in synchronous neural activity between brain regions subserving reward and various cognitive functions may significantly contribute to substance-related disorders. This study presents the first evidence showing that a pro-dopaminergic nutraceutical (KB220Z) significantly enhances, above placebo, functional connectivity between reward and cognitive brain areas in the rat. These include the nucleus accumbens, anterior cingulate gyrus, anterior thalamic nuclei, hippocampus, prelimbic and infralimbic loci. Significant functional connectivity, increased brain connectivity volume recruitment (potentially neuroplasticity), and dopaminergic functionality were found across the brain reward circuitry. Increases in functional connectivity were specific to these regions and were not broadly distributed across the brain. While these initial findings have been observed in drug naïve rodents, this robust, yet selective response implies clinical relevance for addicted individuals at risk for relapse, who show reductions in functional connectivity after protracted withdrawal. Future studies will evaluate KB220Z in animal models of addiction. PMID:28445527
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Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Baron, David; Braverman, Eric R.; Dushaj, Kristina; Li, Mona; Demetrovics, Zsolt; Badgaiyan, Rajendra D.
2017-01-01
We are faced with a worldwide opiate/opioid epidemic that is devastating. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day in America due to narcotic overdose. The Food and Drug Administration (FDA) has approved Medication-Assisted Treatments (MATs) for opiate/opioids as well as alcohol and nicotine. The mechanism of action of most MATS favors either blocking of dopaminergic function or a form of Opiate Substitution Therapy (OST). These treatment options are adequate for short-term treatment of the symptoms of addiction and harm reduction but fail long-term to deal with the cause or lead to recovery. There is a need to continue to seek better treatment options. This mini-review is the history of the development of one such treatment; a glutaminergic-dopaminergic optimization complex called KB220. Growing evidence indicates that brain reward circuitry controls drug addiction, in conjunction with “anti-reward systems” as the “anti-reward systems” can be affected by both glutaminergic and dopaminergic transmission. KB220 may likely alter the function of these regions and provide for the possible eventual balancing the brain reward system and the induction of “dopamine homeostasis.” Many of these concepts have been reported elsewhere and have become an integral part of the addiction science literature. However, the concise review may encourage readership to reconsider these facts and stimulate further research focused on the impact that the induction of “dopamine homeostasis” may have on recovery and relapse prevention. PMID:28804788
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Marijuana and cannabinoid regulation of brain reward circuits.
Lupica, Carl R; Riegel, Arthur C; Hoffman, Alexander F
2004-09-01
The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Delta(9)-THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self-administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Delta(9)-THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Delta(9)-THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA.
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Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.
Bardo, M T
1998-01-01
Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.
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Processing of social and monetary rewards in the human striatum.
Izuma, Keise; Saito, Daisuke N; Sadato, Norihiro
2008-04-24
Despite an increasing focus on the neural basis of human decision making in neuroscience, relatively little attention has been paid to decision making in social settings. Moreover, although human social decision making has been explored in a social psychology context, few neural explanations for the observed findings have been considered. To bridge this gap and improve models of human social decision making, we investigated whether acquiring a good reputation, which is an important incentive in human social behaviors, activates the same reward circuitry as monetary rewards. In total, 19 subjects participated in functional magnetic resonance imaging (fMRI) experiments involving monetary and social rewards. The acquisition of one's good reputation robustly activated reward-related brain areas, notably the striatum, and these overlapped with the areas activated by monetary rewards. Our findings support the idea of a "common neural currency" for rewards and represent an important first step toward a neural explanation for complex human social behaviors.
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Elliott, R; Agnew, Z; Deakin, J F W
2008-05-01
Functional imaging studies in recent years have confirmed the involvement of orbitofrontal cortex (OFC) in human reward processing and have suggested that OFC responses are context-dependent. A seminal electrophysiological experiment in primates taught animals to associate abstract visual stimuli with differently valuable food rewards. Subsequently, pairs of these learned abstract stimuli were presented and firing of OFC neurons to the medium-value stimulus was measured. OFC firing was shown to depend on the relative value context. In this study, we developed a human analogue of this paradigm and scanned subjects using functional magnetic resonance imaging. The analysis compared neuronal responses to two superficially identical events, which differed only in terms of the preceding context. Medial OFC response to the same perceptual stimulus was greater when the stimulus predicted the more valuable of two rewards than when it predicted the less valuable. Additional responses were observed in other components of reward circuitry, the amygdala and ventral striatum. The central finding is consistent with the primate results and suggests that OFC neurons code relative rather than absolute reward value. Amygdala and striatal involvement in coding reward value is also consistent with recent functional imaging data. By using a simpler and less confounded paradigm than many functional imaging studies, we are able to demonstrate that relative financial reward value per se is coded in distinct subregions of an extended reward and decision-making network.
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Simmons, W. Kyle; Burrows, Kaiping; Avery, Jason A.; Kerr, Kara L.; Bodurka, Jerzy; Savage, Cary R.; Drevets, Wayne C.
2016-01-01
Objective Appetite and weight changes are common but variable diagnostic markers in major depressive disorder: some depressed individuals manifest increased appetite, while others lose their appetite. Many of the brain regions implicated in appetitive responses to food have also been implicated in depression. It is thus remarkable that there exists no published research comparing the neural responses to food stimuli of depressed patients with increased versus decreased appetites. Method Using functional magnetic resonance imaging we compared brain activity in unmedicated depressed patients with increased or decreased appetite, and healthy control subjects, while viewing photographs of food and non-food objects. We also measured how resting-state functional connectivity related to subjects’ food pleasantness ratings. Results Within putative reward regions, depressed participants with increased appetites exhibited greater hemodynamic activity to food stimuli than both those reporting appetite decreases and healthy control subjects. In contrast, depressed subjects experiencing appetite loss exhibited hypoactivation within a region of the mid-insula implicated in interoception, with no difference observed in this region between healthy subjects and those with depression-related appetite increases. Mid-insula activity was negatively correlated with food pleasantness ratings of depressed participants with increased appetites, and its functional connectivity to reward circuitry was positively correlated with food pleasantness ratings. Conclusions Depression-related increases in appetite are associated with hyperactivation of putative mesocorticolimbic reward circuitry, while depression-related appetite loss is associated with hypoactivation of insular regions that support monitoring the body’s physiological state. Importantly, the interactions among these regions also contribute to individual differences in the depression-related appetite changes. PMID:26806872
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Simmons, W Kyle; Burrows, Kaiping; Avery, Jason A; Kerr, Kara L; Bodurka, Jerzy; Savage, Cary R; Drevets, Wayne C
2016-04-01
Appetite and weight changes are common but variable diagnostic markers in major depressive disorder: some depressed individuals manifest increased appetite, while others lose their appetite. Many of the brain regions implicated in appetitive responses to food have also been implicated in depression. It is thus remarkable that there exists no published research comparing the neural responses to food stimuli of depressed patients with increased versus decreased appetites. Using functional MRI, brain activity was compared in unmedicated depressed patients with increased or decreased appetite and healthy control subjects while viewing photographs of food and nonfood objects. The authors also measured how resting-state functional connectivity related to subjects' food pleasantness ratings. Within putative reward regions, depressed participants with increased appetites exhibited greater hemodynamic activity to food stimuli than both those reporting appetite decreases and healthy control subjects. In contrast, depressed subjects experiencing appetite loss exhibited hypoactivation within a region of the mid-insula implicated in interoception, with no difference observed in this region between healthy subjects and those with depression-related appetite increases. Mid-insula activity was negatively correlated with food pleasantness ratings of depressed participants with increased appetites, and its functional connectivity to reward circuitry was positively correlated with food pleasantness ratings. Depression-related increases in appetite are associated with hyperactivation of putative mesocorticolimbic reward circuitry, while depression-related appetite loss is associated with hypoactivation of insular regions that support monitoring the body's physiological state. Importantly, the interactions among these regions also contribute to individual differences in the depression-related appetite changes.
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Cox, Anthony; Kohls, Gregor; Naples, Adam J.; Mukerji, Cora E.; Coffman, Marika C.; Rutherford, Helena J. V.; Mayes, Linda C.
2015-01-01
Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASDs). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an Event-related potential incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD. PMID:25752905
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Becker, Alena; Kirsch, Martina; Gerchen, Martin Fungisai; Kiefer, Falk; Kirsch, Peter
2017-05-01
According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit. © 2016 Society for the Study of Addiction.
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Understanding Overbidding: Using the Neural Circuitry of Reward to Design Economic Auctions
Delgado, Mauricio R.; Schotter, Andrew; Ozbay, Erkut Y.; Phelps, Elizabeth A.
2011-01-01
We take advantage of our knowledge of the neural circuitry of reward to investigate a puzzling economic phenomenon: Why do people overbid in auctions? Using functional magnetic resonance imaging (fMRI), we observed that the social competition inherent in an auction results in a more pronounced blood oxygen level–dependent (BOLD) response to loss in the striatum, with greater overbidding correlated with the magnitude of this response. Leveraging these neuroimaging results, we design a behavioral experiment that demonstrates that framing an experimental auction to emphasize loss increases overbidding. These results highlight a role for the contemplation of loss in understanding the tendency to bid “too high.” Current economic theories suggest overbidding may result from either “joy of winning” or risk aversion. By combining neuroeconomic and behavioral economic techniques, we find that another factor, namely loss contemplation in a social context, may mediate overbidding in auctions. PMID:18818362
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Understanding overbidding: using the neural circuitry of reward to design economic auctions.
Delgado, Mauricio R; Schotter, Andrew; Ozbay, Erkut Y; Phelps, Elizabeth A
2008-09-26
We take advantage of our knowledge of the neural circuitry of reward to investigate a puzzling economic phenomenon: Why do people overbid in auctions? Using functional magnetic resonance imaging (fMRI), we observed that the social competition inherent in an auction results in a more pronounced blood oxygen level-dependent (BOLD) response to loss in the striatum, with greater overbidding correlated with the magnitude of this response. Leveraging these neuroimaging results, we design a behavioral experiment that demonstrates that framing an experimental auction to emphasize loss increases overbidding. These results highlight a role for the contemplation of loss in understanding the tendency to bid "too high." Current economic theories suggest overbidding may result from either "joy of winning" or risk aversion. By combining neuroeconomic and behavioral economic techniques, we find that another factor, namely loss contemplation in a social context, may mediate overbidding in auctions.
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Dopamine prediction errors in reward learning and addiction: from theory to neural circuitry
Keiflin, Ronald; Janak, Patricia H.
2015-01-01
Summary Midbrain dopamine (DA) neurons are proposed to signal reward prediction error (RPE), a fundamental parameter in associative learning models. This RPE hypothesis provides a compelling theoretical framework for understanding DA function in reward learning and addiction. New studies support a causal role for DA-mediated RPE activity in promoting learning about natural reward; however, this question has not been explicitly tested in the context of drug addiction. In this review, we integrate theoretical models with experimental findings on the activity of DA systems, and on the causal role of specific neuronal projections and cell types, to provide a circuit-based framework for probing DA-RPE function in addiction. By examining error-encoding DA neurons in the neural network in which they are embedded, hypotheses regarding circuit-level adaptations that possibly contribute to pathological error-signaling and addiction can be formulated and tested. PMID:26494275
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Liu, Xun; Hairston, Jacqueline; Schrier, Madeleine; Fan, Jin
2011-01-01
To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior (ACC) and posterior (PCC) cingulate cortex, as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore distributed and interrelated representations of reward valuation and valence assessment into account. PMID:21185861
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Reward and motivation in pain and pain relief
Navratilova, Edita; Porreca, Frank
2015-01-01
Pain is fundamentally unpleasant, a feature that protects the organism by promoting motivation and learning. Relief of aversive states, including pain, is rewarding. The aversiveness of pain, as well as the reward from relief of pain, is encoded by brain reward/motivational mesocorticolimbic circuitry. In this Review, we describe current knowledge of the impact of acute and chronic pain on reward/motivation circuits gained from preclinical models and from human neuroimaging. We highlight emerging clinical evidence suggesting that anatomical and functional changes in these circuits contribute to the transition from acute to chronic pain. We propose that assessing activity in these conserved circuits can offer new outcome measures for preclinical evaluation of analgesic efficacy to improve translation and speed drug discovery. We further suggest that targeting reward/motivation circuits may provide a path for normalizing the consequences of chronic pain to the brain, surpassing symptomatic management to promote recovery from chronic pain. PMID:25254980
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Reward loss and the basolateral amygdala: A function in reward comparisons.
Kawasaki, Katsuyoshi; Annicchiarico, Iván; Glueck, Amanda C; Morón, Ignacio; Papini, Mauricio R
2017-07-28
The neural circuitry underlying behavior in reward loss situations is poorly understood. We considered two such situations: reward devaluation (from large to small rewards) and reward omission (from large rewards to no rewards). There is evidence that the central nucleus of the amygdala (CeA) plays a role in the negative emotion accompanying reward loss. However, little is known about the function of the basolateral nucleus (BLA) in reward loss. Two hypotheses of BLA function in reward loss, negative emotion and reward comparisons, were tested in an experiment involving pretraining excitotoxic BLA lesions followed by training in four tasks: consummatory successive negative contrast (cSNC), autoshaping (AS) acquisition and extinction, anticipatory negative contrast (ANC), and open field testing (OF). Cell counts in the BLA (but not in the CeA) were significantly lower in animals with lesions vs. shams. BLA lesions eliminated cSNC and ANC, and accelerated extinction of lever pressing in AS. BLA lesions had no effect on OF testing: higher activity in the periphery than in the central area. This pattern of results provides support for the hypothesis that BLA neurons are important for reward comparison. The three affected tasks (cSNC, ANC, and AS extinction) involve reward comparisons. However, ANC does not seem to involve negative emotions and it was affected, whereas OF activity is known to involve negative emotion, but it was not affected. It is hypothesized that a circuit involving the thalamus, insular cortex, and BLA is critically involved in the mechanism comparing current and expected rewards. Copyright © 2017 Elsevier B.V. All rights reserved.
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Differential Recruitment of Distinct Amygdalar Nuclei across Appetitive Associative Learning
ERIC Educational Resources Information Center
Cole, Sindy; Powell, Daniel J.; Petrovich, Gorica D.
2013-01-01
The amygdala is important for reward-associated learning, but how distinct cell groups within this heterogeneous structure are recruited during appetitive learning is unclear. Here we used Fos induction to map the functional amygdalar circuitry recruited during early and late training sessions of Pavlovian appetitive conditioning. We found that a…
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Cox, Anthony; Kohls, Gregor; Naples, Adam J; Mukerji, Cora E; Coffman, Marika C; Rutherford, Helena J V; Mayes, Linda C; McPartland, James C
2015-10-01
Diminished responsivity to reward incentives is a key contributor to the social-communication problems seen in autism spectrum disorders (ASDs). Social motivation theories suggest that individuals with ASD do not experience social interactions as rewarding, leading to negative consequences for the development of brain circuitry subserving social information. In this study, we examined neural responses to social and non-social reward anticipation in 35 typically developing young adults, examining modulation of reward sensitivity by level of autistic traits. Using an Event-related potential incentive-delay task incorporating novel, more ecologically valid forms of reward, higher expression of autistic traits was associated with an attenuated P3 response to the anticipation of social (simulated real-time video feedback from an observer), but not non-social (candy), rewards. Exploratory analyses revealed that this was unrelated to mentalizing ability. The P3 component reflects motivated attention to reward signals, suggesting attenuated motivation allocation specific to social incentives. The study extends prior findings of atypical reward anticipation in ASD, demonstrating that attenuated social reward responsiveness extends to autistic traits in the range of typical functioning. Results support the development of innovative paradigms for investigating social and non-social reward responsiveness. Insight into vulnerabilities in reward processing is critical for understanding social function in ASD. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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Joseph, Jane E.; Zhu, Xun; Lynam, Donald; Kelly, Thomas H.
2015-01-01
Adolescence is a particularly vulnerable period for the onset of substance use disorders and other psychopathology. Individual variability in motivational tendencies and temperament and significant changes in functional brain organization during adolescence are important factors to consider in the development of substance use and dependence. Recent conceptualizations suggest that sensitivity to reward is heightened in adolescence and that this motivation tendency may precipitate subsequent substance abuse. The present study examined the role of personality traits in mesolimbic neurobehavioral response on a monetary incentive delay (MID) task in young adolescents (11–14 years) and emerging adults (18–25 years) using functional magnetic resonance imaging. As a group, adolescents were not more sensitive to gains than losses compared to adults during either anticipatory and feedback phases; instead, compared to adults they showed less sensitivity to incentive magnitude in mesolimbic circuitry during anticipation and feedback stages. However, personality modulated this response such that adolescents high in impulsivity or low in avoidance tendencies showed greater gain sensitivity and adolescents high in avoidance showed greater loss sensitivity during cue anticipation. In adults, mesolimbic response was modulated by the impulsivity construct such that high-impulsive adults showed reduced magnitude sensitivity during both anticipation and feedback compared to low impulsive adults. The present findings suggest that impulsive personality significantly modulates mesolimbic reward response during both adolescence and adulthood but avoidance and approach tendencies also modulate this response in adolescents. Moreover, personality modulated incentive valence in adolescents but incentive magnitude in adults. Collectively, these findings suggest that mesolimbic reward circuitry function is modulated by somewhat different parameters in adolescence than in adulthood. PMID:26690806
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Dillon, Daniel G.; Rosso, Isabelle M.; Pechtel, Pia; Killgore, William D. S.; Rauch, Scott L.; Pizzagalli, Diego A.
2014-01-01
As a step toward addressing limitations in the current psychiatric diagnostic system, the NIMH recently developed the Research Domain Criteria (RDoC) to stimulate integrative research—spanning self-report, behavior, neural circuitry, and molecular/genetic mechanisms—on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses—mediated by circuits connecting the frontal cortex, amygdala, and midbrain—in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision-making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but new optogenetic data in rodents indicate that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression. PMID:24151118
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Brain connectivity reflects human aesthetic responses to music
Sachs, Matthew E.; Ellis, Robert J.; Schlaug, Gottfried
2016-01-01
Abstract Humans uniquely appreciate aesthetics, experiencing pleasurable responses to complex stimuli that confer no clear intrinsic value for survival. However, substantial variability exists in the frequency and specificity of aesthetic responses. While pleasure from aesthetics is attributed to the neural circuitry for reward, what accounts for individual differences in aesthetic reward sensitivity remains unclear. Using a combination of survey data, behavioral and psychophysiological measures and diffusion tensor imaging, we found that white matter connectivity between sensory processing areas in the superior temporal gyrus and emotional and social processing areas in the insula and medial prefrontal cortex explains individual differences in reward sensitivity to music. Our findings provide the first evidence for a neural basis of individual differences in sensory access to the reward system, and suggest that social–emotional communication through the auditory channel may offer an evolutionary basis for music making as an aesthetically rewarding function in humans. PMID:26966157
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Food reward in the absence of taste receptor signaling.
de Araujo, Ivan E; Oliveira-Maia, Albino J; Sotnikova, Tatyana D; Gainetdinov, Raul R; Caron, Marc G; Nicolelis, Miguel A L; Simon, Sidney A
2008-03-27
Food palatability and hedonic value play central roles in nutrient intake. However, postingestive effects can influence food preferences independently of palatability, although the neurobiological bases of such mechanisms remain poorly understood. Of central interest is whether the same brain reward circuitry that is responsive to palatable rewards also encodes metabolic value independently of taste signaling. Here we show that trpm5-/- mice, which lack the cellular machinery required for sweet taste transduction, can develop a robust preference for sucrose solutions based solely on caloric content. Sucrose intake induced dopamine release in the ventral striatum of these sweet-blind mice, a pattern usually associated with receipt of palatable rewards. Furthermore, single neurons in this same ventral striatal region showed increased sensitivity to caloric intake even in the absence of gustatory inputs. Our findings suggest that calorie-rich nutrients can directly influence brain reward circuits that control food intake independently of palatability or functional taste transduction.
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Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits.
Salamone, J D; Correa, M; Farrar, A; Mingote, S M
2007-04-01
Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression.
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Mattfeld, Aaron T.; Gluck, Mark A.; Stark, Craig E.L.
2011-01-01
The goal of the present study was to elucidate the role of the human striatum in learning via reward and punishment during an associative learning task. Previous studies have identified the striatum as a critical component in the neural circuitry of reward-related learning. It remains unclear, however, under what task conditions, and to what extent, the striatum is modulated by punishment during an instrumental learning task. Using high-resolution functional magnetic resonance imaging (fMRI) during a reward- and punishment-based probabilistic associative learning task, we observed activity in the ventral putamen for stimuli learned via reward regardless of whether participants were correct or incorrect (i.e., outcome). In contrast, activity in the dorsal caudate was modulated by trials that received feedback—either correct reward or incorrect punishment trials. We also identified an anterior/posterior dissociation reflecting reward and punishment prediction error estimates. Additionally, differences in patterns of activity that correlated with the amount of training were identified along the anterior/posterior axis of the striatum. We suggest that unique subregions of the striatum—separated along both a dorsal/ventral and anterior/posterior axis— differentially participate in the learning of associations through reward and punishment. PMID:22021252
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Dong, Guangheng; Lin, Xiao; Hu, Yanbo; Xie, Chunming; Du, Xiaoxia
2015-03-17
Literatures have shown that Internet gaming disorder (IGD) subjects show impaired executive control and enhanced reward sensitivities than healthy controls. However, how these two networks jointly affect the valuation process and drive IGD subjects' online-game-seeking behaviors remains unknown. Thirty-five IGD and 36 healthy controls underwent a resting-states scan in the MRI scanner. Functional connectivity (FC) was examined within control and reward network seeds regions, respectively. Nucleus accumbens (NAcc) was selected as the node to find the interactions between these two networks. IGD subjects show decreased FC in the executive control network and increased FC in the reward network when comparing with the healthy controls. When examining the correlations between the NAcc and the executive control/reward networks, the link between the NAcc - executive control network is negatively related with the link between NAcc - reward network. The changes (decrease/increase) in IGD subjects' brain synchrony in control/reward networks suggest the inefficient/overly processing within neural circuitry underlying these processes. The inverse proportion between control network and reward network in IGD suggest that impairments in executive control lead to inefficient inhibition of enhanced cravings to excessive online game playing. This might shed light on the mechanistic understanding of IGD.
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Striatal Sensitivity during Reward Processing in Attention-Deficit/Hyperactivity Disorder
ERIC Educational Resources Information Center
Paloyelis, Yannis; Mehta, Mitul A.; Faraone, Stephen V.; Asherson, Philip; Kuntsi, Jonna
2012-01-01
Objective: Attention-deficit/hyperactivity disorder (ADHD) has been linked to deficits in the dopaminergic reward-processing circuitry; yet, existing evidence is limited, and the influence of genetic variation affecting dopamine signaling remains unknown. We investigated striatal responsivity to rewards in ADHD combined type (ADHD-CT) using…
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Reward loss and addiction: Opportunities for cross-pollination.
Ortega, Leonardo A; Solano, José L; Torres, Carmen; Papini, Mauricio R
2017-03-01
Paradigms used to study the response to and consequences of exposure to reward loss have been underutilized in approaches to the psychobiology of substance use disorders. We propose here that bringing these two areas into contact will help expanding our understanding of both reward loss and addictive behavior, hence opening up opportunities for cross-pollination. This review focuses on two lines of research that point to parallels. First, several neurochemical systems involved in addiction are also involved in the modulation of the behavioral effects of reward loss, including opioid, GABA, and dopamine receptors. Second, there are extensive overlaps in the brain circuitry underlying both reward loss and addiction. Common components of this system include, at least, the amygdala, ventral and dorsal striatum, and various prefrontal cortex regions. Four emerging avenues of research that benefit from emphasis on the common ground between reward loss and addiction are reviewed, namely, the neural circuitry involved in reward devaluation, the influence of genetic and reward history on the behavioral vulnerability and resilience, the role of competing natural rewards, and emotional self-medication. An understanding of the role of reward loss in addiction will point to a deeper understanding of the initiation and maintenance of substance use disorders. Copyright © 2017 Elsevier Inc. All rights reserved.
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Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain
Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.
2015-01-01
Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050
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Maternal Depression and Warmth During Childhood Predict Age 20 Neural Response to Reward
Morgan, Judith K.; Shaw, Daniel S.; Forbes, Erika E.
2014-01-01
Objective Early parenting experiences likely shape children’s brain development, with consequences potentially extending into adulthood. Parents’ affective disorders and expressions of positive affect could exert an influence on affect-related circuitry. The current study evaluated how maternal depression and maternal warmth assessed in early childhood and early adolescence were related to boys’ reward function during early adulthood. Method Participants were 120 boys at socioeconomic risk for emotional problems. Mothers’ history of depression during the child’s lifetime was measured when boys were 42 months old and 10/11 years old. Maternal warmth was observed during mother–child interactions at 18 and 24 months and at 10 and 11 years. Results Maternal warmth during early childhood was associated with less activation in the medial prefrontal cortex (mPFC) when anticipating and experiencing reward loss. Maternal warmth during early adolescence was associated with less activation in the mPFC when winning rewards and greater activation in the caudate when experiencing loss. The association between maternal warmth during early childhood and early adolescence and reward function in the striatum and mPFC was stronger for boys exposed to maternal depression relative to boys who were not. Conclusions The experience of warmth and affection from mothers may be a protective factor for reward function in boys exposed to maternal depression, possibly by engaging vulnerable neural reward systems through affiliation. PMID:24342390
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Geier, Charles F; Sweitzer, Maggie M; Denlinger, Rachel; Sparacino, Gina; Donny, Eric C
2014-08-30
Chronic smoking may result in reduced sensitivity to non-drug rewards (e.g., money), a phenomenon particularly salient during abstinence. During a quit attempt, this effect may contribute to biased decision-making (smoking>alternative reinforcers) and relapse. Although relevant for quitting, characterization of reduced reward function in abstinent smokers remains limited. Moreover, how attenuated reward function affects other brain systems supporting decision-making has not been established. Here, we use a rewarded antisaccade (rAS) task to characterize non-drug reward processing and its influence on inhibitory control, key elements underlying decision-making, in abstinent smokers vs. non-smokers. Abstinent (12-hours) adult daily smokers (N=23) and non-smokers (N=11) underwent fMRI while performing the rAS. Behavioral performances improved on reward vs. neutral trials. Smokers showed attenuated activation in ventral striatum during the reward cue and in superior precentral sulcus and posterior parietal cortex during response preparation, but greater responses during the saccade response in posterior cingulate and parietal cortices. Smokers' attenuated anticipatory responses suggest reduced motivation from monetary reward, while heightened activation during the saccade response suggests that additional circuitry may be engaged later to enhance inhibitory task performance. Overall, this preliminary study highlights group differences in decision-making components and the utility of the rAS to characterize these effects. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Are You Smarter Than a Teenager? Maybe Not When It Comes to Reinforcement Learning.
DiMenichi, Brynne C; Tricomi, Elizabeth
2016-10-05
Adolescence is a time of tumultuous behavior that may result, in part, from brain circuitry that enhances reward seeking. In this issue of Neuron, Davidow et al. (2016) present a convincing argument that adolescent brain functionality can be adaptive in certain contexts, particularly probabilistic learning environments. Copyright © 2016. Published by Elsevier Inc.
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Epigenetic dysregulation of the dopamine system in diet-induced obesity.
Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M
2012-03-01
Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
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Kullmann, Stephanie; Frank, Sabine; Heni, Martin; Ketterer, Caroline; Veit, Ralf; Häring, Hans-Ulrich; Fritsche, Andreas; Preissl, Hubert
2013-01-01
There is accumulating evidence that food consumption is controlled by a wide range of brain circuits outside of the homeostatic system. Activation in these brain circuits may override the homeostatic system and also contribute to the enormous increase of obesity. However, little is known about the influence of hormonal signals on the brain's non-homeostatic system. Thus, selective insulin action in the brain was investigated by using intranasal application. We performed 'resting-state' functional magnetic resonance imaging in 17 healthy lean female subjects to assess intrinsic brain activity by fractional amplitude of low-frequency fluctuations (fALFF) before, 30 and 90 min after application of intranasal insulin. Here, we showed that insulin modulates intrinsic brain activity in the hypothalamus and orbitofrontal cortex. Furthermore, we could show that the prefrontal and anterior cingulate cortex response to insulin is associated with body mass index. This demonstrates that hormonal signals as insulin may reduce food intake by modifying the reward and prefrontal circuitry of the human brain, thereby potentially decreasing the rewarding properties of food. Due to the alarming increase in obesity worldwide, it is of great importance to identify neural mechanisms of interaction between the homeostatic and non-homeostatic system to generate new targets for obesity therapy. Copyright © 2012 S. Karger AG, Basel.
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Dissociable Frontostriatal White Matter Connectivity Underlies Reward and Motor Impulsivity
Hampton, William H.; Alm, Kylie H.; Venkatraman, Vinod; Nugiel, Tehila; Olson, Ingrid R.
2017-01-01
Dysfunction of cognitive control often leads to impulsive decision-making in clinical and healthy populations. Some research suggests that a generalized cognitive control mechanism underlies the ability to modulate various types of impulsive behavior, while other evidence suggests different forms of impulsivity are dissociable, and rely on distinct neural circuitry. Past research consistently implicates several brain regions, such as the striatum and portions of the prefrontal cortex, in impulsive behavior. However the ventral and dorsal striatum are distinct in regards to function and connectivity. Nascent evidence points to the importance of frontostriatal white matter connectivity in impulsivity, yet it remains unclear whether particular tracts relate to different control behaviors. Here we used probabilistic tractography of diffusion imaging data to relate ventral and dorsal frontostriatal connectivity to reward and motor impulsivity measures. We found a double dissociation such that individual differences in white matter connectivity between the ventral striatum and the ventromedial prefrontal cortex and dorsolateral prefrontal cortex was associated with reward impulsivity, as measured by delay discounting, whereas connectivity between dorsal striatum and supplementary motor area was associated with motor impulsivity, but not vice versa. Our findings suggest that (a) structural connectivity can is associated with a large amount of behavioral variation; (b) different types of impulsivity are driven by dissociable frontostriatal neural circuitry. PMID:28189592
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Reward Circuitry Plasticity in Pain Perception and Modulation
DosSantos, Marcos F.; Moura, Brenda de Souza; DaSilva, Alexandre F.
2017-01-01
Although pain is a widely known phenomenon and an important clinical symptom that occurs in numerous diseases, its mechanisms are still barely understood. Owing to the scarce information concerning its pathophysiology, particularly what is involved in the transition from an acute state to a chronic condition, pain treatment is frequently unsatisfactory, therefore contributing to the amplification of the chronic pain burden. In fact, pain is an extremely complex experience that demands the recruitment of an intricate set of central nervous system components. This includes cortical and subcortical areas involved in interpretation of the general characteristics of noxious stimuli. It also comprises neural circuits that process the motivational-affective dimension of pain. Hence, the reward circuitry represents a vital element for pain experience and modulation. This review article focuses on the interpretation of the extensive data available connecting the major components of the reward circuitry to pain suffering, including the nucleus accumbens, ventral tegmental area, and the medial prefrontal cortex; with especial attention dedicated to the evaluation of neuroplastic changes affecting these structures found in chronic pain syndromes, such as migraine, trigeminal neuropathic pain, chronic back pain, and fibromyalgia. PMID:29209204
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Berridge, Kent C.; Kringelbach, Morten L.
2015-01-01
Pleasure is mediated by well-developed mesocorticolimbic circuitry, and serves adaptive functions. In affective disorders anhedonia (lack of pleasure) or dysphoria (negative affect) can result from breakdowns of that hedonic system. Human neuroimaging studies indicate that surprisingly similar circuitry is activated by quite diverse pleasures, suggesting a common neural currency shared by all. Wanting for rewards is generated by a large and distributed brain system. Liking, or pleasure itself, is generated by a smaller set of hedonic hotspots within limbic circuitry. Those hotspots also can be embedded in broader anatomical patterns of valence organization, such as in a keyboard pattern of nucleus accumbens generators for desire versus dread. In contrast, some of the best known textbook candidates for pleasure generators, including classic pleasure electrodes and the mesolimbic dopamine system, may not generate pleasure after all. These emerging insights into brain pleasure mechanisms may eventually facilitate better treatments for affective disorders. PMID:25950633
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Dutcher, Janine M; Creswell, J David; Pacilio, Laura E; Harris, Peter R; Klein, William M P; Levine, John M; Bower, Julienne E; Muscatell, Keely A; Eisenberger, Naomi I
2016-04-01
Self-affirmation (reflecting on important personal values) has been shown to have a range of positive effects; however, the neural basis of self-affirmation is not known. Building on studies showing that thinking about self-preferences activates neural reward pathways, we hypothesized that self-affirmation would activate brain reward circuitry during functional MRI (fMRI) studies. In Study 1, with college students, making judgments about important personal values during self-affirmation activated neural reward regions (i.e., ventral striatum), whereas making preference judgments that were not self-relevant did not. Study 2 replicated these results in a community sample, again showing that self-affirmation activated the ventral striatum. These are among the first fMRI studies to identify neural processes during self-affirmation. The findings extend theory by showing that self-affirmation may be rewarding and may provide a first step toward identifying a neural mechanism by which self-affirmation may produce a wide range of beneficial effects. © The Author(s) 2016.
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Brain connectivity reflects human aesthetic responses to music.
Sachs, Matthew E; Ellis, Robert J; Schlaug, Gottfried; Loui, Psyche
2016-06-01
Humans uniquely appreciate aesthetics, experiencing pleasurable responses to complex stimuli that confer no clear intrinsic value for survival. However, substantial variability exists in the frequency and specificity of aesthetic responses. While pleasure from aesthetics is attributed to the neural circuitry for reward, what accounts for individual differences in aesthetic reward sensitivity remains unclear. Using a combination of survey data, behavioral and psychophysiological measures and diffusion tensor imaging, we found that white matter connectivity between sensory processing areas in the superior temporal gyrus and emotional and social processing areas in the insula and medial prefrontal cortex explains individual differences in reward sensitivity to music. Our findings provide the first evidence for a neural basis of individual differences in sensory access to the reward system, and suggest that social-emotional communication through the auditory channel may offer an evolutionary basis for music making as an aesthetically rewarding function in humans. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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Frank, Guido K.; Shott, Megan E.; Hagman, Jennifer O.; Mittal, Vijay A.
2013-01-01
Objective The pathophysiology of the eating disorder anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. Here we assessed taste pleasantness and reward sensitivity in relation to brain structure, which might be related to food avoidance commonly seen in eating disorders. Method We used structural magnetic resonance brain imaging to study gray and white matter volumes in individuals with restricting type currently ill (n = 19) or recovered-anorexia nervosa (n = 24), bulimia nervosa (n= 19) and healthy control women (n=24). Results All eating disorder groups showed increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manually tracing confirmed larger gyrus rectus volume, and predicted taste pleasantness across all groups. The analyses also indicated other morphological differences between diagnostic categories: Ill and recovered-anorexia nervosa had increased right, while bulimia nervosa had increased left antero-ventral insula gray matter volumes compared to controls. Furthermore, dorsal striatum volumes were reduced in recovered-anorexia and bulimia nervosa, and predicted sensitivity to reward in the eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas when compared to healthy controls. Notably, the results held when controlling for a range of covariates (e.g., age, depression, anxiety, medications). Conclusion Brain structure in medial orbitofrontal cortex, insula and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value. PMID:23680873
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Art for reward's sake: visual art recruits the ventral striatum.
Lacey, Simon; Hagtvedt, Henrik; Patrick, Vanessa M; Anderson, Amy; Stilla, Randall; Deshpande, Gopikrishna; Hu, Xiaoping; Sato, João R; Reddy, Srinivas; Sathian, K
2011-03-01
A recent study showed that people evaluate products more positively when they are physically associated with art images than similar non-art images. Neuroimaging studies of visual art have investigated artistic style and esthetic preference but not brain responses attributable specifically to the artistic status of images. Here we tested the hypothesis that the artistic status of images engages reward circuitry, using event-related functional magnetic resonance imaging (fMRI) during viewing of art and non-art images matched for content. Subjects made animacy judgments in response to each image. Relative to non-art images, art images activated, on both subject- and item-wise analyses, reward-related regions: the ventral striatum, hypothalamus and orbitofrontal cortex. Neither response times nor ratings of familiarity or esthetic preference for art images correlated significantly with activity that was selective for art images, suggesting that these variables were not responsible for the art-selective activations. Investigation of effective connectivity, using time-varying, wavelet-based, correlation-purged Granger causality analyses, further showed that the ventral striatum was driven by visual cortical regions when viewing art images but not non-art images, and was not driven by regions that correlated with esthetic preference for either art or non-art images. These findings are consistent with our hypothesis, leading us to propose that the appeal of visual art involves activation of reward circuitry based on artistic status alone and independently of its hedonic value. Copyright © 2010 Elsevier Inc. All rights reserved.
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Anatomical correlates of reward-seeking behaviours in behavioural variant frontotemporal dementia
Sturm, Virginia E.; Seeley, William W.; Miller, Bruce L.; Kramer, Joel H.; Rosen, Howard J.
2014-01-01
Behavioural variant frontotemporal dementia is characterized by abnormal responses to primary reward stimuli such as food, sex and intoxicants, suggesting abnormal functioning of brain circuitry mediating reward processing. The goal of this analysis was to determine whether abnormalities in reward-seeking behaviour in behavioural variant frontotemporal dementia are correlated with atrophy in regions known to mediate reward processing. Review of case histories in 103 patients with behavioural variant frontotemporal dementia identified overeating or increased sweet food preference in 80 (78%), new or increased alcohol or drug use in 27 (26%), and hypersexuality in 17 (17%). For each patient, a primary reward-seeking score of 0–3 was created with 1 point given for each target behaviour (increased seeking of food, drugs, or sex). Voxel-based morphometry performed in 91 patients with available imaging revealed that right ventral putamen and pallidum atrophy correlated with higher reward-seeking scores. Each of the reward-related behaviours involved partially overlapping right hemisphere reward circuit regions including putamen, globus pallidus, insula and thalamus. These findings indicate that in some patients with behavioural variant frontotemporal dementia, low volume of subcortical reward-related structures is associated with increased pursuit of primary rewards, which may be a product of increased thalamocortical feedback. PMID:24740987
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Schneider, S; Brassen, S; Bromberg, U; Banaschewski, T; Conrod, P; Flor, H; Gallinat, J; Garavan, Hugh; Heinz, A; Martinot, J-L; Nees, F; Rietschel, M; Smolka, M N; Ströhle, A; Struve, M; Schumann, G; Büchel, C
2012-01-01
Considerable animal and human research has been dedicated to the effects of parenting on structural brain development, focusing on hippocampal and prefrontal areas. Conversely, although functional imaging studies suggest that the neural reward circuitry is involved in parental affection, little is known about mothers' interpersonal qualities in relation to their children's brain structure and function. Moreover, gender differences concerning the effect of maternal qualities have rarely been investigated systematically. In 63 adolescents, we assessed structural and functional magnetic resonance imaging as well as interpersonal affiliation in their mothers. This allowed us to associate maternal affiliation with gray matter density and neural responses during different phases of the well-established Monetary Incentive Delay task. Maternal affiliation was positively associated with hippocampal and orbitofrontal gray matter density. Moreover, in the feedback of reward hit as compared with reward miss, an association with caudate activation was found. Although no significant gender effects were observed in these associations, during reward feedback as compared with baseline, maternal affiliation was significantly associated with ventral striatal and caudate activation only in females. Our findings demonstrate that maternal interpersonal affiliation is related to alterations in both the brain structure and reward-related activation in healthy adolescents. Importantly, the pattern is in line with typical findings in depression and post-traumatic stress disorder, suggesting that a lack of maternal affiliation might have a role in the genesis of mental disorders. PMID:23149446
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Pain and suicidality: Insights from reward and addiction neuroscience
Elman, Igor; Borsook, David; Volkow, Nora D.
2016-01-01
Suicidality is exceedingly prevalent in pain patients. Although the pathophysiology of this link remains unclear, it may be potentially related to the partial congruence of physical and emotional pain systems. The latter system’s role in suicide is also conspicuous during setbacks and losses sustained in the context of social attachments. Here we propose a model based on the neural pathways mediating reward and anti-reward (i.e., allostatic adjustment to recurrent activation of the reward circuitry); both are relevant etiologic factors in pain, suicide and social attachments. A comprehensive literature search on neurobiology of pain and suicidality was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) physical and emotional pain, (2) emotional pain and social attachments, (3) pain-and suicide-related alterations of the reward and anti-reward circuits as compared to addiction, which is the premier probe for dysfunction of these circuits and (4) mechanistically informed treatments of co-occurring pain and suicidality. Pain-, stress- and analgesic drugs-induced opponent and proponent states of the mesolimbic dopaminergic pathways may render reward and anti-reward systems vulnerable to sensitization, cross-sensitization and aberrant learning of contents and contexts associated with suicidal acts and behaviors. These findings suggest that pain patients exhibit alterations in the brain circuits mediating reward (depressed function) and anti-reward (sensitized function) that may affect their proclivity for suicide and support pain and suicidality classification among other “reward deficiency syndromes” and a new proposal for “enhanced anti-reward syndromes”. We suggest that interventions aimed at restoring the balance between the reward and anti-reward networks in patients with chronic pain may help decreasing their suicide risk. PMID:23827972
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Pain and suicidality: insights from reward and addiction neuroscience.
Elman, Igor; Borsook, David; Volkow, Nora D
2013-10-01
Suicidality is exceedingly prevalent in pain patients. Although the pathophysiology of this link remains unclear, it may be potentially related to the partial congruence of physical and emotional pain systems. The latter system's role in suicide is also conspicuous during setbacks and losses sustained in the context of social attachments. Here we propose a model based on the neural pathways mediating reward and anti-reward (i.e., allostatic adjustment to recurrent activation of the reward circuitry); both are relevant etiologic factors in pain, suicide and social attachments. A comprehensive literature search on neurobiology of pain and suicidality was performed. The collected articles were critically reviewed and relevant data were extracted and summarized within four key areas: (1) physical and emotional pain, (2) emotional pain and social attachments, (3) pain- and suicide-related alterations of the reward and anti-reward circuits as compared to addiction, which is the premier probe for dysfunction of these circuits and (4) mechanistically informed treatments of co-occurring pain and suicidality. Pain-, stress- and analgesic drugs-induced opponent and proponent states of the mesolimbic dopaminergic pathways may render reward and anti-reward systems vulnerable to sensitization, cross-sensitization and aberrant learning of contents and contexts associated with suicidal acts and behaviors. These findings suggest that pain patients exhibit alterations in the brain circuits mediating reward (depressed function) and anti-reward (sensitized function) that may affect their proclivity for suicide and support pain and suicidality classification among other "reward deficiency syndromes" and a new proposal for "enhanced anti-reward syndromes". We suggest that interventions aimed at restoring the balance between the reward and anti-reward networks in patients with chronic pain may help decreasing their suicide risk. Published by Elsevier Ltd.
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A Role for the Lateral Dorsal Tegmentum in Memory and Decision Neural Circuitry
Redila, Van; Kinzel, Chantelle; Jo, Yong Sang; Puryear, Corey B.; Mizumori, Sheri J.Y.
2017-01-01
A role for the hippocampus in memory is clear, although the mechanism for its contribution remains a matter of debate. Converging evidence suggests that hippocampus evaluates the extent to which context-defining features of events occur as expected. The consequence of mismatches, or prediction error, signals from hippocampus is discussed in terms of its impact on neural circuitry that evaluates the significance of prediction errors: Ventral tegmental area (VTA) dopamine cells burst fire to rewards or cues that predict rewards (Schultz et al., 1997). Although the lateral dorsal tegmentum (LDTg) importantly controls dopamine cell burst firing (Lodge & Grace, 2006) the behavioral significance of the LDTg control is not known. Therefore, we evaluated LDTg functional activity as rats performed a spatial memory task that generates task-dependent reward codes in VTA (Jo et al., 2013; Puryear et al., 2010) and another VTA afferent, the pedunculopontine nucleus (PPTg, Norton et al., 2011). Reversible inactivation of the LDTg significantly impaired choice accuracy. LDTg neurons coded primarily egocentric information in the form of movement velocity, turning behaviors, and behaviors leading up to expected reward locations. A subset of the velocity-tuned LDTg cells also showed high frequency bursts shortly before or after reward encounters, after which they showed tonic elevated firing during consumption of small, but not large, rewards. Cells that fired before reward encounters showed stronger correlations with velocity as rats moved toward, rather than away from, rewarded sites. LDTg neural activity was more strongly regulated by egocentric behaviors than that observed for PPTg or VTA cells that were recorded by Puryear et al. and Norton et al. While PPTg activity was uniquely sensitive to ongoing sensory input, all three regions encoded reward magnitude (although in different ways), reward expectation, and reward encounters. Only VTA encoded reward prediction errors. LDTg may inform VTA about learned goal-directed movement that reflects the current motivational state, and this in turn may guide VTA determination of expected subjective goal values. When combined it is clear the LDTg and PPTg provide only a portion of the information that dopamine cells need to assess the value of prediction errors, a process that is essential to future adaptive decisions and switches of cognitive (i.e. memorial) strategies and behavioral responses. PMID:24910282
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Ghrelin in the CNS: From hunger to a rewarding and memorable meal?
Olszewski, Pawel K.; Schiöth, Helgi B.; Levine, Allen S.
2008-01-01
Ghrelin, the endogenous agonist of the growth hormone secretagogue receptor, has been shown to induce robust feeding responses in numerous experimental models. Although ghrelin comes from both peripheral and central sources, its hyperphagic properties, to a large extent, arise from activity at the brain level. The current review focuses on describing central mechanisms through which this peptide affects consumption. We address the issue of whether ghrelin serves just as a signal of energy needs of the organism or – as suggested by the most recent findings -also affects food intake via other feeding-related mechanisms, including reward and memory. Complexity of ghrelin’s role in the regulation of ingestive behavior is discussed by characterizing its influence on consumption, reward and memory as well as by defining its function within the brain circuitry and interplay with other neuropeptides. PMID:18308399
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Reward, salience, and attentional networks are activated by religious experience in devout Mormons
Ferguson, Michael A.; Nielsen, Jared A.; King, Jace B.; Dai, Li; Giangrasso, Danielle M.; Holman, Rachel; Korenberg, Julie R.; Anderson, Jeffrey S.
2017-01-01
High-level cognitive and emotional experience arises from brain activity, but the specific brain substrates for religious and spiritual euphoria remain unclear. We demonstrate using functional magnetic resonance imaging scans in 19 devout Mormons that a recognizable feeling central to their devotional practice was reproducibly associated with activation in nucleus accumbens, ventromedial prefrontal cortex, and frontal attentional regions. Nucleus accumbens activation preceded peak spiritual feelings by 1–3 s and was replicated in four separate tasks. Attentional activation in the anterior cingulate and frontal eye fields was greater in the right hemisphere. The association of abstract ideas and brain reward circuitry may interact with frontal attentional and emotive salience processing, suggesting a mechanism whereby doctrinal concepts may come to be intrinsically rewarding and motivate behavior in religious individuals. PMID:27834117
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Disambiguating ventral striatum fMRI-related bold signal during reward prediction in schizophrenia
Morris, R W; Vercammen, A; Lenroot, R; Moore, L; Langton, J M; Short, B; Kulkarni, J; Curtis, J; O'Donnell, M; Weickert, C S; Weickert, T W
2012-01-01
Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction-error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia. PMID:21709684
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Dissociable frontostriatal white matter connectivity underlies reward and motor impulsivity.
Hampton, William H; Alm, Kylie H; Venkatraman, Vinod; Nugiel, Tehila; Olson, Ingrid R
2017-04-15
Dysfunction of cognitive control often leads to impulsive decision-making in clinical and healthy populations. Some research suggests that a generalized cognitive control mechanism underlies the ability to modulate various types of impulsive behavior, while other evidence suggests different forms of impulsivity are dissociable, and rely on distinct neural circuitry. Past research consistently implicates several brain regions, such as the striatum and portions of the prefrontal cortex, in impulsive behavior. However the ventral and dorsal striatum are distinct in regards to function and connectivity. Nascent evidence points to the importance of frontostriatal white matter connectivity in impulsivity, yet it remains unclear whether particular tracts relate to different control behaviors. Here we used probabilistic tractography of diffusion imaging data to relate ventral and dorsal frontostriatal connectivity to reward and motor impulsivity measures. We found a double dissociation such that individual differences in white matter connectivity between the ventral striatum and the ventromedial prefrontal cortex and dorsolateral prefrontal cortex was associated with reward impulsivity, as measured by delay discounting, whereas connectivity between dorsal striatum and supplementary motor area was associated with motor impulsivity, but not vice versa. Our findings suggest that (a) structural connectivity can is associated with a large amount of behavioral variation; (b) different types of impulsivity are driven by dissociable frontostriatal neural circuitry. Copyright © 2017 Elsevier Inc. All rights reserved.
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Goldstein-Piekarski, Andrea N; Korgaonkar, Mayuresh S; Green, Erin; Suppes, Trisha; Schatzberg, Alan F; Hastie, Trevor; Nemeroff, Charles B; Williams, Leanne M
2016-10-18
Amygdala circuitry and early life stress (ELS) are both strongly and independently implicated in the neurobiology of depression. Importantly, animal models have revealed that the contribution of ELS to the development and maintenance of depression is likely a consequence of structural and physiological changes in amygdala circuitry in response to stress hormones. Despite these mechanistic foundations, amygdala engagement and ELS have not been investigated as biobehavioral targets for predicting functional remission in translational human studies of depression. Addressing this question, we integrated human neuroimaging and measurement of ELS within a controlled trial of antidepressant outcomes. Here we demonstrate that the interaction between amygdala activation engaged by emotional stimuli and ELS predicts functional remission on antidepressants with a greater than 80% cross-validated accuracy. Our model suggests that in depressed people with high ELS, the likelihood of remission is highest with greater amygdala reactivity to socially rewarding stimuli, whereas for those with low-ELS exposure, remission is associated with lower amygdala reactivity to both rewarding and threat-related stimuli. This full model predicted functional remission over and above the contribution of demographics, symptom severity, ELS, and amygdala reactivity alone. These findings identify a human target for elucidating the mechanisms of antidepressant functional remission and offer a target for developing novel therapeutics. The results also offer a proof-of-concept for using neuroimaging as a target for guiding neuroscience-informed intervention decisions at the level of the individual person.
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Neural systems underlying reward and approach behaviors in childhood and adolescence.
Galván, Adriana
2014-01-01
Transitions into and out of adolescence are critical developmental periods of reward-seeking and approach behaviors. Converging evidence suggests that intriguing reward-related behavioral shifts are mediated by developmental changes in frontostriatal circuitry. This chapter explores how the conceptual frameworks and empirical studies in the field of developmental cognitive neuroscience have contributed to understanding reward-related behavior across development.The chapter concludes with some implications for adaptive and maladaptive behaviors that arise from these behaviors as children transition from childhood to adolescence.
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Jia, Zhiru; Worhunsky, Patrick D; Carroll, Kathleen M; Rounsaville, Bruce J; Stevens, Michael C; Pearlson, Godfrey D; Potenza, Marc N
2011-09-15
Although cocaine dependence (CD) involves abnormalities in drug-related, reward-based decision making, it is not well understood whether these abnormalities generalize to nondrug-related cues and rewards and how neural functions underlying reward processing in cocaine abusers relate to treatment outcome. Twenty CD patients before treatment and 20 matched healthy control (HC) subjects participated in functional magnetic resonance imaging while performing a monetary incentive delay task. Outcomes through 8 weeks were assessed via percent cocaine-negative urine toxicology, self-reported cocaine abstinence, and treatment retention. Among the whole sample, anticipation of working for monetary reward (i.e., reward anticipation) was associated with activation in the ventral striatum (VS), medial frontal gyrus, thalamus, right subcallosal gyrus, right insula, and left amygdala. Cocaine dependence compared with HC participants exhibited greater activation during notification of rewarding outcome (i.e., reward receipt) in left and right VS, right caudate, and right insula. In CD participants during reward anticipation, activation in left and right thalamus and right caudate correlated negatively with percent cocaine-negative urine toxicology, activation in thalamus bilaterally correlated negatively with self-reported abstinence measures, and activation in left amygdala and parahippocampal gyrus correlated negatively with treatment retention. During reward notification, activation in right thalamus, right VS, and left culmen correlated negatively with abstinence and with urine toxicology. These findings suggest that in treatment-seeking CD participants, corticolimbic reward circuitry is relatively overactivated during monetary incentive delay task performance and specific regional activations related to reward processing may predict aspects of treatment outcome and represent important targets for treatment development in CD. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Orbitofrontal cortex mediates pain inhibition by monetary reward.
Becker, Susanne; Gandhi, Wiebke; Pomares, Florence; Wager, Tor D; Schweinhardt, Petra
2017-04-01
Pleasurable stimuli, including reward, inhibit pain, but the level of the neuraxis at which they do so and the cerebral processes involved are unknown. Here, we characterized a brain circuitry mediating pain inhibition by reward. Twenty-four healthy participants underwent functional magnetic resonance imaging while playing a wheel of fortune game with simultaneous thermal pain stimuli and monetary wins or losses. As expected, winning decreased pain perception compared to losing. Inter-individual differences in pain modulation by monetary wins relative to losses correlated with activation in the medial orbitofrontal cortex (mOFC). When pain and reward occured simultaneously, mOFCs functional connectivity changed: the signal time course in the mOFC condition-dependent correlated negatively with the signal time courses in the rostral anterior insula, anterior-dorsal cingulate cortex and primary somatosensory cortex, which might signify moment-to-moment down-regulation of these regions by the mOFC. Monetary wins and losses did not change the magnitude of pain-related activation, including in regions that code perceived pain intensity when nociceptive input varies and/or receive direct nociceptive input. Pain inhibition by reward appears to involve brain regions not typically involved in nociceptive intensity coding but likely mediate changes in the significance and/or value of pain. © The Author (2017). Published by Oxford University Press.
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Synaptic plasticity in drug reward circuitry.
Winder, Danny G; Egli, Regula E; Schramm, Nicole L; Matthews, Robert T
2002-11-01
Drug addiction is a major public health issue worldwide. The persistence of drug craving coupled with the known recruitment of learning and memory centers in the brain has led investigators to hypothesize that the alterations in glutamatergic synaptic efficacy brought on by synaptic plasticity may play key roles in the addiction process. Here we review the present literature, examining the properties of synaptic plasticity within drug reward circuitry, and the effects that drugs of abuse have on these forms of plasticity. Interestingly, multiple forms of synaptic plasticity can be induced at glutamatergic synapses within the dorsal striatum, its ventral extension the nucleus accumbens, and the ventral tegmental area, and at least some of these forms of plasticity are regulated by behaviorally meaningful administration of cocaine and/or amphetamine. Thus, the present data suggest that regulation of synaptic plasticity in reward circuits is a tractable candidate mechanism underlying aspects of addiction.
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Ehrlich, Stefan; Geisler, Daniel; Ritschel, Franziska; King, Joseph A; Seidel, Maria; Boehm, Ilka; Breier, Marion; Clas, Sabine; Weiss, Jessika; Marxen, Michael; Smolka, Michael N; Roessner, Veit; Kroemer, Nils B
2015-09-01
Individuals with anorexia nervosa are thought to exert excessive self-control to inhibit primary drives. This study used functional MRI (fMRI) to interrogate interactions between the neural correlates of cognitive control and motivational processes in the brain reward system during the anticipation of monetary reward and reward-related feedback. In order to avoid confounding effects of undernutrition, we studied female participants recovered from anorexia nervosa and closely matched healthy female controls. The fMRI analysis (including node-to-node functional connectivity) followed a region of interest approach based on models of the brain reward system and cognitive control regions implicated in anorexia nervosa: the ventral striatum, medial orbitofrontal cortex (mOFC) and dorsolateral prefrontal cortex (DLPFC). We included 30 recovered patients and 30 controls in our study. There were no behavioural differences and no differences in hemodynamic responses of the ventral striatum and the mOFC in the 2 phases of the task. However, relative to controls, recovered patients showed elevated DLPFC activity during the anticipation phase, failed to deactivate this region during the feedback phase and displayed greater functional coupling between the DLPFC and mOFC. Recovered patients also had stronger associations than controls between anticipation-related DLPFC responses and instrumental responding. The results we obtained using monetary stimuli might not generalize to other forms of reward. Unaltered neural responses in ventral limbic reward networks but increased recruitment of and connectivity with lateral-frontal brain circuitry in recovered patients suggests an elevated degree of selfregulatory processes in response to rewarding stimuli. An imbalance between brain systems subserving bottom-up and top-down processes may be a trait marker of the disorder.
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Blum, Kenneth; Modestino, Edward J; Febo, Marcelo; Steinberg, Bruce; McLaughlin, Thomas; Fried, Lyle; Baron, David; Siwicki, David; Badgaiyan, Rajendra D
2017-01-01
The principal vector of Lyme disease in the United States is Ixodes scapularis: black legged or deer ticks. There is increased evidence that those infected may be plagued by anxiety or depression as well. Researchers have identified transcripts coding for two putative cytosolic sulfotransferases in these ticks, which recognized phenolic monoamines as their substrates. It is hypothesized that protracted Lyme disease sequelae may be due to impairment of dopaminergic function of the brain reward circuitry. The subsequent recombinant proteins exhibited sulfotransferase function against two neurotransmitters: dopamine and octopamine. This, in itself, can reduce dopamine function leading to many Reward Deficiency Syndrome behaviors, including depression and possibly, anxiety. In fact, it was shown that activity of Ixosc Sult 1 and Sult 2 in the Ixodid tick salivary glands might contain inactivation of the salivation signal through sulfonation of either dopamine or octopamine. This infraction results in a number of clinically observed mood changes, such as anxiety and depression. In fact, there are common symptoms observed for both Parkinson and Lyme diseases. The importance of understanding the mechanistic and neurobiological effects of Lyme on the central nervous system (CNS) provides the basis for pro-dopamine regulation as a treatment. WC 195 PMID:28736624
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Blum, Kenneth; Modestino, Edward J; Febo, Marcelo; Steinberg, Bruce; McLaughlin, Thomas; Fried, Lyle; Baron, David; Siwicki, David; Badgaiyan, Rajendra D
2017-05-01
The principal vector of Lyme disease in the United States is Ixodes scapularis: black legged or deer ticks. There is increased evidence that those infected may be plagued by anxiety or depression as well. Researchers have identified transcripts coding for two putative cytosolic sulfotransferases in these ticks, which recognized phenolic monoamines as their substrates. It is hypothesized that protracted Lyme disease sequelae may be due to impairment of dopaminergic function of the brain reward circuitry. The subsequent recombinant proteins exhibited sulfotransferase function against two neurotransmitters: dopamine and octopamine. This, in itself, can reduce dopamine function leading to many Reward Deficiency Syndrome behaviors, including depression and possibly, anxiety. In fact, it was shown that activity of Ixosc Sult 1 and Sult 2 in the Ixodid tick salivary glands might contain inactivation of the salivation signal through sulfonation of either dopamine or octopamine. This infraction results in a number of clinically observed mood changes, such as anxiety and depression. In fact, there are common symptoms observed for both Parkinson and Lyme diseases. The importance of understanding the mechanistic and neurobiological effects of Lyme on the central nervous system (CNS) provides the basis for pro-dopamine regulation as a treatment. WC 195.
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Altered brain response to reward and punishment in adolescents with Anorexia Nervosa
Bischoff-Grethe, Amanda; McCurdy, Danyale; Grenesko-Stevens, Emily; (Zoe) Irvine, Laura E.; Wagner, Angela; Yau, Wai-Ying Wendy; Fennema-Notestine, Christine; Wierenga, Christina E.; Fudge, Julie L.; Delgado, Mauricio R.; Kaye, Walter H.
2013-01-01
Adults recovered from anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences. PMID:24148909
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Altered brain response to reward and punishment in adolescents with Anorexia nervosa.
Bischoff-Grethe, Amanda; McCurdy, Danyale; Grenesko-Stevens, Emily; Irvine, Laura E Zoe; Wagner, Angela; Yau, Wai-Ying Wendy; Fennema-Notestine, Christine; Wierenga, Christina E; Fudge, Julie L; Delgado, Mauricio R; Kaye, Walter H
2013-12-30
Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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Pathological anxiety and function/dysfunction in the brain's fear/defense circuitry.
Lang, Peter J; McTeague, Lisa M; Bradley, Margaret M
2014-01-01
Research from the University of Florida Center for the Study of Emotion and Attention aims to develop neurobiological measures that objectively discriminate among symptom patterns in patients with anxiety disorders. From this perspective, anxiety and mood pathologies are considered to be brain disorders, resulting from dysfunction and maladaptive plasticity in the neural circuits that determine fearful/defensive and appetitive/reward behavior (Insel et al., 2010). We review recent studies indicating that an enhanced probe startle reflex during the processing of fear memory cues (mediated by cortico-limbic circuitry and thus indicative of plastic brain changes), varies systematically in strength over a spectrum-wide dimension of anxiety pathology-across and within diagnoses-extending from strong focal fear reactions to a consistently blunted reaction in patients with more generalized anxiety and comorbid mood disorders. Preliminary studies with functional magnetic resonance imaging (fMRI) encourage the hypothesis that fear/defense circuit dysfunction covaries with this same dimension of psychopathology. Plans are described for an extended study of the brain's motivation circuitry in anxiety spectrum patients, with the aim of defining the specifics of circuit dysfunction in severe disorders. A sub-project explores the use of real-time fMRI feedback in circuit analysis and as a modality to up-regulate circuit function in the context of blunted affect.
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Neural responses during the anticipation and receipt of olfactory reward and punishment in human.
Zou, Lai-Quan; Zhou, Han-Yu; Zhuang, Yuan; van Hartevelt, Tim J; Lui, Simon S Y; Cheung, Eric F C; Møller, Arne; Kringelbach, Morten L; Chan, Raymond C K
2018-03-01
Pleasure experience is an important part of normal healthy life and is essential for general and mental well-being. Many neuroimaging studies have investigated the underlying neural processing of verbal and visual modalities of reward. However, how the brain processes rewards in the olfactory modality is not fully understood. This study aimed to examine the neural basis of olfactory rewards in 25 healthy participants using functional magnetic resonance imaging (fMRI). We developed an Olfactory Incentive Delay (OLID) imaging task distinguishing between the anticipation and receipt of olfactory rewards and punishments. We found that the pallidum was activated during the anticipation of both olfactory rewards and punishments. The bilateral insula was activated independently from the odours' hedonic valence during the receipt phase. In addition, right caudate activation during the anticipation of unpleasant odours was correlated with self-reported anticipatory hedonic traits, whereas bilateral insular activation during the receipt of pleasant odours was correlated with self-reported consummatory hedonic traits. These findings suggest that activity in the insula and the caudate may be biomarkers of anhedonia. These findings also highlight a useful and valid paradigm to study the neural circuitry underlying reward processing in people with anhedonia. Copyright © 2018 Elsevier Ltd. All rights reserved.
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ART FOR REWARD’S SAKE: VISUAL ART RECRUITS THE VENTRAL STRIATUM
Lacey, Simon; Hagtvedt, Henrik; Patrick, Vanessa M.; Anderson, Amy; Stilla, Randall; Deshpande, Gopikrishna; Hu, Xiaoping; Sato, João R.; Reddy, Srinivas; Sathian, K.
2010-01-01
A recent study showed that people evaluate products more positively when they are physically associated with art images than similar non-art images. Neuroimaging studies of visual art have investigated artistic style and esthetic preference but not brain responses attributable specifically to the artistic status of images. Here we tested the hypothesis that the artistic status of images engages reward circuitry, using event-related functional magnetic resonance imaging (fMRI) during viewing of art and non-art images matched for content. Subjects made animacy judgments in response to each image. Relative to non-art images, art images activated, on both subject- and item-wise analyses, reward-related regions: the ventral striatum, hypothalamus and orbitofrontal cortex. Neither response times nor ratings of familiarity or esthetic preference for art images correlated significantly with activity that was selective for art images, suggesting that these variables were not responsible for the art-selective activations. Investigation of effective connectivity, using time-varying, wavelet-based, correlation-purged Granger causality analyses, further showed that the ventral striatum was driven by visual cortical regions when viewing art images but not non-art images, and was not driven by regions that correlated with esthetic preference for either art or non -art images. These findings are consistent with our hypothesis, leading us to propose that the appeal of visual art involves activation of reward circuitry based on artistic status alone and independently of its hedonic value. PMID:21111833
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Zhu, Xi; Helpman, Liat; Papini, Santiago; Schneier, Franklin; Markowitz, John C; Van Meter, Page E; Lindquist, Martin A; Wager, Tor D; Neria, Yuval
2017-07-01
Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD-MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD-MDD is associated with different network connectivity abnormalities than PTSD alone. We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs-FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD-alone (n = 27), PTSD-MDD (n = 21), and trauma-exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc). Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA-orbitalfrontal cortex (OFC) and CMA-thalamus pathways, key to fear processing, and fear expression, respectively. PTSD-MDD, compared to PTSD-alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal-subcortical pathways: BLA-OFC, NAcc-thalamus, and NAcc-hippocampus. Further, while both the BLA-OFC and the NAcc-thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA-OFC; CMA-thalamus) only. Comorbid PTSD-MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed. © 2016 Wiley Periodicals, Inc.
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Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory.
Ikemoto, Satoshi
2010-11-01
Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures-the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area. Published by Elsevier Ltd.
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Targeting circuits of sexual desire as a treatment strategy for hypoactive sexual desire disorder.
Stahl, Stephen M
2010-07-01
Hypoactive sexual desire disorder (HSDD) is hypothesized to be a disorder of the brain's reward circuitry. Neurotransmitters in reward circuits are thus therapeutic targets for improving sexual desire. Novel treatment strategies are to enhance dopamine (DA) actions, reduce serotonin (5-HT) actions, or both. (c) Copyright 2010 Physicians Postgraduate Press, Inc.
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Peers Increase Adolescent Risk Taking by Enhancing Activity in the Brain's Reward Circuitry
ERIC Educational Resources Information Center
Chein, Jason; Albert, Dustin; O'Brien, Lia; Uckert, Kaitlyn; Steinberg, Laurence
2011-01-01
The presence of peers increases risk taking among adolescents but not adults. We posited that the presence of peers may promote adolescent risk taking by sensitizing brain regions associated with the anticipation of potential rewards. Using fMRI, we measured brain activity in adolescents, young adults, and adults as they made decisions in a…
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From prediction error to incentive salience: mesolimbic computation of reward motivation
Berridge, Kent C.
2011-01-01
Reward contains separable psychological components of learning, incentive motivation and pleasure. Most computational models have focused only on the learning component of reward, but the motivational component is equally important in reward circuitry, and even more directly controls behavior. Modeling the motivational component requires recognition of additional control factors besides learning. Here I will discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g., drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously-learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. Thus a consequence of the difference between incentive salience and learning can be to decouple cue-triggered motivation of the moment from previously learned values of how good the associated reward has been in the past. Another consequence can be to produce irrationally strong motivation urges that are not justified by any memories of previous reward values (and without distorting associative predictions of future reward value). Such irrationally strong motivation may be especially problematic in addiction. To comprehend these phenomena, future models of mesocorticolimbic reward function should address the neurobiological state factors that participate to control generation of incentive salience. PMID:22487042
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von Rhein, Daniel; Cools, Roshan; Zwiers, Marcel P; van der Schaaf, Marieke; Franke, Barbara; Luman, Marjolein; Oosterlaan, Jaap; Heslenfeld, Dirk J; Hoekstra, Pieter J; Hartman, Catharina A; Faraone, Stephen V; van Rooij, Daan; van Dongen, Eelco V; Lojowska, Maria; Mennes, Maarten; Buitelaar, Jan
2015-05-01
Attention-deficit/hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder associated with abnormal reward processing. Limited and inconsistent data exist about the neural mechanisms underlying this abnormality. Furthermore, it is not known whether reward processing is abnormal in unaffected siblings of participants with ADHD. We used event-related functional magnetic resonance imaging (fMRI) to investigate brain responses during reward anticipation and receipt with an adapted monetary incentive delay task in a large sample of adolescents and young adults with ADHD (n = 150), their unaffected siblings (n = 92), and control participants (n = 108), all of the same age. Participants with ADHD showed, relative to control participants, increased responses in the anterior cingulate, anterior frontal cortex, and cerebellum during reward anticipation, and in the orbitofrontal, occipital cortex and ventral striatum. Responses of unaffected siblings were increased in these regions as well, except for the cerebellum during anticipation and ventral striatum during receipt. ADHD in adolescents and young adults is associated with enhanced neural responses in frontostriatal circuitry to anticipation and receipt of reward. The findings support models emphasizing aberrant reward processing in ADHD, and suggest that processing of reward is subject to familial influences. Future studies using standard monetary incentive delay task parameters are needed to replicate our findings. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
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Liking, wanting, and the incentive-sensitization theory of addiction.
Berridge, Kent C; Robinson, Terry E
2016-11-01
Rewards are both "liked" and "wanted," and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of "wanting" a particular reward is dissociable from circuitry that mediates the degree to which it is "liked." Incentive salience or "wanting," a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, "liking," or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological "wanting," especially triggered by cues, without necessarily an amplification of "liking." This is because of long-lasting changes in dopamine-related motivation systems of susceptible individuals, called "neural sensitization." A quarter-century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. (PsycINFO Database Record (c) 2016 APA, all rights reserved).
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Liking, Wanting and the Incentive-Sensitization Theory of Addiction
Berridge, Kent C.; Robinson, Terry E.
2016-01-01
Rewards are both ‘liked’ and ‘wanted’, and those two words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of ‘wanting’ a particular reward is dissociable from circuitry that mediates the degree to which it is ‘liked’. Incentive salience or ‘wanting’, a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, ‘liking’, or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological ‘wanting’, especially triggered by cues, without necessarily an amplification of ‘liking’. This is due to long-lasting changes in dopamine-related motivation systems of susceptible individuals, called neural sensitization. A quarter-century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. PMID:27977239
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Hashmi, Javeria A; Baliki, Marwan N; Huang, Lejian; Baria, Alex T; Torbey, Souraya; Hermann, Kristina M; Schnitzer, Thomas J; Apkarian, A Vania
2013-09-01
Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.
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Hashmi, Javeria A.; Baliki, Marwan N.; Huang, Lejian; Baria, Alex T.; Torbey, Souraya; Hermann, Kristina M.; Schnitzer, Thomas J.; Apkarian, A. Vania
2013-01-01
Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain. PMID:23983029
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Gauthier, Jamie M; Tassin, David H; Dwoskin, Linda P; Kantak, Kathleen M
2014-07-15
Attention Deficit Hyperactivity Disorder (ADHD) is associated with dysfunctional prefrontal and striatal circuitry and dysregulated dopamine neurotransmission. Spontaneously Hypertensive Rats (SHR), a heuristically useful animal model of ADHD, were evaluated against normotensive Wistar (WIS) controls to determine whether dopamine D1 receptor blockade of either prelimbic prefrontal cortex (plPFC) or lateral dorsal striatum (lDST) altered learning functions of both interconnected sites. A strategy set shifting task measured plPFC function (behavioral flexibility/executive function) and a reward devaluation task measured lDST function (habitual responding). Prior to tests, rats received bilateral infusions of SCH 23390 (1.0 μg/side) or vehicle into plPFC or lDST. Following vehicle, SHR exhibited longer lever press reaction times, more trial omissions, and fewer completed trials during the set shift test compared to WIS, indicating slower decision-making and attentional/motivational impairment in SHR. After reward devaluation, vehicle-treated SHR responded less than WIS, indicating relatively less habitual responding in SHR. After SCH 23390 infusions into plPFC, WIS expressed the same behavioral phenotype as vehicle-treated SHR during set shift and reward devaluation tests. In SHR, SCH 23390 infusions into plPFC exacerbated behavioral deficits in the set shift test and maintained the lower rate of responding in the reward devaluation test. SCH 23390 infusions into lDST did not modify set shifting in either strain, but produced lower rates of responding than vehicle infusions after reward devaluation in WIS. This research provides pharmacological evidence for unidirectional interactions between prefrontal and striatal brain regions, which has implications for the neurological basis of ADHD and its treatment. Copyright © 2014 Elsevier B.V. All rights reserved.
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Moran, James K.; Weierstall, Roland; Elbert, Thomas
2014-01-01
Aggressive behavior is thought to divide into two motivational elements: The first being a self-defensively motivated aggression against threat and a second, hedonically motivated “appetitive” aggression. Appetitive aggression is the less understood of the two, often only researched within abnormal psychology. Our approach is to understand it as a universal and adaptive response, and examine the functional neural activity of ordinary men (N = 50) presented with an imaginative listening task involving a murderer describing a kill. We manipulated motivational context in a between-subjects design to evoke appetitive or reactive aggression, against a neutral control, measuring activity with Magnetoencephalography (MEG). Results show differences in left frontal regions in delta (2–5 Hz) and alpha band (8–12 Hz) for aggressive conditions and right parietal delta activity differentiating appetitive and reactive aggression. These results validate the distinction of reward-driven appetitive aggression from reactive aggression in ordinary populations at the level of functional neural brain circuitry. PMID:25538590
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Reversal learning as a measure of impulsive and compulsive behavior in addictions.
Izquierdo, Alicia; Jentsch, J David
2012-01-01
Our ability to measure the cognitive components of complex decision-making across species has greatly facilitated our understanding of its neurobiological mechanisms. One task in particular, reversal learning, has proven valuable in assessing the inhibitory processes that are central to executive control. Reversal learning measures the ability to actively suppress reward-related responding and to disengage from ongoing behavior, phenomena that are biologically and descriptively related to impulsivity and compulsivity. Consequently, reversal learning could index vulnerability for disorders characterized by impulsivity such as proclivity for initial substance abuse as well as the compulsive aspects of dependence. Though we describe common variants and similar tasks, we pay particular attention to discrimination reversal learning, its supporting neural circuitry, neuropharmacology and genetic determinants. We also review the utility of this task in measuring impulsivity and compulsivity in addictions. We restrict our review to instrumental, reward-related reversal learning studies as they are most germane to addiction. The research reviewed here suggests that discrimination reversal learning may be used as a diagnostic tool for investigating the neural mechanisms that mediate impulsive and compulsive aspects of pathological reward-seeking and -taking behaviors. Two interrelated mechanisms are posited for the neuroadaptations in addiction that often translate to poor reversal learning: frontocorticostriatal circuitry dysregulation and poor dopamine (D2 receptor) modulation of this circuitry. These data suggest new approaches to targeting inhibitory control mechanisms in addictions.
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Keistler, Colby; Barker, Jacqueline M.
2015-01-01
Although several studies have examined the subcortical circuitry underlying Pavlovian-to-instrumental transfer (PIT), the role of medial prefrontal cortex in this behavior is largely unknown. Elucidating the cortical contributions to PIT will be key for understanding how reward-paired cues control behavior in both adaptive and maladaptive context (i.e., addiction). Here we use bilateral lesions in a rat model to show that infralimbic prefrontal cortex (ilPFC) is necessary for appropriate expression of PIT. Further, we show that ilPFC mediates this effect via functional connectivity with nucleus accumbens shell (NAcS). Together, these data provide the first demonstration that a specific cortico-striatal circuit is necessary for cue-invigorated reward seeking during specific PIT. PMID:26373829
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Bench to Bedside: From the Science to the Practice of Addiction Medicine.
Levounis, Petros
2016-03-01
The current understanding of addiction is based on a biopsychosocial model of illness. From a neurobiological perspective, addiction can be seen as the hijacking of the pleasure-reward pathways of the brain with a concomitant weakening of its executive function. The fundamental model has been expanded to include newer concepts such as multiple levels of severity of illness, motivational circuitry, and anti-reward pathways. These neurobiological concepts can explain some of the successes and failures of addiction treatment in the second half of the 20th century and the beginning of the 21st century. Psychosocial interventions (primarily cognitive behavior therapy, mutual help groups, and motivational interviewing) and pharmacological treatments (such as agonists, antagonists, and partial agonists) form the basis of addiction treatment today.
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The addictive dimensionality of obesity.
Volkow, Nora D; Wang, Gene-Jack; Tomasi, Dardo; Baler, Ruben D
2013-05-01
Our brains are hardwired to respond and seek immediate rewards. Thus, it is not surprising that many people overeat, which in some can result in obesity, whereas others take drugs, which in some can result in addiction. Though food intake and body weight are under homeostatic regulation, when highly palatable food is available, the ability to resist the urge to eat hinges on self-control. There is no homeostatic regulator to check the intake of drugs (including alcohol); thus, regulation of drug consumption is mostly driven by self-control or unwanted effects (i.e., sedation for alcohol). Disruption in both the neurobiological processes that underlie sensitivity to reward and those that underlie inhibitory control can lead to compulsive food intake in some individuals and compulsive drug intake in others. There is increasing evidence that disruption of energy homeostasis can affect the reward circuitry and that overconsumption of rewarding food can lead to changes in the reward circuitry that result in compulsive food intake akin to the phenotype seen with addiction. Addiction research has produced new evidence that hints at significant commonalities between the neural substrates underlying the disease of addiction and at least some forms of obesity. This recognition has spurred a healthy debate to try and ascertain the extent to which these complex and dimensional disorders overlap and whether or not a deeper understanding of the crosstalk between the homeostatic and reward systems will usher in unique opportunities for prevention and treatment of both obesity and drug addiction. Published by Elsevier Inc.
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Kamarajan, Chella; Rangaswamy, Madhavi; Manz, Niklas; Chorlian, David B; Pandey, Ashwini K; Roopesh, Bangalore N; Porjesz, Bernice
2012-05-01
Recent studies have linked alcoholism with a dysfunctional neural reward system. Although several electrophysiological studies have explored reward processing in healthy individuals, such studies in alcohol-dependent individuals are quite rare. The present study examines theta oscillations during reward processing in abstinent alcoholics. The electroencephalogram (EEG) was recorded in 38 abstinent alcoholics and 38 healthy controls as they performed a single outcome gambling task, which involved outcomes of either loss or gain of an amount (10 or 50¢) that was bet. Event-related theta band (3.0-7.0 Hz) power following each outcome stimulus was computed using the S-transform method. Theta power at the time window of the outcome-related negativity (ORN) and positivity (ORP) (200-500 ms) was compared across groups and outcome conditions. Additionally, behavioral data of impulsivity and task performance were analyzed. The alcoholic group showed significantly decreased theta power during reward processing compared to controls. Current source density (CSD) maps of alcoholics revealed weaker and diffuse source activity for all conditions and weaker bilateral prefrontal sources during the Loss 50 condition when compared with controls who manifested stronger and focused midline sources. Furthermore, alcoholics exhibited increased impulsivity and risk-taking on the behavioral measures. A strong association between reduced anterior theta power and impulsive task-performance was observed. It is suggested that decreased power and weaker and diffuse CSD in alcoholics may be due to dysfunctional neural reward circuitry. The relationship among alcoholism, theta oscillations, reward processing, and impulsivity could offer clues to understand brain circuitries that mediate reward processing and inhibitory control. Copyright © 2011 Wiley-Liss, Inc.
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Kamarajan, Chella; Rangaswamy, Madhavi; Manz, Niklas; Chorlian, David B.; Pandey, Ashwini K.; Roopesh, Bangalore N.; Porjesz, Bernice
2013-01-01
Recent studies have linked alcoholism with a dysfunctional neural reward system. Although several electrophysiological studies have explored reward processing in healthy individuals, such studies in alcohol dependent individuals are quite rare. The present study examines theta oscillations during reward processing in abstinent alcoholics. The electroencephalogram (EEG) was recorded in 38 abstinent alcoholics and 38 healthy controls as they performed a single outcome gambling task which involved outcomes of either loss or gain of an amount (10¢ or 50¢) that was bet. Event-related theta band (3.0–7.0 Hz) power following each outcome stimulus was computed using the S-transform method. Theta power at the time window of the outcome-related negativity (ORN) and positivity (ORP) (200–500 ms) was compared across groups and outcome conditions. Additionally, behavioral data of impulsivity and task performance were analyzed. The alcoholic group showed significantly decreased theta power during reward processing compared to controls. Current Source Density (CSD) maps of alcoholics revealed weaker and diffuse source activity for all conditions and weaker bilateral prefrontal sources during the Loss 50 condition as compared to controls who manifested stronger and focused midline sources. Further, alcoholics exhibited increased impulsivity and risk-taking on the behavioral measures. A strong association between reduced anterior theta power and impulsive task-performance was observed. It is suggested that decreased power and weaker and diffuse CSD in alcoholics may be due to dysfunctional neural reward circuitry. The relationship among alcoholism, theta oscillations, reward processing and impulsivity could offer clues to understand brain circuitries that mediate reward processing and inhibitory control. PMID:21520344
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Mapping brain circuits of reward and motivation: in the footsteps of Ann Kelley.
Richard, Jocelyn M; Castro, Daniel C; Difeliceantonio, Alexandra G; Robinson, Mike J F; Berridge, Kent C
2013-11-01
Ann Kelley was a scientific pioneer in reward neuroscience. Her many notable discoveries included demonstrations of accumbens/striatal circuitry roles in eating behavior and in food reward, explorations of limbic interactions with hypothalamic regulatory circuits, and additional interactions of motivation circuits with learning functions. Ann Kelley's accomplishments inspired other researchers to follow in her footsteps, including our own laboratory group. Here we describe results from several lines of our research that sprang in part from earlier findings by Kelley and colleagues. We describe hedonic hotspots for generating intense pleasure 'liking', separate identities of 'wanting' versus 'liking' systems, a novel role for dorsal neostriatum in generating motivation to eat, a limbic keyboard mechanism in nucleus accumbens for generating intense desire versus intense dread, and dynamic limbic transformations of learned memories into motivation. We describe how origins for each of these themes can be traced to fundamental contributions by Ann Kelley. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Galli, Lisa; Schott, Björn H.; Wold, Andrew; van der Schalk, Job; Manstead, Antony S. R.; Scherer, Klaus; Walter, Henrik
2015-01-01
Humans have a strong tendency to affiliate with other people, especially in emotional situations. Here, we suggest that a critical mechanism underlying this tendency is that socially sharing emotional experiences is in itself perceived as hedonically positive and thereby contributes to the regulation of individual emotions. We investigated the effect of social sharing of emotions on subjective feelings and neural activity by having pairs of friends view emotional (negative and positive) and neutral pictures either alone or with the friend. While the two friends remained physically separated throughout the experiment—with one undergoing functional magnetic resonance imaging and the other performing the task in an adjacent room—they were made aware on a trial-by-trial basis whether they were seeing pictures simultaneously with their friend (shared) or alone (unshared). Ratings of subjective feelings were improved significantly when participants viewed emotional pictures together than alone, an effect that was accompanied by activity increase in ventral striatum and medial orbitofrontal cortex, two important components of the reward circuitry. Because these effects occurred without any communication or interaction between the friends, they point to an important proximate explanation for the basic human motivation to affiliate with others, particularly in emotional situations. PMID:25298009
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Wagner, Ullrich; Galli, Lisa; Schott, Björn H; Wold, Andrew; van der Schalk, Job; Manstead, Antony S R; Scherer, Klaus; Walter, Henrik
2015-06-01
Humans have a strong tendency to affiliate with other people, especially in emotional situations. Here, we suggest that a critical mechanism underlying this tendency is that socially sharing emotional experiences is in itself perceived as hedonically positive and thereby contributes to the regulation of individual emotions. We investigated the effect of social sharing of emotions on subjective feelings and neural activity by having pairs of friends view emotional (negative and positive) and neutral pictures either alone or with the friend. While the two friends remained physically separated throughout the experiment-with one undergoing functional magnetic resonance imaging and the other performing the task in an adjacent room-they were made aware on a trial-by-trial basis whether they were seeing pictures simultaneously with their friend (shared) or alone (unshared). Ratings of subjective feelings were improved significantly when participants viewed emotional pictures together than alone, an effect that was accompanied by activity increase in ventral striatum and medial orbitofrontal cortex, two important components of the reward circuitry. Because these effects occurred without any communication or interaction between the friends, they point to an important proximate explanation for the basic human motivation to affiliate with others, particularly in emotional situations. © The Author (2014). Published by Oxford University Press.
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Underconnectivity between voice-selective cortex and reward circuitry in children with autism.
Abrams, Daniel A; Lynch, Charles J; Cheng, Katherine M; Phillips, Jennifer; Supekar, Kaustubh; Ryali, Srikanth; Uddin, Lucina Q; Menon, Vinod
2013-07-16
Individuals with autism spectrum disorders (ASDs) often show insensitivity to the human voice, a deficit that is thought to play a key role in communication deficits in this population. The social motivation theory of ASD predicts that impaired function of reward and emotional systems impedes children with ASD from actively engaging with speech. Here we explore this theory by investigating distributed brain systems underlying human voice perception in children with ASD. Using resting-state functional MRI data acquired from 20 children with ASD and 19 age- and intelligence quotient-matched typically developing children, we examined intrinsic functional connectivity of voice-selective bilateral posterior superior temporal sulcus (pSTS). Children with ASD showed a striking pattern of underconnectivity between left-hemisphere pSTS and distributed nodes of the dopaminergic reward pathway, including bilateral ventral tegmental areas and nucleus accumbens, left-hemisphere insula, orbitofrontal cortex, and ventromedial prefrontal cortex. Children with ASD also showed underconnectivity between right-hemisphere pSTS, a region known for processing speech prosody, and the orbitofrontal cortex and amygdala, brain regions critical for emotion-related associative learning. The degree of underconnectivity between voice-selective cortex and reward pathways predicted symptom severity for communication deficits in children with ASD. Our results suggest that weak connectivity of voice-selective cortex and brain structures involved in reward and emotion may impair the ability of children with ASD to experience speech as a pleasurable stimulus, thereby impacting language and social skill development in this population. Our study provides support for the social motivation theory of ASD.
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From prediction error to incentive salience: mesolimbic computation of reward motivation.
Berridge, Kent C
2012-04-01
Reward contains separable psychological components of learning, incentive motivation and pleasure. Most computational models have focused only on the learning component of reward, but the motivational component is equally important in reward circuitry, and even more directly controls behavior. Modeling the motivational component requires recognition of additional control factors besides learning. Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. Thus, one consequence of the difference between incentive salience and learning can be to decouple cue-triggered motivation of the moment from previously learned values of how good the associated reward has been in the past. Another consequence can be to produce irrationally strong motivation urges that are not justified by any memories of previous reward values (and without distorting associative predictions of future reward value). Such irrationally strong motivation may be especially problematic in addiction. To understand these phenomena, future models of mesocorticolimbic reward function should address the neurobiological state factors that participate to control generation of incentive salience. © 2012 The Author. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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Bae, Sujin; Han, Doug Hyun; Jung, Jaebum; Nam, Ki Chun; Renshaw, Perry F
2017-12-01
Background and aims Given the similarities in clinical symptoms, Internet gaming disorder (IGD) is thought to be diagnostically similar to Internet-based gambling disorder (ibGD). However, cognitive enhancement and educational use of Internet gaming suggest that the two disorders derive from different neurobiological mechanisms. The goal of this study was to compare subjects with ibGD to those with IGD. Methods Fifteen patients with IGD, 14 patients with ibGD, and 15 healthy control subjects were included in this study. Resting-state functional magnetic resonance imaging data for all participants were acquired using a 3.0 Tesla MRI scanner (Philips, Eindhoven, The Netherlands). Seed-based analyses, the three brain networks of default mode, cognitive control, and reward circuitry, were performed. Results Both IGD and ibGD groups demonstrated decreased functional connectivity (FC) within the default-mode network (DMN) (family-wise error p < .001) compared with healthy control subjects. However, the IGD group demonstrated increased FC within the cognitive network compared with both the ibGD (p < .01) and healthy control groups (p < .01). In contrast, the ibGD group demonstrated increased FC within the reward circuitry compared with both IGD (p < .01) and healthy control subjects (p < .01). Discussion and conclusions The IGD and ibGD groups shared the characteristic of decreased FC in the DMN. However, the IGD group demonstrated increased FC within the cognitive network compared with both ibGD and healthy comparison groups.
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Anabolic-androgenic steroids and decision making: Probability and effort discounting in male rats.
Wallin, Kathryn G; Alves, Jasmin M; Wood, Ruth I
2015-07-01
Anabolic-androgenic steroid (AAS) abuse is implicated in maladaptive behaviors such as increased aggression and risk taking. Impaired judgment due to changes in the mesocorticolimbic dopamine system may contribute to these behavioral changes. While AAS are known to influence dopamine function in mesocorticolimbic circuitry, the effects on decision making are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for cost/benefit decision making in two discounting paradigms. Rats chose between a small reward (1 sugar pellet) and a large discounted reward (3 or 4 pellets). Probability discounting (PD) measures sensitivity to reward uncertainty by decreasing the probability (100, 75, 50, 25, 0%) of receiving the large reward in successive blocks of each daily session. Effort discounting (ED) measures sensitivity to a work cost by increasing the lever presses required to earn the large reward (1, 2, 5, 10, 15 presses). In PD, testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls. However, during ED, testosterone-treated rats selected the large/high effort reward significantly more than controls. These studies show that testosterone has divergent effects on different aspects of decision making. Specifically, testosterone increases aversion to uncertainty but decreases sensitivity to the output of effort for reward. These results have implications for understanding maladaptive behavioral changes in human AAS users. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Amphetamine sensitization alters reward processing in the human striatum and amygdala.
O'Daly, Owen G; Joyce, Daniel; Tracy, Derek K; Azim, Adnan; Stephan, Klaas E; Murray, Robin M; Shergill, Sukhwinder S
2014-01-01
Dysregulation of mesolimbic dopamine transmission is implicated in a number of psychiatric illnesses characterised by disruption of reward processing and goal-directed behaviour, including schizophrenia, drug addiction and impulse control disorders associated with chronic use of dopamine agonists. Amphetamine sensitization (AS) has been proposed to model the development of this aberrant dopamine signalling and the subsequent dysregulation of incentive motivational processes. However, in humans the effects of AS on the dopamine-sensitive neural circuitry associated with reward processing remains unclear. Here we describe the effects of acute amphetamine administration, following a sensitising dosage regime, on blood oxygen level dependent (BOLD) signal in dopaminoceptive brain regions during a rewarded gambling task performed by healthy volunteers. Using a randomised, double-blind, parallel-groups design, we found clear evidence for sensitization to the subjective effects of the drug, while rewarded reaction times were unchanged. Repeated amphetamine exposure was associated with reduced dorsal striatal BOLD signal during decision making, but enhanced ventromedial caudate activity during reward anticipation. The amygdala BOLD response to reward outcomes was blunted following repeated amphetamine exposure. Positive correlations between subjective sensitization and changes in anticipation- and outcome-related BOLD signal were seen for the caudate nucleus and amygdala, respectively. These data show for the first time in humans that AS changes the functional impact of acute stimulant exposure on the processing of reward-related information within dopaminoceptive regions. Our findings accord with pathophysiological models which implicate aberrant dopaminergic modulation of striatal and amygdala activity in psychosis and drug-related compulsive disorders.
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Guevara, Amanda; Gates, Hillary; Urbina, Brianna; French, Rachael
2018-01-01
Food intake is necessary for survival, and natural reward circuitry has evolved to help ensure that animals ingest sufficient food to maintain development, growth, and survival. Drugs of abuse, including alcohol, co-opt the natural reward circuitry in the brain, and this is a major factor in the reinforcement of drug behaviors leading to addiction. At the junction of these two aspects of reward are alterations in feeding behavior due to alcohol consumption. In particular, developmental alcohol exposure (DAE) results in a collection of physical and neurobehavioral disorders collectively referred to as Fetal Alcohol Spectrum Disorder (FASD). The deleterious effects of DAE include intellectual disabilities and other neurobehavioral changes, including altered feeding behaviors. Here we use Drosophila melanogaster as a genetic model organism to study the effects of DAE on feeding behavior and the expression and function of Neuropeptide F. We show that addition of a defined concentration of ethanol to food leads to reduced feeding at all stages of development. Further, genetic conditions that reduce or eliminate NPF signaling combine with ethanol exposure to further reduce feeding, and the distribution of NPF is altered in the brains of ethanol-supplemented larvae. Most strikingly, we find that the vast majority of flies with a null mutation in the NPF receptor die early in larval development when reared in ethanol, and provide evidence that this lethality is due to voluntary starvation. Collectively, we find a critical role for NPF signaling in protecting against altered feeding behavior induced by developmental ethanol exposure. PMID:29623043
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Bebko, Genna; Bertocci, Michele A; Fournier, Jay C; Hinze, Amanda K; Bonar, Lisa; Almeida, Jorge R C; Perlman, Susan B; Versace, Amelia; Schirda, Claudiu; Travis, Michael; Gill, Mary Kay; Demeter, Christine; Diwadkar, Vaibhav A; Ciuffetelli, Gary; Rodriguez, Eric; Olino, Thomas; Forbes, Erika; Sunshine, Jeffrey L; Holland, Scott K; Kowatch, Robert A; Birmaher, Boris; Axelson, David; Horwitz, Sarah M; Arnold, L Eugene; Fristad, Mary A; Youngstrom, Eric A; Findling, Robert L; Phillips, Mary L
2014-01-01
Pediatric disorders characterized by behavioral and emotional dysregulation pose diagnostic and treatment challenges because of high comorbidity, suggesting that they may be better conceptualized dimensionally rather than categorically. Identifying neuroimaging measures associated with behavioral and emotional dysregulation in youth may inform understanding of underlying dimensional vs disorder-specific pathophysiologic features. To identify, in a large cohort of behaviorally and emotionally dysregulated youth, neuroimaging measures that (1) are associated with behavioral and emotional dysregulation pathologic dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory 10-Item Mania Scale [PGBI-10M], mania, depression, and anxiety) or (2) differentiate diagnostic categories (bipolar spectrum disorders, attention-deficit/hyperactivity disorder, anxiety, and disruptive behavior disorders). A multisite neuroimaging study was conducted from February 1, 2011, to April 15, 2012, at 3 academic medical centers: University Hospitals Case Medical Center, Cincinnati Children's Hospital Medical Center, and University of Pittsburgh Medical Center. Participants included a referred sample of behaviorally and emotionally dysregulated youth from the Longitudinal Assessment of Manic Symptoms (LAMS) study (n = 85) and healthy youth (n = 20). Region-of-interest analyses examined relationships among prefrontal-ventral striatal reward circuitry during a reward paradigm (win, loss, and control conditions), symptom dimensions, and diagnostic categories. Regardless of diagnosis, higher PGBI-10M scores were associated with greater left middle prefrontal cortical activity (r = 0.28) and anxiety with greater right dorsal anterior cingulate cortical (r = 0.27) activity to win. The 20 highest (t = 2.75) and 20 lowest (t = 2.42) PGBI-10M-scoring youth showed significantly greater left middle prefrontal cortical activity to win compared with 20 healthy youth. Disruptive behavior disorders were associated with lower left ventrolateral prefrontal cortex activity to win (t = 2.68) (all P < .05, corrected). Greater PGBI-10M-related left middle prefrontal cortical activity and anxiety-related right dorsal anterior cingulate cortical activity to win may reflect heightened reward sensitivity and greater attention to reward in behaviorally and emotionally dysregulated youth regardless of diagnosis. Reduced left ventrolateral prefrontal cortex activity to win may reflect reward insensitivity in youth with disruptive behavior disorders. Despite a distinct reward-related neurophysiologic feature in disruptive behavior disorders, findings generally support a dimensional approach to studying neural mechanisms in behaviorally and emotionally dysregulated youth.
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Yu, Shou-Yang; Yang, Pei-Run; Qian, Gang; Wu, Ming-Song; Bai, Wei-Feng; Tu, Ping; Luo, Su-Yuan
2013-11-01
To study and compare the effect of Corydalis yanhusuo and L-THP on dopamine neurotransmitter and D2 receptor of reward circuitry in various cerebral areas of conditioned place preference model rats and the comparison of their effects. The CPP model was established by injecting morphine in rats with increasing doses for 10 days. The initial dose of 10 mg x kg(-1), and the final dose of 100 mg x kg(-1), with 10 mg x kg(-1) increased each day. At 48 h after the final training, CPP was adopted to detect the successful establishment of the model. On the same day (12 d), they were orally administered with 2, 1, 0.5 g x kg(-1) C. yanhusuo (containing 0.153, 0.077 and 0.038 mg L-THP) and L-THP (3.76, 1.88, 0.94 mg x kg(-1)) for six days. On 18 d, CPP test was performed again. Next day, HPLC was adopted to determine the content of dopamine neurotransmitters of reward circuitry in VTA-NAc-PFC; Immunohistochemistry and Western blotting were adopted to detect the expression of D2 receptors. Compared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76, 1.88 mg x kg(-1)) groups showed that rats stayed in a notably shorter period in white boxes (morphine-accompanied boxes) (P < 0.01 or P < 0.05), and revealed a remarkably lower dopamine content in VTA, NAc and PFC and the significant increase in the expression of D2 receptor (P < 0.01 or P < 0.05). The down-regulation of the increased dopamine content in reward nervous circuitry and the up-regulation of the expression of D2 receptor may be one of mechanisms of C. yanhusuo and L-THP in accelerating the recession of morphine's CPP effect Regarding the inhibition of morphine's CPP effect and the effect on dopamine system, the effect of C. yanhusuo traditional Chinese medicine containing one-fold L-THP monomer is equal to that of the independent application of around 24-fold L-THP monomer.
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The effects of oxytocin on social reward learning in humans.
Clark-Elford, Rebecca; Nathan, Pradeep J; Auyeung, Bonnie; Voon, Valerie; Sule, Akeem; Müller, Ulrich; Dudas, Robert; Sahakian, Barbara J; Phan, K Luan; Baron-Cohen, Simon
2014-02-01
It has been hypothesised that the mechanisms modulating social affiliation are regulated by reward circuitry. Oxytocin, previously shown to support affiliative behaviour and the processing of socio-emotional stimuli, is expressed in areas of the brain involved in reward and motivation. However, limited data are available that test if oxytocin is directly involved in reward learning, or whether oxytocin can modulate the effect of emotion on reward learning. In a double-blind, randomised, placebo-controlled, within-group study design, 24 typical male volunteers were administered 24 IU of oxytocin or placebo and subsequently completed an affective reward learning task. Oxytocin selectively reduced performance of learning rewards, but not losses, from happy faces. The mechanism by which oxytocin may be exerting this effect is discussed in terms of whether oxytocin is affecting identity recognition via affecting the salience of happy faces. We conclude that oxytocin detrimentally affects learning rewards from happy faces in certain contexts.
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Dopaminergic circuitry and risk/reward decision making: implications for schizophrenia.
Stopper, Colin M; Floresco, Stan B
2015-01-01
Abnormal reinforcement learning and representations of reward value are present in schizophrenia, and these impairments can manifest as deficits in risk/reward decision making. These abnormalities may be due in part to dopaminergic dysfunction within cortico-limbic-striatal circuitry. Evidence from studies with laboratory animal have revealed that normal DA activity within different nodes of these circuits is critical for mediating dissociable processes that can refine decision biases. Moreover, both phasic and tonic dopamine transmission appear to play separate yet complementary roles in these processes. Tonic dopamine release within the prefrontal cortex and nucleus accumbens, serves as a "running rate-meter" of reward and reflects contextual information such as reward uncertainty and overt choice behavior. On the other hand, manipulations of outcome-related phasic dopamine bursts and dips suggest these signals provide rapid feedback to allow for quick adjustments in choice as reward contingencies change. The lateral habenula is a key input to the DA system that phasic signals is necessary for expressing subjective decision biases; as suppression of activity within this nucleus leads to catastrophic impairments in decision making and random patterns of choice behavior. As schizophrenia is characterized by impairments in using positive and negative feedback to appropriately guide decision making, these findings suggest that these deficits in these processes may be mediated, at least in part, by abnormalities in both tonic and phasic dopamine transmission. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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DiFeliceantonio, Alexandra G.; Berridge, Kent C.
2016-01-01
Pavlovian cues for rewards can become attractive incentives: approached and ‘wanted’ as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here we report that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits was suggested by: 1) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection, and 2) DAMGO in DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, our results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. PMID:26924040
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The neural signatures of distinct psychopathic traits
Carré, Justin M.; Hyde, Luke W.; Neumann, Craig S.; Viding, Essi; Hariri, Ahmad R.
2016-01-01
Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy. PMID:22775289
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The neural signatures of distinct psychopathic traits.
Carré, Justin M; Hyde, Luke W; Neumann, Craig S; Viding, Essi; Hariri, Ahmad R
2013-01-01
Recent studies suggest that psychopathy may be associated with dysfunction in the neural circuitry supporting both threat- and reward-related processes. However, these studies have involved small samples and often focused on extreme groups. Thus, it is unclear to what extent current findings may generalize to psychopathic traits in the general population. Furthermore, no studies have systematically and simultaneously assessed associations between distinct psychopathy facets and both threat- and reward-related brain function in the same sample of participants. Here, we examined the relationship between threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity and variation in four facets of self-reported psychopathy in a sample of 200 young adults. Path models indicated that amygdala reactivity to fearful facial expressions is negatively associated with the interpersonal facet of psychopathy, whereas amygdala reactivity to angry facial expressions is positively associated with the lifestyle facet. Furthermore, these models revealed that differential VS reactivity to positive versus negative feedback is negatively associated with the lifestyle facet. There was suggestive evidence for gender-specific patterns of association between brain function and psychopathy facets. Our findings are the first to document differential associations between both threat- and reward-related neural processes and distinct facets of psychopathy and thus provide a more comprehensive picture of the pattern of neural vulnerabilities that may predispose to maladaptive outcomes associated with psychopathy.
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Motivational deficits after brain injury: effects of bromocriptine in 11 patients.
Powell, J H; al-Adawi, S; Morgan, J; Greenwood, R J
1996-01-01
OBJECTIVE: To test the hypothesis that treatment with bromocriptine would ameliorate deficits in clinical motivation, responsiveness to reward, and frontal cognitive function after brain injury. METHOD: An open trial in six men and five women who had had either traumatic brain injury or subarachnoid haemorrhage between two months and five years previously. After repeated baseline assessments, bromocriptine was given in gradually increasing doses. Assessments were repeated at increasing doses, during maintenance, and after withdrawal. Novel structured instruments for quantifying motivation were developed; measures of anxiety and depression, and cognitive tests sensitive to motivation or frontal lobe involvement were also given. RESULTS: Bromocriptine treatment was followed by improved scores on all measures other than mood. Improvement was maintained after bromocriptine withdrawal in eight of the patients. CONCLUSION: Poor motivation in patients with brain injury may result from dysfunction in the mesolimbic/mesocortical dopaminergic circuitry, giving rise to associated deficiencies in reward responsiveness and frontal cognitive function. PMID:8774407
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Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards.
Damiano, Cara R; Aloi, Joseph; Dunlap, Kaitlyn; Burrus, Caley J; Mosner, Maya G; Kozink, Rachel V; McLaurin, Ralph Edward; Mullette-Gillman, O'Dhaniel A; Carter, Ronald McKell; Huettel, Scott A; McClernon, Francis Joseph; Ashley-Koch, Allison; Dichter, Gabriel S
2014-01-31
There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI). The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task. T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes. This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation.
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Structural connectivity of neural reward networks in youth at risk for substance use disorders.
Squeglia, Lindsay M; Sorg, Scott F; Jacobus, Joanna; Brumback, Ty; Taylor, Charles T; Tapert, Susan F
2015-07-01
Having a positive family history of alcohol use disorders (FHP), as well as aberrant reward circuitry, has been implicated in the initiation of substance use during adolescence. This study explored the relationship between FHP status and reward circuitry in substance naïve youth to better understand future risky behaviors. Participants were 49 FHP and 45 demographically matched family history negative (FHN) substance-naïve 12-14 year-olds (54 % female). Subjects underwent structural magnetic resonance imaging, including diffusion tensor imaging. Nucleus accumbens and orbitofrontal cortex volumes were derived using FreeSurfer, and FSL probabilistic tractography probed structural connectivity and differences in white matter diffusivity estimates (e.g. fractional anisotropy, and mean, radial, and axial diffusivity) between fiber tracts connecting these regions. FHP and FHN youth did not differ on nucleus accumbens or orbitofrontal cortex volumes, white matter tract volumes, or percentages of streamlines (a proxy for fiber tract count) connecting these regions. However, within white matter tracts connecting the nucleus accumbens to the orbitofrontal cortex, FHP youth had significantly lower mean and radial diffusivity (ps < 0.03) than FHN youth. While white matter macrostructure between salience and reward regions did not differ between FHP and FHN youth, FHP youth showed greater white matter coherence within these tracts than FHN youth. Aberrant connectivity between reward regions in FHP youth could be linked to an increased risk for substance use initiation.
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The neurobiological basis of binge-eating disorder.
Kessler, Robert M; Hutson, Peter H; Herman, Barry K; Potenza, Marc N
2016-04-01
Relatively little is known about the neuropathophysiology of binge-eating disorder (BED). Here, the evidence from neuroimaging, neurocognitive, genetics, and animal studies are reviewed to synthesize our current understanding of the pathophysiology of BED. Binge-eating disorder may be conceptualized as an impulsive/compulsive disorder, with altered reward sensitivity and food-related attentional biases. Neuroimaging studies suggest there are corticostriatal circuitry alterations in BED similar to those observed in substance abuse, including altered function of prefrontal, insular, and orbitofrontal cortices and the striatum. Human genetics and animal studies suggest that there are changes in neurotransmitter networks, including dopaminergic and opioidergic systems, associated with binge-eating behaviors. Overall, the current evidence suggests that BED may be related to maladaptation of the corticostriatal circuitry regulating motivation and impulse control similar to that found in other impulsive/compulsive disorders. Further studies are needed to understand the genetics of BED and how neurotransmitter activity and neurocircuitry function are altered in BED and how pharmacotherapies may influence these systems to reduce BED symptoms. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Neural substrates of approach-avoidance conflict decision-making
Aupperle, Robin L.; Melrose, Andrew J.; Francisco, Alex; Paulus, Martin P.; Stein, Murray B.
2014-01-01
Animal approach-avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal-striatal-amygdala neural circuitry is important for approach-avoidance learning. However, the neural basis of decision-making is much less clear in this context. Thus, we combined a recently developed human approach-avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach-avoidance conflict decision-making. Fifteen healthy adults completed the approach-avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to non-conflict (avoid-threat and approach-reward) conditions and to compare level of reward points offered during the decision phase. Trial-by-trial amplitude modulation analyses were used to delineate brain areas underlying decision-making in the context of approach/avoidance behavior. Conflict trials as compared to the non-conflict trials elicited greater activation within bilateral anterior cingulate cortex (ACC), anterior insula, and caudate, as well as right dorsolateral prefrontal cortex. Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial-by-trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal-striatal-insula circuitry determines the degree of approach versus avoidance decision-making. Moreover, the degree of caudate and lateral PFC activation is related to individual differences in approach-avoidance decision-making. Therefore, the AAC paradigm is ideally suited to probe anxiety-related processing differences during approach-avoidance decision-making. PMID:25224633
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Neural substrates of approach-avoidance conflict decision-making.
Aupperle, Robin L; Melrose, Andrew J; Francisco, Alex; Paulus, Martin P; Stein, Murray B
2015-02-01
Animal approach-avoidance conflict paradigms have been used extensively to operationalize anxiety, quantify the effects of anxiolytic agents, and probe the neural basis of fear and anxiety. Results from human neuroimaging studies support that a frontal-striatal-amygdala neural circuitry is important for approach-avoidance learning. However, the neural basis of decision-making is much less clear in this context. Thus, we combined a recently developed human approach-avoidance paradigm with functional magnetic resonance imaging (fMRI) to identify neural substrates underlying approach-avoidance conflict decision-making. Fifteen healthy adults completed the approach-avoidance conflict (AAC) paradigm during fMRI. Analyses of variance were used to compare conflict to nonconflict (avoid-threat and approach-reward) conditions and to compare level of reward points offered during the decision phase. Trial-by-trial amplitude modulation analyses were used to delineate brain areas underlying decision-making in the context of approach/avoidance behavior. Conflict trials as compared to the nonconflict trials elicited greater activation within bilateral anterior cingulate cortex, anterior insula, and caudate, as well as right dorsolateral prefrontal cortex (PFC). Right caudate and lateral PFC activation was modulated by level of reward offered. Individuals who showed greater caudate activation exhibited less approach behavior. On a trial-by-trial basis, greater right lateral PFC activation related to less approach behavior. Taken together, results suggest that the degree of activation within prefrontal-striatal-insula circuitry determines the degree of approach versus avoidance decision-making. Moreover, the degree of caudate and lateral PFC activation related to individual differences in approach-avoidance decision-making. Therefore, the approach-avoidance conflict paradigm is ideally suited to probe anxiety-related processing differences during approach-avoidance decision-making. © 2014 Wiley Periodicals, Inc.
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Fricchione, Gregory; Stefano, George B
2005-05-01
Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.
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Emotions and motivated behavior converge on an amygdala-like structure in the zebrafish
von Trotha, Jakob William; Vernier, Philippe; Bally-Cuif, Laure
2014-01-01
The brain reward circuitry plays a key role in emotional and motivational behaviors, and its dysfunction underlies neuropsychiatric disorders such as schizophrenia, depression and drug addiction. Here, we characterized the neuronal activity pattern induced by acute amphetamine administration and during drug-seeking behavior in the zebrafish, and demonstrate the existence of conserved underlying brain circuitry. Combining quantitative analyses of cfos expression with neuronal subtype-specific markers at single-cell resolution, we show that acute d-amphetamine administration leads to both increased neuronal activation and the recruitment of neurons in the medial (Dm) and the lateral (Dl) domains of the adult zebrafish pallium, which contain homologous structures to the mammalian amygdala and hippocampus, respectively. Calbindin-positive and glutamatergic neurons are recruited in Dm, and glutamatergic and γ-aminobutyric acid (GABAergic) neurons in Dl. The drug-activated neurons in Dm and Dl are born at juvenile stage rather than in the embryo or during adulthood. Furthermore, the same territory in Dm is activated during both drug-seeking approach and light avoidance behavior, while these behaviors do not elicit activation in Dl. These data identify the pallial territories involved in acute psychostimulant response and reward formation in the adult zebrafish. They further suggest an evolutionarily conserved function of amygdala-like structures in positive emotions and motivated behavior in zebrafish and mammals. PMID:25145867
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The neurobiology of pleasure, reward processes, addiction and their health implications.
Esch, Tobias; Stefano, George B
2004-08-01
Modern science begins to understand pleasure as a potential component of salutogenesis. Thereby, pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. Further, health implications related to pleasurable activities are analyzed. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors, i.e., motivational toxicity. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, endorphin and endogenous morphinergic mechanisms may play a role. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways. Thus, the concrete outcome of pleasant experiences may be a question of dose. Moderate pleasurable experiences are able to enhance biological flexibility and health. Hence, pleasure can be a resistance resource or may serve salutogenesis. Natural rewards are mediated by sensory organ stimulation, thereby exhibiting a potential association with complementary medical approaches. Trust and belief can be part of a self-healing potential connected with rewarding stimuli. Further, the placebo response physiologically resembles pleasure phenomena, since both involve brain's reward circuitry stimulation and subjective feelings of well-being. Pleasurable activities can stimulate personal growth and may help to induce healthy behavioral changes, including stress management. However, more research is needed to better understand the nature, neurobiology and maybe dangerous aspects of pleasure. Also, a possible involvement of endogenous morphinergic signaling has to be studied further.
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Blum, Kenneth; Oscar-Berman, Marlene; Demetrovics, Zsolt; Barh, Debmalya; Gold, Mark S
2014-12-01
We have published extensively on the neurogenetics of brain reward systems with reference to the genes related to dopaminergic function in particular. In 1996, we coined "Reward Deficiency Syndrome" (RDS), to portray behaviors found to have gene-based association with hypodopaminergic function. RDS as a useful concept has been embraced in many subsequent studies, to increase our understanding of Substance Use Disorder (SUD), addictions, and other obsessive, compulsive, and impulsive behaviors. Interestingly, albeit others, in one published study, we were able to describe lifetime RDS behaviors in a recovering addict (17 years sober) blindly by assessing resultant Genetic Addiction Risk Score (GARS™) data only. We hypothesize that genetic testing at an early age may be an effective preventive strategy to reduce or eliminate pathological substance and behavioral seeking activity. Here, we consider a select number of genes, their polymorphisms, and associated risks for RDS whereby, utilizing GWAS, there is evidence for convergence to reward candidate genes. The evidence presented serves as a plausible brain-print providing relevant genetic information that will reinforce targeted therapies, to improve recovery and prevent relapse on an individualized basis. The primary driver of RDS is a hypodopaminergic trait (genes) as well as epigenetic states (methylation and deacetylation on chromatin structure). We now have entered a new era in addiction medicine that embraces the neuroscience of addiction and RDS as a pathological condition in brain reward circuitry that calls for appropriate evidence-based therapy and early genetic diagnosis and that requires further intensive investigation.
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Norepinephrine and Stimulant Addiction
Sofuoglu, Mehmet; Sewell, R. Andrew
2008-01-01
No pharmacotherapies are approved for stimulant use disorders, which are an important public health problem. Stimulants increase synaptic levels of the monoamines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Stimulant reward is attributable mostly to increased DA in the reward circuitry, although DA stimulation alone cannot explain the rewarding effects of stimulants. The noradrenergic system, which uses NE as the main chemical messenger, serves multiple brain functions including arousal, attention, mood, learning, memory, and stress response. In preclinical models of addiction, NE is critically involved in mediating stimulant effects including sensitization, drug discrimination, and reinstatement of drug seeking. In clinical studies, adrenergic blockers have shown promise as treatments for cocaine abuse and dependence, especially in patients experiencing severe withdrawal symptoms. Disulfiram, which blocks NE synthesis, increased the number of cocaine-negative urines in five randomized clinical trials. Lofexidine, an α2-adrenergic agonist, reduces the craving induced by stress and drug cues in drug users. In addition, the norepinephrine transporter (NET) inhibitor atomoxetine attenuates some of d-amphetamine’s subjective and physiological effects in humans. These findings warrant further studies evaluating noradrenergic medications as treatments for stimulant addiction. PMID:18811678
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DiFeliceantonio, Alexandra G; Berridge, Kent C
2016-05-01
Pavlovian cues for rewards can become attractive incentives: approached and 'wanted' as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here it was reported that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs. goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in the DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in the DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits, was suggested by: (i) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection; and (ii) DAMGO in the DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, the current results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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Doremus-Fitzwater, Tamara L.; Spear, Linda P.
2016-01-01
Adolescence is an evolutionarily conserved developmental period, with neural circuits and behaviors contributing to the detection, procurement, and receipt of rewards bearing similarity across species. Studies with laboratory animals suggest that adolescence is typified by a “reward-centric” phenotype—an increased sensitivity to rewards relative to adults. In contrast, adolescent rodents are reportedly less sensitive to the aversive properties of many drugs and naturally aversive stimuli. Alterations within the mesocorticolimbic dopamine and endocannabinoid systems likely contribute to an adolescent reward-sensitive, yet aversion-resistant, phenotype. Although early hypotheses postulated that developmental changes in dopaminergic circuitry would result in a “reward deficiency” syndrome, evidence now suggests the opposite: that adolescents are uniquely poised to seek out hedonic stimuli, experience greater “pleasure” from rewards, and consume rewarding stimuli in excess. Future studies that more clearly define the role of specific brain regions and neurotransmitter systems in the expression of behaviors toward reward- and aversive-related cues and stimuli are necessary to more fully understand an adolescent-proclivity for and vulnerability to rewards and drugs of potential abuse. PMID:27524639
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Doremus-Fitzwater, Tamara L; Spear, Linda P
2016-11-01
Adolescence is an evolutionarily conserved developmental period, with neural circuits and behaviors contributing to the detection, procurement, and receipt of rewards bearing similarity across species. Studies with laboratory animals suggest that adolescence is typified by a "reward-centric" phenotype-an increased sensitivity to rewards relative to adults. In contrast, adolescent rodents are reportedly less sensitive to the aversive properties of many drugs and naturally aversive stimuli. Alterations within the mesocorticolimbic dopamine and endocannabinoid systems likely contribute to an adolescent reward-sensitive, yet aversion-resistant, phenotype. Although early hypotheses postulated that developmental changes in dopaminergic circuitry would result in a "reward deficiency" syndrome, evidence now suggests the opposite: that adolescents are uniquely poised to seek out hedonic stimuli, experience greater "pleasure" from rewards, and consume rewarding stimuli in excess. Future studies that more clearly define the role of specific brain regions and neurotransmitter systems in the expression of behaviors toward reward- and aversive-related cues and stimuli are necessary to more fully understand an adolescent-proclivity for and vulnerability to rewards and drugs of potential abuse. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Greene, R K; Spanos, M; Alderman, C; Walsh, E; Bizzell, J; Mosner, M G; Kinard, J L; Stuber, G D; Chandrasekhar, T; Politte, L C; Sikich, L; Dichter, G S
2018-03-27
Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD. In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes. Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards. The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.
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How the Brain Wants What the Body Needs: The Neural Basis of Positive Alliesthesia.
Avery, Jason A; Burrows, Kaiping; Kerr, Kara L; Bodurka, Jerzy; Khalsa, Sahib S; Paulus, Martin P; Simmons, W Kyle
2017-03-01
Discontinuing unhealthy behaviors, such as overeating or drug use, depends upon an individual's ability to overcome the influence of environmental reward cues. The strength of that influence, however, varies greatly depending upon the internal state of the body. Characterizing the relationship between interoceptive signaling and shifting drug cue valuation provides an opportunity for understanding the neural bases of how changing internal states alter reward processing more generally. A total of 17 cigarette smokers rated the pleasantness of cigarette pictures when they were nicotine sated or nicotine abstinent. On both occasions, smokers also underwent functional magnetic resonance imaging (fMRI) scanning while performing a visceral interoceptive attention task and a resting-state functional connectivity scan. Hemodynamic, physiological, and behavioral parameters were compared between sated and abstinent scans. The relationships between changes in these parameters across scan sessions were also examined. Smokers rated cigarette pictures as significantly more pleasant while nicotine abstinent than while nicotine sated. Comparing abstinent with sated scans, smokers also exhibited significantly decreased mid-insula, amygdala, and orbitofrontal activity while attending to interoceptive signals from the body. Change in interoceptive activity within the left mid-insula predicted the increase in smoker's pleasantness ratings of cigarette cues. This increase in pleasantness ratings was also correlated with an increase in resting-state functional connectivity between the mid-insula and the ventral striatum and ventral pallidum. These findings support a model wherein interoceptive processing in the mid-insula of withdrawal signals from the body potentiates the motivational salience of reward cues through the recruitment of hedonic 'hot spots' within the brain's reward circuitry.
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Context-driven Salt Seeking Test (Rats)
Chang, Stephen E.; Smith, Kyle S.
2018-01-01
Changes in reward seeking behavior often occur through incremental learning based on the difference between what is expected and what actually happens. Behavioral flexibility of this sort requires experience with rewards as better or worse than expected. However, there are some instances in which behavior can change through non-incremental learning, which requires no further experience with an outcome. Such an example of non-incremental learning is the salt appetite phenomenon. In this case, animals such as rats will immediately seek out a highly-concentrated salt solution that was previously undesired when they are put in a novel state of sodium deprivation. Importantly, this adaptive salt-seeking behavior occurs despite the fact that the rats never tasted salt in the depleted state, and therefore never tasted it as a highly desirable reward. The following protocol is a method to investigate the neural circuitry mediating adaptive salt seeking using a conditioned place preference (CPP) procedure. The procedure is designed to provide an opportunity to discover possible dissociations between the neural circuitry mediating salt seeking and salt consumption to replenish the bodily deficit after sodium depletion. Additionally, this procedure is amenable to incorporating a number of neurobiological techniques for studying the brain basis of this behavior.
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Blum, K; Febo, M; Badgaiyan, RD
2016-01-01
Dopamine along with other chemical messengers like serotonin, cannabinoids, endorphins and glutamine, play significant roles in brain reward processing. There is a devastating opiate/opioid epidemicin the United States. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day due to narcotic overdose and alarmingly heroin overdose is on the rise. The Food and Drug Administration (FDA) has approved some Medication-Assisted Treatments (MATs) for alcoholism, opiate and nicotine dependence, but nothing for psychostimulant and cannabis abuse. While these pharmaceuticals are essential for the short-term induction of “psychological extinction,” in the long-term caution is necessary because their use favors blocking dopaminergic function indispensable for achieving normal satisfaction in life. The two institutions devoted to alcoholism and drug dependence (NIAAA & NIDA) realize that MATs are not optimal and continue to seek better treatment options. We review, herein, the history of the development of a glutaminergic-dopaminergic optimization complex called KB220 to provide for the possible eventual balancing of the brain reward system and the induction of “dopamine homeostasis.” This complex may provide substantial clinical benefit to the victims of Reward Deficiency Syndrome (RDS) and assist in recovery from iatrogenically induced addiction to unwanted opiates/opioids and other addictive behaviors. PMID:27840857
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Worhunsky, Patrick D.; Malison, Robert T.; Rogers, Robert D.; Potenza, Marc N.
2014-01-01
Background Individuals with gambling or substance-use disorders exhibit similar functional alterations in reward circuitry suggestive of a shared underlying vulnerability in addictive disorders. Additional research into common and unique alterations in reward-processing in substance-related and non-substance-related addictions may identify neural factors that could be targeted in treatment development for these disorders. Methods To investigate contextual reward-processing in pathological gambling, a slot-machine fMRI task was performed by three groups (with pathological gambling, cocaine dependence and neither disorder; N=24 each) to determine the extent to which two groups with addictions (non-substance-related and substance-related) showed similarities and differences with respect to each other and a non-addicted group during anticipatory periods and following the delivery of winning, losing and ‘near-miss’ outcomes. Results Individuals with pathological gambling or cocaine dependence compared to those with neither disorder exhibited exaggerated anticipatory activity in mesolimbic and ventrocortical regions, with pathological-gambling participants displaying greater positive possible-reward anticipation and cocaine-dependent participants displaying more negative certain-loss anticipation. Neither clinical sample exhibited medial frontal or striatal responses that were observed following near-miss outcomes in healthy comparison participants. Conclusions Alterations in anticipatory processing may be sensitive to the valence of rewards and content-disorder-specific. Common and unique findings in pathological gambling and cocaine dependence with respect to anticipatory reward and near-miss loss processing suggest shared and unique elements that might be targeted through behavioral or pharmacological interventions in the treatment of addictions. PMID:25448081
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Todokoro, Ayako; Tanaka, Saori C; Kawakubo, Yuki; Yahata, Noriaki; Ishii-Takahashi, Ayaka; Nishimura, Yukika; Kano, Yukiko; Ohtake, Fumio; Kasai, Kiyoto
2018-04-24
Impulsivity, which significantly affects social adaptation, is an important target behavioral characteristic in interventions for attention-deficit hyperactivity disorder (ADHD). Typically, people are willing to wait longer to acquire greater rewards. Impulsivity in ADHD may be associated with brain dysfunction in decision-making involving waiting behavior under such situations. We tested the hypothesis that brain circuitry during a period of waiting (i.e., prior to the acquisition of reward) is altered in adults with ADHD. The participants included 14 medication-free adults with ADHD and 16 healthy controls matched for age, sex, IQ, and handedness. The behavioral task had participants choose between a delayed, larger monetary reward and an immediate, smaller monetary reward, where the reward waiting time actually occurred during functional magnetic resonance imaging measurement. We tested for group differences in the contrast values of blood-oxygen-level dependent signals associated with the length of waiting time, calculated using the parametric modulation method. While the two groups did not differ in the time discounting rate, the delay-sensitive contrast values were significantly lower in the caudate and visual cortex in individuals with ADHD. The higher impulsivity scores were significantly associated with lower delay-sensitive contrast values in the caudate and visual cortex. These results suggest that deficient neural activity affects decision-making involving reward waiting time during intertemporal choice tasks, and provide an explanation for the basis of impulsivity in adult ADHD. © 2018 The Author. Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology.
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Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso
2016-01-01
The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user's loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards.
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Rosell-Negre, Patricia; Bustamante, Juan-Carlos; Fuentes-Claramonte, Paola; Costumero, Víctor; Llopis-Llacer, Juan-José; Barrós-Loscertales, Alfonso
2016-01-01
The dopaminergic system provides the basis for the interaction between motivation and cognition. It is triggered by the possibility of obtaining rewards to initiate the neurobehavioral adaptations necessary to achieve them by directing the information from motivational circuits to cognitive and action circuits. In drug addiction, the altered dopamine (DA) modulation of the meso-cortico-limbic reward circuitry, such as the prefrontal cortex (PFC), underlies the disproportionate motivational value of drug use at the expense of other non-drug reinforcers and the user’s loss of control over his/her drug intake. We examine how the magnitude of the reward affects goal-directed processes in healthy control (HC) subjects and abstinent cocaine dependent (ACD) patients by using functional magnetic resonance imaging (fMRI) during a counting Stroop task with blocked levels of monetary incentives of different magnitudes (€0, €0.01, €0.5, €1 or €1.5). Our results showed that increasing reward magnitude enhances (1) performance facilitation in both groups; (2) left dorsolateral prefrontal cortex (DLPFC) activity in HC and left superior occipital cortex activity in ACD; and (3) left DLPFC and left putamen connectivity in ACD compared to HC. Moreover, we observed that (4) dorsal striatal and pallidum activity was associated with craving and addiction severity during the parametric increases in the monetary reward. In conclusion, the brain response to gradients in monetary value was different in HC and ACD, but both groups showed improved task performance due to the possibility of obtaining greater monetary rewards. PMID:27907134
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The Sensitivity of the Crayfish Reward System to Mammalian Drugs of Abuse.
Shipley, Adam T; Imeh-Nathaniel, Adebobola; Orfanakos, Vasiliki B; Wormack, Leah N; Huber, Robert; Nathaniel, Thomas I
2017-01-01
The idea that addiction occurs when the brain is not able to differentiate whether specific reward circuits were triggered by adaptive natural rewards or falsely activated by addictive drugs exist in several models of drug addiction. The suitability of crayfish ( Orconectes rusticus ) for drug addiction research arises from developmental variation of growth, life span, reproduction, behavior and some quantitative traits, especially among isogenic mates reared in the same environment. This broad spectrum of traits makes it easier to analyze the effect of mammalian drugs of abuse in shaping behavioral phenotype. Moreover, the broad behavioral repertoire allows the investigation of self-reinforcing circuitries involving appetitive and exploratory motor behavior, while the step-wise alteration of the phenotype by metamorphosis allows accurate longitudinal analysis of different behavioral states. This paper reviews a series of recent experimental findings that evidence the suitability of crayfish as an invertebrate model system for the study of drug addiction. Results from these studies reveal that unconditioned exposure to mammalian drugs of abuse produces a variety of stereotyped behaviors. Moreover, if presented in the context of novelty, drugs directly stimulate exploration and appetitive motor patterns along with molecular processes for drug conditioned reward. Findings from these studies indicate the existence of drug sensitive circuitry in crayfish that facilitates exploratory behavior and appetitive motor patterns via increased incentive salience of environmental stimuli or by increasing exploratory motor patterns. This work demonstrates the potential of crayfish as a model system for research into the neural mechanisms of addiction, by contributing an evolutionary, comparative context to our understanding of natural reward as an important life-sustaining process.
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Ridderinkhof, K. Richard; van Wouwe, Nelleke C.; Band, Guido P. H.; Wylie, Scott A.; Van der Stigchel, Stefan; van Hees, Pieter; Buitenweg, Jessika; van de Vijver, Irene; van den Wildenberg, Wery P. M.
2012-01-01
Reward-based decision-learning refers to the process of learning to select those actions that lead to rewards while avoiding actions that lead to punishments. This process, known to rely on dopaminergic activity in striatal brain regions, is compromised in Parkinson’s disease (PD). We hypothesized that such decision-learning deficits are alleviated by induced positive affect, which is thought to incur transient boosts in midbrain and striatal dopaminergic activity. Computational measures of probabilistic reward-based decision-learning were determined for 51 patients diagnosed with PD. Previous work has shown these measures to rely on the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that induced positive affect facilitated learning, through its effects on reward prediction rather than outcome evaluation. Viewing a few minutes of comedy clips served to remedy dopamine-related problems associated with frontostriatal circuitry and, consequently, learning to predict which actions will yield reward. PMID:22707944
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Foldi, Claire J; Milton, Laura K; Oldfield, Brian J
2017-11-01
Patients suffering from anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the characteristics of the human condition, including anhedonia, and allows investigation of the underlying neurobiology of AN. The potential for increased neuronal activity in reward/hedonic circuits to prevent and rescue weight loss is investigated in this model. The mesolimbic pathway extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) was activated using a dual viral strategy, involving retrograde transport of Cre (CAV-2-Cre) to the VTA and coincident injection of DREADD receptors (AAV-hSyn-DIO-hM3D(Gq)-mCherry). Systemic clozapine-n-oxide (CNO; 0.3 mg/kg) successfully recruited a large proportion of the VTA-NAc dopaminergic projections, with activity evidenced by colocalization with elevated levels of Fos protein. The effects of reward circuit activation on energy balance and predicted survival was investigated in female Sprague-Dawley rats, where free access to running wheels was paired with time-limited (90 min) access to food, a paradigm (ABA) which will cause anorexia and death if unchecked. Excitation of the reward pathway substantially increased food intake and food anticipatory activity (FAA) to prevent ABA-associated weight loss, while overall locomotor activity was unchanged. Similar activation of reward circuitry, delayed until establishment of the ABA phenotype, rescued rats from their precipitous weight loss. Although these data are consistent with shifts primarily in food intake, the contribution of mechanisms including energy expenditure to survival remains to be determined. These results will inform the neurobiological underpinnings of AN, and provide insight into the mechanisms of reward circuitry relevant to feeding and weight loss.
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Evans, Simon; Fleming, Stephen M.; Dolan, Raymond J.; Averbeck, Bruno B.
2012-01-01
Real-world decision-making often involves social considerations. Consequently, the social value of stimuli can induce preferences in choice behavior. However, it is unknown how financial and social values are integrated in the brain. Here, we investigated how smiling and angry face stimuli interacted with financial reward feedback in a stochastically-rewarded decision-making task. Subjects reliably preferred the smiling faces despite equivalent reward feedback, demonstrating a socially driven bias. We fit a Bayesian reinforcement learning model to factor the effects of financial rewards and emotion preferences in individual subjects, and regressed model predictions on the trial-by-trial fMRI signal. Activity in the sub-callosal cingulate and the ventral striatum, both involved in reward learning, correlated with financial reward feedback, whereas the differential contribution of social value activated dorsal temporo-parietal junction and dorsal anterior cingulate cortex, previously proposed as components of a mentalizing network. We conclude that the impact of social stimuli on value-based decision processes is mediated by effects in brain regions partially separable from classical reward circuitry. PMID:20946058
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Reward-Guided Learning with and without Causal Attribution
Jocham, Gerhard; Brodersen, Kay H.; Constantinescu, Alexandra O.; Kahn, Martin C.; Ianni, Angela M.; Walton, Mark E.; Rushworth, Matthew F.S.; Behrens, Timothy E.J.
2016-01-01
Summary When an organism receives a reward, it is crucial to know which of many candidate actions caused this reward. However, recent work suggests that learning is possible even when this most fundamental assumption is not met. We used novel reward-guided learning paradigms in two fMRI studies to show that humans deploy separable learning mechanisms that operate in parallel. While behavior was dominated by precise contingent learning, it also revealed hallmarks of noncontingent learning strategies. These learning mechanisms were separable behaviorally and neurally. Lateral orbitofrontal cortex supported contingent learning and reflected contingencies between outcomes and their causal choices. Amygdala responses around reward times related to statistical patterns of learning. Time-based heuristic mechanisms were related to activity in sensorimotor corticostriatal circuitry. Our data point to the existence of several learning mechanisms in the human brain, of which only one relies on applying known rules about the causal structure of the task. PMID:26971947
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Dopamine and extinction: A convergence of theory with fear and reward circuitry
Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew
2014-01-01
Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353
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Dopamine and extinction: a convergence of theory with fear and reward circuitry.
Abraham, Antony D; Neve, Kim A; Lattal, K Matthew
2014-02-01
Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.
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Blum, Kenneth; Chen, Thomas J H; Chen, Amanda L H; Madigan, Margaret; Downs, B William; Waite, Roger L; Braverman, Eric R; Kerner, Mallory; Bowirrat, Abdalla; Giordano, John; Henshaw, Harry; Gold, Mark S
2010-03-01
Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction. Copyright (c) 2009 Elsevier Ltd. All rights reserved.
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Chronic wheel running affects cocaine-induced c-Fos expression in brain reward areas in rats.
Zlebnik, Natalie E; Hedges, Valerie L; Carroll, Marilyn E; Meisel, Robert L
2014-03-15
Emerging evidence from human and animal studies suggests that exercise is a highly effective treatment for drug addiction. However, most work has been done in behavioral models, and the effects of exercise on the neurobiological substrates of addiction have not been identified. Specifically, it is unknown whether prior exercise exposure alters neuronal activation of brain reward circuitry in response to drugs of abuse. To investigate this hypothesis, rats were given 21 days of daily access to voluntary wheel running in a locked or unlocked running wheel. Subsequently, they were challenged with a saline or cocaine (15 mg/kg, i.p.) injection and sacrificed for c-Fos immunohistochemistry. The c-Fos transcription factor is a measure of cellular activity and was used to quantify cocaine-induced activation of reward-processing areas of the brain: nucleus accumbens (NAc), caudate putamen (CPu), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). The mean fold change in cocaine-induced c-Fos cell counts relative to saline-induced c-Fos cell counts was significantly higher in exercising compared to control rats in the NAc core, dorsomedial and dorsolateral CPu, the prelimbic area, and the OFC, indicating differential cocaine-specific cellular activation of brain reward circuitry between exercising and control animals. These results suggest neurobiological mechanisms by which voluntary wheel running attenuates cocaine-motivated behaviors and provide support for exercise as a novel treatment for drug addiction. Copyright © 2013 Elsevier B.V. All rights reserved.
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Molecular mechanism: ERK signaling, drug addiction and behavioral effects
Sun, Wei-Lun; Quizon, Pamela M.; Zhu, Jun
2017-01-01
Addiction to psychostimulants has been considered as a chronic psychiatric disorder, characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that results in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction. PMID:26809997
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de Boer, Sietse F; Buwalda, Bauke; Koolhaas, Jaap M
2017-03-01
Considerable individual differences exist in trait-like patterns of behavioral and physiological responses to salient environmental challenges. This individual variation in stress coping styles has an important functional role in terms of health and fitness. Hence, understanding the neural embedding of coping style variation is fundamental for biobehavioral neurosciences in probing individual disease susceptibility. This review outlines individual differences in trait-aggressiveness as an adaptive component of the natural sociobiology of rats and mice, and highlights that these reflect the general style of coping that varies from proactive (aggressive) to reactive (docile). We propose that this qualitative coping style can be disentangled into multiple quantitative behavioral domains, e.g., flexibility/impulse control, emotional reactivity and harm avoidance/reward processing, that each are encoded into selective neural circuitries. Since functioning of all these brain circuitries rely on fine-tuned serotonin signaling, autoinhibitory control mechanisms of serotonergic neuron (re)activity are crucial in orchestrating general coping style. Untangling the precise neuromolecular mechanisms of different coping styles will provide a roadmap for developing better therapeutic strategies of stress-related diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Motivation and timing: Clues for modeling the reward system
Galtress, Tiffany; Marshall, Andrew T.; Kirkpatrick, Kimberly
2012-01-01
There is growing evidence that a change in reward magnitude or value alters interval timing, indicating that motivation and timing are not independent processes as was previously believed. The present paper reviews several recent studies, as well as presenting some new evidence with further manipulations of reward value during training vs. testing on a peak procedure. The combined results cannot be accounted for by any of the current psychological timing theories. However, in examining the neural circuitry of the reward system, it is not surprising that motivation has an impact on timing because the motivation/valuation system directly interfaces with the timing system. A new approach is proposed for the development of the next generation of timing models, which utilizes knowledge of the neuroanatomy and neurophysiology of the reward system to guide the development of a neurocomputational model of the reward system. The initial foundation along with heuristics for proceeding with developing such a model is unveiled in an attempt to stimulate new theoretical approaches in the field. PMID:22421220
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Riday, Thorfinn T.; Kosofsky, Barry E.; Malanga, C.J.
2011-01-01
Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood. Intracranial self-stimulation (ICSS) was measured concurrently with locomotor activity to determine if acute intermittent cocaine administration had distinguishable effects on motor behavior and perception of brain stimulation-reward (BSR) in the same mice. Sensitization is associated with changes in neuronal activity and glutamatergic neurotransmission in brain reward circuitry. Expression of AMPA receptor subunits (GluR1 and GluR2) and CRE binding protein (CREB) was measured in the ventral tegmental area (VTA), dorsolateral striatum (STR) and nucleus accumbens (NAc) before and after a sensitizing regimen of cocaine, with and without ICSS. Repeated cocaine administration sensitized mice to its locomotor stimulating effects but not its ability to potentiate BSR. ICSS increased GluR1 in the VTA but not NAc or STR, demonstrating selective changes in protein expression with electrical stimulation of discrete brain structures. Repeated cocaine reduced GluR1, GluR2 and CREB expression in the NAc, and reductions of GluR1 and GluR2 but not CREB were further enhanced by ICSS. These data suggest that the effects of repeated cocaine exposure on reward and motor processes are dissociable in mice, and that reduction of excitatory neurotransmission in the NAc may predict altered motor function independently from changes in reward perception. PMID:22197517
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Aberrant mesolimbic dopamine-opiate interaction in obesity.
Tuominen, Lauri; Tuulari, Jetro; Karlsson, Henry; Hirvonen, Jussi; Helin, Semi; Salminen, Paulina; Parkkola, Riitta; Hietala, Jarmo; Nuutila, Pirjo; Nummenmaa, Lauri
2015-11-15
Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity. Copyright © 2015 Elsevier Inc. All rights reserved.
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Zeuner, Kirsten E; Knutzen, Arne; Granert, Oliver; Sablowsky, Simone; Götz, Julia; Wolff, Stephan; Jansen, Olav; Dressler, Dirk; Schneider, Susanne A; Klein, Christine; Deuschl, Günther; van Eimeren, Thilo; Witt, Karsten
2016-01-01
Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp.
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Effects of Direct Social Experience on Trust Decisions and Neural Reward Circuitry
Fareri, Dominic S.; Chang, Luke J.; Delgado, Mauricio R.
2012-01-01
The human striatum is integral for reward-processing and supports learning by linking experienced outcomes with prior expectations. Recent endeavors implicate the striatum in processing outcomes of social interactions, such as social approval/rejection, as well as in learning reputations of others. Interestingly, social impressions often influence our behavior with others during interactions. Information about an interaction partner’s moral character acquired from biographical information hinders updating of expectations after interactions via top down modulation of reward circuitry. An outstanding question is whether initial impressions formed through experience similarly modulate the ability to update social impressions at the behavioral and neural level. We investigated the role of experienced social information on trust behavior and reward-related BOLD activity. Participants played a computerized ball-tossing game with three fictional partners manipulated to be perceived as good, bad, or neutral. Participants then played an iterated trust game as investors with these same partners while undergoing fMRI. Unbeknownst to participants, partner behavior in the trust game was random and unrelated to their ball-tossing behavior. Participants’ trust decisions were influenced by their prior experience in the ball-tossing game, investing less often with the bad partner compared to the good and neutral. Reinforcement learning models revealed that participants were more sensitive to updating their beliefs about good and bad partners when experiencing outcomes consistent with initial experience. Increased striatal and anterior cingulate BOLD activity for positive versus negative trust game outcomes emerged, which further correlated with model-derived prediction error learning signals. These results suggest that initial impressions formed from direct social experience can be continually shaped by consistent information through reward learning mechanisms. PMID:23087604
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Blum, Kenneth; Simpatico, Thomas; Badgaiyan, Rajendra D.; Demetrovics, Zsolt; Fratantonio, James; Agan, Gozde; Febo, Marcelo; Gold, Mark S.
2016-01-01
Earlier work from our laboratory, showing anti-addiction activity of a nutraceutical consisting of amino-acid precursors and enkephalinase inhibition properties and our discovery of the first polymorphic gene (Dopamine D2 Receptor Gene [DRD2]) to associate with severe alcoholism serves as a blue-print for the development of “Personalized Medicine” in addiction. Prior to the later genetic finding, we developed the concept of Brain Reward Cascade, which continues to act as an important component for stratification of addiction risk through neurogenetics. In 1996 our laboratory also coined the term “Reward Deficiency Syndrome (RDS)” to define a common genetic rubric for both substance and non-substance related addictive behaviors. Following many reiterations we utilized polymorphic targets of a number of reward genes (serotonergic, Opioidergic, GABAergic and Dopaminergic) to customize KB220 [Neuroadaptogen- amino-acid therapy (NAAT)] by specific algorithms. Identifying 1,000 obese subjects in the Netherlands a subsequent small subset was administered various KB220Z formulae customized according to respective DNA polymorphisms individualized that translated to significant decreases in both Body Mass Index (BMI) and weight in pounds. Following these experiments, we have been successfully developing a panel of genes known as “Genetic Addiction Risk Score” (GARSpDX)™. Selection of 10 genes with appropriate variants, a statistically significant association between the ASI-Media Version-alcohol and drug severity scores and GARSpDx was found A variant of KB220Z in abstinent heroin addicts increased resting state functional connectivity in a putative network including: dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. In addition, we show that KB220Z significantly activates, above placebo, seed regions of interest including the left nucleus accumbens, cingulate gyrus, anterior thalamic nuclei, hippocampus, pre-limbic and infra-limbic loci. KB220Z demonstrates significant functional connectivity, increased brain volume recruitment and enhanced dopaminergic functionality across the brain reward circuitry. We propose a Reward Deficiency System Solution that promotes early identification and stratification of risk alleles by utilizing GARSDx, allowing for customized nutrigenomic targeting of these risk alleles by altering KB220Z ingredients as an algorithmic function of carrying these polymorphic DNA–SNPS, potentially yielding the first ever nutrigenomic solution for addiction and pain. PMID:27617300
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Addiction: beyond dopamine reward circuitry.
Volkow, Nora D; Wang, Gene-Jack; Fowler, Joanna S; Tomasi, Dardo; Telang, Frank
2011-09-13
Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.
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The neural correlates of maternal and romantic love.
Bartels, Andreas; Zeki, Semir
2004-03-01
Romantic and maternal love are highly rewarding experiences. Both are linked to the perpetuation of the species and therefore have a closely linked biological function of crucial evolutionary importance. Yet almost nothing is known about their neural correlates in the human. We therefore used fMRI to measure brain activity in mothers while they viewed pictures of their own and of acquainted children, and of their best friend and of acquainted adults as additional controls. The activity specific to maternal attachment was compared to that associated to romantic love described in our earlier study and to the distribution of attachment-mediating neurohormones established by other studies. Both types of attachment activated regions specific to each, as well as overlapping regions in the brain's reward system that coincide with areas rich in oxytocin and vasopressin receptors. Both deactivated a common set of regions associated with negative emotions, social judgment and 'mentalizing', that is, the assessment of other people's intentions and emotions. We conclude that human attachment employs a push-pull mechanism that overcomes social distance by deactivating networks used for critical social assessment and negative emotions, while it bonds individuals through the involvement of the reward circuitry, explaining the power of love to motivate and exhilarate.
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Zeki, S
2007-06-12
Romantic and maternal love are highly rewarding experiences. Both are linked to the perpetuation of the species and therefore have a closely linked biological function of crucial evolutionary importance. The newly developed ability to study the neural correlates of subjective mental states with brain imaging techniques has allowed neurobiologists to learn something about the neural bases of both romantic and maternal love. Both types of attachment activate regions specific to each, as well as overlapping regions in the brain's reward system that coincide with areas rich in oxytocin and vasopressin receptors. Both deactivate a common set of regions associated with negative emotions, social judgment and 'mentalizing' that is, the assessment of other people's intentions and emotions. Human attachment seems therefore to employ a push-pull mechanism that overcomes social distance by deactivating networks used for critical social assessment and negative emotions, while it bonds individuals through the involvement of the reward circuitry, explaining the power of love to motivate and exhilarate. Yet the biological study of love, and especially romantic love, must go beyond and look for biological insights that can be derived from studying the world literature of love, and thus bring the output of the humanities into its orbit.
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Frank, G K W; Shott, M E; Riederer, J; Pryor, T L
2016-11-01
Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive-emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction.
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Recurrent, Robust and Scalable Patterns Underlie Human Approach and Avoidance
Kennedy, David N.; Lehár, Joseph; Lee, Myung Joo; Blood, Anne J.; Lee, Sang; Perlis, Roy H.; Smoller, Jordan W.; Morris, Robert; Fava, Maurizio
2010-01-01
Background Approach and avoidance behavior provide a means for assessing the rewarding or aversive value of stimuli, and can be quantified by a keypress procedure whereby subjects work to increase (approach), decrease (avoid), or do nothing about time of exposure to a rewarding/aversive stimulus. To investigate whether approach/avoidance behavior might be governed by quantitative principles that meet engineering criteria for lawfulness and that encode known features of reward/aversion function, we evaluated whether keypress responses toward pictures with potential motivational value produced any regular patterns, such as a trade-off between approach and avoidance, or recurrent lawful patterns as observed with prospect theory. Methodology/Principal Findings Three sets of experiments employed this task with beautiful face images, a standardized set of affective photographs, and pictures of food during controlled states of hunger and satiety. An iterative modeling approach to data identified multiple law-like patterns, based on variables grounded in the individual. These patterns were consistent across stimulus types, robust to noise, describable by a simple power law, and scalable between individuals and groups. Patterns included: (i) a preference trade-off counterbalancing approach and avoidance, (ii) a value function linking preference intensity to uncertainty about preference, and (iii) a saturation function linking preference intensity to its standard deviation, thereby setting limits to both. Conclusions/Significance These law-like patterns were compatible with critical features of prospect theory, the matching law, and alliesthesia. Furthermore, they appeared consistent with both mean-variance and expected utility approaches to the assessment of risk. Ordering of responses across categories of stimuli demonstrated three properties thought to be relevant for preference-based choice, suggesting these patterns might be grouped together as a relative preference theory. Since variables in these patterns have been associated with reward circuitry structure and function, they may provide a method for quantitative phenotyping of normative and pathological function (e.g., psychiatric illness). PMID:20532247
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Choi, Jung-Seok; Shin, Young-Chul; Jung, Wi Hoon; Jang, Joon Hwan; Kang, Do-Hyung; Choi, Chi-Hoon; Choi, Sam-Wook; Lee, Jun-Young; Hwang, Jae Yeon; Kwon, Jun Soo
2012-01-01
Background Pathological gambling (PG) and obsessive-compulsive disorder (OCD) are conceptualized as a behavioral addiction, with a dependency on repetitive gambling behavior and rewarding effects following compulsive behavior, respectively. However, no neuroimaging studies to date have examined reward circuitry during the anticipation phase of reward in PG compared with in OCD while considering repetitive gambling and compulsion as addictive behaviors. Methods/Principal Findings To elucidate the neural activities specific to the anticipation phase of reward, we performed event-related functional magnetic resonance imaging (fMRI) in young adults with PG and compared them with those in patients with OCD and healthy controls. Fifteen male patients with PG, 13 patients with OCD, and 15 healthy controls, group-matched for age, gender, and IQ, participated in a monetary incentive delay task during fMRI scanning. Neural activation in the ventromedial caudate nucleus during anticipation of both gain and loss decreased in patients with PG compared with that in patients with OCD and healthy controls. Additionally, reduced activation in the anterior insula during anticipation of loss was observed in patients with PG compared with that in patients with OCD which was intermediate between that in OCD and healthy controls (healthy controls < PG < OCD), and a significant positive correlation between activity in the anterior insula and South Oaks Gambling Screen score was found in patients with PG. Conclusions Decreased neural activity in the ventromedial caudate nucleus during anticipation may be a specific neurobiological feature for the pathophysiology of PG, distinguishing it from OCD and healthy controls. Correlation of anterior insular activity during loss anticipation with PG symptoms suggests that patients with PG fit the features of OCD associated with harm avoidance as PG symptoms deteriorate. Our findings have identified functional disparities and similarities between patients with PG and OCD related to the neural responses associated with reward anticipation. PMID:23029329
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Kenny, Paul J; Chartoff, Elena; Roberto, Marisa; Carlezon, William A; Markou, Athina
2009-01-01
Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.
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Morales, Angelica M; Jones, Scott A; Ehlers, Alissa; Lavine, Jessye B; Nagel, Bonnie J
2018-05-07
Beginning to engage in heavy alcohol use during adolescence, as opposed to later in life, is associated with elevated risk for a variety of negative consequences, including the development of an alcohol use disorder. Behavioral studies suggest that poor decision making predicts alcohol use during adolescence; however, more research is needed to determine the neurobiological risk factors that underlie this association. Using functional magnetic resonance imaging, brain activation during decision making involving risk and reward was assessed in 47 adolescents (14-15 years old) with no significant history or alcohol or drug use. After baseline assessment, participants completed follow-up interviews every 3 months to assess the duration to onset of binge drinking. Adolescents who made a greater number of risky selections and had greater activation in the nucleus accumbens, precuneus, and occipital cortex during decision making involving greater potential for risk and reward began binge drinking sooner. Findings suggest that heightened activation of reward circuitry during decision making under risk is a neurobiological risk factor for earlier onset of binge drinking. Furthermore, brain activation was a significant predictor of onset to binge drinking, even after controlling for decision-making behavior, suggesting that neurobiological markers may provide additional predictive validity over behavioral assessments. Interventions designed to modify these behavioral and neurobiological risk factors may be useful for curbing heavy alcohol use during adolescence.
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The influence of emotion regulation on decision-making under risk.
Martin, Laura N; Delgado, Mauricio R
2011-09-01
Cognitive strategies typically involved in regulating negative emotions have recently been shown to also be effective with positive emotions associated with monetary rewards. However, it is less clear how these strategies influence behavior, such as preferences expressed during decision-making under risk, and the underlying neural circuitry. That is, can the effective use of emotion regulation strategies during presentation of a reward-conditioned stimulus influence decision-making under risk and neural structures involved in reward processing such as the striatum? To investigate this question, we asked participants to engage in imagery-focused regulation strategies during the presentation of a cue that preceded a financial decision-making phase. During the decision phase, participants then made a choice between a risky and a safe monetary lottery. Participants who successfully used cognitive regulation, as assessed by subjective ratings about perceived success and facility in implementation of strategies, made fewer risky choices in comparison with trials where decisions were made in the absence of cognitive regulation. Additionally, BOLD responses in the striatum were attenuated during decision-making as a function of successful emotion regulation. These findings suggest that exerting cognitive control over emotional responses can modulate neural responses associated with reward processing (e.g., striatum) and promote more goal-directed decision-making (e.g., less risky choices), illustrating the potential importance of cognitive strategies in curbing risk-seeking behaviors before they become maladaptive (e.g., substance abuse).
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Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.
Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X; Wu, Yu-Wei; Park, Esther; Huang, Eric J; Chen, Lu; Ding, Jun B
2015-10-02
Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. Copyright © 2015, American Association for the Advancement of Science.
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Gordon, Ilanit; Jack, Allison; Pretzsch, Charlotte M; Vander Wyk, Brent; Leckman, James F; Feldman, Ruth; Pelphrey, Kevin A
2016-11-15
Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.
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Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.
Wang, Huikun; Treadway, Tyler; Covey, Daniel P; Cheer, Joseph F; Lupica, Carl R
2015-09-29
Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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Hammond, Christopher J.; Mayes, Linda C.; Potenza, Marc N.
2015-01-01
Psychoactive substance and nonsubstance/behavioral addictions are major public health concerns associated with significant societal cost. Adolescence is a period of dynamic biologic, psychological, and behavioral changes. Adolescence is also associated with an increased risk for substance use and addictive disorders. During adolescence, developmental changes in neural circuitry of reward processing, motivation, cognitive control, and stress may contribute to vulnerability for increased levels of engagement in substance use and nonsubstance addictive behaviors. Current biologic models of adolescent vulnerability for addictions incorporate existing data on allostatic changes in function and structure of the midbrain dopaminergic system, stress-associated neuroplasticity, and maturational imbalances between cognitive control and reward reactivity. When characterizing adolescent vulnerability, identifying subgroups of adolescents at high risk for addictive behaviors is a major goal of the addiction field. Genetics, epigenetics, and intermediate phenotypes/endophenotypes may assist in characterizing children and adolescents at risk. Improved understanding of the neurobiology of adolescence and addiction vulnerability has the potential to refine screening, enhance prevention and intervention strategies, and inform public policy. PMID:25022184
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Psychopathy to Altruism: Neurobiology of the Selfish-Selfless Spectrum.
Sonne, James W H; Gash, Don M
2018-01-01
The age-old philosophical, biological, and social debate over the basic nature of humans as being "universally selfish" or "universally good" continues today highlighting sharply divergent views of natural social order. Here we analyze advances in biology, genetics and neuroscience increasing our understanding of the evolution, features and neurocircuitry of the human brain underlying behavior in the selfish-selfless spectrum. First, we examine evolutionary pressures for selection of altruistic traits in species with protracted periods of dependence on parents and communities for subsistence and acquisition of learned behaviors. Evidence supporting the concept that altruistic potential is a common feature in human populations is developed. To go into greater depth in assessing critical features of the social brain, the two extremes of selfish-selfless behavior, callous unemotional psychopaths and zealous altruists who take extreme measures to help others, are compared on behavioral traits, structural/functional neural features, and the relative contributions of genetic inheritance versus acquired cognitive learning to their mindsets. Evidence from population groups ranging from newborns, adopted children, incarcerated juveniles, twins and mindfulness meditators point to the important role of neuroplasticity and the dopaminergic reward systems in forming and reforming neural circuitry in response to personal experience and cultural influences in determining behavior in the selfish-selfless spectrum. The underlying neural circuitry differs between psychopaths and altruists with emotional processing being profoundly muted in psychopaths and significantly enhanced in altruists. But both groups are characterized by the reward system of the brain shaping behavior. Instead of rigid assignment of human nature as being "universally selfish" or "universally good," both characterizations are partial truths based on the segments of the selfish-selfless spectrum being examined. In addition, individuals and populations can shift in the behavioral spectrum in response to cognitive therapy and social and cultural experience, and approaches such as mindfulness training for introspection and reward-activating compassion are entering the mainstream of clinical care for managing pain, depression, and stress.
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Psychopathy to Altruism: Neurobiology of the Selfish–Selfless Spectrum
Sonne, James W. H.; Gash, Don M.
2018-01-01
The age-old philosophical, biological, and social debate over the basic nature of humans as being “universally selfish” or “universally good” continues today highlighting sharply divergent views of natural social order. Here we analyze advances in biology, genetics and neuroscience increasing our understanding of the evolution, features and neurocircuitry of the human brain underlying behavior in the selfish–selfless spectrum. First, we examine evolutionary pressures for selection of altruistic traits in species with protracted periods of dependence on parents and communities for subsistence and acquisition of learned behaviors. Evidence supporting the concept that altruistic potential is a common feature in human populations is developed. To go into greater depth in assessing critical features of the social brain, the two extremes of selfish–selfless behavior, callous unemotional psychopaths and zealous altruists who take extreme measures to help others, are compared on behavioral traits, structural/functional neural features, and the relative contributions of genetic inheritance versus acquired cognitive learning to their mindsets. Evidence from population groups ranging from newborns, adopted children, incarcerated juveniles, twins and mindfulness meditators point to the important role of neuroplasticity and the dopaminergic reward systems in forming and reforming neural circuitry in response to personal experience and cultural influences in determining behavior in the selfish–selfless spectrum. The underlying neural circuitry differs between psychopaths and altruists with emotional processing being profoundly muted in psychopaths and significantly enhanced in altruists. But both groups are characterized by the reward system of the brain shaping behavior. Instead of rigid assignment of human nature as being “universally selfish” or “universally good,” both characterizations are partial truths based on the segments of the selfish–selfless spectrum being examined. In addition, individuals and populations can shift in the behavioral spectrum in response to cognitive therapy and social and cultural experience, and approaches such as mindfulness training for introspection and reward-activating compassion are entering the mainstream of clinical care for managing pain, depression, and stress. PMID:29725317
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Changes in reward-induced brain activation in opiate addicts.
Martin-Soelch, C; Chevalley, A F; Künig, G; Missimer, J; Magyar, S; Mino, A; Schultz, W; Leenders, K L
2001-10-01
Many studies indicate a role of the cerebral dopaminergic reward system in addiction. Motivated by these findings, we examined in opiate addicts whether brain regions involved in the reward circuitry also react to human prototypical rewards. We measured regional cerebral blood flow (rCBF) with H(2)(15)O positron emission tomography (PET) during a visuo-spatial recognition task with delayed response in control subjects and in opiate addicts participating in a methadone program. Three conditions were defined by the types of feedback: nonsense feedback; nonmonetary reinforcement; or monetary reward, received by the subjects for a correct response. We found in the control subjects rCBF increases in regions associated with the meso-striatal and meso-corticolimbic circuits in response to both monetary reward and nonmonetary reinforcement. In opiate addicts, these regions were activated only in response to monetary reward. Furthermore, nonmonetary reinforcement elicited rCBF increases in limbic regions of the opiate addicts that were not activated in the control subjects. Because psychoactive drugs serve as rewards and directly affect regions of the dopaminergic system like the striatum, we conclude that the differences in rCBF increases between controls and addicts can be attributed to an adaptive consequence of the addiction process.
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Stress, eating and the reward system.
Adam, Tanja C; Epel, Elissa S
2007-07-24
An increasing number of people report concerns about the amount of stress in their life. At the same time obesity is an escalating health problem worldwide. Evidence is accumulating rapidly that stress related chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and resulting excess glucocorticoid exposure may play a potential role in the development of visceral obesity. Since adequate regulation of energy and food intake under stress is important for survival, it is not surprising that the HPA axis is not only the 'conductor' of an appropriate stress response, but is also tightly intertwined with the endocrine regulation of appetite. Here we attempt to link animal and human literatures to tease apart how different types of psychological stress affect eating. We propose a theoretical model of Reward Based Stress Eating. This model emphasizes the role of cortisol and reward circuitry on motivating calorically dense food intake, and elucidating potential neuroendocrine mediators in the relationship between stress and eating. The addiction literature suggests that the brain reward circuitry may be a key player in stress-induced food intake. Stress as well as palatable food can stimulate endogenous opioid release. In turn, opioid release appears to be part of an organisms' powerful defense mechanism protecting from the detrimental effects of stress by decreasing activity of the HPA axis and thus attenuating the stress response. Repeated stimulation of the reward pathways through either stress induced HPA stimulation, intake of highly palatable food or both, may lead to neurobiological adaptations that promote the compulsive nature of overeating. Cortisol may influence the reward value of food via neuroendocrine/peptide mediators such as leptin, insulin and neuropeptide Y (NPY). Whereas glucocorticoids are antagonized by insulin and leptin acutely, under chronic stress, that finely balanced system is dysregulated, possibly contributing to increased food intake and visceral fat accumulation. While these mechanisms are only starting to be elucidated in humans, it appears the obesity epidemic may be exacerbated by the preponderance of chronic stress, unsuccessful attempts at food restriction, and their independent and possibly synergistic effects on increasing the reward value of highly palatable food.
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Stefano, George B; Bianchi, Enrica; Guarna, Massimo; Fricchione, Gregory L; Zhu, Wei; Cadet, Patrick; Mantione, Kirk J; Casares, Federico M; Kream, Richard M; Esch, Tobias
2007-06-01
Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.
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Developmental origins of brain disorders: roles for dopamine
Money, Kelli M.; Stanwood, Gregg D.
2013-01-01
Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541
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AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors
Dietrich, Marcelo O; Bober, Jeremy; Ferreira, Jozélia G; Tellez, Luis A; Mineur, Yann S; Souza, Diogo O; Gao, Xiao-Bing; Picciotto, Marina R; Araújo, Ivan; Liu, Zhong-Wu; Horvath, Tamas L
2012-01-01
It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit–impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing–dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors. PMID:22729177
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Johnson, Patricia L; Potts, Geoffrey F; Sanchez-Ramos, Juan; Cimino, Cynthia R
2017-09-01
Few studies have directly investigated impulsivity in Huntington's disease (HD) despite known changes in dopaminergic and frontal functioning, changes that have been associated with impulsivity in other disorders and in the normal population. This study sought to further categorize impulsivity in HD through examining differences in self-reported impulsivity between community controls and HD patients, the relationship between executive dysfunction and impulsivity, and the relationship of a reward/punishment behavioral inhibition task in relation to these self-report measures. It was expected that HD patients would report higher impulsivity and executive dysfunction and that these measures would relate to a reward/punishment behavioral inhibition task. The Barratt Impulsivity Scale (BIS-11) and Behavioral Inhibition/Behavioral Activation Scale (BIS/BAS) were completed, and the Mini-Mental State Examination (MMSE) and a reward-based flanker task with punishing and rewarding conditions were administered to 22 HD patients and 14 control participants. HD patients reported higher trait impulsivity (BIS-11) and executive dysfunction (Frontal Systems Behavior Scale, FrSBE) but not increased impulsivity on the BIS/BAS relative to controls. Higher BIS-11 scores were related to increased self-reported executive dysfunction and the attention/working memory factor of the MMSE. On a reward/punishment behavioral inhibition task, BAS was uniquely related to increased accuracy on rewarding trials of the flanker task, but was not related to punishing trials in HD patients. The relationships found suggest that trait impulsivity is reported higher in HD and may not be driven by altered reward evaluation and the appetitive nature of stimuli but rather by increased executive dysfunction and lack of sensitivity to punishment. Impulsivity in HD may represent a combination of trait impulsivity, altered dopaminergic circuitry, and executive dysfunction. Understanding impulsivity in HD is important as it is related to increased risk to the patient and difficult behaviors for the caregiver, and sheds light on the disease process.
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Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar
Domingos, Ana I; Sordillo, Aylesse; Dietrich, Marcelo O; Liu, Zhong-Wu; Tellez, Luis A; Vaynshteyn, Jake; Ferreira, Jozelia G; Ekstrand, Mats I; Horvath, Tamas L; de Araujo, Ivan E; Friedman, Jeffrey M
2013-01-01
Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5−/− mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward. DOI: http://dx.doi.org/10.7554/eLife.01462.001 PMID:24381247
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Motivation and timing: clues for modeling the reward system.
Galtress, Tiffany; Marshall, Andrew T; Kirkpatrick, Kimberly
2012-05-01
There is growing evidence that a change in reward magnitude or value alters interval timing, indicating that motivation and timing are not independent processes as was previously believed. The present paper reviews several recent studies, as well as presenting some new evidence with further manipulations of reward value during training vs. testing on a peak procedure. The combined results cannot be accounted for by any of the current psychological timing theories. However, in examining the neural circuitry of the reward system, it is not surprising that motivation has an impact on timing because the motivation/valuation system directly interfaces with the timing system. A new approach is proposed for the development of the next generation of timing models, which utilizes knowledge of the neuroanatomy and neurophysiology of the reward system to guide the development of a neurocomputational model of the reward system. The initial foundation along with heuristics for proceeding with developing such a model is unveiled in an attempt to stimulate new theoretical approaches in the field. Copyright © 2012 Elsevier B.V. All rights reserved.
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Adolescent Depression: Stress and Reward Dysfunction
Auerbach, Randy P.; Admon, Roee; Pizzagalli, Diego A.
2014-01-01
Adolescence is a peak period for the onset of depression, and it is also a time marked by substantial stress as well as neural development within the brain reward circuitry. In the current review, we provide a selective overview of current animal and human research investigating the relationship among reward processes, stress, and depression. Three separate, but related, etiological models examine the differential roles that stress may play with regard to reward dysfunction and adolescent depression. First, the reward mediation model suggests that acute and chronic stress contribute to reward deficits, which in turn, potentiate depressive symptoms and/or increase the risk for depression. Second, in line with the stress generation perspective, it is plausible that premorbid reward-related dysfunction generates stress, in particular interpersonal stress, which then leads to the manifestation of depressive symptoms. Last, consistent with a diathesis-stress model, the interaction between stress and premorbid reward dysfunction may contribute to the onset of depression. Given the equifinal nature of depression, these models could shed important light on different etiological pathways during adolescence, particularly as they may relate to understanding the heterogeneity of depression. To highlight the translational potential of these insights, a hypothetical case study is provided as means of demonstrating the importance of targeting reward dysfunction in both assessment and treatment of adolescent depression. PMID:24704785
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Griffiths, Kristi R.; Morris, Richard W.; Balleine, Bernard W.
2014-01-01
The ability to learn contingencies between actions and outcomes in a dynamic environment is critical for flexible, adaptive behavior. Goal-directed actions adapt to changes in action-outcome contingencies as well as to changes in the reward-value of the outcome. When networks involved in reward processing and contingency learning are maladaptive, this fundamental ability can be lost, with detrimental consequences for decision-making. Impaired decision-making is a core feature in a number of psychiatric disorders, ranging from depression to schizophrenia. The argument can be developed, therefore, that seemingly disparate symptoms across psychiatric disorders can be explained by dysfunction within common decision-making circuitry. From this perspective, gaining a better understanding of the neural processes involved in goal-directed action, will allow a comparison of deficits observed across traditional diagnostic boundaries within a unified theoretical framework. This review describes the key processes and neural circuits involved in goal-directed decision-making using evidence from animal studies and human neuroimaging. Select studies are discussed to outline what we currently know about causal judgments regarding actions and their consequences, action-related reward evaluation, and, most importantly, how these processes are integrated in goal-directed learning and performance. Finally, we look at how adaptive decision-making is impaired across a range of psychiatric disorders and how deepening our understanding of this circuitry may offer insights into phenotypes and more targeted interventions. PMID:24904322
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Molecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects.
Sun, Wei-Lun; Quizon, Pamela M; Zhu, Jun
2016-01-01
Addiction to psychostimulants has been considered as a chronic psychiatric disorder characterized by craving and compulsive drug seeking and use. Over the past two decades, accumulating evidence has demonstrated that repeated drug exposure causes long-lasting neurochemical and cellular changes that result in enduring neuroadaptation in brain circuitry and underlie compulsive drug consumption and relapse. Through intercellular signaling cascades, drugs of abuse induce remodeling in the rewarding circuitry that contributes to the neuroplasticity of learning and memory associated with addiction. Here, we review the role of the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase, and its related intracellular signaling pathways in drug-induced neuroadaptive changes that are associated with drug-mediated psychomotor activity, rewarding properties and relapse of drug seeking behaviors. We also discuss the neurobiological and behavioral effects of pharmacological and genetic interferences with ERK-associated molecular cascades in response to abused substances. Understanding the dynamic modulation of ERK signaling in response to drugs may provide novel molecular targets for therapeutic strategies to drug addiction. Copyright © 2016. Published by Elsevier Inc.
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Barlow, Rebecca L; Gorges, Martin; Wearn, Alfie; Niessen, Heiko G; Kassubek, Jan; Dalley, Jeffrey W; Pekcec, Anton
2018-03-15
Low dopamine D2/3 receptor availability in the nucleus accumbens (NAcb) shell is associated with highly-impulsive behavior in rats, as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the NAcb is equally linked to intolerance for delayed rewards, a related form of impulsivity. We investigated the relationship between D2/3 receptor availability in the NAcb and impulsivity in a delay-discounting task (DDT) where animals must choose between immediate small-magnitude rewards and delayed larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high-, and low-impulsivity using in-vivo [18F]fallypride positron emission tomography (PET) and ex-vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. DDT impulsivity was inversely related to D2/3 receptor availability in the NAcb core but not the dorsal striatum with higher D2/3 binding in the NAcb shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high versus low impulsive rats. We conclude that DDT impulsivity is associated with low D2/3 receptor binding in the NAcb core. Thus two related forms of waiting impulsivity - premature responding and delay intolerance in a delay-of-reward task - implicate an involvement of D2/3 receptor availability in the NAcb shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction and other psychiatric disorders.
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Harasta, Anne E; Power, John M; von Jonquieres, Georg; Karl, Tim; Drucker, Daniel J; Housley, Gary D; Schneider, Miriam; Klugmann, Matthias
2015-01-01
Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction. However, the role of endogenous GLP-1 in the attenuation of reward-oriented behavior, and the essential domains of the mesolimbic system mediating these beneficial effects, are largely unknown. We hypothesized that the central regions of highest Glp-1r gene activity are essential in mediating responses to drugs of abuse. Here, we show that Glp-1r-deficient (Glp-1r−/−) mice have greatly augmented cocaine-induced locomotor responses and enhanced conditional place preference compared with wild-type (Glp-1r+/+) controls. Employing mRNA in situ hybridization we located peak Glp-1r mRNA expression in GABAergic neurons of the dorsal lateral septum, an anatomical site with a crucial function in reward perception. Whole-cell patch-clamp recordings of dorsal lateral septum neurons revealed that genetic Glp-1r ablation leads to increased excitability of these cells. Viral vector-mediated Glp-1r gene delivery to the dorsal lateral septum of Glp-1r−/− animals reduced cocaine-induced locomotion and conditional place preference to wild-type levels. This site-specific genetic complementation did not affect the anxiogenic phenotype observed in Glp-1r−/− controls. These data reveal a novel role of GLP-1R in dorsal lateral septum function driving behavioral responses to cocaine. PMID:25669605
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Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction.
Blum, Kenneth; Thanos, Peter K; Oscar-Berman, Marlene; Febo, Marcelo; Baron, David; Badgaiyan, Rajendra D; Gardner, Eliot; Demetrovics, Zsolt; Fahlke, Claudia; Haberstick, Brett C; Dushaj, Kristina; Gold, Mark S
Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes "surfeit" compared to" deficit" in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: "liking", "learning", and "wanting". They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the "surfeit theory". Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The "dopamine hypotheses" originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied to dopamine deficiency. Vulnerability to addiction and relapse may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants and elevated stress levels. We therefore propose that dopamine homeostasis may be a preferred goal to combat relapse.
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Frank, G K W; Shott, M E; Riederer, J; Pryor, T L
2016-01-01
Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive–emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction. PMID:27801897
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Age Differences in the Impact of Peers on Adolescents’ and Adults’ Neural Response to Reward
Smith, Ashley R.; Steinberg, Laurence; Strang, Nicole; Chein, Jason
2014-01-01
Prior research suggests that increased adolescent risk-taking in the presence of peers may be linked to the influence of peers on the valuation and processing of rewards during decision-making. The current study explores this idea by examining how peer observation impacts the processing of rewards when such processing is isolated from other facets of risky decision-making (e.g. risk-perception and preference, inhibitory processing, etc.). In an fMRI paradigm, a sample of adolescents (ages 14–19) and adults (ages 25–35) completed a modified High/Low Card Guessing Task that included rewarded and un-rewarded trials. Social context was manipulated by having participants complete the task both alone and while being observed by two, same-age, same-sex peers. Results indicated an interaction of age and social context on the activation of reward circuitry during the receipt of reward; when observed by peers adolescents exhibited greater ventral striatal activation than adults, but no age-related differences were evinced when the task was completed alone. These findings suggest that, during adolescence, peers influence recruitment of reward-related regions even when they are engaged outside of the context of risk-taking. Implications for engagement in prosocial, as well as risky, behaviors during adolescence are discussed. PMID:25280778
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Piantadosi, Patrick T; Yeates, Dylan C M; Wilkins, Mathew; Floresco, Stan B
2017-04-01
The involvement of different nodes within meso-cortico-limbic-striatal circuitry in mediating reward-seeking has been well described, yet comparatively less is known about how such circuitry may regulate appetitively-motivated behaviors that may be punished. The basolateral amygdala (BLA) is one nucleus that has been implicated in suppressing punished reward-seeking, and this structure can modulate goal-directed behavior via projections to subregions of the nucleus accumbens (NAc). Here, we examined the effects of reversible inactivations of the BLA, NAc Shell (NAcS), and core (NAcC) on performance of a "Conflict" task where rats pressed a lever for sucrose reinforcement during three distinct 5min phases. During the first and last phases of a session, rats lever-pressed for food reward delivered on a VI-15/FR5 schedule. In between these phases was a signaled "Conflict" period, where each lever-press yielded food, but 50% of presses were also punished with foot-shock. Under control conditions, well-trained rats responded vigorously during the two "safe" VI-15/FR5 periods, but reduced responding during the punished Conflict period. Inactivation of either the BLA or the NAcS via infusions of baclofen/muscimol disinhibited punished seeking, increasing lever-pressing during the conflict period, while attenuating pressing during VI-15/FR5 phases. In contrast, NAcC inactivation markedly decreased responding across all three phases. Similar inactivation of the BLA or NAcS did not alter responding in a separate control experiment where rats pressed for food on schedules identical to the Conflict task in the absence of any punishment, while NAcC inactivation again suppressed responding. These results imply that BLA and NAcS are part of a circuit that suppresses reward-seeking in the face of danger, which in turn may have implications for disorders characterized by punishment resistance, including substance abuse and obsessive-compulsive disorder. Copyright © 2017 Elsevier Inc. All rights reserved.
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Let's chat: developmental neural bases of social motivation during real-time peer interaction.
Warnell, Katherine Rice; Sadikova, Eleonora; Redcay, Elizabeth
2018-05-01
Humans are motivated to interact with each other, but the neural bases of social motivation have been predominantly examined in non-interactive contexts. Understanding real-world social motivation is of special importance during middle childhood (ages 8-12), a period when social skills improve, social networks grow, and social brain networks specialize. To assess interactive social motivation, the current study used a novel fMRI paradigm in which children believed they were chatting with a peer. The design targeted two phases of interaction: (1) Initiation, in which children engaged in a social bid via sharing a like or hobby, and (2) Reply, in which children received either an engaged ("Me too") or non-engaged ("I'm away") reply from the peer. On control trials, children were told that their answers were not shared and that they would receive either engaged ("Matched") or non-engaged ("Disconnected") replies from the computer. Results indicated that during Initiation and Reply, key components of reward circuitry (e.g., ventral striatum) were more active for the peer than the computer trials. In addition, during Reply, social cognitive regions were more activated by the peer, and this social cognitive specialization increased with age. Finally, the effect of engagement type on reward circuitry activation was larger for social than non-social trials, indicating developmental sensitivity to social contingency. These findings demonstrate that both reward and social cognitive brain systems support real-time social interaction in middle childhood. An interactive approach to understanding social reward has implications for clinical disorders, where social motivation is more affected in real-world contexts. © 2017 John Wiley & Sons Ltd.
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The Influence of Emotion Regulation on Decision-making under Risk
Martin, Laura N.; Delgado, Mauricio R.
2011-01-01
Cognitive strategies typically involved in regulating negative emotions have recently been shown to also be effective with positive emotions associated with monetary rewards. However, it is less clear how these strategies influence behavior, such as preferences expressed during decision-making under risk, and the underlying neural circuitry. That is, can the effective use of emotion regulation strategies during presentation of a reward-conditioned stimulus influence decision-making under risk and neural structures involved in reward processing such as the striatum? To investigate this question, we asked participants to engage in imagery-focused regulation strategies during the presentation of a cue that preceded a financial decision-making phase. During the decision phase, participants then made a choice between a risky and a safe monetary lottery. Participants who successfully used cognitive regulation, as assessed by subjective ratings about perceived success and facility in implementation of strategies, made fewer risky choices in comparison to trials where decisions were made in the absence of cognitive regulation. Additionally, blood-oxygen-level-dependent (BOLD) responses in the striatum were attenuated during decision-making as a function of successful emotion regulation. These findings suggest that exerting cognitive control over emotional responses can modulate neural responses associated with reward processing (e.g., striatum), and promote more goal-directed decision-making (e.g., less risky choices), illustrating the potential importance of cognitive strategies in curbing risk-seeking behaviors before they become maladaptive (e.g., substance abuse). PMID:21254801
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ERIC Educational Resources Information Center
Keistler, Colby; Barker, Jacqueline M.; Taylor, Jane R.
2015-01-01
Although several studies have examined the subcortical circuitry underlying Pavlovian-to-instrumental transfer (PIT), the role of medial prefrontal cortex in this behavior is largely unknown. Elucidating the cortical contributions to PIT will be key for understanding how reward-paired cues control behavior in both adaptive and maladaptive context…
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Dawson, Geraldine; Webb, Sara Jane; Wijsman, Ellen; Schellenberg, Gerard; Estes, Annette; Munson, Jeffrey; Faja, Susan
2005-01-01
Neuroimaging and behavioral studies have shown that children and adults with autism have impaired face recognition. Individuals with autism also exhibit atypical event-related brain potentials to faces, characterized by a failure to show a negative component (N170) latency advantage to face compared to nonface stimuli and a bilateral, rather than right lateralized, pattern of N170 distribution. In this report, performance by 143 parents of children with autism on standardized verbal, visual-spatial, and face recognition tasks was examined. It was found that parents of children with autism exhibited a significant decrement in face recognition ability relative to their verbal and visual spatial abilities. Event-related brain potentials to face and nonface stimuli were examined in 21 parents of children with autism and 21 control adults. Parents of children with autism showed an atypical event-related potential response to faces, which mirrored the pattern shown by children and adults with autism. These results raise the possibility that face processing might be a functional trait marker of genetic susceptibility to autism. Discussion focuses on hypotheses regarding the neurodevelopmental and genetic basis of altered face processing in autism. A general model of the normal emergence of social brain circuitry in the first year of life is proposed, followed by a discussion of how the trajectory of normal development of social brain circuitry, including cortical specialization for face processing, is altered in individuals with autism. The hypothesis that genetic-mediated dysfunction of the dopamine reward system, especially its functioning in social contexts, might account for altered face processing in individuals with autism and their relatives is discussed.
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Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective.
Figlewicz, Dianne P
2015-01-01
Palatable foods are frequently high in energy density. Chronic consumption of high-energy density foods can contribute to the development of cardiometabolic pathology including obesity, diabetes, and cardiovascular disease. This article reviews the contributions of extrinsic and intrinsic factors that influence the reward components of food intake. A narrative review was conducted to determine the behavioral and central nervous system (CNS) related processes involved in the reward components of high-energy density food intake. The rewarding aspects of food, particularly palatable and preferred foods, are regulated by CNS circuitry. Overlaying this regulation is modulation by intrinsic endocrine systems and metabolic hormones relating to energy homeostasis, developmental stage, or gender. It is now recognized that extrinsic or environmental factors, including ambient diet composition and the provocation of stress or anxiety, also contribute substantially to the expression of food reward behaviors such as motivation for, and seeking of, preferred foods. High-energy density food intake is influenced by both physiological and pathophysiological processes. Contextual, behavioral, and psychological factors and CNS-related processes represent potential targets for multiple types of therapeutic intervention.
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Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back
Coccurello, Roberto; Maccarrone, Mauro
2018-01-01
Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin), and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior. PMID:29740277
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Neurogenetics and Epigenetics in Impulsive Behaviour: Impact on Reward Circuitry
Archer, Trevor; Oscar-Berman, Marlene; Blum, Kenneth; Gold, Mark
2012-01-01
Adverse, unfavourable life conditions, particularly during early life stages and infancy, can lead to epigenetic regulation of genes involved in stress-response, behavioral disinhibition, and cognitive-emotional systems. Over time, the ultimate final outcome can be expressed through behaviors bedeviled by problems with impulse control, such as eating disorders, alcoholism, and indiscriminate social behavior. While many reward gene polymorphisms are involved in impulsive behaviors, a polymorphism by itself may not translate to the development of a particular behavioral disorder unless it is impacted by epigenetic effects. Brain-derived neurotrophic factor (BDNF) affects the development and integrity of the noradrenergic, dopaminergic, serotonergic, glutamatergic, and cholinergic neurotransmitter systems, and plasma levels of the neurotrophin are associated with both cognitive and aggressive impulsiveness. Epigenetic mechanisms associated with a multitude of environmental factors, including premature birth, low birth weight, prenatal tobacco exposure, non-intact family, young maternal age at birth of the target child, paternal history of antisocial behavior, and maternal depression, alter the developmental trajectories for several neuropsychiatric disorders. These mechanisms affect brain development and integrity at several levels that determine structure and function in resolving the final behavioral expressions. PMID:23264884
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Hormonal gain control of a medial preoptic area social reward circuit
McHenry, Jenna A.; Otis, James M.; Rossi, Mark A.; Robinson, J. Elliott; Kosyk, Oksana; Miller, Noah W.; McElligott, Zoe A.; Budygin, Evgeny A.; Rubinow, David R.; Stuber, Garret D.
2017-01-01
Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and invigorate social interactions. However, the neurocircuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors and is comprised of molecularly-diverse neurons with widespread projections. Here, we identify a steroid-responsive subset of neurotensin (Nts) expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially-engaged reward circuit. Using in vivo 2-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to non-social appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach, and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically-relevant stimuli and co-opt midbrain reward circuits to promote prosocial behavior critical for species survival. PMID:28135243
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Park, Il Ho; Lee, Boung Chul; Kim, Jae-Jin; Kim, Joong Il; Koo, Min-Seung
2017-04-19
Amotivation is a common phenotype of major depressive disorder and schizophrenia, which are clinically distinct disorders. Effective treatment targets and strategies can be discovered by examining the dopaminergic reward network function underlying amotivation between these disorders. We conducted an fMRI study in healthy human participants and medicated patients with depression and schizophrenia using an effort-based reinforcement task. We examined regional activations related to reward type (positive and negative reinforcement), effort level, and their composite value, as well as resting-state functional connectivities within the meso-striatal-prefrontal pathway. We found that integrated reward and effort values of low effort-positive reinforcement and high effort-negative reinforcement were behaviorally anticipated and represented in the putamen and medial orbitofrontal cortex activities. Patients with schizophrenia and depression did not show anticipation-related and work-related reaction time reductions, respectively. Greater amotivation severity correlated with smaller work-related putamen activity changes according to reward type in schizophrenia and effort level in depression. Patients with schizophrenia showed feedback-related putamen hyperactivity of low effort compared with healthy controls and depressed patients. The strength of medial orbitofrontal-striatal functional connectivity predicted work-related reaction time reduction of high effort negative reinforcement in healthy controls and amotivation severity in both patients with schizophrenia and those with depression. Patients with depression showed deficient medial orbitofrontal-striatal functional connectivity compared with healthy controls and patients with schizophrenia. These results indicate that amotivation in depression and schizophrenia involves different pathophysiology in the prefrontal-striatal circuitry. SIGNIFICANCE STATEMENT Amotivation is present in both depression and schizophrenia. However, treatment involves the use of drugs that enhance serotonin activity in depression and inhibit serotonin and dopamine activity in schizophrenia. Understanding how motivation processed in the mesocorticolimbic and nigostriatal pathways is affected in depression and schizophrenia is important in discovering treatment targets and strategies for amotivation. To our knowledge, this is the first study to compare patients with depression and schizophrenia in a common functional construct. By using an effort-based reinforcement task and examining resting-state functional connectivity in the dopaminergic network, we propose that difference in striato-orbitofrontal dysfunction in effort-based reinforcement between depression and schizophrenia may be related to differences in the extent of functional dysconnectivity in the dopaminergic pathway. Copyright © 2017 the authors 0270-6474/17/374371-11$15.00/0.
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Blum, Kenneth; Liu, Yijun; Wang, Wei; Wang, Yarong; Zhang, Yi; Oscar-Berman, Marlene; Smolen, Andrew; Febo, Marcelo; Han, David; Simpatico, Thomas; Cronjé, Frans J; Demetrovics, Zsolt; Gold, Mark S.
2016-01-01
Recently Willuhn et al. reported that cocaine use and even non-substance related addictive behavior, increases, as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors, also associated with lower activation to cues in occipital cortex and cerebellum in a recent PET study from Volkow’s group. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220Z™ on reward circuitry of ten heroin addicts undergoing protracted abstinence, an average 16.9 months. In a randomized placebo-controlled crossover study of KB220Z™ five subjects completed a triple blinded–experiment in which the subject, the person administering the treatment and the person evaluating the response to treatment were blinded as to which treatment any particular subject was receiving. In addition, nine subjects total were genotyped utilizing the GARSRX™ test. We preliminarily report that KB220Z ™ induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following one-hour acute administration. Furthermore, KB220Z™ also reduced resting state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all ten abstinent heroin-dependent subjects, three brain regions of interest (ROIs) we observed to be significantly activated from resting state by KB220Z compared to placebo (P < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas and cerebellum. These results and other qEEG study results suggest a putative anti-craving/anti-relapse role for KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results and confirmation with additional research and ongoing rodent and human studies of KB220Z, is required. PMID:25526228
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A Psycho-Genetic Study of Hedonic Responsiveness in Relation to “Food Addiction”
Davis, Caroline; Loxton, Natalie J.
2014-01-01
While food addiction has no formally-recognized definition, it is typically operationalized according to the diagnostic principles established by the Yale Food Addiction Scale—an inventory based on the symptom criteria for substance dependence in the DSM-IV. Currently, there is little biologically-based research investigating the risk factors for food addiction. What does exist has focused almost exclusively on dopaminergic reward pathways in the brain. While brain opioid signaling has also been strongly implicated in the control of food intake, there is no research examining this neural circuitry in the association with food addiction. The purpose of the study was therefore to test a model predicting that a stronger activation potential of opioid circuitry-as indicated by the functional A118G marker of the mu-opioid receptor gene-would serve as an indirect risk factor for food addiction via a heightened hedonic responsiveness to palatable food. Results confirmed these relationships. In addition, our findings that the food-addiction group had significantly higher levels of hedonic responsiveness to food suggests that this bio-behavioral trait may foster a proneness to overeating, to episodes of binge eating, and ultimately to a compulsive and addictive pattern of food intake. PMID:25325253
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A psycho-genetic study of hedonic responsiveness in relation to "food addiction".
Davis, Caroline; Loxton, Natalie J
2014-10-16
While food addiction has no formally-recognized definition, it is typically operationalized according to the diagnostic principles established by the Yale Food Addiction Scale-an inventory based on the symptom criteria for substance dependence in the DSM-IV. Currently, there is little biologically-based research investigating the risk factors for food addiction. What does exist has focused almost exclusively on dopaminergic reward pathways in the brain. While brain opioid signaling has also been strongly implicated in the control of food intake, there is no research examining this neural circuitry in the association with food addiction. The purpose of the study was therefore to test a model predicting that a stronger activation potential of opioid circuitry-as indicated by the functional A118G marker of the mu-opioid receptor gene-would serve as an indirect risk factor for food addiction via a heightened hedonic responsiveness to palatable food. Results confirmed these relationships. In addition, our findings that the food-addiction group had significantly higher levels of hedonic responsiveness to food suggests that this bio-behavioral trait may foster a proneness to overeating, to episodes of binge eating, and ultimately to a compulsive and addictive pattern of food intake.
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Jenni, Nicole L; Larkin, Joshua D; Floresco, Stan B
2017-06-28
Mesocortical dopamine (DA) regulates a variety of cognitive functions via actions on D 1 and/or D 2 receptors. For example, risk/reward decision making is modulated differentially by these two receptors within the prefrontal cortex (PFC), with D 2 receptors enabling flexible decision making and D 1 receptors promoting persistence in choice biases. However, it is unclear how DA mediates opposing patterns of behavior by acting on different receptors within the same terminal region. We explored the possibility that DA may act on separate networks of PFC neurons that are modulated by D 1 or D 2 receptors and in turn interface with divergent downstream structures such as the basolateral amygdala (BLA) or nucleus accumbens (NAc). Decision making was assessed using a probabilistic discounting task in which well trained male rats chose between small/certain or large/risky rewards, with the odds of obtaining the larger reward changing systematically within a session. Selective disruption of D 1 or D 2 modulation of separate PFC output pathways was achieved using unilateral intra-PFC infusions of DA antagonists combined with contralateral inactivation of the BLA or NAc. Disrupting D 2 (but not D 1 ) modulation of PFC→BLA circuitry impaired adjustments in decision biases in response to changes in reward probabilities. In contrast, disrupting D 1 modulation of PFC→NAc networks reduced risky choice, attenuating reward sensitivity and increasing sensitivity to reward omissions. These findings reveal that mesocortical DA can facilitate dissociable components of reward seeking and action selection by acting on different functional networks of PFC neurons that can be distinguished by the subcortical projection targets with which they interface. SIGNIFICANCE STATEMENT Prefrontal cortical dopamine regulates a variety of executive functions governed by the frontal lobes via actions on D 1 and D 2 receptors. These receptors can in some instances mediate different patterns of behavior, but the mechanisms underlying these dissociable actions are unclear. Using a selective disconnection approach, we reveal that D 1 and D 2 receptors can facilitate diverse aspects of decision making by acting on separate networks of prefrontal neurons that interface with distinct striatal or amygdalar targets. These findings reveal an additional level of complexity in how mesocortical DA regulates different forms of cognition via actions on different receptors, highlighting how it may act upon distinct cortical microcircuits to drive different patterns of behavior. Copyright © 2017 the authors 0270-6474/17/376200-14$15.00/0.
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Age differences in the impact of peers on adolescents' and adults' neural response to reward.
Smith, Ashley R; Steinberg, Laurence; Strang, Nicole; Chein, Jason
2015-02-01
Prior research suggests that increased adolescent risk-taking in the presence of peers may be linked to the influence of peers on the valuation and processing of rewards during decision-making. The current study explores this idea by examining how peer observation impacts the processing of rewards when such processing is isolated from other facets of risky decision-making (e.g. risk-perception and preference, inhibitory processing, etc.). In an fMRI paradigm, a sample of adolescents (ages 14-19) and adults (ages 25-35) completed a modified High/Low Card Guessing Task that included rewarded and un-rewarded trials. Social context was manipulated by having participants complete the task both alone and while being observed by two, same-age, same-sex peers. Results indicated an interaction of age and social context on the activation of reward circuitry during the receipt of reward; when observed by peers adolescents exhibited greater ventral striatal activation than adults, but no age-related differences were evinced when the task was completed alone. These findings suggest that, during adolescence, peers influence recruitment of reward-related regions even when they are engaged outside of the context of risk-taking. Implications for engagement in prosocial, as well as risky, behaviors during adolescence are discussed. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Casement, Melynda D; Guyer, Amanda E; Hipwell, Alison E; McAloon, Rose L; Hoffmann, Amy M; Keenan, Kathryn E; Forbes, Erika E
2014-04-01
Developmental models of psychopathology posit that exposure to social stressors may confer risk for depression in adolescent girls by disrupting neural reward circuitry. The current study tested this hypothesis by examining the relationship between early adolescent social stressors and later neural reward processing and depressive symptoms. Participants were 120 girls from an ongoing longitudinal study of precursors to depression across adolescent development. Low parental warmth, peer victimization, and depressive symptoms were assessed when the girls were 11 and 12 years old, and participants completed a monetary reward guessing fMRI task and assessment of depressive symptoms at age 16. Results indicate that low parental warmth was associated with increased response to potential rewards in the medial prefrontal cortex (mPFC), striatum, and amygdala, whereas peer victimization was associated with decreased response to potential rewards in the mPFC. Furthermore, concurrent depressive symptoms were associated with increased reward anticipation response in mPFC and striatal regions that were also associated with early adolescent psychosocial stressors, with mPFC and striatal response mediating the association between social stressors and depressive symptoms. These findings are consistent with developmental models that emphasize the adverse impact of early psychosocial stressors on neural reward processing and risk for depression in adolescence. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
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Phillips, Mary L.; Chase, Henry W.; Sheline, Yvette I.; Etkin, Amit; Almeida, Jorge R.C.; Deckersbach, Thilo; Trivedi, Madhukar H.
2015-01-01
Objective Despite significant advances in neuroscience and treatment development, no widely accepted biomarkers are available to inform diagnostics or identify preferred treatments for individuals with major depressive disorder. Method In this critical review, the authors examine the extent to which multimodal neuroimaging techniques can identify biomarkers reflecting key pathophysiologic processes in depression and whether such biomarkers may act as predictors, moderators, and mediators of treatment response that might facilitate development of personalized treatments based on a better understanding of these processes. Results The authors first highlight the most consistent findings from neuroimaging studies using different techniques in depression, including structural and functional abnormalities in two parallel neural circuits: serotonergically modulated implicit emotion regulation circuitry, centered on the amygdala and different regions in the medial prefrontal cortex; and dopaminergically modulated reward neural circuitry, centered on the ventral striatum and medial prefrontal cortex. They then describe key findings from the relatively small number of studies indicating that specific measures of regional function and, to a lesser extent, structure in these neural circuits predict treatment response in depression. Conclusions Limitations of existing studies include small sample sizes, use of only one neuroimaging modality, and a focus on identifying predictors rather than moderators and mediators of differential treatment response. By addressing these limitations and, most importantly, capitalizing on the benefits of multimodal neuroimaging, future studies can yield moderators and mediators of treatment response in depression to facilitate significant improvements in shorter- and longer-term clinical and functional outcomes. PMID:25640931
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Aznar, Susana; Klein, Anders B
2013-12-01
The prefrontal cortex (PFC) is involved in mediating important higher-order cognitive processes such as decision making, prompting thereby our actions. At the same time, PFC activation is strongly influenced by emotional reactions through its functional interaction with the amygdala and the striatal circuitry, areas involved in emotion and reward processing. The PFC, however, is able to modulate amygdala reactivity via a feedback loop to this area. A role for serotonin in adjusting for this circuitry of cognitive regulation of emotion has long been suggested based primarily on the positive pharmacological effect of elevating serotonin levels in anxiety regulation. Recent animal and human functional magnetic resonance studies have pointed to a specific involvement of the 5-hydroxytryptamine (5-HT)2A serotonin receptor in the PFC feedback regulatory projection onto the amygdala. This receptor is highly expressed in the prefrontal cortex areas, playing an important role in modulating cortical activity and neural oscillations (brain waves). This makes it an interesting potential pharmacological target for the treatment of neuropsychiatric modes characterized by lack of inhibitory control of emotion-based actions, such as addiction and other impulse-related behaviors. In this review, we give an overview of the 5-HT2A receptor distribution (neuronal, intracellular, and anatomical) along with its functional and physiological effect on PFC activation, and how that relates to more recent findings of a regulatory effect of the PFC on the emotional control of our actions.
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Inflammation Effects on Motivation and Motor Activity: Role of Dopamine
Felger, Jennifer C; Treadway, Michael T
2017-01-01
Motivational and motor deficits are common in patients with depression and other psychiatric disorders, and are related to symptoms of anhedonia and motor retardation. These deficits in motivation and motor function are associated with alterations in corticostriatal neurocircuitry, which may reflect abnormalities in mesolimbic and mesostriatal dopamine (DA). One pathophysiologic pathway that may drive changes in DAergic corticostriatal circuitry is inflammation. Biomarkers of inflammation such as inflammatory cytokines and acute-phase proteins are reliably elevated in a significant proportion of psychiatric patients. A variety of inflammatory stimuli have been found to preferentially target basal ganglia function to lead to impaired motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal neural responses to reward anticipation, decreased DA and DA metabolites in cerebrospinal fluid, and decreased availability, and release of striatal DA, all of which correlated with symptoms of reduced motivation and/or motor retardation. Importantly, inflammation-associated symptoms are often difficult to treat, and evidence suggests that inflammation may decrease DA synthesis and availability, thus circumventing the efficacy of standard pharmacotherapies. This review will highlight the impact of administration of inflammatory stimuli on the brain in relation to motivation and motor function. Recent data demonstrating similar relationships between increased inflammation and altered DAergic corticostriatal circuitry and behavior in patients with major depressive disorder will also be presented. Finally, we will discuss the mechanisms by which inflammation affects DA neurotransmission and relevance to novel therapeutic strategies to treat reduced motivation and motor symptoms in patients with high inflammation. PMID:27480574
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Social ‘wanting’ dysfunction in autism: neurobiological underpinnings and treatment implications
2012-01-01
Most behavioral training regimens in autism spectrum disorders (ASD) rely on reward-based reinforcement strategies. Although proven to significantly increase both cognitive and social outcomes and successfully reduce aberrant behaviors, this approach fails to benefit a substantial number of affected individuals. Given the enormous amount of clinical and financial resources devoted to behavioral interventions, there is a surprisingly large gap in our knowledge of the basic reward mechanisms of learning in ASD. Understanding the mechanisms for reward responsiveness and reinforcement-based learning is urgently needed to better inform modifications that might improve current treatments. The fundamental goal of this review is to present a fine-grained literature analysis of reward function in ASD with reference to a validated neurobiological model of reward: the ‘wanting’/’liking’ framework. Despite some inconsistencies within the available literature, the evaluation across three converging sets of neurobiological data (neuroimaging, electrophysiological recordings, and neurochemical measures) reveals good evidence for disrupted reward-seeking tendencies in ASD, particularly in social contexts. This is most likely caused by dysfunction of the dopaminergic–oxytocinergic ‘wanting’ circuitry, including the ventral striatum, amygdala, and ventromedial prefrontal cortex. Such a conclusion is consistent with predictions derived from diagnostic criteria concerning the core social phenotype of ASD, which emphasize difficulties with spontaneous self-initiated seeking of social encounters (that is, social motivation). Existing studies suggest that social ‘wanting’ tendencies vary considerably between individuals with ASD, and that the degree of social motivation is both malleable and predictive of intervention response. Although the topic of reward responsiveness in ASD is very new, with much research still needed, the current data clearly point towards problems with incentive-based motivation and learning, with clear and important implications for treatment. Given the reliance of behavioral interventions on reinforcement-based learning principles, we believe that a systematic focus on the integrity of the reward system in ASD promises to yield many important clues, both to the underlying mechanisms causing ASD and to enhancing the efficacy of existing and new interventions. PMID:22958468
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Reduced posterior mesofrontal cortex activation by risky rewards in substance-dependent patients.
Bjork, James M; Momenan, Reza; Smith, Ashley R; Hommer, Daniel W
2008-05-01
Substance-dependent individuals show disadvantageous decision-making, as well as alterated frontocortical recruitment when performing experimental tasks. We investigated whether substance-dependent patients (SDP) would show blunted recruitment of posterior mesofrontal cortex (PMC) by a conflict between concurrently increasing reward and risk of penalty in a monetary game of "chicken." SDP and controls performed: motor control (no reward) trials, guaranteed reward trials in which reward was not at risk, and risky trials where subjects were required to terminate their reward accrual before a secret varying time limit or else "bust" and forfeit that trial's winnings (low penalty) or the current trial's winnings plus an equal amount of previous winnings (high penalty). Reward accrual duration at risk of "busting" correlated negatively with trait neuroticism. The contrast between winning guaranteed reward versus non-reward activated the caudate head bilaterally in SDP but not controls. Accumulation of money at risk of low- or high-penalty (contrasted with accumulating guaranteed money) activated the PMC in both groups, but with a greater magnitude and more anterior extent in controls. Pre-decision signal increase in a PMC volume of interest negatively correlated with risk-taking in low-penalty trials, and was blunted in SDP relative to controls under both penalty conditions after controlling for individual differences in actual risk-taking and the higher neuroticism of SDP. These data suggest that SDP are characterized by a combination of: (a) striatal hypersensitivity to reward, and (b) under-recruitment of the specialized conflict-monitoring circuitry of the PMC when reward entails potential penalties.
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Dingess, Paige M; Darling, Rebecca A; Derman, Rifka C; Wulff, Shaun S; Hunter, Melissa L; Ferrario, Carrie R; Brown, Travis E
2017-11-01
Urges to consume food can be driven by stimuli in the environment that are associated with previous food experience. Identifying adaptations within brain reward circuits that facilitate cue-induced food seeking is critical for understanding and preventing the overconsumption of food and subsequent weight gain. Utilizing electrophysiological, biochemical, and DiI labeling, we examined functional and structural changes in the nucleus accumbens (NAc) and prefrontal cortex (PFC) associated with time-dependent increases in food craving ('incubation of craving'). Rats self-administered 60% high fat or chow 45 mg pellets and were then tested for incubation of craving either 1 or 30 days after training. High fat was chosen for comparison to determine whether palatability differentially affected incubation and/or plasticity. Rats showed robust incubation of craving for both food rewards, although responding for cues previously associated with high fat was greater than chow at both 1 and 30 days. In addition, previous experience with high-fat consumption reduced dendritic spine density in the PFC at both time points. In contrast, incubation was associated with an increase in NAc spine density and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission at 30 days in both groups. Finally, incubation of craving for chow and high fat was accompanied by an increase in calcium-permeable and calcium-impermeable AMPARs, respectively. Our results suggest that incubation of food craving alters brain reward circuitry and macronutrient composition specifically induces cortical changes in a way that may facilitate maladaptive food-seeking behaviors.
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Neural correlates of reward processing in adults with 22q11 deletion syndrome.
van Duin, Esther D A; Goossens, Liesbet; Hernaus, Dennis; da Silva Alves, Fabiana; Schmitz, Nicole; Schruers, Koen; van Amelsvoort, Therese
2016-01-01
22q11.2 deletion syndrome (22q11DS) is caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk to develop psychosis. The gene coding for catechol-O-methyl-transferase (COMT) is located at the deleted region, resulting in disrupted dopaminergic neurotransmission in 22q11DS, which may contribute to the increased vulnerability for psychosis. A dysfunctional motivational reward system is considered one of the salient features in psychosis and thought to be related to abnormal dopaminergic neurotransmission. The functional anatomy of the brain reward circuitry has not yet been investigated in 22q11DS. This study aims to investigate neural activity during anticipation of reward and loss in adult patients with 22q11DS. We measured blood-oxygen-level dependent (BOLD) activity in 16 patients with 22q11DS and 12 healthy controls during a monetary incentive delay task using a 3T Philips Intera MRI system. Data were analysed using SPM8. During anticipation of reward, the 22q11DS group alone displayed significant activation in bilateral middle frontal and temporal brain regions. Compared to healthy controls, significantly less activation in bilateral cingulate gyrus extending to premotor, primary motor and somatosensory areas was found. During anticipation of loss, the 22q11DS group displayed activity in the left middle frontal gyrus and anterior cingulate cortex, and relative to controls, they showed reduced brain activation in bilateral (pre)cuneus and left posterior cingulate. Within the 22q11DS group, COMT Val hemizygotes displayed more activation compared to Met hemizygotes in right posterior cingulate and bilateral parietal regions during anticipation of reward. During anticipation of loss, COMT Met hemizygotes compared to Val hemizygotes showed more activation in bilateral insula, striatum and left anterior cingulate. This is the first study to investigate reward processing in 22q11DS. Our preliminary results suggest that people with 22q11DS engage a fronto-temporal neural network. Compared to healthy controls, people with 22q11DS primarily displayed reduced activity in medial frontal regions during reward anticipation. COMT hemizygosity affects responsivity of the reward system in this condition. Alterations in reward processing partly underlain by the dopamine system may play a role in susceptibility for psychosis in 22q11DS.
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Reidy, Dennis E; Krusemark, Elizabeth; Kosson, David S; Kearns, Megan C; Smith-Darden, Joanne; Kiehl, Kent A
2017-12-01
Psychopathic traits are a manifestation of a personality pathology that comprises a core affective-interpersonal dysfunction (callous-unemotional traits) and an impulsive-antisocial behavioral component. Of particular importance, psychopathic traits are associated with the perpetration of some of the most severe acts of violence, and they appear to indicate a subset of youth at risk for earlier onset, greater frequency, and persistence of violent offending. Although these youth represent a minority of the population, they commit a significant proportion of the violence in the general community. In our review, we highlight evidence of a unique neurobiological predisposition that underlies the core affective deficits and describe contemporary accounts for the developmental processes leading to the antisocial behavior associated with psychopathy. Current evidence suggests that, for this subset of youth, the structure and function of neural circuitry supporting emotion processing, reward learning, decision making, and the development of emotion related to empathy may be crucial to understanding why they are at risk for violence. In particular, a reward dominant pattern of neurobehavioral conditioning may explain how these youth progress to some of the most severe and persistent forms of violence. However, this pattern of conditioning may also be essential to the primary prevention of such deleterious behavior. We suspect that effective strategies to prevent such violence may ultimately be informed by understanding these affective and motivational mechanisms.
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The Lateral Habenula Circuitry: Reward Processing and Cognitive Control
Baker, Phillip M.; Jhou, Thomas; Matsumoto, Masayuki; Mizumori, Sheri J.Y.; Stephenson-Jones, Marcus
2016-01-01
There has been a growing interest in understanding the role of the lateral habenula (LHb) in reward processing, affect regulation, and goal-directed behaviors. The LHb gets major inputs from the habenula-projecting globus pallidus and the mPFC, sending its efferents to the dopaminergic VTA and SNc, serotonergic dorsal raphe nuclei, and the GABAergic rostromedial tegmental nucleus. Recent studies have made advances in our understanding of the LHb circuit organization, yet the precise mechanisms of its involvement in complex behaviors are largely unknown. To begin to address this unresolved question, we present here emerging cross-species perspectives with a goal to provide a more refined understanding of the role of the LHb circuits in reward and cognition. We begin by highlighting recent findings from rodent experiments using optogenetics, electrophysiology, molecular, pharmacology, and tracing techniques that reveal diverse neural phenotypes in the LHb circuits that may underlie previously undescribed behavioral functions. We then discuss results from electrophysiological studies in macaques that suggest that the LHb cooperates with the anterior cingulate cortex to monitor action outcomes and signal behavioral adjustment. Finally, we provide an integrated summary of cross-species findings and discuss how further research on the connectivity, neural signaling, and physiology of the LHb circuits can deepen our understanding of the role of the LHb in normal and maladaptive behaviors associated with mental illnesses and drug abuse. PMID:27911751
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Human aging reduces the neurobehavioral influence of motivation on episodic memory.
Geddes, Maiya R; Mattfeld, Aaron T; Angeles, Carlo de Los; Keshavan, Anisha; Gabrieli, John D E
2018-05-01
The neural circuitry mediating the influence of motivation on long-term declarative or episodic memory formation is delineated in young adults, but its status is unknown in healthy aging. We examined the effect of reward and punishment anticipation on intentional declarative memory formation for words using an event-related functional magnetic resonance imaging (fMRI) monetary incentive encoding task in twenty-one younger and nineteen older adults. At 24-hour memory retrieval testing, younger adults were significantly more likely to remember words associated with motivational cues than neutral cues. Motivational enhancement of memory in younger adults occurred only for recollection ("remember" responses) and not for familiarity ("familiar" responses). Older adults had overall diminished memory and did not show memory gains in association with motivational cues. Memory encoding associated with monetary rewards or punishments activated motivational (substantia nigra/ventral tegmental area) and memory-related (hippocampus) brain regions in younger, but not older, adults during the target word periods. In contrast, older and younger adults showed similar activation of these brain regions during the anticipatory motivational cue interval. In a separate monetary incentive delay task that did not require learning, we found evidence for relatively preserved striatal reward anticipation in older adults. This supports a potential dissociation between incidental and intentional motivational processes in healthy aging. The finding that motivation to obtain rewards and avoid punishments had reduced behavioral and neural influence on intentional episodic memory formation in older compared to younger adults is relevant to life-span theories of cognitive aging including the dopaminergic vulnerability hypothesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Cognitive and emotional biomarkers of melancholic depression: An iSPOT-D report.
Day, Claire V; Gatt, Justine M; Etkin, Amit; DeBattista, Charles; Schatzberg, Alan F; Williams, Leanne M
2015-05-01
Depressed patients with melancholic features have distinct impairments in cognition and anhedonia, but it remains unknown whether these impairments can be quantified on neurocognitive biomarker tests of behavioral performance. We compared melancholic major depressive disorder (MDD) patients to non-melancholic MDD patients and controls on a neurocognitive test battery that assesses eight general and emotional cognitive domains including the hypothesized decision-making and reward-threat perception. MDD outpatients (n=1008) were assessed using a computerized battery of tests. MDD participants met DSM-IV criteria for MDD and had a score ≥16 on the 17-item Hamilton Rating Scale for Depression. Melancholic MDD was defined using the Mini-International Neuropsychiatric Interview and a psychomotor disturbance observer-rated CORE measure score >7. Controls were age- and gender-matched with no previous DSM-IV or significant medical history. Melancholic participants (33.7% of the MDD sample) exhibited significantly poorer performance than controls across each domain of cognitive function and for speed of emotion identification and implicit emotion priming. Compared to the non-melancholic group, specific disturbances were seen on tests of information speed, decision speed, and reward-relevant emotional processing of happy expressions, even after co-varying for symptom severity. Assessments were taken at only one medication-free time point. Reward was investigated using an emotional faces task. Melancholic MDD is distinguished by a specific neurocognitive marker profile consistent with reduced decision-making capacity under time demands and loss of reward sensitivity. This profile suggests an underlying deficit in mesolimbic-cortical circuitry for motivationally-directed behavior. Copyright © 2015 Elsevier B.V. All rights reserved.
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Striatal hyper-sensitivity during stress in remitted individuals with recurrent depression
Admon, Roee; Holsen, Laura M.; Aizley, Harlyn; Remington, Anne; Whitfield-Gabrieli, Susan; Goldstein, Jill M.; Pizzagalli, Diego A.
2014-01-01
Background Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of Major Depressive Disorder (MDD) that may persist following remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward, but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. Methods Thirty three remitted individuals with a history of recurrent MDD (rMDD) and 35 matched healthy controls underwent a validated mild psychological stress task involving viewing of negative stimuli during fMRI. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens (Nacc), and putamen. Psychophysiological interaction (PPI) analyses probed connectivity of those regions with central structures of the neural stress circuitry, the amygdala and hippocampus. Results The task increased cortisol and anxiety levels, although to a greater extent in rMDD than healthy controls. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, Nacc, and putamen activations, as well as increased caudate-amygdala and caudate-hippocampus connectivity. Conclusions Findings highlight striatal hyper-sensitivity in response to a mild psychological stress in rMDD, as manifested by hyper-activation and hyper-connectivity with the amygdala and hippocampus. Striatal hyper-sensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD. PMID:25483401
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A Role for Brain Stress Systems in Addiction
Koob, George F.
2009-01-01
Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry. PMID:18614026
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Savoring the past: Positive memories evoke value representations in the striatum
Speer, Megan E.; Bhanji, Jamil P.; Delgado, Mauricio R.
2014-01-01
Summary Reminders of happy memories can bring back pleasant feelings tied to the original experience, suggesting an intrinsic value in reminiscing about the positive past. However, the neural circuitry underlying the rewarding aspects of autobiographical memory is poorly understood. Using fMRI, we observed enhanced activity during the recall of positive relative to neutral autobiographical memories in corticostriatal circuits that also responded to monetary rewards. Enhanced activity in the striatum and medial prefrontal cortex was associated with increases in positive emotion during recall and striatal engagement further correlated with individual measures of resiliency. Striatal response to the recall of positive memories was greater in individuals whose mood improved after the task. Notably, participants were willing to sacrifice more tangible monetary rewards in order to reminisce about positive past experiences. Our findings suggest that recalling positive autobiographical memories is intrinsically valuable, which may be adaptive for regulating positive emotion and promoting better well-being. PMID:25451197
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Neurochemical and behavioral indices of exercise reward are independent of exercise controllability
Herrera, Jonathan J; Fedynska, Sofiya; Ghasem, Parsa R; Wieman, Tyler; Clark, Peter J; Gray, Nathan; Loetz, Esteban; Campeau, Serge; Fleshner, Monika; Greenwood, Benjamin N
2016-01-01
Brain reward circuits are implicated in stress-related psychiatric disorders. Exercise reduces the incidence of stress-related disorders, but the contribution of exercise reward to stress resistance is unknown. Exercise-induced stress resistance is independent of exercise controllability; both voluntary and forced wheel running protect rats against anxiety- and depression-like behavioral consequences of stress. Voluntary exercise is a natural reward, but whether rats find forced wheel running rewarding is unknown. Moreover, the contribution of dopamine (DA) and striatal reward circuits to exercise reward is not well characterized. Adult, male rats were assigned to locked wheels, voluntary running (VR), or forced running (FR) groups. FR rats were forced to run in a pattern resembling rats' natural wheel running behavior. Both VR and FR increased the reward-related plasticity marker ΔFosB in the dorsal striatum (DS) and nucleus accumbens (NAc), and increased activity of DA neurons in the lateral ventral tegmental area (VTA), as revealed by immunohistochemistry for tyrosine hydroxylase (TH) and pCREB. Both VR and FR rats developed conditioned place preference (CPP) to the side of a CPP chamber paired with exercise. Re-exposure to the exercise-paired side of the CPP chamber elicited conditioned increases in cfos mRNA in direct pathway (dynorphin-positive) neurons in the DS and NAc in both VR and FR rats, and in TH-positive neurons in the lateral VTA of VR rats only. Results suggest that the rewarding effects of exercise are independent of exercise controllability and provide insight into the DA and striatal circuitries involved in exercise reward and exercise-induced stress resistance. PMID:26833814
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Response of neural reward regions to food cues in autism spectrum disorders
2012-01-01
Background One hypothesis for the social deficits that characterize autism spectrum disorders (ASD) is diminished neural reward response to social interaction and attachment. Prior research using established monetary reward paradigms as a test of non-social reward to compare with social reward may involve confounds in the ability of individuals with ASD to utilize symbolic representation of money and the abstraction required to interpret monetary gains. Thus, a useful addition to our understanding of neural reward circuitry in ASD includes a characterization of the neural response to primary rewards. Method We asked 17 children with ASD and 18 children without ASD to abstain from eating for at least four hours before an MRI scan in which they viewed images of high-calorie foods. We assessed the neural reward network for increases in the blood oxygenation level dependent (BOLD) signal in response to the food images Results We found very similar patterns of increased BOLD signal to these images in the two groups; both groups showed increased BOLD signal in the bilateral amygdala, as well as in the nucleus accumbens, orbitofrontal cortex, and insula. Direct group comparisons revealed that the ASD group showed a stronger response to food cues in bilateral insula along the anterior-posterior gradient and in the anterior cingulate cortex than the control group, whereas there were no neural reward regions that showed higher activation for controls than for ASD. Conclusion These results suggest that neural response to primary rewards is not diminished but in fact shows an aberrant enhancement in children with ASD. PMID:22958533
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Siporin, Sheldon
2014-01-01
Maladaptive patterns of substance use are serious social problems. Both pharmacological and nonpharmacological treatments are available, but nondrug options may be preferable because they avoid the expense and adverse side effects of psychotropic medication. Contingency management (CM) and nondrug social and recreational activities (NDSRAs) are based on operant conditioning principles and seek to decrease substance use by means of nondrug rewards. However, their efficacy may be hindered where brain reward circuitry is dysfunctional. Research shows that substance abuse biases neural reward systems in favor of drug-induced highs, while disrupting circadian-based rhythms. Circadian systems also have been found to influence human reward pathways. Possibly, a bidirectional relationship exists between circadian disturbance and substance abuse effects. If so, repair of abnormal circadian rhythms might help normalize reward response in substance abusers, with positive effects on CM or NDSRA treatment outcomes. Phototherapy has been effective in repairing circadian rhythms in persons with seasonal affective disorder and other chronobiological conditions. This article proposes that it similarly may repair circadian response in substance abusers, thereby normalizing brain reward systems. By doing so, it would enhance the efficacy of CM and NDSRA therapies and may also help prevent relapse. Given its low cost and ease of administration, phototherapy seems a promising avenue to pursue.
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Model-based learning and the contribution of the orbitofrontal cortex to the model-free world
McDannald, Michael A.; Takahashi, Yuji K.; Lopatina, Nina; Pietras, Brad W.; Jones, Josh L.; Schoenbaum, Geoffrey
2012-01-01
Learning is proposed to occur when there is a discrepancy between reward prediction and reward receipt. At least two separate systems are thought to exist: one in which predictions are proposed to be based on model-free or cached values; and another in which predictions are model-based. A basic neural circuit for model-free reinforcement learning has already been described. In the model-free circuit the ventral striatum (VS) is thought to supply a common-currency reward prediction to midbrain dopamine neurons that compute prediction errors and drive learning. In a model-based system, predictions can include more information about an expected reward, such as its sensory attributes or current, unique value. This detailed prediction allows for both behavioral flexibility and learning driven by changes in sensory features of rewards alone. Recent evidence from animal learning and human imaging suggests that, in addition to model-free information, the VS also signals model-based information. Further, there is evidence that the orbitofrontal cortex (OFC) signals model-based information. Here we review these data and suggest that the OFC provides model-based information to this traditional model-free circuitry and offer possibilities as to how this interaction might occur. PMID:22487030
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Social and monetary reward processing in autism spectrum disorders
2012-01-01
Background Social motivation theory suggests that deficits in social reward processing underlie social impairments in autism spectrum disorders (ASD). However, the extent to which abnormalities in reward processing generalize to other classes of stimuli remains unresolved. The aim of the current study was to examine if reward processing abnormalities in ASD are specific to social stimuli or can be generalized to other classes of reward. Additionally, we sought to examine the results in the light of behavioral impairments in ASD. Methods Participants performed adapted versions of the social and monetary incentive delay tasks. Data from 21 unmedicated right-handed male participants with ASD and 21 age- and IQ-matched controls were analyzed using a factorial design to examine the blood-oxygen-level-dependent (BOLD) response during the anticipation and receipt of both reward types. Results Behaviorally, the ASD group showed less of a reduction in reaction time (RT) for rewarded compared to unrewarded trials than the control group. In terms of the fMRI results, there were no significant group differences in reward circuitry during reward anticipation. During the receipt of rewards, there was a significant interaction between group and reward type in the left dorsal striatum (DS). The ASD group showed reduced activity in the DS compared to controls for social rewards but not monetary rewards and decreased activation for social rewards compared to monetary rewards. Controls showed no significant difference between the two reward types. Increased activation in the DS during social reward processing was associated with faster response times for rewarded trials, compared to unrewarded trials, in both groups. This is in line with behavioral results indicating that the ASD group showed less of a reduction in RT for rewarded compared to unrewarded trials. Additionally, de-activation to social rewards was associated with increased repetitive behavior in ASD. Conclusions In line with social motivation theory, the ASD group showed reduced activation, compared to controls, during the receipt of social rewards in the DS. Groups did not differ significantly during the processing of monetary rewards. BOLD activation in the DS, during social reward processing, was associated with behavioral impairments in ASD. PMID:23014171
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Social and monetary reward processing in autism spectrum disorders.
Delmonte, Sonja; Balsters, Joshua H; McGrath, Jane; Fitzgerald, Jacqueline; Brennan, Sean; Fagan, Andrew J; Gallagher, Louise
2012-09-26
Social motivation theory suggests that deficits in social reward processing underlie social impairments in autism spectrum disorders (ASD). However, the extent to which abnormalities in reward processing generalize to other classes of stimuli remains unresolved. The aim of the current study was to examine if reward processing abnormalities in ASD are specific to social stimuli or can be generalized to other classes of reward. Additionally, we sought to examine the results in the light of behavioral impairments in ASD. Participants performed adapted versions of the social and monetary incentive delay tasks. Data from 21 unmedicated right-handed male participants with ASD and 21 age- and IQ-matched controls were analyzed using a factorial design to examine the blood-oxygen-level-dependent (BOLD) response during the anticipation and receipt of both reward types. Behaviorally, the ASD group showed less of a reduction in reaction time (RT) for rewarded compared to unrewarded trials than the control group. In terms of the fMRI results, there were no significant group differences in reward circuitry during reward anticipation. During the receipt of rewards, there was a significant interaction between group and reward type in the left dorsal striatum (DS). The ASD group showed reduced activity in the DS compared to controls for social rewards but not monetary rewards and decreased activation for social rewards compared to monetary rewards. Controls showed no significant difference between the two reward types. Increased activation in the DS during social reward processing was associated with faster response times for rewarded trials, compared to unrewarded trials, in both groups. This is in line with behavioral results indicating that the ASD group showed less of a reduction in RT for rewarded compared to unrewarded trials. Additionally, de-activation to social rewards was associated with increased repetitive behavior in ASD. In line with social motivation theory, the ASD group showed reduced activation, compared to controls, during the receipt of social rewards in the DS. Groups did not differ significantly during the processing of monetary rewards. BOLD activation in the DS, during social reward processing, was associated with behavioral impairments in ASD.
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Neural origins of psychosocial functioning impairments in major depression.
Pulcu, Erdem; Elliott, Rebecca
2015-09-01
Major depressive disorder, a complex neuropsychiatric condition, is associated with psychosocial functioning impairments that could become chronic even after symptoms remit. Social functioning impairments in patients could also pose coping difficulties to individuals around them. In this Personal View, we trace the potential neurobiological origins of these impairments down to three candidate domains-namely, social perception and emotion processing, motivation and reward value processing, and social decision making. We argue that the neural basis of abnormalities in these domains could be detectable at different temporal stages during social interactions (eg, before and after decision stages), particularly within frontomesolimbic networks (ie, frontostriatal and amygdala-striatal circuitries). We review some of the experimental designs used to probe these circuits and suggest novel, integrative approaches. We propose that an understanding of the interactions between these domains could provide valuable insights for the clinical stratification of major depressive disorder subtypes and might inform future developments of novel treatment options in return. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Ochoa, Melissa; Malbert, Charles-Henri; Meurice, Paul; Val-Laillet, David
2016-01-01
Excessive sugar intake might increase the risk to develop eating disorders via an altered reward circuitry, but it remains unknown whether different sugar sources induce different neural effects and whether these effects are dependent from body weight. Therefore, we compared the effects of three high-fat and isocaloric diets varying only in their carbohydrate sources on brain activity of reward-related regions, and assessed whether brain activity is dependent on insulin sensitivity. Twenty-four minipigs underwent 18FDG PET brain imaging following 7-month intake of high-fat diets of which 20% in dry matter weight (36.3% of metabolisable energy) was provided by starch, glucose or fructose (n = 8 per diet). Animals were then subjected to a euglycemic hyperinsulinemic clamp to determine peripheral insulin sensitivity. After a 7-month diet treatment, all groups had substantial increases in body weight (from 36.02±0.85 to 63.33±0.81 kg; P<0.0001), regardless of the diet. All groups presented similar insulin sensitivity index (ISI = 1.39±0.10 mL·min-1·μUI·kg). Compared to starch, chronic exposure to fructose and glucose induced bilateral brain activations, i.e. increased basal cerebral glucose metabolism, in several reward-related brain regions including the anterior and dorsolateral prefrontal cortex, the orbitofrontal cortex, the anterior cingulate cortex, the caudate and putamen. The lack of differences in insulin sensitivity index and body weight suggests that the observed differences in basal brain glucose metabolism are not related to differences in peripheral insulin sensitivity and weight gain. The differences in basal brain metabolism in reward-related brain areas suggest the onset of cerebral functional alterations induced by chronic consumption of dietary sugars. Further studies should explore the underlying mechanisms, such as the availability of intestinal and brain sugar transporter, or the appearance of addictive-like behavioral correlates of these brain functional characteristics.
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Wyk, Brent C. Vander; Eilbott, Jeffrey A.; McCauley, Spencer A.; Ibrahim, Karim; Crowley, Michael J.; Pelphrey, Kevin A.
2016-01-01
Abstract Objective: We present the rationale and design of a randomized controlled trial of cognitive-behavioral therapy (CBT) for aggression in children and adolescents, which is conducted in response to the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) approach initiative. Specifically, the study is focused on the brain-behavior associations within the RDoC construct of frustrative non-reward. On the behavioral level, this construct is defined by reactions elicited in response to withdrawal or prevention of reward, most notably reactive aggression. This study is designed to test the functional magnetic resonance (fMRI) and electrophysiological (EEG) correlates of aggression and its reduction after CBT. Methods: Eighty children and adolescents with high levels of aggression across multiple traditional diagnostic categories, ages 8–16, will be randomly assigned to receive 12 sessions of CBT or 12 sessions of supportive psychotherapy. Clinical outcomes will be measured by the ratings of aggressive behavior collected at baseline, midpoint, and endpoint evaluations, and by the Improvement Score of the Clinical Global Impressions Scale assigned by an independent evaluator (blinded rater). Subjects will also perform a frustration-induction Go-NoGo task and a task of emotional face perception during fMRI scanning and EEG recording at baseline and endpoint. Results: Consistent with the NIMH strategic research priorities, if functional neuroimaging and EEG variables can identify subjects who respond to CBT for aggression, this can provide a neuroscience-based classification scheme that will improve treatment outcomes for children and adolescents with aggressive behavior. Conclusions: Demonstrating that a change in the key nodes of the emotion regulation circuitry is associated with a reduction of reactive aggression will provide evidence to support the validity of the frustrative non-reward construct. PMID:26784537
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Neural systems and hormones mediating attraction to infant and child faces
Luo, Lizhu; Ma, Xiaole; Zheng, Xiaoxiao; Zhao, Weihua; Xu, Lei; Becker, Benjamin; Kendrick, Keith M.
2015-01-01
We find infant faces highly attractive as a result of specific features which Konrad Lorenz termed “Kindchenschema” or “baby schema,” and this is considered to be an important adaptive trait for promoting protective and caregiving behaviors in adults, thereby increasing the chances of infant survival. This review first examines the behavioral support for this effect and physical and behavioral factors which can influence it. It then provides details of the increasing number of neuroimaging and electrophysiological studies investigating the neural circuitry underlying this baby schema effect in parents and non-parents of both sexes. Next it considers potential hormonal contributions to the baby schema effect in both sexes and the neural effects associated with reduced responses to infant cues in post-partum depression, anxiety and drug taking. Overall the findings reviewed reveal a very extensive neural circuitry involved in our perception of cuteness in infant faces, with enhanced activation compared to adult faces being found in brain regions involved in face perception, attention, emotion, empathy, memory, reward and attachment, theory of mind and also control of motor responses. Both mothers and fathers also show evidence for enhanced responses in these same neural systems when viewing their own as opposed to another child. Furthermore, responses to infant cues in many of these neural systems are reduced in mothers with post-partum depression or anxiety or have taken addictive drugs throughout pregnancy. In general reproductively active women tend to rate infant faces as cuter than men, which may reflect both heightened attention to relevant cues and a stronger activation in their brain reward circuitry. Perception of infant cuteness may also be influenced by reproductive hormones with the hypothalamic neuropeptide oxytocin being most strongly associated to date with increased attention and attraction to infant cues in both sexes. PMID:26236256
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Neural systems and hormones mediating attraction to infant and child faces.
Luo, Lizhu; Ma, Xiaole; Zheng, Xiaoxiao; Zhao, Weihua; Xu, Lei; Becker, Benjamin; Kendrick, Keith M
2015-01-01
We find infant faces highly attractive as a result of specific features which Konrad Lorenz termed "Kindchenschema" or "baby schema," and this is considered to be an important adaptive trait for promoting protective and caregiving behaviors in adults, thereby increasing the chances of infant survival. This review first examines the behavioral support for this effect and physical and behavioral factors which can influence it. It then provides details of the increasing number of neuroimaging and electrophysiological studies investigating the neural circuitry underlying this baby schema effect in parents and non-parents of both sexes. Next it considers potential hormonal contributions to the baby schema effect in both sexes and the neural effects associated with reduced responses to infant cues in post-partum depression, anxiety and drug taking. Overall the findings reviewed reveal a very extensive neural circuitry involved in our perception of cuteness in infant faces, with enhanced activation compared to adult faces being found in brain regions involved in face perception, attention, emotion, empathy, memory, reward and attachment, theory of mind and also control of motor responses. Both mothers and fathers also show evidence for enhanced responses in these same neural systems when viewing their own as opposed to another child. Furthermore, responses to infant cues in many of these neural systems are reduced in mothers with post-partum depression or anxiety or have taken addictive drugs throughout pregnancy. In general reproductively active women tend to rate infant faces as cuter than men, which may reflect both heightened attention to relevant cues and a stronger activation in their brain reward circuitry. Perception of infant cuteness may also be influenced by reproductive hormones with the hypothalamic neuropeptide oxytocin being most strongly associated to date with increased attention and attraction to infant cues in both sexes.
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(1)H-magnetic resonance spectroscopy in social anxiety disorder.
Howells, Fleur M; Hattingh, Coenraad J; Syal, Supriya; Breet, Elsie; Stein, Dan J; Lochner, Christine
2015-04-03
Social anxiety disorder (SAD) is characterized by excessive anxiety about social interaction or performance situations, leading to avoidance and clinically significant distress. A growing literature on the neurobiology of SAD has suggested that the reward/avoidance basal ganglia circuitry in general and the glutamatergic system in particular may play a role. In the current study, we investigated (1)H-magnetic resonance spectroscopy ((1)H-MRS) concentrations in cortical, striatal, and thalamic circuitry, as well as their associations with measures of social anxiety and related symptoms, in patients with primary SAD. Eighteen adult individuals with SAD and 19 age- and sex- matched controls participated in this study. (1)H-MRS was used to determine relative metabolite concentrations in the anterior cingulate cortex (ACC) using single voxel spectroscopy (reporting relative N-acetyl-aspartate (NAA), N-acetyl-aspartate with N-acetyl-aspartyl-glutamate (NAA+NAAG), glycerophosphocholine with phosphocholine (GPC+PCh), myo-inositol, glutamate (Glu), and glutamate with its precursor glutamine (Glu+Gln)), and the caudate, putamen and thalami bilaterally using two dimensional chemical shift imaging (reporting relative NAA+NAAG and GPC+PCh). Relationships between metabolite concentrations and measures of social anxiety and related symptoms were also determined. Measures of social anxiety included symptom severity, blushing propensity, and gaze anxiety/avoidance. We found, first, decreased relative glutamate concentration in the ACC of SAD and changes in myo-inositol with measures of social anxiety. Second, NAA metabolite concentration was increased in thalamus of SAD, and choline metabolite concentrations were related to measures of social anxiety. Lastly, choline metabolite concentration in the caudate and putamen showed changes in relation to measures of social anxiety. These findings are consistent with evidence that the reward/avoidance basal ganglia circuitry, as well as the glutamatergic system, play a role in mediating SAD symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.
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An Anatomical Basis for Opponent Process Mechanisms of Opiate Withdrawal
Radke, Anna K.; Rothwell, Patrick E.; Gewirtz, Jonathan C.
2011-01-01
Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal. PMID:21593338
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Torres-Altoro, Melissa I.; Mathur, Brian N.; Drerup, Justin M.; Thomas, Rachel; Lovinger, David; O’Callaghan, James P.; Bibb, James A.
2011-01-01
The neurological effects of organophosphate pesticides, commonly used on foods and in households, are an important public health concern. Furthermore, subclinical exposure to combinations of organophosphates is implicated in Gulf War illness. Here we characterized the effects of the broadly-used insecticide chlorpyrifos on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. Chlorpyrifos potentiated PKA-dependent phosphorylation of the striatal protein DARPP-32 and the GluR1 subunit of AMPA receptors in mouse brain slices. It also increased GluR1 phosphorylation by PKA when administered systemically. This correlated with enhanced glutamate release from cortical projections in rat striatum. Similar effects were induced by the sarin congener, diisopropyl fluorophosphate, alone or in combination with the putative neuroprotectant, pyridostigmine bromide and the pesticide DEET. This combination, meant to mimic the neurotoxicant exposure encountered by veterans of the 1991 Persian Gulf War, also induced hyperphosphorylation of the neurofibrillary tangle-associated protein tau. Diisopropyl fluorophosphate and pyrodostigmine bromide, alone or in combination, also increased the aberrant activity of the protein kinase, Cdk5, as indicated by conversion of its activating cofactor p35 to p25. Thus consistent with recent findings in humans and animals, organophosphate exposure causes dysregulation in the motor/reward circuitry and invokes mechanisms associated with neurological disorders and neurodegeneration. PMID:21848865
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Howe, William M; Tierney, Patrick L; Young, Damon A; Oomen, Charlotte; Kozak, Rouba
2015-11-01
Gestational day 17 methylazoxymethanol (MAM) treatment has been shown to reproduce, in rodents, some of the alterations in cortical and mesolimbic circuitries thought to contribute to schizophrenia. We characterized the behavior of MAM animals in tasks dependent on these circuitries to see what behavioral aspects of schizophrenia the model captures. We then characterized the integrity of mesolimbic dopamine neurotransmission in a subset of animals used in the behavioral experiments. MAM animals' capacity for working memory, attention, and resilience to distraction was tested with two different paradigms. Cue-reward learning and motivation were assayed with Pavlovian conditioned approach. Measurements of electrically stimulated phasic and tonic DA release in the nucleus accumbens with fast-scan cyclic voltammetry were obtained from the same animals used in the Pavlovian task. MAM animals' basic attentional capacities were intact. MAM animals took longer to acquire the working memory task, but once learned, performed at the same level as shams. MAM animals were also slower to develop a Pavlovian conditioned response, but otherwise no different from controls. These same animals showed alterations in terminal DA release that were unmasked by an amphetamine challenge. The predominant behavioral-cognitive feature of the MAM model is a learning impairment that is evident in acquisition of executive function tasks as well as basic Pavlovian associations. MAM animals also have dysregulated terminal DA release, and this may contribute to observed behavioral differences. The MAM model captures some functional impairments of schizophrenia, particularly those related to acquisition of goal-directed behavior.
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Neural processes underlying cultural differences in cognitive persistence.
Telzer, Eva H; Qu, Yang; Lin, Lynda C
2017-08-01
Self-improvement motivation, which occurs when individuals seek to improve upon their competence by gaining new knowledge and improving upon their skills, is critical for cognitive, social, and educational adjustment. While many studies have delineated the neural mechanisms supporting extrinsic motivation induced by monetary rewards, less work has examined the neural processes that support intrinsically motivated behaviors, such as self-improvement motivation. Because cultural groups traditionally vary in terms of their self-improvement motivation, we examined cultural differences in the behavioral and neural processes underlying motivated behaviors during cognitive persistence in the absence of extrinsic rewards. In Study 1, 71 American (47 females, M=19.68 years) and 68 Chinese (38 females, M=19.37 years) students completed a behavioral cognitive control task that required cognitive persistence across time. In Study 2, 14 American and 15 Chinese students completed the same cognitive persistence task during an fMRI scan. Across both studies, American students showed significant declines in cognitive performance across time, whereas Chinese participants demonstrated effective cognitive persistence. These behavioral effects were explained by cultural differences in self-improvement motivation and paralleled by increasing activation and functional coupling between the inferior frontal gyrus (IFG) and ventral striatum (VS) across the task among Chinese participants, neural activation and coupling that remained low in American participants. These findings suggest a potential neural mechanism by which the VS and IFG work in concert to promote cognitive persistence in the absence of extrinsic rewards. Thus, frontostriatal circuitry may be a neurobiological signal representing intrinsic motivation for self-improvement that serves an adaptive function, increasing Chinese students' motivation to engage in cognitive persistence. Copyright © 2017 Elsevier Inc. All rights reserved.
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Gass, Natalia; Becker, Robert; Sack, Markus; Schwarz, Adam J; Reinwald, Jonathan; Cosa-Linan, Alejandro; Zheng, Lei; von Hohenberg, Christian Clemm; Inta, Dragos; Meyer-Lindenberg, Andreas; Weber-Fahr, Wolfgang; Gass, Peter; Sartorius, Alexander
2018-04-01
Evidence indicates that ketamine's rapid antidepressant efficacy likely results from its antagonism of NR2B-subunit-containing NMDA receptors (NMDAR). Since ketamine equally blocks NR2A- and NR2B-containing NMDAR, and has affinity to other receptors, NR2B-selective drugs might have improved therapeutic efficiency and side effect profile. We aimed to compare the effects of (S)-ketamine and two different types of NR2B-selective antagonists on functional brain networks in rats, in order to find common circuits, where their effects intersect, and that might explain their antidepressant action. The experimental design comprised four parallel groups of rats (N = 37), each receiving (S)-Ketamine, CP-101,606, Ro 25-6981 or saline. After compound injection, we acquired resting-state functional magnetic resonance imaging time series. We used graph theoretical approach to calculate brain network properties. Ketamine and CP-101,606 diminished the global clustering coefficient and small-worldness index. At the nodal level, all compounds induced increased connectivity of the regions mediating reward and cognitive aspects of emotional processing, such as ventromedial prefrontal cortex, septal nuclei, and nucleus accumbens. The dorsal hippocampus and regions involved in sensory processing and aversion, such as superior and inferior colliculi, exhibited an opposite effect. The effects common to ketamine and NR2B-selective compounds were localized to the same brain regions as those reported in depression, but in the opposite direction. The upregulation of the reward circuitry might partially underlie the antidepressant and anti-anhedonic effects of the antagonists and could potentially serve as a translational imaging phenotype for testing putative antidepressants, especially those targeting the NR2B receptor subtype.
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Smith-Anttila, Casey J.A.; Nordenankar, Karin; Arvidsson, Emma; Mahmoudi, Souha; Zampera, André; Wärner Jonsson, Hanna; Bergquist, Jonas; Lévesque, Daniel; Andersson, Malin; Dumas, Sylvie
2016-01-01
The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson’s disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system. PMID:27699212
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Schweizer, Nadine; Viereckel, Thomas; Smith-Anttila, Casey J A; Nordenankar, Karin; Arvidsson, Emma; Mahmoudi, Souha; Zampera, André; Wärner Jonsson, Hanna; Bergquist, Jonas; Lévesque, Daniel; Konradsson-Geuken, Åsa; Andersson, Malin; Dumas, Sylvie; Wallén-Mackenzie, Åsa
2016-01-01
The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene ( Vglut2/Slc17a6 ) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system.
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McLaughlin, Thomas; Blum, Kenneth; Oscar-Berman, Marlene; Febo, Marcelo; Agan, Gozde; Fratantonio, James L; Simpatico, Thomas; Gold, Mark S
2015-06-01
Lucid dreams are frequently pleasant and training techniques have been developed to teach dreamers to induce them. In addition, the induction of lucid dreams has also been used as a way to ameliorate nightmares. On the other hand, lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. In the latter conditions, lucid dreams can assume an unpleasant and frequently terrifying character. We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. In the first case study, a 51-year-old, obese woman, diagnosed with PTSD and depression, had attempted suicide and experienced terrifying lucid nightmares linked to sexual/physical abuse from early childhood by family members including her alcoholic father. Her vivid "bad dreams" remained refractory in spite of 6 months of treatment with Dialectical Behavioral Therapy (DBT) and standard pharmaceutical agents which included prazosin, clonidie and Adderall. The second 39-year-old PTSD woman patient had also suffered from lucid nightmares. The medication visit notes reveal changes in the frequency, intensity and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient's regimen. The patient reported her first experience of an extended period of happy dreams. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter. These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies.
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Larkin, Joshua D; Jenni, Nicole L; Floresco, Stan B
2016-01-01
Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown. We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task. Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 μg) or D2 (eticlopride, 0.1-1 μg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 μg) and D2 (quinpirole, 1-10 μg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice. BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior. These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.
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Sripada, Chandra; Angstadt, Michael; Liberzon, Israel; McCabe, Kevin; Phan, K Luan
2013-04-01
Generalized social anxiety disorder (GSAD) is characterized by excessive fear of public scrutiny and reticence in social engagement. Previous studies have probed the neural basis of GSAD often using static, noninteractive stimuli (e.g., face photographs) and have identified dysfunction in fear circuitry. We sought to investigate brain-based dysfunction in GSAD during more real-world, dynamic social interactions, focusing on the role of reward-related regions that are implicated in social decision-making. Thirty-six healthy individuals (healthy control [HC]) and 36 individuals with GSAD underwent functional magnetic resonance imaging (fMRI) scanning while participating in a behavioral economic game ("Trust Game") involving iterative exchanges with fictive partners who acquire differential reputations for reciprocity. We investigated brain responses to reciprocation of trust in one's social partner, and how these brain responses are modulated by partner reputation for repayment. In both HC and GSAD, receipt of reciprocity robustly engaged ventral striatum, a region implicated in reward. In HC, striatal responses to reciprocity were specific to partners who have consistently returned the investment ("cooperative partners"), and were absent for partners who lack a cooperative reputation. In GSAD, modulation of striatal responses by partner reputation was absent. Social anxiety severity predicted diminished responses to cooperative partners. These results suggest abnormalities in GSAD in reward-related striatal mechanisms that may be important for the initiation, valuation, and maintenance of cooperative social relationships. Moreover, this study demonstrates that dynamic, interactive task paradigms derived from economics can help illuminate novel mechanisms of pathology in psychiatric illnesses in which social dysfunction is a cardinal feature. © 2013 Wiley Periodicals, Inc.
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Neuroimaging and Drug Taking in Primates Abbreviated title: Neuroimaging and Drug taking
Murnane, Kevin S.; Howell, Leonard L.
2011-01-01
Rationale Neuroimaging techniques have led to significant advances in our understanding of the neurobiology of drug-taking and the treatment of drug addiction in humans. Neuroimaging approaches provide a powerful translational approach that can link findings from humans and laboratory animals. Objective This review describes the utility of neuroimaging toward understanding the neurobiological basis of drug taking, and documents the close concordance that can be achieved among neuroimaging, neurochemical and behavioral endpoints. Results The study of drug interactions with dopamine and serotonin transporters in vivo has identified pharmacological mechanisms of action associated with the abuse liability of stimulants. Neuroimaging has identified the extended limbic system, including the prefrontal cortex and anterior cingulate, as important neuronal circuitry that underlies drug taking. The ability to conduct within-subject, longitudinal assessments of brain chemistry and neuronal function has enhanced our efforts to document long-term changes in dopamine D2 receptors, monoamine transporters, and prefrontal metabolism due to chronic drug exposure. Dysregulation of dopamine function and brain metabolic changes in areas involved in reward circuitry have been linked to drug-taking behavior, cognitive impairment and treatment response. Conclusions Experimental designs employing neuroimaging should consider well-documented determinants of drug taking, including pharmacokinetic considerations, subject history and environmental variables. Methodological issues to consider include limited molecular probes, lack of neurochemical specificity in brain activation studies, and the potential influence of anesthetics in animal studies. Nevertheless, these integrative approaches should have important implications for understanding drug-taking behavior and the treatment of drug addiction. PMID:21360099
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de Almeida, Jorge Renner Cardoso; Phillips, Mary Louise
2012-01-01
Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a “call to action” to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at risk individuals, and more novel neuroimaging approaches, such as, connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD, and biological targets for more personalized treatment and new treatment developments for BD and UD depression. PMID:22784485
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Fervaha, Gagan; Graff-Guerrero, Ariel; Zakzanis, Konstantine K; Foussias, George; Agid, Ofer; Remington, Gary
2013-11-01
Motivational impairments are a core feature of schizophrenia and although there are numerous reports studying this feature using clinical rating scales, objective behavioural assessments are lacking. Here, we use a translational paradigm to measure incentive motivation in individuals with schizophrenia. Sixteen stable outpatients with schizophrenia and sixteen matched healthy controls completed a modified version of the Effort Expenditure for Rewards Task that accounts for differences in motoric ability. Briefly, subjects were presented with a series of trials where they may choose to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Additionally, the probability of receiving money for a given trial was varied at 12%, 50% and 88%. Clinical and other reward-related variables were also evaluated. Patients opted to expend greater effort significantly less than controls for trials of high, but uncertain (i.e. 50% and 88% probability) incentive value, which was related to amotivation and neurocognitive deficits. Other abnormalities were also noted but were related to different clinical variables such as impulsivity (low reward and 12% probability). These motivational deficits were not due to group differences in reward learning, reward valuation or hedonic capacity. Our findings offer novel support for incentive motivation deficits in schizophrenia. Clinical amotivation is associated with impairments in the computation of effort during cost-benefit decision-making. This objective translational paradigm may guide future investigations of the neural circuitry underlying these motivational impairments. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Basolateral Amygdala to Orbitofrontal Cortex Projections Enable Cue-Triggered Reward Expectations.
Lichtenberg, Nina T; Pennington, Zachary T; Holley, Sandra M; Greenfield, Venuz Y; Cepeda, Carlos; Levine, Michael S; Wassum, Kate M
2017-08-30
To make an appropriate decision, one must anticipate potential future rewarding events, even when they are not readily observable. These expectations are generated by using observable information (e.g., stimuli or available actions) to retrieve often quite detailed memories of available rewards. The basolateral amygdala (BLA) and orbitofrontal cortex (OFC) are two reciprocally connected key nodes in the circuitry supporting such outcome-guided behaviors. But there is much unknown about the contribution of this circuit to decision making, and almost nothing known about the whether any contribution is via direct, monosynaptic projections, or the direction of information transfer. Therefore, here we used designer receptor-mediated inactivation of OFC→BLA or BLA→OFC projections to evaluate their respective contributions to outcome-guided behaviors in rats. Inactivation of BLA terminals in the OFC, but not OFC terminals in the BLA, disrupted the selective motivating influence of cue-triggered reward representations over reward-seeking decisions as assayed by Pavlovian-to-instrumental transfer. BLA→OFC projections were also required when a cued reward representation was used to modify Pavlovian conditional goal-approach responses according to the reward's current value. These projections were not necessary when actions were guided by reward expectations generated based on learned action-reward contingencies, or when rewards themselves, rather than stored memories, directed action. These data demonstrate that BLA→OFC projections enable the cue-triggered reward expectations that can motivate the execution of specific action plans and allow adaptive conditional responding. SIGNIFICANCE STATEMENT Deficits anticipating potential future rewarding events are associated with many psychiatric diseases. Presently, we know little about the neural circuits supporting such reward expectation. Here we show that basolateral amygdala to orbitofrontal cortex projections are required for expectations of specific available rewards to influence reward seeking and decision making. The necessity of these projections was limited to situations in which expectations were elicited by reward-predictive cues. These projections therefore facilitate adaptive behavior by enabling the orbitofrontal cortex to use environmental stimuli to generate expectations of potential future rewarding events. Copyright © 2017 the authors 0270-6474/17/378374-11$15.00/0.
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Basolateral Amygdala to Orbitofrontal Cortex Projections Enable Cue-Triggered Reward Expectations
Lichtenberg, Nina T.; Pennington, Zachary T.; Holley, Sandra M.; Greenfield, Venuz Y.; Levine, Michael S.
2017-01-01
To make an appropriate decision, one must anticipate potential future rewarding events, even when they are not readily observable. These expectations are generated by using observable information (e.g., stimuli or available actions) to retrieve often quite detailed memories of available rewards. The basolateral amygdala (BLA) and orbitofrontal cortex (OFC) are two reciprocally connected key nodes in the circuitry supporting such outcome-guided behaviors. But there is much unknown about the contribution of this circuit to decision making, and almost nothing known about the whether any contribution is via direct, monosynaptic projections, or the direction of information transfer. Therefore, here we used designer receptor-mediated inactivation of OFC→BLA or BLA→OFC projections to evaluate their respective contributions to outcome-guided behaviors in rats. Inactivation of BLA terminals in the OFC, but not OFC terminals in the BLA, disrupted the selective motivating influence of cue-triggered reward representations over reward-seeking decisions as assayed by Pavlovian-to-instrumental transfer. BLA→OFC projections were also required when a cued reward representation was used to modify Pavlovian conditional goal-approach responses according to the reward's current value. These projections were not necessary when actions were guided by reward expectations generated based on learned action-reward contingencies, or when rewards themselves, rather than stored memories, directed action. These data demonstrate that BLA→OFC projections enable the cue-triggered reward expectations that can motivate the execution of specific action plans and allow adaptive conditional responding. SIGNIFICANCE STATEMENT Deficits anticipating potential future rewarding events are associated with many psychiatric diseases. Presently, we know little about the neural circuits supporting such reward expectation. Here we show that basolateral amygdala to orbitofrontal cortex projections are required for expectations of specific available rewards to influence reward seeking and decision making. The necessity of these projections was limited to situations in which expectations were elicited by reward-predictive cues. These projections therefore facilitate adaptive behavior by enabling the orbitofrontal cortex to use environmental stimuli to generate expectations of potential future rewarding events. PMID:28743727
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Optogenetic Activation of a Lateral Hypothalamic-Ventral Tegmental Drive-Reward Pathway.
Gigante, Eduardo D; Benaliouad, Faiza; Zamora-Olivencia, Veronica; Wise, Roy A
2016-01-01
Electrical stimulation of the lateral hypothalamus can motivate feeding or can serve as a reward in its own right. It remains unclear whether the same or independent but anatomically overlapping circuitries mediate the two effects. Electrical stimulation findings implicate medial forebrain bundle (MFB) fibers of passage in both effects, and optogenetic studies confirm a contribution from fibers originating in the lateral hypothalamic area and projecting to or through the ventral tegmental area. Here we report that optogenetic activation of ventral tegmental fibers from cells of origin in more anterior or posterior portions of the MFB failed to induce either reward or feeding. The feeding and reward induced by optogenetic activation of fibers from the lateral hypothalamic cells of origin were influenced similarly by variations in stimulation pulse width and pulse frequency, consistent with the hypothesis of a common substrate for the two effects. There were, however, several cases where feeding but not self-stimulation or self-stimulation but not feeding were induced, consistent with the hypothesis that distinct but anatomically overlapping systems mediate the two effects. Thus while optogenetic stimulation provides a more selective tool for characterizing the mechanisms of stimulation-induced feeding and reward, it does not yet resolve the question of common or independent substrates.
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Neural correlates of water reward in thirsty Drosophila
Lin, Suewei; Owald, David; Chandra, Vikram; Talbot, Clifford; Huetteroth, Wolf; Waddell, Scott
2014-01-01
Drinking water is innately rewarding to thirsty animals. In addition, the consumed value can be assigned to behavioral actions and predictive sensory cues by associative learning. Here we show that thirst converts water avoidance into water-seeking in naïve Drosophila. Thirst also permits flies to learn olfactory cues paired with water reward. Water learning requires water taste and <40 water-responsive dopaminergic neurons that innervate a restricted zone of the mushroom body γ lobe. These water learning neurons are different from those that are critical to convey the reinforcing effects of sugar. Naïve water-seeking behavior in thirsty flies does not require water taste but relies on another subset of water-responsive dopaminergic neurons that target the mushroom body β′ lobe. Furthermore, these naïve water-approach neurons are not required for learned water-seeking. Our results therefore demonstrate that naïve and learned water-seeking, and water learning, utilize separable neural circuitry in the brain of thirsty flies. PMID:25262493
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Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.
Nestor, Liam; Hester, Robert; Garavan, Hugh
2010-01-01
Despite an increased understanding of the pharmacology and long-term cognitive effects of cannabis in humans, there has been no research to date examining its chronic effects upon reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The reward deficiency syndrome (RDS) of addiction posits that there are deficits in dopamine (DA) motivational circuitry for non-drug rewards, such that only drugs of abuse are capable of normalizing DA in the ventral striatum (VS). Alternatively, the opponent process theory (OPT) holds that in individuals prone to drug use, there exists some form of mesolimbic hyperactivity, in which there is a bias towards reward-centred behaviour concomitant with impulsivity. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naive controls during a monetary incentive delay (MID) task. Despite no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. We also observed a number of group differences following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards.
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Samaha, Anne-Noël
2013-01-01
Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain’s dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. PMID:22927669
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Receptor-specific modulation of risk-based decision making by nucleus accumbens dopamine.
Stopper, Colin M; Khayambashi, Shahin; Floresco, Stan B
2013-04-01
The nucleus accumbens (NAc) serves as an integral node within cortico-limbic circuitry that regulates various forms of cost-benefit decision making. The dopamine (DA) system has also been implicated in enabling organisms to overcome a variety of costs to obtain more valuable rewards. However, it remains unclear how DA activity within the NAc may regulate decision making involving reward uncertainty. This study investigated the contribution of different DA receptor subtypes in the NAc to risk-based decision making, assessed with a probabilistic discounting task. In well-trained rats, D1 receptor blockade with SCH 23,390 decreased preference for larger, uncertain rewards, which was associated with enhanced negative-feedback sensitivity (ie, an increased tendency to select a smaller/certain option after an unrewarded risky choice). Treatment with a D1 agonist (SKF 81,297) optimized decision making, increasing choice of the risky option when reward probability was high, and decreasing preference under low probability conditions. In stark contrast, neither blockade of NAc D2 receptors with eticlopride, nor stimulation of these receptors with quinpirole or bromocriptine influenced risky choice. In comparison, infusion of the D3-preferring agonist PD 128,907 decreased reward sensitivity and risky choice. Collectively, these results show that mesoaccumbens DA refines risk-reward decision biases via dissociable mechanisms recruiting D1 and D3, but not D2 receptors. D1 receptor activity mitigates the effect of reward omissions on subsequent choices to promote selection of reward options that may have greater long-term utility, whereas excessive D3 receptor activity blunts the impact that larger/uncertain rewards have in promoting riskier choices.
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Role of the limbic system in dependence on drugs.
Rodríguez de Fonseca, F; Navarro, M
1998-08-01
The limbic system is a group of structurally and functionally related areas of the brain that provides the anatomical substrate for emotions and motivated behaviour, including the circuitry for the stress response and reward-related events. This system is strongly implicated in drug abuse from the pleasure and/or positive side associated with acute exposure to the dysphoria and craving associated with withdrawal. The contribution of the main cortical and subcortical elements of the limbic system to drug dependence is briefly reviewed in the present work with a focus on the role of the extended amygdala and its connections as well as on the peripheral feedback signals mediated by adrenal glucocorticoids. The elucidation of the neuroadaptive responses of the limbic system to chronic drug exposure will undoubtedly help to design rational strategies for the treatment of addiction.
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Forebrain networks and the control of feeding by environmental learned cues
Petrovich, Gorica D.
2013-01-01
The motivation to eat is driven by a complex sum of physiological and non-physiological influences computed by the brain. Physiological signals that inform the brain about energy and nutrient needs are the primary drivers, but environmental signals unrelated to energy balance also control appetite and eating. The two components could act in concert to support the homeostatic regulation of food intake. Often, however, environmental influences rival physiological control and stimulate eating irrespective of satiety, or inhibit eating irrespective of hunger. If persistent, such maladaptive challenges to the physiological system could lead to dysregulated eating and ultimately to eating disorders. Nevertheless, the brain mechanisms underlying environmental contribution in the control of food intake are poorly understood. This paper provides an overview in recent advances in deciphering the critical brain systems using rodent models for environmental control by learned cues. These models use associative learning to compete with the physiological control, and in one preparation food cues stimulate a meal despite satiety, while in another preparation fear cues stop a meal despite hunger. Thus far, four forebrain regions have been identified as part of the essential cue induced feeding circuitry. These are telencephalic areas critical for associative learning, memory encoding, and decision making, the amygdala, hippocampus and prefrontal cortex and the lateral hypothalamus, which functions to integrate feeding, reward, and motivation. This circuitry also engages two orexigenic peptides, ghrelin and orexin. A parallel amygdalar circuitry supports fear cue cessation of feeding. These findings illuminate the brain mechanisms underlying environmental control of food intake and might be also relevant to aspects of human appetite and maladaptive overeating and undereating. PMID:23562305
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Guastella, Adam J; Hickie, Ian B
2016-02-01
Observed impairment in reciprocal social interaction is a diagnostic hallmark of autism spectrum disorders. There is no effective medical treatment for these problems. Psychological treatments remain costly, time intensive, and developmentally sensitive for efficacy. In this review, we explore the potential of oxytocin-based therapies for social impairments in autism. Evidence shows that acute oxytocin administration improves numerous markers critical to the social circuitry underlying social deficits in autism. Oxytocin may optimize these circuits and enhance reward, motivation, and learning to improve therapeutic outcomes. Despite this, the current evidence of therapeutic benefit from extended oxytocin treatment remains very limited. We highlight complexity in crossing from the laboratory to the autism clinical setting in evaluation of this therapeutic. We discuss a clinical trial approach that provides optimal opportunity for therapeutic response by using personalized methods that better target specific circuitry to define who will obtain benefit, at what stage of development, and the optimal delivery approach for circuitry manipulation. For the autism field, the therapeutic challenges will be resolved by a range of treatment strategies, including greater focus on specific interventions, such as oxytocin, that have a strong basis in the fundamental neurobiology of social behavior. More sophisticated and targeted clinical trials utilizing such approaches are now required, placing oxytocin into the autism context. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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Clop, Alex; Sharaf, Abdoallah; Castelló, Anna; Ramos-Onsins, Sebastián; Cirera, Susanna; Mercadé, Anna; Derdak, Sophia; Beltran, Sergi; Huisman, Abe; Fredholm, Merete; van As, Pieter; Sánchez, Armand
2016-08-26
Taste receptors (TASRs) are essential for the body's recognition of chemical compounds. In the tongue, TASRs sense the sweet and umami and the toxin-related bitter taste thus promoting a particular eating behaviour. Moreover, their relevance in other organs is now becoming evident. In the intestine, they regulate nutrient absorption and gut motility. Upon ligand binding, TASRs activate the appetite-reward circuitry to signal the nervous system and keep body homeostasis. With the aim to identify genetic variation in the swine TASRs and in the genes from the appetite and the reward pathways, we have sequenced the exons of 201 TASRs and appetite-reward genes from 304 pigs belonging to ten breeds, wild boars and to two phenotypically extreme groups from a F2 resource with data on growth and fat deposition. We identified 2,766 coding variants 395 of which were predicted to have a strong impact on protein sequence and function. 334 variants were present in only one breed and at predicted alternative allele frequency (pAAF) ≥ 0.1. The Asian pigs and the wild boars showed the largest proportion of breed specific variants. We also compared the pAAF of the two F2 groups and found that variants in TAS2R39 and CD36 display significant differences suggesting that these genes could influence growth and fat deposition. We developed a 128-variant genotyping assay and confirmed 57 of these variants. We have identified thousands of variants affecting TASRs as well as genes involved in the appetite and the reward mechanisms. Some of these genes have been already associated to taste preferences, appetite or behaviour in humans and mouse. We have also detected indications of a potential relationship of some of these genes with growth and fat deposition, which could have been caused by changes in taste preferences, appetite or reward and ultimately impact on food intake. A genotyping array with 57 variants in 31 of these genes is now available for genotyping and start elucidating the impact of genetic variation in these genes on pig biology and breeding.
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Reward-dependent learning in neuronal networks for planning and decision making.
Dehaene, S; Changeux, J P
2000-01-01
Neuronal network models have been proposed for the organization of evaluation and decision processes in prefrontal circuitry and their putative neuronal and molecular bases. The models all include an implementation and simulation of an elementary reward mechanism. Their central hypothesis is that tentative rules of behavior, which are coded by clusters of active neurons in prefrontal cortex, are selected or rejected based on an evaluation by this reward signal, which may be conveyed, for instance, by the mesencephalic dopaminergic neurons with which the prefrontal cortex is densely interconnected. At the molecular level, the reward signal is postulated to be a neurotransmitter such as dopamine, which exerts a global modulatory action on prefrontal synaptic efficacies, either via volume transmission or via targeted synaptic triads. Negative reinforcement has the effect of destabilizing the currently active rule-coding clusters; subsequently, spontaneous activity varies again from one cluster to another, giving the organism the chance to discover and learn a new rule. Thus, reward signals function as effective selection signals that either maintain or suppress currently active prefrontal representations as a function of their current adequacy. Simulations of this variation-selection have successfully accounted for the main features of several major tasks that depend on prefrontal cortex integrity, such as the delayed-response test, the Wisconsin card sorting test, the Tower of London test and the Stroop test. For the more complex tasks, we have found it necessary to supplement the external reward input with a second mechanism that supplies an internal reward; it consists of an auto-evaluation loop which short-circuits the reward input from the exterior. This allows for an internal evaluation of covert motor intentions without actualizing them as behaviors, by simply testing them covertly by comparison with memorized former experiences. This element of architecture gives access to enhanced rates of learning via an elementary process of internal or covert mental simulation. We have recently applied these ideas to a new model, developed with M. Kerszberg, which hypothesizes that prefrontal cortex and its reward-related connections contribute crucially to conscious effortful tasks. This model distinguishes two main computational spaces within the human brain: a unique global workspace composed of distributed and heavily interconnected neurons with long-range axons, and a set of specialized and modular perceptual, motor, memory, evaluative and attentional processors. We postulate that workspace neurons are mobilized in effortful tasks for which the specialized processors do not suffice; they selectively mobilize or suppress, through descending connections, the contribution of specific processor neurons. In the course of task performance, workspace neurons become spontaneously co-activated, forming discrete though variable spatio-temporal patterns subject to modulation by vigilance signals and to selection by reward signals. A computer simulation of the Stroop task shows workspace activation to increase during acquisition of a novel task, effortful execution, and after errors. This model makes predictions concerning the spatio-temporal activation patterns during brain imaging of cognitive tasks, particularly concerning the conditions of activation of dorsolateral prefrontal cortex and anterior cingulate, their relation to reward mechanisms, and their specific reaction during error processing.
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Compulsivity in anorexia nervosa: a transdiagnostic concept
Godier, Lauren R.; Park, Rebecca J.
2014-01-01
The compulsive nature of weight loss behaviors central to anorexia nervosa (AN), such as relentless self-starvation and over-exercise, has led to the suggestion of parallels between AN and other compulsive disorders such as obsessive–compulsive disorder (OCD) and addictions. There is a huge unmet need for effective treatments in AN, which has high rates of morbidity and the highest mortality rate of any psychiatric disorder, yet a grave paucity of effective treatments. Viewing compulsivity as a transdiagnostic concept, seen in various manifestations across disorders, may help delineate the mechanisms responsible for the persistence of AN, and aid treatment development. We explore models of compulsivity that suggest dysfunction in cortico-striatal circuitry underpins compulsive behavior, and consider evidence of aberrancies in this circuitry across disorders. Excessive habit formation is considered as a mechanism by which initially rewarding weight loss behavior in AN may become compulsive over time, and the complex balance between positive and negative reinforcement in this process is considered. The physiological effects of starvation in promoting compulsivity, positive reinforcement, and habit formation are also discussed. Further research in AN may benefit from a focus on processes potentially underlying the development of compulsivity, such as aberrant reward processing and habit formation. We discuss the implications of a transdiagnostic perspective on compulsivity, and how it may contribute to the development of novel treatments for AN. PMID:25101036
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Medial prefrontal brain activation to anticipated reward and loss in obsessive–compulsive disorder☆
Kaufmann, C.; Beucke, J.C.; Preuße, F.; Endrass, T.; Schlagenhauf, F.; Heinz, A.; Juckel, G.; Kathmann, N.
2013-01-01
Obsessive–compulsive disorder (OCD) is associated with dysfunctional brain activity in several regions which are also involved in the processing of motivational stimuli. Processing of reward and punishment appears to be of special importance to understand clinical symptoms. There is evidence for higher sensitivity to punishment in patients with OCD which raises the question how avoidance of punishment relates to activity within the brain's reward circuitry. We employed the monetary incentive delay task paradigm optimized for modeling the anticipation phase of immediate reward and punishment, in the context of a cross-sectional event-related FMRI study comparing OCD patients and healthy control participants (n = 19 in each group). While overall behavioral performance was similar in both groups, patients showed increased activation upon anticipated losses in a medial and superior frontal cortex region extending into the cingulate cortex, and decreased activation upon anticipated rewards. No evidence was found for altered activation of dorsal or ventral striatal regions. Patients also showed more delayed responses for anticipated rewards than for anticipated losses whereas the reverse was true in healthy participants. The medial prefrontal cortex has been shown to implement a domain-general process comprising negative affect, pain and cognitive control. This process uses information about punishment to control aversively motivated actions by integrating signals arriving from subcortical regions. Our results support the notion that OCD is associated with altered sensitivity to anticipated rewards and losses in a medial prefrontal region whereas there is no significant aberrant activation in ventral or dorsal striatal brain regions during processing of reinforcement anticipation. PMID:24179774
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Medial prefrontal brain activation to anticipated reward and loss in obsessive-compulsive disorder.
Kaufmann, C; Beucke, J C; Preuße, F; Endrass, T; Schlagenhauf, F; Heinz, A; Juckel, G; Kathmann, N
2013-01-01
Obsessive-compulsive disorder (OCD) is associated with dysfunctional brain activity in several regions which are also involved in the processing of motivational stimuli. Processing of reward and punishment appears to be of special importance to understand clinical symptoms. There is evidence for higher sensitivity to punishment in patients with OCD which raises the question how avoidance of punishment relates to activity within the brain's reward circuitry. We employed the monetary incentive delay task paradigm optimized for modeling the anticipation phase of immediate reward and punishment, in the context of a cross-sectional event-related FMRI study comparing OCD patients and healthy control participants (n = 19 in each group). While overall behavioral performance was similar in both groups, patients showed increased activation upon anticipated losses in a medial and superior frontal cortex region extending into the cingulate cortex, and decreased activation upon anticipated rewards. No evidence was found for altered activation of dorsal or ventral striatal regions. Patients also showed more delayed responses for anticipated rewards than for anticipated losses whereas the reverse was true in healthy participants. The medial prefrontal cortex has been shown to implement a domain-general process comprising negative affect, pain and cognitive control. This process uses information about punishment to control aversively motivated actions by integrating signals arriving from subcortical regions. Our results support the notion that OCD is associated with altered sensitivity to anticipated rewards and losses in a medial prefrontal region whereas there is no significant aberrant activation in ventral or dorsal striatal brain regions during processing of reinforcement anticipation.
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Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa.
Oberndorfer, Tyson A; Frank, Guido K W; Simmons, Alan N; Wagner, Angela; McCurdy, Danyale; Fudge, Julie L; Yang, Tony T; Paulus, Martin P; Kaye, Walter H
2013-10-01
Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods. Participants who had recovered from anorexia nervosa and bulimia nervosa were studied to avoid confounding effects of altered nutritional state. Functional MRI measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and noncaloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest. Relative to matched comparison women (N=14), women recovered from anorexia nervosa (N=14) had significantly diminished and women recovered from bulimia nervosa (N=14) had significantly elevated hemodynamic response to tastes of sucrose in the right anterior insula. Anterior insula response to sucrose compared with sucralose was exaggerated in the recovered group (lower in women recovered from anorexia nervosa and higher in women recovered from bulimia nervosa). The anterior insula integrates sensory reward aspects of taste in the service of nutritional homeostasis. One possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments.
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The emotional power of poetry: neural circuitry, psychophysiology and compositional principles
Koelsch, Stefan; Wagner, Valentin; Jacobsen, Thomas; Menninghaus, Winfried
2017-01-01
Abstract It is a common experience—and well established experimentally—that music can engage us emotionally in a compelling manner. The mechanisms underlying these experiences are receiving increasing scrutiny. However, the extent to which other domains of aesthetic experience can similarly elicit strong emotions is unknown. Using psychophysiology, neuroimaging and behavioral responses, we show that recited poetry can act as a powerful stimulus for eliciting peak emotional responses, including chills and objectively measurable goosebumps that engage the primary reward circuitry. Importantly, while these responses to poetry are largely analogous to those found for music, their neural underpinnings show important differences, specifically with regard to the crucial role of the nucleus accumbens. We also go beyond replicating previous music-related studies by showing that peak aesthetic pleasure can co-occur with physiological markers of negative affect. Finally, the distribution of chills across the trajectory of poems provides insight into compositional principles of poetry. PMID:28460078
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Externalizing proneness and brain response during pre-cuing and viewing of emotional pictures
Foell, Jens; Brislin, Sarah J.; Strickland, Casey M.; Seo, Dongju; Sabatinelli, Dean
2016-01-01
Externalizing proneness, or trait disinhibition, is a concept relevant to multiple high-impact disorders involving impulsive-aggressive behavior. Its mechanisms remain disputed: major models posit hyperresponsive reward circuitry or heightened threat-system reactivity as sources of disinhibitory tendencies. This study evaluated alternative possibilities by examining relations between trait disinhibition and brain reactivity during preparation for and processing of visual affective stimuli. Forty females participated in a functional neuroimaging procedure with stimuli presented in blocks containing either pleasurable or aversive pictures interspersed with neutral, with each picture preceded by a preparation signal. Preparing to view elicited activation in regions including nucleus accumbens, whereas visual regions and bilateral amygdala were activated during viewing of emotional pictures. High disinhibition predicted reduced nucleus accumbens activation during preparation within pleasant/neutral picture blocks, along with enhanced amygdala reactivity during viewing of pleasant and aversive pictures. Follow-up analyses revealed that the augmented amygdala response was related to reduced preparatory activation. Findings indicate that participants high in disinhibition are less able to process implicit cues and mentally prepare for upcoming stimuli, leading to limbic hyperreactivity during processing of actual stimuli. This outcome is helpful for integrating findings from studies suggesting reward-system hyperreactivity and others suggesting threat-system hyperreactivity as mechanisms for externalizing proneness. PMID:26113614
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Conic section function neural network circuitry for offline signature recognition.
Erkmen, Burcu; Kahraman, Nihan; Vural, Revna A; Yildirim, Tulay
2010-04-01
In this brief, conic section function neural network (CSFNN) circuitry was designed for offline signature recognition. CSFNN is a unified framework for multilayer perceptron (MLP) and radial basis function (RBF) networks to make simultaneous use of advantages of both. The CSFNN circuitry architecture was developed using a mixed mode circuit implementation. The designed circuit system is problem independent. Hence, the general purpose neural network circuit system could be applied to various pattern recognition problems with different network sizes on condition with the maximum network size of 16-16-8. In this brief, CSFNN circuitry system has been applied to two different signature recognition problems. CSFNN circuitry was trained with chip-in-the-loop learning technique in order to compensate typical analog process variations. CSFNN hardware achieved highly comparable computational performances with CSFNN software for nonlinear signature recognition problems.
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Transfer Function Control for Biometric Monitoring System
NASA Technical Reports Server (NTRS)
Chmiel, Alan J. (Inventor); Grodinsky, Carlos M. (Inventor); Humphreys, Bradley T. (Inventor)
2015-01-01
A modular apparatus for acquiring biometric data may include circuitry operative to receive an input signal indicative of a biometric condition, the circuitry being configured to process the input signal according to a transfer function thereof and to provide a corresponding processed input signal. A controller is configured to provide at least one control signal to the circuitry to programmatically modify the transfer function of the modular system to facilitate acquisition of the biometric data.
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Probing Compulsive and Impulsive Behaviors, from Animal Models to Endophenotypes: A Narrative Review
Fineberg, Naomi A; Potenza, Marc N; Chamberlain, Samuel R; Berlin, Heather A; Menzies, Lara; Bechara, Antoine; Sahakian, Barbara J; Robbins, Trevor W; Bullmore, Edward T; Hollander, Eric
2010-01-01
Failures in cortical control of fronto-striatal neural circuits may underpin impulsive and compulsive acts. In this narrative review, we explore these behaviors from the perspective of neural processes and consider how these behaviors and neural processes contribute to mental disorders such as obsessive–compulsive disorder (OCD), obsessive–compulsive personality disorder, and impulse-control disorders such as trichotillomania and pathological gambling. We present findings from a broad range of data, comprising translational and human endophenotypes research and clinical treatment trials, focussing on the parallel, functionally segregated, cortico-striatal neural projections, from orbitofrontal cortex (OFC) to medial striatum (caudate nucleus), proposed to drive compulsive activity, and from the anterior cingulate/ventromedial prefrontal cortex to the ventral striatum (nucleus accumbens shell), proposed to drive impulsive activity, and the interaction between them. We suggest that impulsivity and compulsivity each seem to be multidimensional. Impulsive or compulsive behaviors are mediated by overlapping as well as distinct neural substrates. Trichotillomania may stand apart as a disorder of motor-impulse control, whereas pathological gambling involves abnormal ventral reward circuitry that identifies it more closely with substance addiction. OCD shows motor impulsivity and compulsivity, probably mediated through disruption of OFC-caudate circuitry, as well as other frontal, cingulate, and parietal connections. Serotonin and dopamine interact across these circuits to modulate aspects of both impulsive and compulsive responding and as yet unidentified brain-based systems may also have important functions. Targeted application of neurocognitive tasks, receptor-specific neurochemical probes, and brain systems neuroimaging techniques have potential for future research in this field. PMID:19940844
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Cardoso de Almeida, Jorge Renner; Phillips, Mary Louise
2013-01-15
Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date have directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward, and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a call to action to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at-risk individuals, and more novel neuroimaging approaches, such as connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD and biological targets for more personalized treatment and new treatment developments for BD and UD depression. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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CART in the brain of vertebrates: circuits, functions and evolution.
Subhedar, Nishikant K; Nakhate, Kartik T; Upadhya, Manoj A; Kokare, Dadasaheb M
2014-04-01
Cocaine- and amphetamine-regulated transcript peptide (CART) with its wide distribution in the brain of mammals has been the focus of considerable research in recent years. Last two decades have witnessed a steady rise in the information on the genes that encode this neuropeptide and regulation of its transcription and translation. CART is highly enriched in the hypothalamic nuclei and its relevance to energy homeostasis and neuroendocrine control has been understood in great details. However, the occurrence of this peptide in a range of diverse circuitries for sensory, motor, vegetative, limbic and higher cortical areas has been confounding. Evidence that CART peptide may have role in addiction, pain, reward, learning and memory, cognition, sleep, reproduction and development, modulation of behavior and regulation of autonomic nervous system are accumulating, but an integration has been missing. A steady stream of papers has been pointing at the therapeutic potentials of CART. The current review is an attempt at piecing together the fragments of available information, and seeks meaning out of the CART elements in their anatomical niche. We try to put together the CART containing neuronal circuitries that have been conclusively demonstrated as well as those which have been proposed, but need confirmation. With a view to finding out the evolutionary antecedents, we visit the CART systems in sub-mammalian vertebrates and seek the answer why the system is shaped the way it is. We enquire into the conservation of the CART system and appreciate its functional diversity across the phyla. Copyright © 2014 Elsevier Inc. All rights reserved.
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O'Mara, Shane M; Sanchez-Vives, Maria V; Brotons-Mas, Jorge R; O'Hare, Eugene
2009-08-01
The subiculum is in a pivotal position governing the output of the hippocampal formation. Despite this, it is a rather under-explored and sometimes ignored structure. Here, we discuss recent data indicating that the subiculum participates in a wide range of neurocognitive functions and processes. Some of the functions of subiculum are relatively well-known-these include providing a relatively coarse representation of space and participating in, and supporting certain aspects of, memory (particularly in the dynamic bridging of temporal intervals). The subiculum also participates in a wide variety of other neurocognitive functions too, however. Much less well-known are roles for the subiculum, and particularly the ventral subiculum, in the response to fear, stress and anxiety, and in the generation of motivated behaviour (particularly the behaviour that underlies drug addiction and the response to reward). There is an emerging suggestion that the subiculum participates in the temporal control of behaviour. It is notable that these latter findings have emerged from a consideration of instrumental behaviour using operant techniques; it may well be the case that the use of the watermaze or similar spatial tasks to assess subicular function (on the presumption that its functions are very similar to the hippocampus proper) has obscured rather than revealed neurocognitive functions of subiculum. The anatomy of subiculum suggests it participates in a rather subtle fashion in a very broad range of functions, rather than in a relatively more isolated fashion in a narrower range of functions, as might be the case for "earlier" components of hippocampal circuitry, such as the CA1 and CA3 subfields. Overall, there appears to a strong dorso-ventral segregation of function within subiculum, with the dorsal subiculum relatively more concerned with space and memory, and the ventral hippocampus concerned with stress, anxiety and reward. Finally, it may be the case that the whole subiculum participates in the temporal control of reinforced behaviour, although further experimentation is required to clarify this hypothesis.
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Neural network alterations across eating disorders: a narrative review of fMRI studies.
Steward, Trevor; Menchón, José M; Jiménez-Murcia, Susana; Soriano-Mas, Carles; Fernández-Aranda, Fernando
2017-10-17
Functional magnetic resonance imaging (fMRI) has provided insight on how neural abnormalities are related to the symptomatology of the eating disorders (EDs): anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). More specifically, an increasingly growing number of brain imaging studies has shed light on how functionally connected brain networks contribute not only to disturbed eating behavior, but also to transdiagnostic alterations in body/interoceptive perception, reward processing and executive functions. This narrative review aims to summarize recent advances in fMRI studies of patients with EDs by highlighting studies investigating network alterations that are shared across EDs. Findings on reward processing in both AN and BN patients point to the presence of altered sensitivity to salient food stimuli in striatal regions and to the possibility of hypothalamic inputs being overridden by top-down cognitive control regions. Additionally, innovative new lines of research suggest that increased activations in fronto-striatal circuits are strongly associated with the maintenance of restrictive eating habits in AN patients. Although significantly fewer studies have been carried out in patients with BN and BED, aberrant neural responses to both food cues and anticipated food receipt appear to occur in these populations. These altered responses, coupled with diminished recruitment of prefrontal cognitive control circuitry, are believed to contribute to the binge eating of palatable foods. Results from functional network connectivity studies are diverse, but findings tend to converge on indicating disrupted resting-state connectivity in executive networks, the default-mode network and the salience network across EDs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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Model-based learning and the contribution of the orbitofrontal cortex to the model-free world.
McDannald, Michael A; Takahashi, Yuji K; Lopatina, Nina; Pietras, Brad W; Jones, Josh L; Schoenbaum, Geoffrey
2012-04-01
Learning is proposed to occur when there is a discrepancy between reward prediction and reward receipt. At least two separate systems are thought to exist: one in which predictions are proposed to be based on model-free or cached values; and another in which predictions are model-based. A basic neural circuit for model-free reinforcement learning has already been described. In the model-free circuit the ventral striatum (VS) is thought to supply a common-currency reward prediction to midbrain dopamine neurons that compute prediction errors and drive learning. In a model-based system, predictions can include more information about an expected reward, such as its sensory attributes or current, unique value. This detailed prediction allows for both behavioral flexibility and learning driven by changes in sensory features of rewards alone. Recent evidence from animal learning and human imaging suggests that, in addition to model-free information, the VS also signals model-based information. Further, there is evidence that the orbitofrontal cortex (OFC) signals model-based information. Here we review these data and suggest that the OFC provides model-based information to this traditional model-free circuitry and offer possibilities as to how this interaction might occur. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.
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Dual roles of dopamine in food- and drug-seeking: the drive-reward paradox
Wise, Roy A.
2012-01-01
The question of whether (or to what degree) obesity reflects addiction to high energy foods often narrows to the question of whether the overeating of these foods causes the same long-term neuroadaptations as are identified with the late stages of addiction. Of equal or perhaps greater interest is the question of whether common brain mechanisms mediate the acquisition and development of eating and drug-taking habits. The earliest evidence on this question is rooted in early studies of brain stimulation reward. Lateral hypothalamic electrical stimulation can be reinforcing in some conditions and can motivate feeding in others. That stimulation of the same brain region should be both reinforcing and drive-inducing is paradoxical; why should an animal work to induce a drive-like state such as hunger? This is known as the “drive-reward paradox.” Insights into the substrates of the drive-reward paradox suggest an answer to the controversial question of whether the dopamine system—a system “downstream” from the stimulated fibers of the lateral hypothalamus—is more critically involved in “wanting” or in “liking” of various rewards including food and addictive drugs. That the same brain circuitry is implicated in the motivation for and the reinforcement by both food and addictive drugs extends the argument for a common mechanism underlying compulsive overeating and compulsive drug-taking. PMID:23044182
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Sexual dimorphism in striatal dopaminergic responses promotes monogamy in social songbirds.
Tokarev, Kirill; Hyland Bruno, Julia; Ljubičić, Iva; Kothari, Paresh J; Helekar, Santosh A; Tchernichovski, Ofer; Voss, Henning U
2017-08-11
In many songbird species, males sing to attract females and repel rivals. How can gregarious, non-territorial songbirds such as zebra finches, where females have access to numerous males, sustain monogamy? We found that the dopaminergic reward circuitry of zebra finches can simultaneously promote social cohesion and breeding boundaries. Surprisingly, in unmated males but not in females, striatal dopamine neurotransmission was elevated after hearing songs. Behaviorally too, unmated males but not females persistently exchanged mild punishments in return for songs. Song reinforcement diminished when dopamine receptors were blocked. In females, we observed song reinforcement exclusively to the mate's song, although their striatal dopamine neurotransmission was only slightly elevated. These findings suggest that song-triggered dopaminergic activation serves a dual function in social songbirds: as low-threshold social reinforcement in males and as ultra-selective sexual reinforcement in females. Co-evolution of sexually dimorphic reinforcement systems can explain the coexistence of gregariousness and monogamy.
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Sexual dimorphism in striatal dopaminergic responses promotes monogamy in social songbirds
Hyland Bruno, Julia; Ljubičić, Iva; Kothari, Paresh J; Helekar, Santosh A; Tchernichovski, Ofer; Voss, Henning U
2017-01-01
In many songbird species, males sing to attract females and repel rivals. How can gregarious, non-territorial songbirds such as zebra finches, where females have access to numerous males, sustain monogamy? We found that the dopaminergic reward circuitry of zebra finches can simultaneously promote social cohesion and breeding boundaries. Surprisingly, in unmated males but not in females, striatal dopamine neurotransmission was elevated after hearing songs. Behaviorally too, unmated males but not females persistently exchanged mild punishments in return for songs. Song reinforcement diminished when dopamine receptors were blocked. In females, we observed song reinforcement exclusively to the mate’s song, although their striatal dopamine neurotransmission was only slightly elevated. These findings suggest that song-triggered dopaminergic activation serves a dual function in social songbirds: as low-threshold social reinforcement in males and as ultra-selective sexual reinforcement in females. Co-evolution of sexually dimorphic reinforcement systems can explain the coexistence of gregariousness and monogamy. PMID:28826502
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Satiety and the role of μ-opioid receptors in the portal vein.
De Vadder, Filipe; Gautier-Stein, Amandine; Mithieux, Gilles
2013-12-01
Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Diet-induced obesity attenuates fasting-induced hyperphagia.
Briggs, D I; Lemus, M B; Kua, E; Andrews, Z B
2011-07-01
Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti-releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the present study, we investigated the effect of diet-induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high-fat feeding attenuates fasting-induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting-induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.
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Peer Influence Via Instagram: Effects on Brain and Behavior in Adolescence and Young Adulthood.
Sherman, Lauren E; Greenfield, Patricia M; Hernandez, Leanna M; Dapretto, Mirella
2018-01-01
Mobile social media often feature the ability to "Like" content posted by others. This study examined the effect of Likes on youths' neural and behavioral responses to photographs. High school and college students (N = 61, ages 13-21) viewed theirs and others' Instagram photographs while undergoing functional Magnetic Resonance Imaging (fMRI). Participants more often Liked photographs that appeared to have received many (vs. few) Likes. Popular photographs elicited greater activity in multiple brain regions, including the nucleus accumbens (NAcc), a hub of the brain's reward circuitry. NAcc responsivity increased with age for high school but not college students. When viewing images depicting risk-taking (vs. nonrisky photographs), high school students, but not college students, showed decreased activation of neural regions implicated in cognitive control. © 2017 The Authors. Child Development © 2017 Society for Research in Child Development, Inc.
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The intersection of stress and reward: BNST modulation of aversive and appetitive states.
Ch'ng, Sarah; Fu, Jingjing; Brown, Robyn M; McDougall, Stuart J; Lawrence, Andrew J
2018-01-09
The bed nucleus of the stria terminalis (BNST) is widely acknowledged as a brain structure that regulates stress and anxiety states, as well as aversive and appetitive behaviours. The diverse roles of the BNST are afforded by its highly modular organisation, neurochemical heterogeneity, and complex intrinsic and extrinsic circuitry. There has been growing interest in the BNST in relation to psychopathologies such as anxiety and addiction. Although research on the human BNST is still in its infancy, there have been extensive preclinical studies examining the molecular signature and hodology of the BNST and their involvement in stress and reward seeking behaviour. This review examines the neurochemical phenotype and connectivity of the BNST, as well as electrophysiological correlates of plasticity in the BNST mediated by stress and/or drugs of abuse. Copyright © 2018 Elsevier Inc. All rights reserved.
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Skvortsova, Vasilisa; Degos, Bertrand; Welter, Marie-Laure; Vidailhet, Marie; Pessiglione, Mathias
2017-06-21
Instrumental learning is a fundamental process through which agents optimize their choices, taking into account various dimensions of available options such as the possible reward or punishment outcomes and the costs associated with potential actions. Although the implication of dopamine in learning from choice outcomes is well established, less is known about its role in learning the action costs such as effort. Here, we tested the ability of patients with Parkinson's disease (PD) to maximize monetary rewards and minimize physical efforts in a probabilistic instrumental learning task. The implication of dopamine was assessed by comparing performance ON and OFF prodopaminergic medication. In a first sample of PD patients ( n = 15), we observed that reward learning, but not effort learning, was selectively impaired in the absence of treatment, with a significant interaction between learning condition (reward vs effort) and medication status (OFF vs ON). These results were replicated in a second, independent sample of PD patients ( n = 20) using a simplified version of the task. According to Bayesian model selection, the best account for medication effects in both studies was a specific amplification of reward magnitude in a Q-learning algorithm. These results suggest that learning to avoid physical effort is independent from dopaminergic circuits and strengthen the general idea that dopaminergic signaling amplifies the effects of reward expectation or obtainment on instrumental behavior. SIGNIFICANCE STATEMENT Theoretically, maximizing reward and minimizing effort could involve the same computations and therefore rely on the same brain circuits. Here, we tested whether dopamine, a key component of reward-related circuitry, is also implicated in effort learning. We found that patients suffering from dopamine depletion due to Parkinson's disease were selectively impaired in reward learning, but not effort learning. Moreover, anti-parkinsonian medication restored the ability to maximize reward, but had no effect on effort minimization. This dissociation suggests that the brain has evolved separate, domain-specific systems for instrumental learning. These results help to disambiguate the motivational role of prodopaminergic medications: they amplify the impact of reward without affecting the integration of effort cost. Copyright © 2017 the authors 0270-6474/17/376087-11$15.00/0.
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Areno, Matthew
2015-12-08
Techniques and mechanisms for providing a value from physically unclonable function (PUF) circuitry for a cryptographic operation of a security module. In an embodiment, a cryptographic engine receives a value from PUF circuitry and based on the value, outputs a result of a cryptographic operation to a bus of the security module. The bus couples the cryptographic engine to control logic or interface logic of the security module. In another embodiment, the value is provided to the cryptographic engine from the PUF circuitry via a signal line which is distinct from the bus, where any exchange of the value by either of the cryptographic engine and the PUF circuitry is for communication of the first value independent of the bus.
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The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics.
Sonuga-Barke, Edmund J S
2003-11-01
The currently dominant neuro-cognitive model of Attention Deficit Hyperactivity Disorder (AD/HD) presents the condition as executive dysfunction (EDF) underpinned by disturbances in the fronto-dorsal striatal circuit and associated dopaminergic branches (e.g. meso-cortical). In contrast, motivationally-based accounts focus on altered reward processes and implicate fronto-ventral striatal reward circuits and those meso-limbic branches that terminate in the ventral striatum especially the nucleus accumbens. One such account, delay aversion (DEL), presents AD/HD as a motivational style-characterised by attempts to escape or avoid delay-arising from fundamental disturbances in these reward centres. While traditionally regarded as competing, EDF and DEL models have recently been presented as complimentary accounts of two psycho-patho-physiological subtypes of AD/HD with different developmental pathways, underpinned by different cortico-striatal circuits and modulated by different branches of the dopamine system. In the current paper we describe the development of this model in more detail. We elaborate on the neuro-circuitry possibly underpinning these two pathways and explore their developmental significance within a neuro-ecological framework.
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Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E.; Redhi, Godfrey H.; Panlilio, Leigh V.; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D.; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R.
2013-01-01
In the reward circuitry of the brain, alpha-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of delta-9-tetrahydrocannabinol (THC), marijuana’s main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by re-exposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are currently no medications approved for treatment of marijuana dependence. Modulation of KYNA provides a novel pharmacological strategy for achieving abstinence from marijuana and preventing relapse. PMID:24121737
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Justinova, Zuzana; Mascia, Paola; Wu, Hui-Qiu; Secci, Maria E; Redhi, Godfrey H; Panlilio, Leigh V; Scherma, Maria; Barnes, Chanel; Parashos, Alexandra; Zara, Tamara; Fratta, Walter; Solinas, Marcello; Pistis, Marco; Bergman, Jack; Kangas, Brian D; Ferré, Sergi; Tanda, Gianluigi; Schwarcz, Robert; Goldberg, Steven R
2013-11-01
In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ(9)-tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.
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Genetic and pharmacological antagonism of NK1 receptor prevents opiate abuse potential.
Sandweiss, A J; McIntosh, M I; Moutal, A; Davidson-Knapp, R; Hu, J; Giri, A K; Yamamoto, T; Hruby, V J; Khanna, R; Largent-Milnes, T M; Vanderah, T W
2017-05-09
Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK 1 R) in the VTA renders morphine non-rewarding. Complementing our genetic approach, we demonstrate utility of a bivalent pharmacophore with dual activity as a μ/δ opioid agonist and NK 1 R antagonist in inhibiting nociception in an animal model of acute pain while lacking any positive reinforcement. These data indicate that dual targeting of the dopaminergic reward circuitry and pain pathways with a multifunctional opioid agonist-NK 1 R antagonist may be an efficacious strategy in developing future analgesics that lack abuse potential.Molecular Psychiatry advance online publication, 9 May 2017; doi:10.1038/mp.2017.102.
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Jenkins, Lisanne M; Skerrett, Kristy A; DelDonno, Sophie R; Patrón, Víctor G; Meyers, Kortni K; Peltier, Scott; Zubieta, Jon-Kar; Langenecker, Scott A; Starkman, Monica N
2018-05-30
We investigated the ability of preferred classical music to activate the nucleus accumbens in patients with Major depressive disorder (MDD). Twelve males with MDD and 10 never mentally ill male healthy controls (HC) completed measures of anhedonia and depression severity, and listened to 90-second segments of preferred classical music during fMRI. Compared to HCs, individuals with MDD showed less activation of the left nucleus accumbens (NAcc). Individuals with MDD showed attenuation of the left NAcc response in later compared to earlier parts of the experiment, supporting theories that MDD involves an inability to sustain reward network activation. Counter intuitively, we found that NAcc activity during early music listening was associated with greater depression severity. In whole-brain analyses, anhedonia scores predicted activity in regions within the default mode network, supporting previous findings. Our results support theories that MDD involves an inability to sustain reward network activation. It also highlights that pleasant classical music can engage critical neural reward circuitry in MDD. Copyright © 2018 Elsevier B.V. All rights reserved.
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Neural correlates of nesting behavior in zebra finches (Taeniopygia guttata).
Hall, Zachary J; Bertin, Marion; Bailey, Ida E; Meddle, Simone L; Healy, Susan D
2014-05-01
Nest building in birds involves a behavioral sequence (nest material collection and deposition in the nest) that offers a unique model for addressing how the brain sequences motor actions. In this study, we identified brain regions involved in nesting behavior in male and female zebra finches (Taeniopygia guttata). We used Fos immunohistochemistry to quantify production of the immediate early gene protein product Fos (a molecular indicator of neuronal activity) in the brain correlated this expression with the variation in nesting behavior. Using this technique, we found that neural circuitry involved in motor sequencing, social behavior, reward and motivation were active during nesting. Within pairs of nesting birds, the number of times a male picked up or deposited nesting material and the amount of time a female spent in the nest explained the variation in Fos expression in the anterior motor pathway, social behavior network, and reward neural circuits. Identification of the brain regions that are involved in nesting enables us to begin studying the roles of motor sequencing, context, and reward in construction behavior at the neural level. Copyright © 2014 Elsevier B.V. All rights reserved.
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Neural correlates of nesting behavior in zebra finches (Taeniopygia guttata)
Hall, Zachary J.; Bertin, Marion; Bailey, Ida E.; Meddle, Simone L.; Healy, Susan D.
2014-01-01
Nest building in birds involves a behavioral sequence (nest material collection and deposition in the nest) that offers a unique model for addressing how the brain sequences motor actions. In this study, we identified brain regions involved in nesting behavior in male and female zebra finches (Taeniopygia guttata). We used Fos immunohistochemistry to quantify production of the immediate early gene protein product Fos (a molecular indicator of neuronal activity) in the brain correlated this expression with the variation in nesting behavior. Using this technique, we found that neural circuitry involved in motor sequencing, social behavior, reward and motivation were active during nesting. Within pairs of nesting birds, the number of times a male picked up or deposited nesting material and the amount of time a female spent in the nest explained the variation in Fos expression in the anterior motor pathway, social behavior network, and reward neural circuits. Identification of the brain regions that are involved in nesting enables us to begin studying the roles of motor sequencing, context, and reward in construction behavior at the neural level. PMID:24508238
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The Reward-Based Eating Drive Scale: A Self-Report Index of Reward-Based Eating
Mason, Ashley E.; Laraia, Barbara A.; Hartman, William; Ready, Karen; Acree, Michael; Adam, Tanja C.; St. Jeor, Sachiko; Kessler, David
2014-01-01
Why are some individuals more vulnerable to persistent weight gain and obesity than are others? Some obese individuals report factors that drive overeating, including lack of control, lack of satiation, and preoccupation with food, which may stem from reward-related neural circuitry. These are normative and common symptoms and not the sole focus of any existing measures. Many eating scales capture these common behaviors, but are confounded with aspects of dysregulated eating such as binge eating or emotional overeating. Across five studies, we developed items that capture this reward-based eating drive (RED). Study 1 developed the items in lean to obese individuals (n = 327) and examined changes in weight over eight years. In Study 2, the scale was further developed and expert raters evaluated the set of items. Study 3 tested psychometric properties of the final 9 items in 400 participants. Study 4 examined psychometric properties and race invariance (n = 80 women). Study 5 examined psychometric properties and age/gender invariance (n = 381). Results showed that RED scores correlated with BMI and predicted earlier onset of obesity, greater weight fluctuations, and greater overall weight gain over eight years. Expert ratings of RED scale items indicated that the items reflected characteristics of reward-based eating. The RED scale evidenced high internal consistency and invariance across demographic factors. The RED scale, designed to tap vulnerability to reward-based eating behavior, appears to be a useful brief tool for identifying those at higher risk of weight gain over time. Given the heterogeneity of obesity, unique brief profiling of the reward-based aspect of obesity using a self-report instrument such as the RED scale may be critical for customizing effective treatments in the general population. PMID:24979216
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Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward.
Skibicka, Karolina P; Shirazi, Rozita H; Hansson, Caroline; Dickson, Suzanne L
2012-03-01
Ghrelin, a stomach-derived hormone, is an orexigenic peptide that was recently shown to potently increase food reward behavior. The neurochemical circuitry that links ghrelin to the mesolimbic system and food reward behavior remains unclear. Here we examined the contribution of neuropeptide Y (NPY) and opioids to ghrelin's effects on food motivation and intake. Both systems have well-established links to the mesolimbic ventral tegmental area (VTA) and reward/motivation control. NPY mediates the effect of ghrelin on food intake via activation of NPY-Y1 receptor (NPY-Y1R); their connection with respect to motivated behavior is unexplored. The role of opioids in any aspect of ghrelin's action on food-oriented behaviors is unknown. Rats were trained in a progressive ratio sucrose-induced operant schedule to measure food reward/motivation behavior. Chow intake was measured immediately after the operant test. In separate experiments, we explored the suppressive effects of a selective NPY-Y1R antagonist or opioid receptor antagonist naltrexone, injected either intracerebroventricularly or intra-VTA, on ghrelin-induced food reward behavior. The ventricular ghrelin-induced increase in sucrose-motivated behavior and chow intake were completely blocked by intracerebroventricular pretreatment with either an NPY-Y1R antagonist or naltrexone. The intra-VTA ghrelin-induced sucrose-motivated behavior was blocked only by intra-VTA naltrexone. In contrast, the intra-VTA ghrelin-stimulated chow intake was attenuated only by intra-VTA NPY-Y1 blockade. Finally, ghrelin infusion was associated with an elevated VTA μ-opioid receptor expression. Thus, we identify central NPY and opioid signaling as the necessary mediators of food intake and reward effects of ghrelin and localize these interactions to the mesolimbic VTA.
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Cocaine decreases saccharin preference without altering sweet taste sensitivity.
Roebber, Jennifer K; Izenwasser, Sari; Chaudhari, Nirupa
2015-06-01
In rodents, saccharin consumption is suppressed when the sweet taste stimulus is paired with moderate doses of cocaine. Several hypotheses have been used to explain the seemingly contradictory effect of decreased consumption of a normally preferred substance following a highly rewarding drug. A common theme across these hypotheses is that saccharin is interpreted as less rewarding after cocaine pairing. We considered the alternative possibility that suppression is caused not by a change in reward circuitry, but rather by a change in taste detection, for instance by altering the afferent taste response and decreasing sensitivity to sweet taste stimuli. To evaluate this possibility, we measured saccharin taste sensitivity of mice before and after a standard cocaine-pairing paradigm. We measured taste sensitivity using a brief-access lickometer equipped with multiple concentrations of saccharin solution and established concentration-response curves before and after saccharin-cocaine pairing. Our results indicate that the EC50 for saccharin was unaltered following pairing. Instead, the avidity of licking saccharin, an indicator of motivation, was depressed. Latency to first-lick, a negative indicator of motivation, was also dramatically increased. Thus, our findings are consistent with the interpretation that saccharin-cocaine pairing results in devaluing of the sweet taste reward. Copyright © 2015 Elsevier Inc. All rights reserved.
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Ely, Alice V; Wierenga, Christina E; Bischoff-Grethe, Amanda; Bailer, Ursula F; Berner, Laura A; Fudge, Julie L; Paulus, Martin P; Kaye, Walter H
2017-07-01
Individuals with bulimia nervosa (BN) engage in episodes of binge eating, marked by loss of control and eating despite fullness. Does altered reward and metabolic state contribute to BN pathophysiology? Normally, hunger increases (and satiety decreases) reward salience to regulate eating. We investigated whether BN is associated with an abnormal response in a neural circuit involved in translating taste signals into motivated behavior, when hungry and fed. Twenty-six women remitted from BN (RBN) and 22 control women (CW) were administered water and sucrose during 2 counterbalanced fMRI visits, following a 16-hr fast or a standardized breakfast. Significant Group × Condition interactions were found in the left putamen, insula, and amygdala. Post hoc analyses revealed CW were significantly more responsive to taste stimuli when hungry versus fed in the left putamen and amygdala. In contrast, RBN response did not differ between conditions. Further, RBN had greater activation in the left amygdala compared with CW when fed. Findings suggest that RBN neural response to rewarding stimuli may not be modulated by metabolic state. Data raise the possibility that disinhibited eating in BN could result from a failure to devalue food reward when fed, resulting in an exaggerated response. (PsycINFO Database Record (c) 2017 APA, all rights reserved).
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The contribution of brain reward circuits to the obesity epidemic
Stice, Eric; Figlewicz, Dianne P.; Gosnell, Blake A.; Levine, Allen S.; Pratt, Wayne E.
2012-01-01
One of the defining characteristics of the research of Ann E. Kelley was her recognition that the neuroscience underlying basic learning and motivation processes also shed significant light upon mechanisms underlying drug addiction and maladaptive eating patterns. In this review, we examine the parallels that exist in the neural pathways that process both food and drug reward, as determined by recent studies in animal models and human neuroimaging experiments. We discuss contemporary research that suggests that hyperphagia leading to obesity is associated with substantial neurochemical changes in the brain. These findings verify the relevance of reward pathways for promoting consumption of palatable, calorically dense foods, and lead to the important question of whether changes in reward circuitry in response to intake of such foods serve a causal role in the development and maintenance of some cases of obesity. Finally, we discuss the potential value for future studies at the intersection of the obesity epidemic and the neuroscience of motivation, as well as the potential concerns that arise from viewing excessive food intake as an “addiction”. We suggest that it might be more useful to focus on overeating that results in frank obesity, and multiple health, interpersonal, and occupational negative consequences as a form of food “abuse”. PMID:23237885
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Cholinergic control over attention in rats prone to attribute incentive salience to reward cues
Paolone, Giovanna; Angelakos, Christopher C.; Meyer, Paul J.; Robinson, Terry E.; Sarter, Martin
2013-01-01
Some rats (sign-trackers, ST) are especially prone to attribute incentive salience to reward cues, relative to others (goal-trackers, GT). Thus, reward cues are more likely to promote maladaptive reward-seeking behavior in ST than GT. Here, we asked whether ST and GT differ on another trait that can contribute to poor restraint over behavior evoked by reward cues. We report that, relative to GT, ST have poor control over attentional performance, due in part to insufficient cholinergic stimulation of cortical circuitry. We found that, relative to GT, ST showed poor performance on a sustained attention task (SAT). Furthermore, their performance fluctuated rapidly between periods of good to near-chance performance. This finding was reproduced using a separate cohort of rats. As demonstrated earlier, performance on the SAT was associated with increases in extracellular levels of cortical acetylcholine (ACh); however, SAT performance-associated increases in ACh levels were significantly attenuated in ST relative to GT. Consistent with the view that the modulatory effects of ACh involves stimulation of α4β2* nicotinic acetylcholine receptors (nAChRs), systemic administration of the partial nAChR agonist ABT-089 improved SAT performance in ST and abolished the difference between SAT-associated ACh levels in ST and GT. Neither the nonselective nAChR agonist nicotine nor the psychostimulant amphetamine improved SAT performance. These findings suggest that individuals who have a propensity to attribute high incentive salience to reward cues also exhibit relatively poor attentional control. A combination of these traits may render individuals especially vulnerable to disorders such as obesity and addiction. PMID:23658172
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McLaughlin, Thomas; Blum, Kenneth; Oscar-Berman, Marlene; Febo, Marcelo; Agan, Gozde; Fratantonio, James L.; Simpatico, Thomas; Gold, Mark S.
2015-01-01
Background Lucid dreams are frequently pleasant and training techniques have been developed to teach dreamers to induce them. In addition, the induction of lucid dreams has also been used as a way to ameliorate nightmares. On the other hand, lucid dreams may be associated with psychiatric conditions, including Post-Traumatic Stress Disorder (PTSD) and Reward Deficiency Syndrome-associated diagnoses. In the latter conditions, lucid dreams can assume an unpleasant and frequently terrifying character. Case Presentations We present two cases of dramatic alleviation of terrifying lucid dreams in patients with PTSD. In the first case study, a 51-year-old, obese woman, diagnosed with PTSD and depression, had attempted suicide and experienced terrifying lucid nightmares linked to sexual/physical abuse from early childhood by family members including her alcoholic father. Her vivid “bad dreams” remained refractory in spite of 6 months of treatment with Dialectical Behavioral Therapy (DBT) and standard pharmaceutical agents which included prazosin, clonidie and Adderall. The second 39-year-old PTSD woman patient had also suffered from lucid nightmares. Results The medication visit notes reveal changes in the frequency, intensity and nature of these dreams after the complex putative dopamine agonist KB220Z was added to the first patient’s regimen. The patient reported her first experience of an extended period of happy dreams. The second PTSD patient, who had suffered from lucid nightmares, was administered KB220Z to attenuate methadone withdrawal symptoms and incidentally reported dreams full of happiness and laughter. Conclusions These cases are discussed with reference to the known effects of KB220Z including enhanced dopamine homeostasis and functional connectivity of brain reward circuitry in rodents and humans. Their understanding awaits intensive investigation involving large-population, double-blinded studies. PMID:26132915
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Razavi, Yasaman; Alamdary, Shabnam Zeighamy; Katebi, Seyedeh-Najmeh; Khodagholi, Fariba; Haghparast, Abbas
2014-03-01
Some data suggest that morphine induces apoptosis in neurons, while other evidences show that morphine could have protective effects against cell death. In this study, we suggested that there is a parallel role of morphine in reward circuitry and apoptosis processing. Therefore, we investigated the effect of morphine on modifications of apoptotic factors in the ventral tegmental area (VTA) and hippocampus (HPC) which are involved in the reward circuitry after the acquisition and extinction periods of conditioned place preference (CPP). In behavioral experiments, different doses of morphine (0.5, 5, and 10 mg/kg) and saline were examined in the CPP paradigm. Conditioning score and locomotor activity were recorded by Ethovision software after acquisition on the post-conditioning day, and days 4 and 8 of extinction periods. In order to investigate the molecular mechanisms in each group, we then dissected the brains and measured the expression of apoptotic factors in the VTA and HPC by western blotting analysis. All of the morphine-treated groups showed an increase of apoptotic factors in these regions during acquisition but not in extinction period. In the HPC, morphine significantly increased the ratio of Bax/Bcl-2, caspases-3, and PARP by the lowest dose (0.5 mg/kg), but, in the VTA, a considerable increase was seen in the dose of 5 mg/kg; promotion of apoptotic factors in the HPC and VTA insinuates that morphine can affect the molecular mechanisms that interfere with apoptosis through different receptors. Our findings suggest that a specific opioid receptor involves in modification of apoptotic factors expression in these areas. It seems that the reduction of cell death in response to high dose of morphine in the VTA and HPC may be due to activation of low affinity opioid receptors which are involved in neuroprotective features of morphine.
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Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa
Oberndorfer, Tyson A.; Frank, Guido K.W.; Simmons, Alan N.; Wagner, Angela; McCurdy, Danyale; Fudge, Julie L.; Yang, Tony T.; Paulus, Martin P.; Kaye, Walter H.
2014-01-01
Objective Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods. Method Subjects recovered from anorexia and bulimia were studied to avoid confounding effects of altered nutritional state. Functional magnetic resonance imaging measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and non-caloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest. Results Compared to matched control women (n=14), women recovered from anorexia (n=14) had diminished (F(1,27)=7.79, p=0.01) and women recovered from bulimia (n=14) had exaggerated (F(1,27)=6.12, p=0.02) right anterior insula hemodynamic response to tastes of sucrose. Furthermore, anterior insula responses to sucrose compared to sucralose was exaggerated in recovered subjects (lower in women recovered from anorexia and higher in women recovered from bulimia). Conclusions The anterior insula integrates sensory/reward aspects of taste in the service of nutritional homeostasis. For example, one possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments. PMID:23732817
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The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure
Soares-Cunha, C; Coimbra, B; Borges, S; Carvalho, M M; Rodrigues, A J; Sousa, N
2014-01-01
Exposure to elevated levels of glucocorticoids (GCs) during neurodevelopment has been identified as a triggering factor for the development of reward-associated disorders in adulthood. Disturbances in the neural networks responsible for the complex processes that assign value to rewards and associated stimuli are critical for disorders such as depression, obsessive–compulsive disorders, obesity and addiction. Essential in the understanding on how cues influence behavior is the Pavlovian–instrumental transfer (PIT), a phenomenon that refers to the capacity of a Pavlovian stimulus that predicts a reward to elicit instrumental responses for that same reward. Here, we demonstrate that in utero exposure to GCs (iuGC) impairs both general and selective versions of the PIT paradigm, suggestive of deficits in motivational drive. The iuGC animals presented impaired neuronal activation pattern upon PIT performance in cortical and limbic regions, as well as morphometric changes and reduced levels of dopamine in prefrontal and orbitofrontal cortices, key regions involved in the integration of Pavlovian and instrumental stimuli. Normalization of dopamine levels rescued this behavior, a process that relied on D2/D3, but not D1, dopamine receptor activation. In summary, iuGC exposure programs the mesocorticolimbic dopaminergic circuitry, leading to a reduction in the attribution of the incentive salience to cues, in a dopamine-D2/D3-dependent manner. Ultimately, these results are important to understand how GCs bias incentive processes, a fact that is particularly relevant for disorders where differential attribution of incentive salience is critical. PMID:25928947
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Jentsch, James David; Woods, Jason A; Groman, Stephanie M; Seu, Emanuele
2010-07-01
The tendency for some individuals to partake in high-risk behaviors (eg, substance abuse, gambling, risky sexual activities) is a matter of great public health concern, yet the characteristics and neural bases of this vulnerability are largely unknown. Recent work shows that this susceptibility can be partially predicted by laboratory measures of reward seeking under risk, including the Balloon Analog Risk Task. Rats were trained to respond on two levers: one of which (the 'add lever') increased the size of a potential food reward and a second (the 'cash-out lever') that led to delivery of accrued reward. Crucially, each add-lever response was also associated with a risk that the trial would fail and no reward would be delivered. The relative probabilities that each add-lever press would lead to an addition food pellet or to trial failure (risk) were orthogonally varied. Rats exhibited a pattern of responding characteristic of incentive motivation and risk aversion, with a subset of rats showing traits of high-risk taking and/or suboptimal responding. Neural inactivation studies suggest that the orbitofrontal cortex supports greater reward seeking in the presence or absence of risk, whereas the medial prefrontal cortex is required for optimization of patterns of responding. These findings provide new information about the neural circuitry of decision making under risk and reveal new insights into the biological determinants of risk-taking behaviors that may be useful in developing biomarkers of vulnerability.
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Tsutsui-Kimura, Iku; Takiue, Hiroyuki; Yoshida, Keitaro; Xu, Ming; Yano, Ryutaro; Ohta, Hiroyuki; Nishida, Hiroshi; Bouchekioua, Youcef; Okano, Hideyuki; Uchigashima, Motokazu; Watanabe, Masahiko; Takata, Norio; Drew, Michael R; Sano, Hiromi; Mimura, Masaru; Tanaka, Kenji F
2017-02-01
Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington's disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.
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Region specific up-regulation of oxytocin receptors in the opioid oprm1 (-/-) mouse model of autism.
Gigliucci, Valentina; Leonzino, Marianna; Busnelli, Marta; Luchetti, Alessandra; Palladino, Viola Stella; D'Amato, Francesca R; Chini, Bice
2014-01-01
Autism spectrum disorders (ASDs) are characterized by impaired communication, social impairments, and restricted and repetitive behaviors and interests. Recently, altered motivation and reward processes have been suggested to participate in the physiopathology of ASDs, and μ-opioid receptors (MORs) have been investigated in relation to social reward due to their involvement in the neural circuitry of reward. Mice lacking a functional MOR gene (Oprm1 (-/-) mice) display abnormal social behavior and major autistic-like core symptoms, making them an animal model of autism. The oxytocin (OXT) system is a key regulator of social behavior and co-operates with the opioidergic system in the modulation of social behavior. To better understand the opioid-OXT interplay in the central nervous system, we first determined the expression of the oxytocin receptor (OXTR) in the brain of WT C57BL6/J mice by quantitative autoradiography; we then evaluated OXTR regional alterations in Oprm1 (-/-) mice. Moreover, we tested these mice in a paradigm of social behavior, the male-female social interaction test, and analyzed the effects of acute intranasal OXT treatment on their performance. In autoradiography, Oprm1 (-/-) mice selectively displayed increased OXTR expression in the Medial Anterior Olfactory Nucleus, the Central and Medial Amygdaloid nuclei, and the Nucleus Accumbens. Our behavioral results confirmed that Oprm1 (-/-) male mice displayed social impairments, as indicated by reduced ultrasonic calls, and that these were rescued by a single intranasal administration of OXT. Taken together, our results provide evidence of an interaction between OXT and opioids in socially relevant brain areas and in the modulation of social behavior. Moreover, they suggest that the oxytocinergic system may act as a compensative mechanism to bypass and/or restore alterations in circuits linked to impaired social behavior.
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Goldman, Marina; Szucs-Reed, Regina P; Jagannathan, Kanchana; Ehrman, Ronald N; Wang, Ze; Li, Yin; Suh, Jesse J; Kampman, Kyle; O'Brien, Charles P; Childress, Anna Rose; Franklin, Teresa R
2013-01-01
: Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain's response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects. : Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire-Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues. : Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001). : This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.
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Lesage, Elise; Aronson, Sarah E; Sutherland, Matthew T; Ross, Thomas J; Salmeron, Betty Jo; Stein, Elliot A
2017-06-01
Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others. clinicaltrials.gov Identifier: NCT00830739.
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Externalizing proneness and brain response during pre-cuing and viewing of emotional pictures.
Foell, Jens; Brislin, Sarah J; Strickland, Casey M; Seo, Dongju; Sabatinelli, Dean; Patrick, Christopher J
2016-07-01
Externalizing proneness, or trait disinhibition, is a concept relevant to multiple high-impact disorders involving impulsive-aggressive behavior. Its mechanisms remain disputed: major models posit hyperresponsive reward circuitry or heightened threat-system reactivity as sources of disinhibitory tendencies. This study evaluated alternative possibilities by examining relations between trait disinhibition and brain reactivity during preparation for and processing of visual affective stimuli. Forty females participated in a functional neuroimaging procedure with stimuli presented in blocks containing either pleasurable or aversive pictures interspersed with neutral, with each picture preceded by a preparation signal. Preparing to view elicited activation in regions including nucleus accumbens, whereas visual regions and bilateral amygdala were activated during viewing of emotional pictures. High disinhibition predicted reduced nucleus accumbens activation during preparation within pleasant/neutral picture blocks, along with enhanced amygdala reactivity during viewing of pleasant and aversive pictures. Follow-up analyses revealed that the augmented amygdala response was related to reduced preparatory activation. Findings indicate that participants high in disinhibition are less able to process implicit cues and mentally prepare for upcoming stimuli, leading to limbic hyperreactivity during processing of actual stimuli. This outcome is helpful for integrating findings from studies suggesting reward-system hyperreactivity and others suggesting threat-system hyperreactivity as mechanisms for externalizing proneness. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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How placebos change the patient's brain.
Benedetti, Fabrizio; Carlino, Elisa; Pollo, Antonella
2011-01-01
Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.
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Altered Reward Function in Adolescent Depression: What, When, and How?
Forbes, Erika E.; Dahl, Ronald E.
2011-01-01
Background Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology, and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. Methods This conceptual review describes the what, when, and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo, and ScienceDirect for the years 1990–2010. Results A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Conclusions Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions, and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. PMID:22117893
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Downs, B. William; Bowirrat, Abdalla; Waite, Roger L.; Braverman, Eric R.; Madigan, Margaret; Oscar-Berman, Marlene; DiNubile, Nicholas; Gold, Mark
2013-01-01
Background and Hypothesis It is well known that after prolonged abstinence, individuals who imbibe or use their drug of choice experience a powerful euphoria that precipitates serious relapse. While a biological explanation for this conundrum has remained elusive, we hypothesize that this clinically observed “super sensitivity” might be tied to genetic dopaminergic polymorphisms. Another therapeutic conundrum relates to the paradoxical finding that the dopaminergic agonist bromocriptine induces stronger activation of brain reward circuitry in individuals who carry the DRD2 A1 allele compared to DRD2 A2 allele carriers. Based upon the fact that carriers of the A1 allele relative to the A2 allele of the DRD2 gene have significantly lower D2 receptor density, a reduced sensitivity to dopamine agonist activity would be expected in the former. Thus, it is perplexing that with low D2 density there is an increase in reward sensitivity with the dopamine agonist bromocriptine. Moreover, under chronic or long-term therapy, the potential proliferation of D2 receptors with bromocriptine has been shown in vitro. This seems to lead to a positive outcome and significantly better treatment compliance only in A1 carriers. Proposal and Conclusion We propose that low D2 receptor density and polymorphisms of the D2 gene are associated with risk for relapse of substance abuse including alcohol dependence, heroin craving, cocaine dependence, methamphetamine abuse, nicotine sensitization, and glucose craving. With this in mind, we suggest a putative physiological mechanism that may help to explain the enhanced sensitivity following intense acute dopaminergic D2 receptor activation: “denervation supersensitivity.” Thus, the administration of dopamine D2 agonists would target D2 sensitization and attenuate relapse, especially in D2 receptor A1 allele carriers. This hypothesized mechanism is supported by clinical trials utilizing the amino-acid neurotransmitter precursors, enkephalinase and catechol-O-methyl-transferase (COMT) enzyme inhibition, which have resulted in attenuated relapse rates in Reward Deficiency Syndrome (RDS) probands. Future warranted translational research with positive outcome showing prevented or lower relapse in RDS will ultimately support the proposed concept, which we term “Deprivation-Amplification Relapse Therapy (DART).” PMID:19940429
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Siep, Nicolette; Roefs, Anne; Roebroeck, Alard; Havermans, Remco; Bonte, Milene L; Jansen, Anita
2009-03-02
Research indicates that dysfunctional food reward processing may contribute to pathological eating behaviour. It is widely recognized that both the amygdala and the orbitofrontal cortex (OFC) are essential parts of the brain's reward circuitry. The aims of this fMRI study were (1) to examine the effects of food deprivation and calorie content on reward processing in the amygdala and the OFC, and (2) to examine whether an explicit evaluation of foods is necessary for OFC, but not amygdalar activity. Addressing the first aim, healthy females were presented with high and low calorie food pictures while being either hungry or satiated. For the second aim, attention focus was manipulated by directing participants' attention either to the food or to a neutral aspect. This study shows that hunger interacts with the energy content of foods, modulating activity in the posterior cingulate cortex, medial OFC, insula, caudate putamen and fusiform gyrus. Results show that satiated healthy females show an increased reward processing in response to low calorie foods. Confirming our hypothesis, food deprivation increased activity following the presentation of high calorie foods, which may explain why treatments of obesity energy restricting diets often are unsuccessful. Interestingly, activity in both the amygdala and mOFC was only evident when participants explicitly evaluated foods. However, attention independent activity was found in the mPFC following the high calorie foods cues when participants where hungry. Current findings indicate that research on how attention modulates food reward processing might prove especially insightful in the study of the neural substrates of healthy and pathological eating behaviour.
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Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4
Bachtell, Ryan; Hutchinson, Mark R.; Wang, Xiaohui; Rice, Kenner C.; Maier, Steven F; Watkins, Linda R.
2017-01-01
There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drug-primed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse. PMID:26022268
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Dopaminergic Modulation of Risky Decision-Making
Simon, Nicholas W.; Montgomery, Karienn S.; Beas, Blanca S.; Mitchell, Marci R.; LaSarge, Candi L.; Mendez, Ian A.; Bañuelos, Cristina; Vokes, Colin M.; Taylor, Aaron B.; Haberman, Rebecca P.; Bizon, Jennifer L.; Setlow, Barry
2012-01-01
Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a “Risky Decision-making Task” that involves choices between small “safe” rewards and large “risky” rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal corticalstriatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences. PMID:22131407
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The Role of the Anterior Insula in Adolescent Decision Making
Smith, Ashley R.; Steinberg, Laurence; Chein, Jason
2017-01-01
Much recent research on adolescent decision making has sought to characterize the neurobiological mechanisms that underlie the proclivity of adolescents to engage in risky behavior. One class of influential neurodevelopmental models focuses on the asynchronous development of neural systems, particularly those responsible for self-regulation and reward seeking. While this work has largely focused on the development of prefrontal (self-regulation) and striatal (reward processing) circuitry, the present article explores the significance of a different region, the anterior insular cortex (AIC), in adolescent decision making. Although the AIC is known for its role as a cognitive-emotional hub, and is included in some models of adult self-regulation and reward seeking, the importance of the AIC and its maturation in adolescent risk taking has not been extensively explored. In this article we discuss evidence on AIC development, and consider how age-related differences in AIC engagement may contribute to heightened risk taking during adolescence. Based on this review, we propose a model in which the engagement of adolescents in risk taking may be linked in part to the maturation of the AIC and its connectivity to the broader brain networks in which it participates. PMID:24853135
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The medial prefrontal cortex exhibits money illusion
Weber, Bernd; Rangel, Antonio; Wibral, Matthias; Falk, Armin
2009-01-01
Behavioral economists have proposed that money illusion, which is a deviation from rationality in which individuals engage in nominal evaluation, can explain a wide range of important economic and social phenomena. This proposition stands in sharp contrast to the standard economic assumption of rationality that requires individuals to judge the value of money only on the basis of the bundle of goods that it can buy—its real value—and not on the basis of the actual amount of currency—its nominal value. We used fMRI to investigate whether the brain's reward circuitry exhibits money illusion. Subjects received prizes in 2 different experimental conditions that were identical in real economic terms, but differed in nominal terms. Thus, in the absence of money illusion there should be no differences in activation in reward-related brain areas. In contrast, we found that areas of the ventromedial prefrontal cortex (vmPFC), which have been previously associated with the processing of anticipatory and experienced rewards, and the valuation of goods, exhibited money illusion. We also found that the amount of money illusion exhibited by the vmPFC was correlated with the amount of money illusion exhibited in the evaluation of economic transactions. PMID:19307555
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Own-gender imitation activates the brain's reward circuitry
Iacoboni, Macro; Martin, Alia; Dapretto, Mirella
2012-01-01
Imitation is an important component of human social learning throughout life. Theoretical models and empirical data from anthropology and psychology suggest that people tend to imitate self-similar individuals, and that such imitation biases increase the adaptive value (e.g., self-relevance) of learned information. It is unclear, however, what neural mechanisms underlie people's tendency to imitate those similar to themselves. We focused on the own-gender imitation bias, a pervasive bias thought to be important for gender identity development. While undergoing fMRI, participants imitated own- and other-gender actors performing novel, meaningless hand signs; as control conditions, they also simply observed such actions and viewed still portraits of the same actors. Only the ventral and dorsal striatum, orbitofrontal cortex and amygdala were more active when imitating own- compared to other-gender individuals. A Bayesian analysis of the BrainMap neuroimaging database demonstrated that the striatal region preferentially activated by own-gender imitation is selectively activated by classical reward tasks in the literature. Taken together, these findings reveal a neurobiological mechanism associated with the own-gender imitation bias and demonstrate a novel role of reward-processing neural structures in social behavior. PMID:22383803
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Research Review: altered reward function in adolescent depression: what, when and how?
Forbes, Erika E; Dahl, Ronald E
2012-01-01
Conceptual models and recent evidence indicate that neural response to reward is altered in depression. Taking a developmental approach to investigating reward function in adolescent depression can elucidate the etiology, pathophysiology and course of depression, a disorder that typically begins during adolescence and has high rates of recurrence. This conceptual review describes the what, when and how of altered reward function in adolescent depression. With the goal of generating new, testable hypotheses within a developmental affective neuroscience framework, we critically review findings and suggest future directions. Peer-reviewed empirical papers for inclusion in this critical review were obtained by searching PubMed, PsycInfo and ScienceDirect for the years 1990-2010. A pattern of low striatal response and high medial prefrontal response to reward is evident in adolescents and adults with depression. Given the salience of social stimuli for positive affect and depression, reward function might be especially disrupted in response to social rewards. Because of changes in the dopamine system and reward function with aging, altered reward function in depression might be more evident during adolescence than later in life; however, low reward function may also be a stable characteristic of people who experience depression. Mechanisms of altered reward function in depression could include disrupted balance of corticostriatal circuit function, with disruption occurring as aberrant adolescent brain development. Future studies should examine responses to social rewards; employ longitudinal and prospective designs; and investigate patterns of functional connectivity in reward circuits. Understanding altered reward function in depression has potential implications for treatment development. A more rigorous approach to investigating anhedonia, threat-reward interactions and comorbid anxiety will be valuable to future progress in describing the role of reward function in the pathophysiology of depression. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.
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Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.
Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim
2018-07-01
The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.
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Crayfish Self-Administer Amphetamine in a Spatially Contingent Task.
Datta, Udita; van Staaden, Moira; Huber, Robert
2018-01-01
Natural reward is an essential element of any organism's ability to adapt to environmental variation. Its underlying circuits and mechanisms guide the learning process as they help associate an event, or cue, with the perception of an outcome's value. More generally, natural reward serves as the fundamental generator of all motivated behavior. Addictive plant alkaloids are able to activate this circuitry in taxa ranging from planaria to humans. With modularly organized nervous systems and confirmed vulnerabilities to human drugs of abuse, crayfish have recently emerged as a compelling model for the study of the addiction cycle, including psychostimulant effects, sensitization, withdrawal, reinstatement, and drug reward in conditioned place preference paradigms. Here we extend this work with the demonstration of a spatially contingent, operant drug self-administration paradigm for amphetamine. When the animal enters a quadrant of the arena with a particular textured substrate, a computer-based control system delivers amphetamine through an indwelling fine-bore cannula. Resulting reward strength, dose-response, and the time course of operant conditioning were assessed. Individuals experiencing the drug contingent on their behavior, displayed enhanced rates of operant responses compared to that of their yoked (non-contingent) counterparts. Application of amphetamine near the supra-esophageal ganglion elicited stronger and more robust increases in operant responding than did systemic infusions. This work demonstrates automated implementation of a spatially contingent self-administration paradigm in crayfish, which provides a powerful tool to explore comparative perspectives in drug-sensitive reward, the mechanisms of learning underlying the addictive cycle, and phylogenetically conserved vulnerabilities to psychostimulant compounds.
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Crayfish Self-Administer Amphetamine in a Spatially Contingent Task
Datta, Udita; van Staaden, Moira; Huber, Robert
2018-01-01
Natural reward is an essential element of any organism’s ability to adapt to environmental variation. Its underlying circuits and mechanisms guide the learning process as they help associate an event, or cue, with the perception of an outcome’s value. More generally, natural reward serves as the fundamental generator of all motivated behavior. Addictive plant alkaloids are able to activate this circuitry in taxa ranging from planaria to humans. With modularly organized nervous systems and confirmed vulnerabilities to human drugs of abuse, crayfish have recently emerged as a compelling model for the study of the addiction cycle, including psychostimulant effects, sensitization, withdrawal, reinstatement, and drug reward in conditioned place preference paradigms. Here we extend this work with the demonstration of a spatially contingent, operant drug self-administration paradigm for amphetamine. When the animal enters a quadrant of the arena with a particular textured substrate, a computer-based control system delivers amphetamine through an indwelling fine-bore cannula. Resulting reward strength, dose-response, and the time course of operant conditioning were assessed. Individuals experiencing the drug contingent on their behavior, displayed enhanced rates of operant responses compared to that of their yoked (non-contingent) counterparts. Application of amphetamine near the supra-esophageal ganglion elicited stronger and more robust increases in operant responding than did systemic infusions. This work demonstrates automated implementation of a spatially contingent self-administration paradigm in crayfish, which provides a powerful tool to explore comparative perspectives in drug-sensitive reward, the mechanisms of learning underlying the addictive cycle, and phylogenetically conserved vulnerabilities to psychostimulant compounds.
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Ghrelin at the interface of obesity and reward.
Schellekens, Harriët; Dinan, Timothy G; Cryan, John F
2013-01-01
The prevalence of obesity continues to increase and has reached epidemic proportions. Accumulating data over the past few decades have given us key insights and broadened our understanding of the peripheral and central regulation of energy homeostasis. Despite this, the currently available pharmacological treatments, reducing body weight, remain limited due to poor efficacy and side effects. The gastric peptide ghrelin has been identified as the only orexigenic hormone from the periphery to act in the hypothalamus to stimulate food intake. Recently, a role for ghrelin and its receptor at the interface between homeostatic control of appetite and reward circuitries modulating the hedonic aspects of food has also emerged. Nonhomeostatic factors such as the rewarding and motivational value of food, which increase with food palatability and caloric content, can override homeostatic control of food intake. This nonhomeostatic decision to eat leads to overconsumption beyond nutritional needs and is being recognized as a key component in the underlying causes for the increase in obesity incidence worldwide. In addition, the hedonic feeding behavior has been linked to food addiction and an important role for ghrelin in the development of addiction has been suggested. Moreover, plasma ghrelin levels are responsive to conditions of stress, and recent evidence has implicated ghrelin in stress-induced food-reward behavior. The prominent role of the ghrelinergic system in the regulation of feeding gives rise to it as an effective target for the development of successful antiobesity pharmacotherapies that not only affect satiety but also selectively modulate the rewarding properties of food and reduce the desire to eat. Copyright © 2013 Elsevier Inc. All rights reserved.
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Morita, Kenji; Morishima, Mieko; Sakai, Katsuyuki; Kawaguchi, Yasuo
2013-05-15
Humans and animals take actions quickly when they expect that the actions lead to reward, reflecting their motivation. Injection of dopamine receptor antagonists into the striatum has been shown to slow such reward-seeking behavior, suggesting that dopamine is involved in the control of motivational processes. Meanwhile, neurophysiological studies have revealed that phasic response of dopamine neurons appears to represent reward prediction error, indicating that dopamine plays central roles in reinforcement learning. However, previous attempts to elucidate the mechanisms of these dopaminergic controls have not fully explained how the motivational and learning aspects are related and whether they can be understood by the way the activity of dopamine neurons itself is controlled by their upstream circuitries. To address this issue, we constructed a closed-circuit model of the corticobasal ganglia system based on recent findings regarding intracortical and corticostriatal circuit architectures. Simulations show that the model could reproduce the observed distinct motivational effects of D1- and D2-type dopamine receptor antagonists. Simultaneously, our model successfully explains the dopaminergic representation of reward prediction error as observed in behaving animals during learning tasks and could also explain distinct choice biases induced by optogenetic stimulation of the D1 and D2 receptor-expressing striatal neurons. These results indicate that the suggested roles of dopamine in motivational control and reinforcement learning can be understood in a unified manner through a notion that the indirect pathway of the basal ganglia represents the value of states/actions at a previous time point, an empirically driven key assumption of our model.
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Optogenetic dissection of medial prefrontal cortex circuitry
Riga, Danai; Matos, Mariana R.; Glas, Annet; Smit, August B.; Spijker, Sabine; Van den Oever, Michel C.
2014-01-01
The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders. PMID:25538574
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Optogenetic dissection of medial prefrontal cortex circuitry.
Riga, Danai; Matos, Mariana R; Glas, Annet; Smit, August B; Spijker, Sabine; Van den Oever, Michel C
2014-01-01
The medial prefrontal cortex (mPFC) is critically involved in numerous cognitive functions, including attention, inhibitory control, habit formation, working memory and long-term memory. Moreover, through its dense interconnectivity with subcortical regions (e.g., thalamus, striatum, amygdala and hippocampus), the mPFC is thought to exert top-down executive control over the processing of aversive and appetitive stimuli. Because the mPFC has been implicated in the processing of a wide range of cognitive and emotional stimuli, it is thought to function as a central hub in the brain circuitry mediating symptoms of psychiatric disorders. New optogenetics technology enables anatomical and functional dissection of mPFC circuitry with unprecedented spatial and temporal resolution. This provides important novel insights in the contribution of specific neuronal subpopulations and their connectivity to mPFC function in health and disease states. In this review, we present the current knowledge obtained with optogenetic methods concerning mPFC function and dysfunction and integrate this with findings from traditional intervention approaches used to investigate the mPFC circuitry in animal models of cognitive processing and psychiatric disorders.
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Fischer, Adina S; Whitfield-Gabrieli, Susan; Roth, Robert M; Brunette, Mary F; Green, Alan I
2014-09-01
Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15 mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD. Copyright © 2014. Published by Elsevier B.V.
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Thiebaud, Nicolas; Johnson, Melissa C.; Butler, Jessica L.; Bell, Genevieve A.; Ferguson, Kassandra L.; Fadool, Andrew R.; Fadool, James C.; Gale, Alana M.; Gale, David S.
2014-01-01
Currently, 65% of Americans are overweight, which leads to well-supported cardiovascular and cognitive declines. Little, however, is known concerning obesity's impact on sensory systems. Because olfaction is linked with ingestive behavior to guide food choice, its potential dysfunction during obesity could evoke a positive feedback loop to perpetuate poor ingestive behaviors. To determine the effect of chronic energy imbalance and reveal any structural or functional changes associated with obesity, we induced long-term, diet-induced obesity by challenging mice to high-fat diets: (1) in an obesity-prone (C57BL/6J) and obesity-resistant (Kv1.3−/−) line of mice, and compared this with (2) late-onset, genetic-induced obesity in MC4R−/− mice in which diabetes secondarily precipitates after disruption of the hypothalamic axis. We report marked loss of olfactory sensory neurons and their axonal projections after exposure to a fatty diet, with a concomitant reduction in electro-olfactogram amplitude. Loss of olfactory neurons and associated circuitry is linked to changes in neuronal proliferation and normal apoptotic cycles. Using a computer-controlled, liquid-based olfactometer, mice maintained on fatty diets learn reward-reinforced behaviors more slowly, have deficits in reversal learning demonstrating behavioral inflexibility, and exhibit reduced olfactory discrimination. When obese mice are removed from their high-fat diet to regain normal body weight and fasting glucose, olfactory dysfunctions are retained. We conclude that chronic energy imbalance therefore presents long-lasting structural and functional changes in the operation of the sensory system designed to encode external and internal chemical information and leads to altered olfactory- and reward-driven behaviors. PMID:24828650
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Fischer, Adina S.; Whitfield-Gabrieli, Susan; Roth, Robert M.; Brunette, Mary F.; Green, Alan I.
2016-01-01
Cannabis use disorder (CUD) occurs in up to 42% of patients with schizophrenia and substantially worsens disease progression. The basis of CUD in schizophrenia is unclear and available treatments are rarely successful at limiting cannabis use. We have proposed that a dysregulated brain reward circuit (BRC) may underpin cannabis use in these patients. In the present pilot study, we used whole-brain seed-to-voxel resting state functional connectivity (rs-fc) to examine the BRC of patients with schizophrenia and CUD, and to explore the effects of smoked cannabis and orally administered delta-9-tetrahydrocannabinol (THC) on the BRC. 12 patients with schizophrenia and CUD and 12 control subjects each completed two fMRI resting scans, with patients administered either a 3.6% THC cannabis cigarette (n=6) or a 15mg THC capsule (n=6) prior to their second scan. Results revealed significantly reduced connectivity at baseline in patients relative to controls, with most pronounced hypoconnectivity found between the nucleus accumbens and prefrontal cortical BRC regions (i.e., anterior prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex). Both cannabis and THC administration increased connectivity between these regions, in direct correlation with increases in plasma THC levels. This study is the first to investigate interregional connectivity of the BRC and the effects of cannabis and THC on this circuit in patients with schizophrenia and CUD. The findings from this pilot study support the use of rs-fc as a means of measuring the integrity of the BRC and the effects of pharmacologic agents acting on this circuit in patients with schizophrenia and CUD. PMID:25037524
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Winstanley, Catharine A; Baunez, Christelle; Theobald, David E H; Robbins, Trevor W
2005-06-01
Although the subthalamic nucleus (STN) is involved in regulating motor function, and inactivation of this structure relieves the motor symptoms in Parkinsonian patients, recent data indicate that corticosubthalamic connections are involved in both the regulation of attention and the ability to withhold from responding. Considerable evidence suggests that the neural circuitry underlying such behavioural disinhibition or impulsive action can be at least partially dissociated from that implicated in impulsive decision-making and it has been suggested that the tendency to choose impulsively is related to the ability to form and use Pavlovian associations. To explore these hypotheses further, STN-lesioned rats were tested on the delay-discounting model of impulsive choice, where impulsivity is defined as the selection of a small immediate over a larger delayed reward, as well as in a rodent autoshaping paradigm. In contrast to previous reports of increased impulsive action, STN lesions decreased impulsive choice but dramatically impaired the acquisition of the autoshaping response. When the STN was lesioned after the establishment of autoshaping behaviour, lesioned subjects were more sensitive to the omission of reward, indicative of a reduction in the use of Pavlovian associations to control autoshaping performance. These results emphasize the importance of the STN in permitting conditioned stimulus-unconditioned stimulus associations to regulate goal-seeking, a function which may relate to the alterations in impulsive choice observed in the delay-discounting task. These data bear a striking similarity to those observed after lesions of the orbitofrontal cortex and are suggestive of an important role for corticosubthalamic connections in complex cognitive behaviour.
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Mechanisms of Long Non-Coding RNAs in the Assembly and Plasticity of Neural Circuitry.
Wang, Andi; Wang, Junbao; Liu, Ying; Zhou, Yan
2017-01-01
The mechanisms underlying development processes and functional dynamics of neural circuits are far from understood. Long non-coding RNAs (lncRNAs) have emerged as essential players in defining identities of neural cells, and in modulating neural activities. In this review, we summarized latest advances concerning roles and mechanisms of lncRNAs in assembly, maintenance and plasticity of neural circuitry, as well as lncRNAs' implications in neurological disorders. We also discussed technical advances and challenges in studying functions and mechanisms of lncRNAs in neural circuitry. Finally, we proposed that lncRNA studies would advance our understanding on how neural circuits develop and function in physiology and disease conditions.
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King, S J; Rodrigues, T; Watts, A; Murray, E; Wilson, A; Abizaid, A
2016-04-05
Binge eating is defined by the consumption of an excessive amount of food in a short time, reflecting a form of hedonic eating that is not necessarily motivated by caloric need. Foods consumed during a binge are also often high in fat and/or sugar. Ghrelin, signaling centrally via the growth-hormone secretagogue receptor (GHSR), stimulates growth hormone release and appetite. GHSR signaling also enhances the rewarding value of palatable foods and increases the motivation for such foods. As ghrelin interacts directly with dopaminergic reward circuitry, shown to be involved in binge eating, the current studies explored the role of GHSR signaling in a limited access model of binge eating in mice. In this model, mice received either intermittent (INT) or daily (DAILY) access to a nutritionally complete high-fat diet (HFD) for 2h late in the light cycle, alongside 24-h ad libitum chow. In CD-1 mice, 2-h exposure to HFD generated substantial binge-like intake of HFD, as well as a binge-compensate pattern of 24-h daily intake. INT and daily groups did not differ in 2-h HFD consumption, while INT mice maintained stable intake of chow despite access to HFD. GHSR knock-out (KO) and wild-type (WT) mice both binged during HFD access, and exhibited the same binge-compensate pattern. INT GHSR KO mice did not binge as much as WT, while DAILY KO and WT were comparable. Overall, GHSR KO mice consumed fewer calories from HFD, regardless of access condition. GHSR KO mice also had reduced activation of the nucleus accumbens shell, but not core, following HFD consumption. These data support the ability of INT HFD in mice to induce a binge-compensate pattern of intake that emulates select components of binge eating in humans. There also appears to be a role for GHSR signaling in driving HFD consumption under these conditions, potentially via mediation of reward-related circuitry. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
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Shared neurocircuitry underlying feeding and drugs of abuse in Drosophila.
Landayan, Dan; Wolf, Fred W
2015-12-01
The neural circuitry and molecules that control the rewarding properties of food and drugs of abuse appear to partially overlap in the mammalian brain. This has raised questions about the extent of the overlap and the precise role of specific circuit elements in reward and in other behaviors associated with feeding regulation and drug responses. The much simpler brain of invertebrates including the fruit fly Drosophila, offers an opportunity to make high-resolution maps of the circuits and molecules that govern behavior. Recent progress in Drosophila has revealed not only some common substrates for the actions of drugs of abuse and for the regulation of feeding, but also a remarkable level of conservation with vertebrates for key neuromodulatory transmitters. We speculate that Drosophila may serve as a model for distinguishing the neural mechanisms underlying normal and pathological motivational states that will be applicable to mammals. Copyright © 2016 Chang Gung University. Published by Elsevier B.V. All rights reserved.
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Neural representation of expected value in the adolescent brain.
Barkley-Levenson, Emily; Galván, Adriana
2014-01-28
Previous work shows that the adolescent reward system is hyperactive, but this finding may be confounded by differences in how teens value money. To address this, we examined the neural ontogeny of objective value representation. Adolescent and adult participants performed a monetary gambling task in which they chose to accept or reject gambles of varying expected value. Increasing expected value had a stronger influence over gambling choices in adolescents relative to adults, an effect that was paralleled by greater activation in the ventral striatum in adolescents. This unique adolescent ventral striatum response remained even after matching groups on acceptance behavior. These behavioral and neural data suggest that the value of available options has a greater influence in adolescent versus adult choices, even when objective value and subjective choice are held constant. This research provides further evidence that hyperactivation of reward circuitry in adolescence may be a normative ontogenetic shift that is due to greater valuation in the adolescent brain.
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Neural representation of expected value in the adolescent brain
Barkley-Levenson, Emily; Galván, Adriana
2014-01-01
Previous work shows that the adolescent reward system is hyperactive, but this finding may be confounded by differences in how teens value money. To address this, we examined the neural ontogeny of objective value representation. Adolescent and adult participants performed a monetary gambling task in which they chose to accept or reject gambles of varying expected value. Increasing expected value had a stronger influence over gambling choices in adolescents relative to adults, an effect that was paralleled by greater activation in the ventral striatum in adolescents. This unique adolescent ventral striatum response remained even after matching groups on acceptance behavior. These behavioral and neural data suggest that the value of available options has a greater influence in adolescent versus adult choices, even when objective value and subjective choice are held constant. This research provides further evidence that hyperactivation of reward circuitry in adolescence may be a normative ontogenetic shift that is due to greater valuation in the adolescent brain. PMID:24474790
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Haenicke, Joachim; Yamagata, Nobuhiro; Zwaka, Hanna; Nawrot, Martin; Menzel, Randolf
2018-01-01
The mushroom body (MB) in insects is known as a major center for associative learning and memory, although exact locations for the correlating memory traces remain to be elucidated. Here, we asked whether presynaptic boutons of olfactory projection neurons (PNs) in the main input site of the MB undergo neuronal plasticity during classical odor-reward conditioning and correlate with the conditioned behavior. We simultaneously measured Ca 2+ responses in the boutons and conditioned behavioral responses to learned odors in honeybees. We found that the absolute amount of the neural change for the rewarded but not for the unrewarded odor was correlated with the behavioral learning rate across individuals. The temporal profile of the induced changes matched with odor response dynamics of the MB-associated inhibitory neurons, suggestive of activity modulation of boutons by this neural class. We hypothesize the circuit-specific neural plasticity relates to the learned value of the stimulus and underlies the conditioned behavior of the bees.
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van Holst, Ruth J; Chase, Henry W; Clark, Luke
2014-01-01
Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. 'Near-miss' events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the 'illusion of control'). Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression. For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex. These findings corroborate the 'non-categorical' nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.
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Simons, LE; Pielech, M; Erpelding, N; Linnman, C; Moulton, E; Sava, S; Lebel, A; Serrano, P; Sethna, N; Berde, C; Becerra, L; Borsook, D
2014-01-01
The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-gender matched controls before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared to controls, with differences predominantly in the left amygdala in the pre-treated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy controls from Time 1 to Time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related fear scores and (4) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity following an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response. PMID:24861582
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Fouragnan, Elsa; Retzler, Chris; Philiastides, Marios G
2018-03-25
Learning occurs when an outcome differs from expectations, generating a reward prediction error signal (RPE). The RPE signal has been hypothesized to simultaneously embody the valence of an outcome (better or worse than expected) and its surprise (how far from expectations). Nonetheless, growing evidence suggests that separate representations of the two RPE components exist in the human brain. Meta-analyses provide an opportunity to test this hypothesis and directly probe the extent to which the valence and surprise of the error signal are encoded in separate or overlapping networks. We carried out several meta-analyses on a large set of fMRI studies investigating the neural basis of RPE, locked at decision outcome. We identified two valence learning systems by pooling studies searching for differential neural activity in response to categorical positive-versus-negative outcomes. The first valence network (negative > positive) involved areas regulating alertness and switching behaviours such as the midcingulate cortex, the thalamus and the dorsolateral prefrontal cortex whereas the second valence network (positive > negative) encompassed regions of the human reward circuitry such as the ventral striatum and the ventromedial prefrontal cortex. We also found evidence of a largely distinct surprise-encoding network including the anterior cingulate cortex, anterior insula and dorsal striatum. Together with recent animal and electrophysiological evidence this meta-analysis points to a sequential and distributed encoding of different components of the RPE signal, with potentially distinct functional roles. © 2018 Wiley Periodicals, Inc.
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Floresco, Stan B; Montes, David R; Tse, Maric M T; van Holstein, Mieke
2018-02-21
The nucleus accumbens (NAc) is a key node within corticolimbic circuitry for guiding action selection and cost/benefit decision making in situations involving reward uncertainty. Preclinical studies have typically assessed risk/reward decision making using assays where decisions are guided by internally generated representations of choice-outcome contingencies. Yet, real-life decisions are often influenced by external stimuli that inform about likelihoods of obtaining rewards. How different subregions of the NAc mediate decision making in such situations is unclear. Here, we used a novel assay colloquially termed the "Blackjack" task that models these types of situations. Male Long-Evans rats were trained to choose between one lever that always delivered a one-pellet reward and another that delivered four pellets with different probabilities [either 50% (good-odds) or 12.5% (poor-odds)], which were signaled by one of two auditory cues. Under control conditions, rats selected the large/risky option more often on good-odds versus poor-odds trials. Inactivation of the NAc core caused indiscriminate choice patterns. In contrast, NAc shell inactivation increased risky choice, more prominently on poor-odds trials. Additional experiments revealed that both subregions contribute to auditory conditional discrimination. NAc core or shell inactivation reduced Pavlovian approach elicited by an auditory CS+, yet shell inactivation also increased responding during presentation of a CS-. These data highlight distinct contributions for NAc subregions in decision making and reward seeking guided by discriminative stimuli. The core is crucial for implementation of conditional rules, whereas the shell refines reward seeking by mitigating the allure of larger, unlikely rewards and reducing expression of inappropriate or non-rewarded actions. SIGNIFICANCE STATEMENT Using external cues to guide decision making is crucial for adaptive behavior. Deficits in cue-guided behavior have been associated with neuropsychiatric disorders, such as attention deficit hyperactivity disorder and schizophrenia, which in turn has been linked to aberrant processing in the nucleus accumbens. However, many preclinical studies have often assessed risk/reward decision making in the absence of explicit cues. The current study fills that gap by using a novel task that allows for the assessment of cue-guided risk/reward decision making in rodents. Our findings identified distinct yet complementary roles for the medial versus lateral portions of this nucleus that provide a broader understanding of the differential contributions it makes to decision making and reward seeking guided by discriminative stimuli. Copyright © 2018 the authors 0270-6474/18/381901-14$15.00/0.
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Amotivation in Schizophrenia: Integrated Assessment With Behavioral, Clinical, and Imaging Measures
Wolf, Daniel H.; Satterthwaite, Theodore D.; Kantrowitz, Jacob J.; Katchmar, Natalie; Vandekar, Lillie; Elliott, Mark A.; Ruparel, Kosha
2014-01-01
Motivational deficits play a central role in disability caused by schizophrenia and constitute a major unmet therapeutic need. Negative symptoms have previously been linked to hypofunction in ventral striatum (VS), a core component of brain motivation circuitry. However, it remains unclear to what extent this relationship holds for specific negative symptoms such as amotivation, and this question has not been addressed with integrated behavioral, clinical, and imaging measures. Here, 41 individuals with schizophrenia and 37 controls performed a brief, computerized progressive ratio task (PRT) that quantifies effort exerted in pursuit of monetary reward. Clinical amotivation was assessed using the recently validated Clinical Assessment Interview for Negative Symptoms (CAINS). VS function was probed during functional magnetic resonance imaging using a monetary guessing paradigm. We found that individuals with schizophrenia had diminished motivation as measured by the PRT, which significantly and selectively related to clinical amotivation as measured by the CAINS. Critically, lower PRT motivation in schizophrenia was also dimensionally related to VS hypofunction. Our results demonstrate robust dimensional associations between behavioral amotivation, clinical amotivation, and VS hypofunction in schizophrenia. Integrating behavioral measures such as the PRT will facilitate translational efforts to identify biomarkers of amotivation and to assess response to novel therapeutic interventions. PMID:24657876
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Nectar quality perception by honey bees (Apis mellifera ligustica).
Sanderson, Charlotte E; Cook, Peyton; Hill, Peggy S M; Orozco, Benjamin S; Abramson, Charles I; Wells, Harrington
2013-11-01
In exploring how foragers perceive rewards, we often find that well-motivated individuals are not too choosy and unmotivated individuals are unreliable and inconsistent. Nevertheless, when given a choice we see that individuals can clearly distinguish between rewards. Here we develop the logic of using responses to two-choice problems as a derivative function of perceived reward, and utilize this model to examine honey bee perception of nectar quality. Measuring the derivative allows us to deduce the perceived reward function. The derivative function of the perceived reward equation gives the rate of change of the reward perceived for each reward value. This approach depends on presenting free-flying foragers with a series of two different rewards presented simultaneously (i.e., two-choice, binomial tests). We also examine how honey bees integrate information from a range of reward qualities to formulate a functional response. Results suggest that honey bees overestimate higher quality rewards and that direct comparison is an important step in the integration of information from a range of rewards.
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Method, apparatus and system to compensate for drift by physically unclonable function circuitry
Hamlet, Jason
2016-11-22
Techniques and mechanisms to detect and compensate for drift by a physically uncloneable function (PUF) circuit. In an embodiment, first state information is registered as reference information to be made available for subsequent evaluation of whether drift by PUF circuitry has occurred. The first state information is associated with a first error correction strength. The first state information is generated based on a first PUF value output by the PUF circuitry. In another embodiment, second state information is determined based on a second PUF value that is output by the PUF circuitry. An evaluation of whether drift has occurred is performed based on the first state information and the second state information, the evaluation including determining whether a threshold error correction strength is exceeded concurrent with a magnitude of error being less than the first error correction strength.
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Yang, Hui-Di; Wang, Qian; Wang, De-Hua
2014-06-01
This article is part of a Special Issue "Energy Balance". Effects of γ-aminobutyric acid (GABA) on food hoarding are unknown in rodents, and the effects of energy balance and GABA have not been evaluated in females. To evaluate the role of food deprivation and GABA on food hoarding, female Mongolian gerbils were given i.p. injection of diazepam (1mg/kg and 3mg/kg, respectively), a GABAA receptor agonist. Among food-deprived females, there was a bimodal pattern in the frequency of gerbils with different levels of food hoarding. High food hoarding (HFH) and low food hoarding (LFH) gerbils were analyzed. Diazepam blocked food deprivation-induced food hoarding in HFH gerbils, but not in LFH gerbils. This blockade was associated with increased cellular activation in selected brain areas, such as the nucleus accumbens (NAcc), caudate putamen (CP) and ventral tegmental area (VTA), which suggested that direct activation of GABA in the brain reward circuitry decreased food hoarding in HFH females. Moreover, diazepam increased Fos expression in field CA2 and CA3 of the hippocampus, but had no significant effect on Fos expression in field CA1 and dentate gyrus (DG) of the hippocampus, indicating that the hippocampus has area-specific effects on food hoarding in HFH gerbils. Diazepam did not alter food intake in both HFH and LFH gerbils. In addition, serum corticosterone concentrations were higher in the HFH than in the LFH ones. Together, these data indicated that food deprivation increased food hoarding in female gerbils, diazepam reduced food deprivation-induced food hoarding in HFH gerbils, and that GABA might influence food hoarding via classical reward circuitry via the mesolimbic dopamine system and specific hippocampal areas. Copyright © 2014 Elsevier Inc. All rights reserved.
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Shi, Xiangdang; Miller, Jonathan S; Harper, Lauren J; Poole, Rachel L; Gould, Thomas J; Unterwald, Ellen M
2014-08-01
Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction. The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory. Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine. Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories. These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.
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The Role of GABAA Receptors in the Development of Alcoholism
Enoch, Mary-Anne
2008-01-01
Alcoholism is a common, heritable, chronic relapsing disorder. GABAA receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABAA receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABAA receptors: tolerance is associated with generally decreased GABAA receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABAA receptors may be implicated in the switch from heavy drinking to dependence. GABAA receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABAA receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABAA receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review. PMID:18440057
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Ishikawa, Masago; Otaka, Mami; Neumann, Peter A; Wang, Zhijian; Cook, James M; Schlüter, Oliver M; Dong, Yan; Huang, Yanhua H
2013-01-01
Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well-known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA-to-NAc fast synaptic transmission and its roles in drug-induced adaptations are not well understood. Using viral-mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg−1 day−1× 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA-to-NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA-to-NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine-induced alteration of the brain reward circuitry. PMID:23918773
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Neural correlates of appetitive extinction in humans
Tapia León, Isabell; Stark, Rudolf; Klucken, Tim
2017-01-01
Abstract Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS−) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS−. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS− after conditioning. Furthermore, fMRI-results (CS+ − CS−) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning. PMID:27803289
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The role of GABA(A) receptors in the development of alcoholism.
Enoch, Mary-Anne
2008-07-01
Alcoholism is a common, heritable, chronic relapsing disorder. GABA(A) receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA(A) receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA(A) receptors: tolerance is associated with generally decreased GABA(A) receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA(A) receptors may be implicated in the switch from heavy drinking to dependence. GABA(A) receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA(A) receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA(A) receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.
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A neural circuitry that emphasizes spinal feedback generates diverse behaviours of human locomotion
Song, Seungmoon; Geyer, Hartmut
2015-01-01
Neural networks along the spinal cord contribute substantially to generating locomotion behaviours in humans and other legged animals. However, the neural circuitry involved in this spinal control remains unclear. We here propose a specific circuitry that emphasizes feedback integration over central pattern generation. The circuitry is based on neurophysiologically plausible muscle-reflex pathways that are organized in 10 spinal modules realizing limb functions essential to legged systems in stance and swing. These modules are combined with a supraspinal control layer that adjusts the desired foot placements and selects the leg that is to transition into swing control during double support. Using physics-based simulation, we test the proposed circuitry in a neuromuscular human model that includes neural transmission delays, musculotendon dynamics and compliant foot–ground contacts. We find that the control network is sufficient to compose steady and transitional 3-D locomotion behaviours including walking and running, acceleration and deceleration, slope and stair negotiation, turning, and deliberate obstacle avoidance. The results suggest feedback integration to be functionally more important than central pattern generation in human locomotion across behaviours. In addition, the proposed control architecture may serve as a guide in the search for the neurophysiological origin and circuitry of spinal control in humans. PMID:25920414
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Manning, Joshua; Reynolds, Gretchen; Saygin, Zeynep M; Hofmann, Stefan G; Pollack, Mark; Gabrieli, John D E; Whitfield-Gabrieli, Susan
2015-01-01
We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.
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Cell-type-specific role of ΔFosB in nucleus accumbens in modulating inter-male aggression.
Aleyasin, Hossein; Flanigan, Meghan E; Golden, Sam A; Takahashi, Aki; Menard, Caroline; Pfau, Madeline L; Multer, Jacob; Pina, Jacqueline; McCabe, Kathryn A; Bhatti, Naemal; Hodes, Georgia E; Heshmati, Mitra; Neve, Rachael L; Nestler, Eric J; Heller, Elizabeth A; Russo, Scott J
2018-06-11
A growing number of studies implicate the brain's reward circuitry in aggressive behavior. However, the cellular and molecular mechanisms within brain reward regions that modulate the intensity of aggression as well as motivation for it have been underexplored. Here, we investigate the cell-type-specific influence of ΔFosB, a transcription factor known to regulate a range of reward and motivated behaviors, acting in the nucleus accumbens (NAc)-a key reward region-in male aggression in mice. We show that ΔFosB is specifically increased in dopamine D1 receptor (Drd1) expressing medium spiny neurons (D1-MSNs) in NAc after repeated aggressive encounters. Viral-mediated induction of ΔFosB selectively in D1-MSNs of NAc intensifies aggressive behavior, without affecting the preference for the aggression-paired context in a conditioned place preference (CPP) assay. In contrast, ΔFosB induction selectively in D2-MSNs reduces the time spent exploring the aggression-paired context during CPP without affecting the intensity of aggression per se. These data strongly support a dissociable cell-type-specific role for ΔFosB in the NAc in modulating aggression and aggression reward. Significance Statement: Aggressive behavior is associated with several neuropsychiatric disorders and can be disruptive for the individuals as well as their victims. Studies have shown a positive reinforcement mechanism underlying aggressive behavior that shares many common features with drug addiction. Here, we explore the cell-type-specific role of the addiction-associated transcription factor ΔFosB in the nucleus accumbens (NAc) in aggression. We found that ΔFosB expression promotes aggressive behavior, effects that are dissociable from its effects on aggression reward. This finding is a significant first step in identifying therapeutic targets for the reduction of aggressive behavior across a range of neuropsychiatric illnesses. Copyright © 2018 the authors.
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Goudriaan, Anna E; Veltman, Dick J; van den Brink, Wim; Dom, Geert; Schmaal, Lianne
2013-02-01
Enhanced reactivity to substance related cues is a central characteristic of addiction and has been associated with increased activity in motivation, attention, and memory related brain circuits and with a higher probability of relapse. Modafinil was promising in the first clinical trials in cocaine dependence, and was able to reduce craving in addictive disorders. However, its mechanism of action remains to be elucidated. In this functional magnetic resonance imaging (fMRI) study therefore, cue reactivity in cocaine dependent patients was compared to cue reactivity in healthy controls (HCs) under modafinil and placebo conditions. An fMRI cue reactivity study, with a double-blind, placebo-controlled cross-over challenge with a single dose of modafinil (200mg) was employed in 13 treatment seeking cocaine dependent patients and 16 HCs. In the placebo condition, watching cocaine-related pictures (versus neutral pictures) resulted in higher brain activation in the medial frontal cortex, anterior cingulate cortex, angular gyrus, left orbitofrontal cortex, and ventral tegmental area (VTA) in the cocaine dependent group compared to HCs. However, in the modafinil condition, no differences in brain activation patterns were found between cocaine dependent patients and HCs. Group interactions revealed decreased activity in the VTA and increased activity in the right ACC and putamen in the modafinil condition relative to the placebo condition in cocaine dependent patients, whereas such changes were not present in healthy controls. Decreases in self-reported craving when watching cocaine-related cues after modafinil administration compared to the placebo condition were associated with modafinil-induced increases in ACC and putamen activation. Enhanced cue reactivity in the cocaine dependent group compared to healthy controls was found in brain circuitries related to reward, motivation, and autobiographical memory processes. In cocaine dependent patients, these enhanced brain responses were attenuated by modafinil, mainly due to decreases in cue- reactivity in reward-related brain areas (VTA) and increases in cue reactivity in cognitive control areas (ACC). These modafinil-induced changes in brain activation in response to cocaine-related visual stimuli were associated with diminished self-reported craving. These findings imply that in cocaine dependent patients, modafinil, although mainly known as a cognitive enhancer, acts on both the motivational and the cognitive brain circuitry. Copyright © 2012 Elsevier Ltd. All rights reserved.
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Abbott, Angela E; Linke, Annika C; Nair, Aarti; Jahedi, Afrooz; Alba, Laura A; Keown, Christopher L; Fishman, Inna; Müller, Ralph-Axel
2018-01-01
The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8-17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits. © The Author (2017). Published by Oxford University Press.
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Abbott, Angela E; Linke, Annika C; Nair, Aarti; Jahedi, Afrooz; Alba, Laura A; Keown, Christopher L; Fishman, Inna
2018-01-01
Abstract The neural underpinnings of repetitive behaviors (RBs) in autism spectrum disorders (ASDs), ranging from cognitive to motor characteristics, remain unknown. We assessed RB symptomatology in 50 ASD and 52 typically developing (TD) children and adolescents (ages 8–17 years), examining intrinsic functional connectivity (iFC) of corticostriatal circuitry, which is important for reward-based learning and integration of emotional, cognitive and motor processing, and considered impaired in ASDs. Connectivity analyses were performed for three functionally distinct striatal seeds (limbic, frontoparietal and motor). Functional connectivity with cortical regions of interest was assessed for corticostriatal circuit connectivity indices and ratios, testing the balance of connectivity between circuits. Results showed corticostriatal overconnectivity of limbic and frontoparietal seeds, but underconnectivity of motor seeds. Correlations with RBs were found for connectivity between the striatal motor seeds and cortical motor clusters from the whole-brain analysis, and for frontoparietal/limbic and motor/limbic connectivity ratios. Division of ASD participants into high (n = 17) and low RB subgroups (n = 19) showed reduced frontoparietal/limbic and motor/limbic circuit ratios for high RB compared to low RB and TD groups in the right hemisphere. Results suggest an association between RBs and an imbalance of corticostriatal iFC in ASD, being increased for limbic, but reduced for frontoparietal and motor circuits. PMID:29177509
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Synaptic mechanisms underlying persistent cocaine craving
Wolf, Marina E.
2017-01-01
Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction. PMID:27150400
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Social attention: a possible early indicator of efficacy in autism clinical trials
2012-01-01
For decades, researchers have sought to clarify the nature of the social communication impairments in autism, highlighting impaired or atypical 'social attention' as a key measurable construct that helps to define the core impairment of social communication. In this paper, we provide an overview of research on social attention impairments in autism and their relation to deficiencies in neural circuitry related to social reward. We offer a framework for considering social attention as a potential moderator or mediator of response to early behavioral intervention, and as an early indicator of efficacy of behavioral and/or pharmacological treatments aimed at addressing the social impairments in autism. PMID:22958480
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Progress toward the maintenance and repair of degenerating retinal circuitry.
Vugler, Anthony A
2010-01-01
Retinal diseases such as age-related macular degeneration and retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical trials for treatment of retinal degenerations are underway and advancements in our understanding of retinal biology in health/disease have implications for novel therapies. A review of retinal biology is used to inform a discussion of current strategies to maintain/repair neural circuitry in age-related macular degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. In age-related macular degeneration/retinitis pigmentosa, a progressive loss of rods/cones results in corruption of bipolar cell circuitry, although retinal output neurons/photoreceptive melanopsin cells survive. Visual function can be stabilized/enhanced after treatment in age-related macular degeneration, but in advanced degenerations, reorganization of retinal circuitry may preclude attempts to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can be restored by gene therapy where central cones survive. Remarkable progress has been made in restoring vision to rodents using light-responsive ion channels inserted into bipolar cells/retinal ganglion cells. Advances in genetic, cellular, and prosthetic therapies show varying degrees of promise for treating retinal degenerations. While functional benefits can be obtained after early therapeutic interventions, efforts should be made to minimize circuitry changes as soon as possible after rod/cone loss. Advances in retinal anatomy/physiology and genetic technologies should allow refinement of future reparative strategies.
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Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability
Fowler, Christie D.; Kenny, Paul J.
2013-01-01
Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered. PMID:24055497
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Steinberg, Bruce; Blum, Kenneth; McLaughlin, Thomas; Lubar, Joel; Febo, Marcelo; Braverman, Eric R; Badgaiyan, Rajendra D
Attention Deficit-Hyperactivity Disorder (ADHD) often continues into adulthood. Recent neuroimaging studies found lowered baseline dopamine tone in the brains of affected individuals that may place them at risk for Substance Use Disorder (SUD). This is an observational case study of the potential for novel management of Adult ADHD with a non-addictive glutaminergic-dopaminergic optimization complex KB200z. Low-resolution electromagnetic tomography (LORETA) was used to evaluate the effects of KB220z on a 72-year-old male with ADHD, at baseline and one hour following administration. The resultant z-scores, averaged across Eyes Closed, Eyes Open and Working Memory conditions, increased for each frequency band, in the anterior, dorsal and posterior cingulate regions, as well as the right dorsolateral prefrontal cortex during Working Memory, with KB220z. These scores are consistent with other human and animal neuroimaging studies that demonstrated increased connectivity volumes in reward circuitry and may offer a new approach to ADHD treatment. However, larger randomized trials to confirm these results are required.
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Corticostriatal Regulation of Acute Pain
Martinez, Erik; Lin, Harvey H.; Zhou, Haocheng; Dale, Jahrane; Liu, Kevin; Wang, Jing
2017-01-01
The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC) provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc). This corticostriatal projection forms an important regulatory pathway within the brain’s reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves’ test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP) test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation. PMID:28603489
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Steinberg, Bruce; Blum, Kenneth; McLaughlin, Thomas; Lubar, Joel; Febo, Marcelo; Braverman, Eric R.; Badgaiyan, Rajendra D
2016-01-01
Attention Deficit-Hyperactivity Disorder (ADHD) often continues into adulthood. Recent neuroimaging studies found lowered baseline dopamine tone in the brains of affected individuals that may place them at risk for Substance Use Disorder (SUD). This is an observational case study of the potential for novel management of Adult ADHD with a non-addictive glutaminergic-dopaminergic optimization complex KB200z. Low-resolution electromagnetic tomography (LORETA) was used to evaluate the effects of KB220z on a 72-year-old male with ADHD, at baseline and one hour following administration. The resultant z-scores, averaged across Eyes Closed, Eyes Open and Working Memory conditions, increased for each frequency band, in the anterior, dorsal and posterior cingulate regions, as well as the right dorsolateral prefrontal cortex during Working Memory, with KB220z. These scores are consistent with other human and animal neuroimaging studies that demonstrated increased connectivity volumes in reward circuitry and may offer a new approach to ADHD treatment. However, larger randomized trials to confirm these results are required. PMID:27610420
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van Holst, Ruth J.; Chase, Henry W.; Clark, Luke
2014-01-01
Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. ‘Near-miss’ events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the ‘illusion of control’). Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression. For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex. These findings corroborate the ‘non-categorical’ nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling. PMID:25068112
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Verdejo-Román, Juan; Fornito, Alex; Soriano-Mas, Carles; Vilar-López, Raquel; Verdejo-García, Antonio
2017-02-01
Overvaluation of palatable food is a primary driver of obesity, and is associated with brain regions of the reward system. However, it remains unclear if this network is specialized in food reward, or generally involved in reward processing. We used functional magnetic resonance imaging (fMRI) to characterize functional connectivity during processing of food and monetary rewards. Thirty-nine adults with excess weight and 37 adults with normal weight performed the Willingness to Pay for Food task and the Monetary Incentive Delay task in the fMRI scanner. A data-driven graph approach was applied to compare whole-brain, task-related functional connectivity between groups. Excess weight was associated with decreased functional connectivity during the processing of food rewards in a network involving primarily frontal and striatal areas, and increased functional connectivity during the processing of monetary rewards in a network involving principally frontal and parietal areas. These two networks were topologically and anatomically distinct, and were independently associated with BMI. The processing of food and monetary rewards involve segregated neural networks, and both are altered in individuals with excess weight. Copyright © 2016 Elsevier Inc. All rights reserved.
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Elevated striatal γ-aminobutyric acid in youth with major depressive disorder.
Bradley, Kailyn A; Alonso, Carmen M; Mehra, Lushna M; Xu, Junqian; Gabbay, Vilma
2018-06-08
Alterations in γ-aminobutyric acid (GABA) have been hypothesized to play a role in the pathogenesis of psychiatric illness. Our previous work has specifically linked anterior cingulate cortex (ACC) GABA deficits with anhedonia in youth with major depressive disorder (MDD). As anhedonia reflects alterations within the reward circuitry, we sought to extend this investigation and examine GABA levels in another key reward-related region, the striatum, in the same adolescent population. Thirty-six youth [20 with MDD and 16 healthy controls; (HC)], ages 12 to 21 years old, underwent J-edited proton magnetic resonance spectroscopy ( 1 H MRS) whereby GABA levels were measured in striatal and ACC voxels. GABA levels were compared between groups and between voxel positions and were examined in relation to clinical symptomatology, such as depression severity, anhedonia, anxiety, and suicidality. Depressed youth had unexpectedly higher GABA levels in the striatum compared to HC. In both depressed and healthy youth, GABA levels were higher in the striatum than in the ACC, while the differences in depressed youth were greater. Moreover, in depressed youth, higher striatal GABA above the mean of HCs was correlated with lower ACC GABA below the mean of HCs. Striatal GABA was not correlated with clinical symptomatology in this small sample. Together, these findings suggest that higher striatal GABA levels may serve some compensatory function as a result of lower ACC GABA in depressed adolescents. It is also possible that, like lower ACC GABA, higher striatal GABA might simply be another pathological feature of adolescent depression. Copyright © 2018 Elsevier Inc. All rights reserved.
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Childhood trauma exposure disrupts the automatic regulation of emotional processing.
Marusak, Hilary A; Martin, Kayla R; Etkin, Amit; Thomason, Moriah E
2015-03-13
Early-life trauma is one of the strongest risk factors for later emotional psychopathology. Although research in adults highlights that childhood trauma predicts deficits in emotion regulation that persist decades later, it is unknown whether neural and behavioral changes that may precipitate illness are evident during formative, developmental years. This study examined whether automatic regulation of emotional conflict is perturbed in a high-risk urban sample of trauma-exposed children and adolescents. A total of 14 trauma-exposed and 16 age-, sex-, and IQ-matched comparison youth underwent functional MRI while performing an emotional conflict task that involved categorizing facial affect while ignoring an overlying emotion word. Engagement of the conflict regulation system was evaluated at neural and behavioral levels. Results showed that trauma-exposed youth failed to dampen dorsolateral prefrontal cortex activity and engage amygdala-pregenual cingulate inhibitory circuitry during the regulation of emotional conflict, and were less able to regulate emotional conflict. In addition, trauma-exposed youth showed greater conflict-related amygdala reactivity that was associated with diminished levels of trait reward sensitivity. These data point to a trauma-related deficit in automatic regulation of emotional processing, and increase in sensitivity to emotional conflict in neural systems implicated in threat detection. Aberrant amygdala response to emotional conflict was related to diminished reward sensitivity that is emerging as a critical stress-susceptibility trait that may contribute to the emergence of mental illness during adolescence. These results suggest that deficits in conflict regulation for emotional material may underlie heightened risk for psychopathology in individuals that endure early-life trauma.
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Gilman, Jodi M; Ramchandani, Vijay A; Crouss, Tess; Hommer, Daniel W
2012-01-01
Heavy alcohol consumption during young adulthood is a risk factor for the development of serious alcohol use disorders. Research has shown that individual differences in subjective responses to alcohol may affect individuals' vulnerability to developing alcoholism. Studies comparing the subjective and objective response to alcohol between light and heavy drinkers (HDs), however, have yielded inconsistent results, and neural responses to alcohol in these groups have not been characterized. We performed a double-blind, placebo-controlled, randomized crossover alcohol challenge study comparing functional magnetic resonance imaging and subjective response to intravenously administered 6% v/v ethanol to a target blood alcohol concentration of 0.08% or placebo between HDs and social drinkers (SDs). During the imaging, we presented emotional cues in order to measure how emotion modulated the effects of alcohol on the brain's reward circuitry. We found that, at equivalent blood alcohol concentrations, HDs reported lower subjective alcohol effects than SDs. Alcohol significantly activated the nucleus accumbens in SDs, but not in HDs. Self-reported ratings of intoxication correlated with striatal activation, suggesting that activation may reflect subjective experience of intoxication. Fearful faces significantly activated the amygdala in the SDs only, and this activation was attenuated by alcohol. This study shows that HDs not only experience reduced subjective effects of alcohol, but also demonstrate a blunted response to alcohol in the brain's reward system. Our findings indicate that reduced subjective and neural response to alcohol in HDs may be suggestive of either the development of tolerance to alcohol, or of pre-existing decreased sensitivity to alcohol's effects.
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Slater, Jessica; Ashley, Richard; Tierney, Adam; Kraus, Nina
2018-01-01
Musical rhythm engages motor and reward circuitry that is important for cognitive control, and there is evidence for enhanced inhibitory control in musicians. We recently revealed an inhibitory control advantage in percussionists compared with vocalists, highlighting the potential importance of rhythmic expertise in mediating this advantage. Previous research has shown that better inhibitory control is associated with less variable performance in simple sensorimotor synchronization tasks; however, this relationship has not been examined through the lens of rhythmic expertise. We hypothesize that the development of rhythm skills strengthens inhibitory control in two ways: by fine-tuning motor networks through the precise coordination of movements "in time" and by activating reward-based mechanisms, such as predictive processing and conflict monitoring, which are involved in tracking temporal structure in music. Here, we assess adult percussionists and nonpercussionists on inhibitory control, selective attention, basic drumming skills (self-paced, paced, and continuation drumming), and cortical evoked responses to an auditory stimulus presented on versus off the beat of music. Consistent with our hypotheses, we find that better inhibitory control is correlated with more consistent drumming and enhanced neural tracking of the musical beat. Drumming variability and the neural index of beat alignment each contribute unique predictive power to a regression model, explaining 57% of variance in inhibitory control. These outcomes present the first evidence that enhanced inhibitory control in musicians may be mediated by rhythmic expertise and provide a foundation for future research investigating the potential for rhythm-based training to strengthen cognitive function.
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Positive autobiographical memory retrieval reduces temporal discounting
Lempert, Karolina M; Speer, Megan E; Delgado, Mauricio R
2017-01-01
Abstract People generally prefer rewards sooner rather than later. This phenomenon, temporal discounting, underlies many societal problems, including addiction and obesity. One way to reduce temporal discounting is to imagine positive future experiences. Since there is overlap in the neural circuitry associated with imagining future experiences and remembering past events, here we investigate whether recalling positive memories can also promote more patient choice. We found that participants were more patient after retrieving positive autobiographical memories, but not when they recalled negative memories. Moreover, individuals were more impulsive after imagining novel positive scenes that were not related to their memories, showing that positive imagery alone does not drive this effect. Activity in the striatum and temporo parietal junction during memory retrieval predicted more patient choice, suggesting that to the extent that memory recall is rewarding and involves perspective-taking, it influences decision-making. Furthermore, representational similarity in the ventromedial prefrontal cortex between memory recall and decision phases correlated with the behavioral effect across participants. Thus, we have identified a novel manipulation for reducing temporal discounting—remembering the positive past—and have begun to characterize the psychological and neural mechanisms behind it. PMID:28655195
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Wheel running, voluntary ethanol consumption, and hedonic substitution.
Ozburn, Angela Renee; Harris, R Adron; Blednov, Yuri A
2008-08-01
Few studies have examined the relationship between naturally rewarding behaviors and ethanol drinking behaviors in mice. Although natural and drug reinforcers activate similar brain circuitry, there is behavioral evidence suggesting food and drug rewards differ in perceived value. The primary goal of the present study was to investigate the relationships between naturally reinforcing stimuli and consumption of ethanol in ethanol preferring C57BL/6J mice. Mouse behaviors were observed after the following environmental manipulations: standard or enhanced environment, accessible or inaccessible wheel, and presence or absence of ethanol. Using a high-resolution volumetric drinking monitor and wheel running monitor, we evaluated whether alternating access to wheel running modified ethanol-related behaviors and whether alternating access to ethanol modified wheel running or subsequent ethanol-related behaviors. We found that ethanol consumption remains stable with alternating periods of wheel running. Wheel running increases in the absence of ethanol and decreases upon reintroduction of ethanol. Upon reintroduction of ethanol, an alcohol deprivation effect was seen. Collectively, the results support theories of hedonic substitution and suggest that female C57BL/6J mice express ethanol seeking and craving under these specific conditions.
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Neural correlates of appetitive extinction in humans.
Kruse, Onno; Tapia León, Isabell; Stark, Rudolf; Klucken, Tim
2017-01-01
Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS-) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS-. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS- after conditioning. Furthermore, fMRI-results (CS+ - CS-) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning. © The Author (2016). Published by Oxford University Press.
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Wood, Richard M; Rilling, James K; Sanfey, Alan G; Bhagwagar, Zubin; Rogers, Robert D
2006-05-01
Adaptive social behavior often necessitates choosing to cooperate with others for long-term gains at the expense of noncooperative behaviors giving larger immediate gains. Although little is know about the neural substrates that support cooperative over noncooperative behaviors, recent research has shown that mutually cooperative behavior in the context of a mixed-motive game, the Prisoner's Dilemma (PD), is associated with increased neural activity within reinforcement circuitry. Other research attests to a role for serotonin in the modulation of social behavior and in reward processing. In this study, we used a within-subject, crossover, double-blind design to investigate performance of an iterated, sequential PD game for monetary reward by healthy human adult participants following ingestion of an amino-acid drink that either did (T+) or did not (T-) contain l-tryptophan. Tryptophan depletion produced significant reductions in the level of cooperation shown by participants when playing the game on the first, but not the second, study days. This effect was accompanied by a significantly diminished probability of cooperative responding given previous mutually cooperative behavior. These data suggest that serotonin plays a significant role in the acquisition of socially cooperative behavior in human adult participants, and suggest novel hypotheses concerning the serotonergic modulation of reward information in socially cooperative behavior in both health and psychiatric illness.
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Treadway, Michael T; Admon, Roee; Arulpragasam, Amanda R; Mehta, Malavika; Douglas, Samuel; Vitaliano, Gordana; Olson, David P; Cooper, Jessica A; Pizzagalli, Diego A
2017-10-15
Stress is widely known to alter behavioral responses to rewards and punishments. It is believed that stress may precipitate these changes through modulation of corticostriatal circuitry involved in reinforcement learning and motivation, although the intervening mechanisms remain unclear. One candidate is inflammation, which can rapidly increase following stress and can disrupt dopamine-dependent reward pathways. Here, in a sample of 88 healthy female participants, we first assessed the effect of an acute laboratory stress paradigm on levels of plasma interleukin-6 (IL-6), a cytokine known to be both responsive to stress and elevated in depression. In a second laboratory session, we examined the effects of a second laboratory stress paradigm on reward prediction error (RPE) signaling in the ventral striatum. We show that individual differences in stress-induced increases in IL-6 (session 1) were associated with decreased ventral striatal RPE signaling during reinforcement learning (session 2), though there was no main effect of stress on RPE. Furthermore, changes in IL-6 following stress predicted intraindividual variability in perceived stress during a 4-month follow-up period. Taken together, these data identify a novel link between IL-6 and striatal RPEs during reinforcement learning in the context of acute psychological stress, as well as future appraisal of stressful life events. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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A Developmental Shift from Positive to Negative Connectivity in Human Amygdala-Prefrontal Circuitry
Gee, Dylan G.; Humphreys, Kathryn L.; Flannery, Jessica; Goff, Bonnie; Telzer, Eva H.; Shapiro, Mor; Hare, Todd A.; Bookheimer, Susan Y.; Tottenham, Nim
2013-01-01
Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. While tracing studies have suggested changes in amygdala-cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala-prefrontal circuitry across the ages of 4 to 22 years using task-based functional magnetic resonance imaging (fMRI). Results suggest positive amygdala-prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala-mPFC functional connectivity was significantly positive (greater than zero) among participants younger than ten, whereas functional connectivity was significantly negative (less than zero) among participants ten years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections. PMID:23467374
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Dopamine Reward Prediction Error Responses Reflect Marginal Utility
Stauffer, William R.; Lak, Armin; Schultz, Wolfram
2014-01-01
Summary Background Optimal choices require an accurate neuronal representation of economic value. In economics, utility functions are mathematical representations of subjective value that can be constructed from choices under risk. Utility usually exhibits a nonlinear relationship to physical reward value that corresponds to risk attitudes and reflects the increasing or decreasing marginal utility obtained with each additional unit of reward. Accordingly, neuronal reward responses coding utility should robustly reflect this nonlinearity. Results In two monkeys, we measured utility as a function of physical reward value from meaningful choices under risk (that adhered to first- and second-order stochastic dominance). The resulting nonlinear utility functions predicted the certainty equivalents for new gambles, indicating that the functions’ shapes were meaningful. The monkeys were risk seeking (convex utility function) for low reward and risk avoiding (concave utility function) with higher amounts. Critically, the dopamine prediction error responses at the time of reward itself reflected the nonlinear utility functions measured at the time of choices. In particular, the reward response magnitude depended on the first derivative of the utility function and thus reflected the marginal utility. Furthermore, dopamine responses recorded outside of the task reflected the marginal utility of unpredicted reward. Accordingly, these responses were sufficient to train reinforcement learning models to predict the behaviorally defined expected utility of gambles. Conclusions These data suggest a neuronal manifestation of marginal utility in dopamine neurons and indicate a common neuronal basis for fundamental explanatory constructs in animal learning theory (prediction error) and economic decision theory (marginal utility). PMID:25283778
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Pattwell, Siobhan S.; Lee, Francis S.; Casey, B.J.
2013-01-01
Throughout the past several decades, studies have uncovered a wealth of information about the neural circuitry underlying fear learning and extinction that has helped to inform treatments for fear-related disorders such as post-traumatic stress and anxiety. Yet, up to 40 percent of people do not respond to such treatments. Adolescence, in particular, is a developmental stage during which anxiety disorders peak, yet little is known about the development of fear-related neural circuitry during this period. Moreover, pharmacological and behavioral therapies that have been developed are based on mature circuitry and function. Here, we review neural circuitry implicated in fear learning and data from adolescent mouse and human fear learning studies. In addition, we propose a developmental model of fear neural circuitry that may optimize current treatments and inform when, during development, specific treatments for anxiety may be most effective. PMID:23998679
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Pattwell, Siobhan S; Lee, Francis S; Casey, B J
2013-07-01
Throughout the past several decades, studies have uncovered a wealth of information about the neural circuitry underlying fear learning and extinction that has helped to inform treatments for fear-related disorders such as post-traumatic stress and anxiety. Yet, up to 40% of people do not respond to such treatments. Adolescence, in particular, is a developmental stage during which anxiety disorders peak, yet little is known about the development of fear-related neural circuitry during this period. Moreover, pharmacological and behavioral therapies that have been developed are based on mature circuitry and function. Here, we review neural circuitry implicated in fear learning and data from adolescent mouse and human fear learning studies. In addition, we propose a developmental model of fear neural circuitry that may optimize current treatments and inform when, during development, specific treatments for anxiety may be most effective. Copyright © 2013 Elsevier Inc. All rights reserved.
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Pomeranz, Lisa E.; Ekstrand, Mats I.; Latcha, Kaamashri N.; Smith, Gregory A.; Enquist, Lynn W.
2017-01-01
The mesolimbic dopamine pathway receives inputs from numerous regions of the brain as part of a neural system that detects rewarding stimuli and coordinates a behavioral response. The capacity to simultaneously map and molecularly define the components of this complex multisynaptic circuit would thus advance our understanding of the determinants of motivated behavior. To accomplish this, we have constructed pseudorabies virus (PRV) strains in which viral propagation and fluorophore expression are activated only after exposure to Cre recombinase. Once activated in Cre-expressing neurons, the virus serially labels chains of presynaptic neurons. Dual injection of GFP and mCherry tracing viruses simultaneously illuminates nigrostriatal and mesolimbic circuitry and shows no overlap, demonstrating that PRV transmission is confined to synaptically connected neurons. To molecularly profile mesolimbic dopamine neurons and their presynaptic inputs, we injected Cre-conditional GFP virus into the NAc of (anti-GFP) nanobody-L10 transgenic mice and immunoprecipitated translating ribosomes from neurons infected after retrograde tracing. Analysis of purified RNA revealed an enrichment of transcripts expressed in neurons of the dorsal raphe nuclei and lateral hypothalamus that project to the mesolimbic dopamine circuit. These studies identify important inputs to the mesolimbic dopamine pathway and further show that PRV circuit-directed translating ribosome affinity purification can be broadly applied to identify molecularly defined neurons comprising complex, multisynaptic circuits. SIGNIFICANCE STATEMENT The mesolimbic dopamine circuit integrates signals from key brain regions to detect and respond to rewarding stimuli. To further define this complex multisynaptic circuit, we constructed a panel of Cre recombinase-activated pseudorabies viruses (PRVs) that enabled retrograde tracing of neural inputs that terminate on Cre-expressing neurons. Using these viruses and Retro-TRAP (translating ribosome affinity purification), a previously reported molecular profiling method, we developed a novel technique that provides anatomic as well as molecular information about the neural components of polysynaptic circuits. We refer to this new method as PRV-Circuit-TRAP (PRV circuit-directed TRAP). Using it, we have identified major projections to the mesolimbic dopamine circuit from the lateral hypothalamus and dorsal raphe nucleus and defined a discrete subset of transcripts expressed in these projecting neurons, which will allow further characterization of this important pathway. Moreover, the method we report is general and can be applied to the study of other neural circuits. PMID:28283558
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Forbes, Erika E; Hariri, Ahmad R; Martin, Samantha L; Silk, Jennifer S; Moyles, Donna L; Fisher, Patrick M; Brown, Sarah M; Ryan, Neal D; Birmaher, Boris; Axelson, David A; Dahl, Ronald E
2009-01-01
Alterations in reward-related brain function and phenomenological aspects of positive affect are increasingly examined in the development of major depressive disorder. The authors tested differences in reward-related brain function in healthy and depressed adolescents, and the authors examined direct links between reward-related brain function and positive mood that occurred in real-world contexts. Fifteen adolescents with major depressive disorder and 28 adolescents with no history of psychiatric disorder, ages 8-17 years, completed a functional magnetic resonance imaging guessing task involving monetary reward. Participants also reported their subjective positive affect in natural environments during a 4-day cell-phone-based ecological momentary assessment. Adolescents with major depressive disorder exhibited less striatal response than healthy comparison adolescents during reward anticipation and reward outcome, but more response in dorsolateral and medial prefrontal cortex. Diminished activation in a caudate region associated with this depression group difference was correlated with lower subjective positive affect in natural environments, particularly within the depressed group. Results support models of altered reward processing and related positive affect in young people with major depressive disorder and indicate that depressed adolescents' brain response to monetary reward is related to their affective experience in natural environments. Additionally, these results suggest that reward-processing paradigms capture brain function relevant to real-world positive affect.
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From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.
Howick, Ken; Griffin, Brendan T; Cryan, John F; Schellekens, Harriët
2017-01-27
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrallymediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin's central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry.
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Brain imaging in the context of food perception and eating.
Hollmann, Maurice; Pleger, Burkhard; Villringer, Arno; Horstmann, Annette
2013-02-01
Eating behavior depends heavily on brain function. In recent years, brain imaging has proved to be a powerful tool to elucidate brain function and brain structure in the context of eating. In this review, we summarize recent findings in the fast growing body of literature in the field and provide an overview of technical aspects as well as the basic brain mechanisms identified with imaging. Furthermore, we highlight findings linking neural processing of eating-related stimuli with obesity. The consumption of food is based on a complex interplay between homeostatic and hedonic mechanisms. Several hormones influence brain activity to regulate food intake and interact with the brain's reward circuitry, which is partly mediated by dopamine signaling. Additionally, it was shown that food stimuli trigger cognitive control mechanisms that incorporate internal goals into food choice. The brain mechanisms observed in this context are strongly influenced by genetic factors, sex and personality traits. Overall, a complex picture arises from brain-imaging findings, because a multitude of factors influence human food choice. Although several key mechanisms have been identified, there is no comprehensive model that is able to explain the behavioral observations to date. Especially a careful characterization of patients according to genotypes and phenotypes could help to better understand the current and future findings in neuroimaging studies.
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Brain function during probabilistic learning in relation to IQ and level of education.
van den Bos, Wouter; Crone, Eveline A; Güroğlu, Berna
2012-02-15
Knowing how to adapt your behavior based on feedback lies at the core of successful learning. We investigated the relation between brain function, grey matter volume, educational level and IQ in a Dutch adolescent sample. In total 45 healthy volunteers between ages 13 and 16 were recruited from schools for pre-vocational and pre-university education. For each individual, IQ was estimated using two subtests from the WISC-III-R (similarities and block design). While in the magnetic resonance imaging (MRI) scanner, participants performed a probabilistic learning task. Behavioral comparisons showed that participants with higher IQ used a more adaptive learning strategy after receiving positive feedback. Analysis of neural activation revealed that higher IQ was associated with increased activation in DLPFC and dACC when receiving positive feedback, specifically for rules with low reward probability (i.e., unexpected positive feedback). Furthermore, VBM analyses revealed that IQ correlated positively with grey matter volume within these regions. These results provide support for IQ-related individual differences in the developmental time courses of neural circuitry supporting feedback-based learning. Current findings are interpreted in terms of a prolonged window of flexibility and opportunity for adolescents with higher IQ scores. Copyright © 2011 Elsevier Ltd. All rights reserved.
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From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation
Howick, Ken; Griffin, Brendan T.; Cryan, John F.; Schellekens, Harriët
2017-01-01
Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrally-mediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry. PMID:28134808
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Lau, Brian; Monteiro, Tiago; Paton, Joseph J
2017-10-01
Computational models of reinforcement learning (RL) strive to produce behavior that maximises reward, and thus allow software or robots to behave adaptively [1]. At the core of RL models is a learned mapping between 'states'-situations or contexts that an agent might encounter in the world-and actions. A wealth of physiological and anatomical data suggests that the basal ganglia (BG) is important for learning these mappings [2,3]. However, the computations performed by specific circuits are unclear. In this brief review, we highlight recent work concerning the anatomy and physiology of BG circuits that suggest refinements in our understanding of computations performed by the basal ganglia. We focus on one important component of basal ganglia circuitry, midbrain dopamine neurons, drawing attention to data that has been cast as supporting or departing from the RL framework that has inspired experiments in basal ganglia research over the past two decades. We suggest that the parallel circuit architecture of the BG might be expected to produce variability in the response properties of different dopamine neurons, and that variability in response profile may not reflect variable functions, but rather different arguments that serve as inputs to a common function: the computation of prediction error. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Reward-Related Decision-Making in Pediatric Major Depressive Disorder: An fMRI Study
ERIC Educational Resources Information Center
Forbes, Erika E.; Christopher May, J.; Siegle, Greg J.; Ladouceur, Cecile D.; Ryan, Neal D.; Carter, Cameron S.; Birmaher, Boris; Axelson, David A.; Dahl, Ronald E.
2006-01-01
Background: Although reward processing is considered an important part of affective functioning, few studies have investigated reward-related decisions or responses in young people with affective disorders. Depression is postulated to involve decreased activity in reward-related affective systems. Methods: Using functional magnetic resonance…
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Dopamine reward prediction error responses reflect marginal utility.
Stauffer, William R; Lak, Armin; Schultz, Wolfram
2014-11-03
Optimal choices require an accurate neuronal representation of economic value. In economics, utility functions are mathematical representations of subjective value that can be constructed from choices under risk. Utility usually exhibits a nonlinear relationship to physical reward value that corresponds to risk attitudes and reflects the increasing or decreasing marginal utility obtained with each additional unit of reward. Accordingly, neuronal reward responses coding utility should robustly reflect this nonlinearity. In two monkeys, we measured utility as a function of physical reward value from meaningful choices under risk (that adhered to first- and second-order stochastic dominance). The resulting nonlinear utility functions predicted the certainty equivalents for new gambles, indicating that the functions' shapes were meaningful. The monkeys were risk seeking (convex utility function) for low reward and risk avoiding (concave utility function) with higher amounts. Critically, the dopamine prediction error responses at the time of reward itself reflected the nonlinear utility functions measured at the time of choices. In particular, the reward response magnitude depended on the first derivative of the utility function and thus reflected the marginal utility. Furthermore, dopamine responses recorded outside of the task reflected the marginal utility of unpredicted reward. Accordingly, these responses were sufficient to train reinforcement learning models to predict the behaviorally defined expected utility of gambles. These data suggest a neuronal manifestation of marginal utility in dopamine neurons and indicate a common neuronal basis for fundamental explanatory constructs in animal learning theory (prediction error) and economic decision theory (marginal utility). Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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The Function of Verbal Rewards in the Science Classroom.
ERIC Educational Resources Information Center
Lawlor, Francis Xavier
Contained is a review of the research done on the use of verbal rewards in the classroom. Some verbal rewards are tasks rewards, other rewards are more personal; and still other verbal rewards are impersonal. Verbal rewards, therefore, have both intellectual and emotional implications. Research literature indicates that "verbal reward"…
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Subramaniam, Karuna; Hooker, Christine I; Biagianti, Bruno; Fisher, Melissa; Nagarajan, Srikantan; Vinogradov, Sophia
2015-01-01
Amotivation in schizophrenia is a central predictor of poor functioning, and is thought to occur due to deficits in anticipating future rewards, suggesting that impairments in anticipating pleasure can contribute to functional disability in schizophrenia. In healthy comparison (HC) participants, reward anticipation is associated with activity in frontal-striatal networks. By contrast, schizophrenia (SZ) participants show hypoactivation within these frontal-striatal networks during this motivated anticipatory brain state. Here, we examined neural activation in SZ and HC participants during the anticipatory phase of stimuli that predicted immediate upcoming reward and punishment, and during the feedback/outcome phase, in relation to trait measures of hedonic pleasure and real-world functional capacity. SZ patients showed hypoactivation in ventral striatum during reward anticipation. Additionally, we found distinct differences between HC and SZ groups in their association between reward-related immediate anticipatory neural activity and their reported experience of pleasure. HC participants recruited reward-related regions in striatum that significantly correlated with subjective consummatory pleasure, while SZ patients revealed activation in attention-related regions, such as the IPL, which correlated with consummatory pleasure and functional capacity. These findings may suggest that SZ patients activate compensatory attention processes during anticipation of immediate upcoming rewards, which likely contribute to their functional capacity in daily life.
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Subramaniam, Karuna; Hooker, Christine I.; Biagianti, Bruno; Fisher, Melissa; Nagarajan, Srikantan; Vinogradov, Sophia
2015-01-01
Amotivation in schizophrenia is a central predictor of poor functioning, and is thought to occur due to deficits in anticipating future rewards, suggesting that impairments in anticipating pleasure can contribute to functional disability in schizophrenia. In healthy comparison (HC) participants, reward anticipation is associated with activity in frontal–striatal networks. By contrast, schizophrenia (SZ) participants show hypoactivation within these frontal–striatal networks during this motivated anticipatory brain state. Here, we examined neural activation in SZ and HC participants during the anticipatory phase of stimuli that predicted immediate upcoming reward and punishment, and during the feedback/outcome phase, in relation to trait measures of hedonic pleasure and real-world functional capacity. SZ patients showed hypoactivation in ventral striatum during reward anticipation. Additionally, we found distinct differences between HC and SZ groups in their association between reward-related immediate anticipatory neural activity and their reported experience of pleasure. HC participants recruited reward-related regions in striatum that significantly correlated with subjective consummatory pleasure, while SZ patients revealed activation in attention-related regions, such as the IPL, which correlated with consummatory pleasure and functional capacity. These findings may suggest that SZ patients activate compensatory attention processes during anticipation of immediate upcoming rewards, which likely contribute to their functional capacity in daily life. PMID:26413478
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Neural Correlates of Learning from Induced Insight: A Case for Reward-Based Episodic Encoding
Kizilirmak, Jasmin M.; Thuerich, Hannes; Folta-Schoofs, Kristian; Schott, Björn H.; Richardson-Klavehn, Alan
2016-01-01
Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items—which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning. PMID:27847490
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Neural Correlates of Learning from Induced Insight: A Case for Reward-Based Episodic Encoding.
Kizilirmak, Jasmin M; Thuerich, Hannes; Folta-Schoofs, Kristian; Schott, Björn H; Richardson-Klavehn, Alan
2016-01-01
Experiencing insight when solving problems can improve memory formation for both the problem and its solution. The underlying neural processes involved in this kind of learning are, however, thus far insufficiently understood. Here, we conceptualized insight as the sudden understanding of a novel relationship between known stimuli that fits into existing knowledge and is accompanied by a positive emotional response. Hence, insight is thought to comprise associative novelty, schema congruency, and intrinsic reward, all of which are separately known to enhance memory performance. We examined the neural correlates of learning from induced insight with functional magnetic resonance imaging (fMRI) using our own version of the compound-remote-associates-task (CRAT) in which each item consists of three clue words and a solution word. (Pseudo-)Solution words were presented after a brief period of problem-solving attempts to induce either sudden comprehension (CRA items) or continued incomprehension (control items) at a specific time point. By comparing processing of the solution words of CRA with control items, we found induced insight to elicit activation of the rostral anterior cingulate cortex/medial prefrontal cortex (rACC/mPFC) and left hippocampus. This pattern of results lends support to the role of schema congruency (rACC/mPFC) and associative novelty (hippocampus) in the processing of induced insight. We propose that (1) the mPFC not only responds to schema-congruent information, but also to the detection of novel schemata, and (2) that the hippocampus responds to a form of associative novelty that is not just a novel constellation of familiar items, but rather comprises a novel meaningful relationship between the items-which was the only difference between our insight and no insight conditions. To investigate episodic long-term memory encoding, we compared CRA items whose solution word was recognized 24 h after encoding to those with forgotten solutions. We found activation in the left striatum and parts of the left amygdala, pointing to a potential role of brain reward circuitry in the encoding of the solution words. We propose that learning from induced insight mainly relies on the amygdala evaluating the internal value (as an affective evaluation) of the suddenly comprehended information, and striatum-dependent reward-based learning.
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LeBoeuf, Brigitte; Garcia, L. Rene
2016-01-01
Sexual dimorphism can be achieved using a variety of mechanisms, including sex-specific circuits and sex-specific function of shared circuits, though how these work together to produce sexually dimorphic behaviors requires further investigation. Here, we explore how components of the sex-shared defecation circuitry are incorporated into the sex-specific male mating circuitry in Caenorhabditis elegans to produce successful copulation. Using behavioral studies, calcium imaging, and genetic manipulation, we show that aspects of the defecation system are coopted by the male copulatory circuitry to facilitate intromission and ejaculation. Similar to hermaphrodites, male defecation is initiated by an intestinal calcium wave, but circuit activity is coordinated differently during mating. In hermaphrodites, the tail neuron DVB promotes expulsion of gut contents through the release of the neurotransmitter GABA onto the anal depressor muscle. However, in the male, both neuron and muscle take on modified functions to promote successful copulation. Males require calcium-dependent activator protein for secretion (CAPS)/unc-31, a dense core vesicle exocytosis activator protein, in the DVB to regulate copulatory spicule insertion, while the anal depressor is remodeled to promote release of sperm into the hermaphrodite. This work shows how sex-shared circuitry is modified in multiple ways to contribute to sex-specific mating. PMID:28031243
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fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder.
Smoski, Moria J; Felder, Jennifer; Bizzell, Joshua; Green, Steven R; Ernst, Monique; Lynch, Thomas R; Dichter, Gabriel S
2009-11-01
The purpose of the present investigation was to evaluate reward processing in unipolar major depressive disorder (MDD). Specifically, we investigated whether adults with MDD demonstrated hyporesponsivity in striatal brain regions and/or hyperresponsivity in cortical brain regions involved in conflict monitoring using a Wheel of Fortune task designed to probe responses during reward selection, reward anticipation, and reward feedback. Functional magnetic resonance imaging (fMRI) data indicated that the MDD group was characterized by reduced activation of striatal reward regions during reward selection, reward anticipation, and reward feedback, supporting previous data indicating hyporesponsivity of reward systems in MDD. Support was not found for hyperresponsivity of cognitive control regions during reward selection or reward anticipation. Instead, MDD participants showed hyperresponsivity in orbitofrontal cortex, a region associated with assessment of risk and reward, during reward selection, as well as decreased activation of the middle frontal gyrus and the rostral cingulate gyrus during reward selection and anticipation. Finally, depression severity was predicted by activation in bilateral midfrontal gyrus during reward selection. Results indicate that MDD is characterized by striatal hyporesponsivity, and that future studies of MDD treatments that seek to improve responses to rewarding stimuli should assess striatal functioning.
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Merkel, Steven F; Andrews, Allison M; Lutton, Evan M; Razmpour, Roshanak; Cannella, Lee Anne; Ramirez, Servio H
2017-07-01
Clinical studies have identified traumatic brain injury (TBI) as a risk factor for the development of cocaine dependence. This claim is supported by our recent preclinical studies showing enhancement of the rewarding effects of cocaine in mice sustaining moderate controlled cortical impact (CCI) injury during adolescence. Here we test the efficacy of dexamethasone, an anti-inflammatory corticosteroid, to attenuate augmentation of the behavioral response to cocaine observed in CCI-TBI animals using the conditioned place preference (CPP) assay. These studies were performed in order to determine whether proinflammatory activity in the nucleus accumbens (NAc), a key brain nucleus in the reward pathway, mediates enhanced cocaine-induced CPP in adolescent animals sustaining moderate CCI-TBI. Our data reveal robust glial activation in the NAc following CCI-TBI and a significant increase in the cocaine-induced CPP of untreated CCI-TBI mice. Furthermore, our results show that dexamethasone treatment following CCI-TBI can attenuate the cocaine place preference of injured animals without producing aversion in the CPP assay. Our studies also found that dexamethasone treatment significantly reduced the expression of select immune response genes including Monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 ( ICAM-1), returning their expression to control levels, which prompted an investigation of peripheral blood monocytes in dexamethasone-treated animals. Experimental findings showed that no craniectomy/dexamethasone mice had a significant increase, while CCI-TBI/dexamethasone animals had a significant decrease in the percentage of circulating nonclassical patrolling monocytes. These results suggest that a portion of these monocytes may migrate to the brain in response to CCI-TBI, potentially sparing the development of chronic neuroinflammation in regions associated with the reward circuitry such as the NAc. Overall, our findings indicate that anti-inflammatory agents, such as dexamethasone, may be effective in normalizing the rewarding effects of cocaine following CCI-TBI.
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Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry.
Christiansen, A M; Herman, J P; Ulrich-Lai, Y M
2011-03-01
Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress.
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Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry
Christiansen, A.M.; Herman, J.P.; Ulrich-Lai, Y.M.
2011-01-01
Palatable food intake reduces stress responses, suggesting that individuals may consume such “comfort” food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid (GABA)ergic signaling is critical for both reward and stress regulation suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the current study aimed to determine 1) how palatable “comfort” food alters stress induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry, and 2) identify candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable “snacking” in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis (HPA)-buffering following palatable snacking. Specifically, palatable snacking alone decreased enkephalin mRNA expression in the anterior bed nucleus of the stria terminalis and the nucleus accumbens, as well as decreasing GAD65 mRNA in the posterior bed nucleus of the stria terminalis. Chronic stress alone increased enkephalin mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and bed nucleus of the stria terminalis; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, bed nucleus of the stria terminalis, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress. PMID:21291318
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Barch, Deanna M; Treadway, Michael T; Schoen, Nathan
2014-05-01
One of the most debilitating aspects of schizophrenia is an apparent interest in or ability to exert effort for rewards. Such "negative symptoms" may prevent individuals from obtaining potentially beneficial outcomes in educational, occupational, or social domains. In animal models, dopamine abnormalities decrease willingness to work for rewards, implicating dopamine (DA) function as a candidate substrate for negative symptoms given that schizophrenia involves dysregulation of the dopamine system. We used the effort-expenditure for rewards task (EEfRT) to assess the degree to which individuals with schizophrenia were wiling to exert increased effort for either larger magnitude rewards or for rewards that were more probable. Fifty-nine individuals with schizophrenia and 39 demographically similar controls performed the EEfRT task, which involves making choices between "easy" and "hard" tasks to earn potential rewards. Individuals with schizophrenia showed less of an increase in effort allocation as either reward magnitude or probability increased. In controls, the frequency of choosing the hard task in high reward magnitude and probability conditions was negatively correlated with depression severity and anhedonia. In schizophrenia, fewer hard task choices were associated with more severe negative symptoms and worse community and work function as assessed by a caretaker. Consistent with patterns of disrupted dopamine functioning observed in animal models of schizophrenia, these results suggest that 1 mechanism contributing to impaired function and motivational drive in schizophrenia may be a reduced allocation of greater effort for higher magnitude or higher probability rewards.
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Xie, Chunming; Ma, Lisha; Jiang, Nan; Huang, Ruyan; Li, Li; Gong, Liang; He, Cancan; Xiao, Chaoyong; Liu, Wen; Xu, Shu; Zhang, Zhijun
2017-08-01
Altered reward processing and cognitive deficits are often observed in patients with obsessive-compulsive disorder (OCD); however, whether the imbalance in activity between reward circuits and the cognitive control (CC) system is associated with compulsive behavior remains unknown. Sixty-eight OCD patients and 33 cognitively normal (CN) healthy subjects participated in this resting-state functional magnetic resonance imaging study. Alterations in the functional connectivity between reward circuits and the CC system were quantitatively assessed and compared between the groups. A Granger causality analysis was used to determine the causal informational influence between and within reward circuits and the CC system across all subjects. OCD patients showed a dichotomous pattern of enhanced functional coupling in their reward circuits and a weakened functional coupling in their CC system when compared to CN subjects. Neural correlates of compulsive behavior were primarily located in the reward circuits and CC system in OCD patients. Importantly, the CC system exerted a reduced interregional causal influence over the reward system in OCD patients relative to its effect in CN subjects. The limitations of this study are that it was a cross-sectional study and the potential effects of environmental and genetic factors were not explored. OCD patients showed an imbalance in the functional link between reward circuits and the CC system at rest. This bias toward a loss of control may define a pathological state in which subjects are more vulnerable to engaging in compulsive behaviors.
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Fee, Michale S.
2012-01-01
In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current “time” in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources. PMID:22754501
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Fee, Michale S
2012-01-01
In its simplest formulation, reinforcement learning is based on the idea that if an action taken in a particular context is followed by a favorable outcome, then, in the same context, the tendency to produce that action should be strengthened, or reinforced. While reinforcement learning forms the basis of many current theories of basal ganglia (BG) function, these models do not incorporate distinct computational roles for signals that convey context, and those that convey what action an animal takes. Recent experiments in the songbird suggest that vocal-related BG circuitry receives two functionally distinct excitatory inputs. One input is from a cortical region that carries context information about the current "time" in the motor sequence. The other is an efference copy of motor commands from a separate cortical brain region that generates vocal variability during learning. Based on these findings, I propose here a general model of vertebrate BG function that combines context information with a distinct motor efference copy signal. The signals are integrated by a learning rule in which efference copy inputs gate the potentiation of context inputs (but not efference copy inputs) onto medium spiny neurons in response to a rewarded action. The hypothesis is described in terms of a circuit that implements the learning of visually guided saccades. The model makes testable predictions about the anatomical and functional properties of hypothesized context and efference copy inputs to the striatum from both thalamic and cortical sources.
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Hedonic sensitivity to natural rewards is affected by prenatal stress in a sex-dependent manner.
Reynaert, Marie-Line; Marrocco, Jordan; Mairesse, Jérôme; Lionetto, Luana; Simmaco, Maurizio; Deruyter, Lucie; Allorge, Delphine; Moles, Anna; Pittaluga, Anna; Maccari, Stefania; Morley-Fletcher, Sara; Van Camp, Gilles; Nicoletti, Ferdinando
2016-11-01
Palatable food is a strong activator of the reward circuitry and may cause addictive behavior leading to eating disorders. How early life events and sex interact in shaping hedonic sensitivity to palatable food is largely unknown. We used prenatally restraint stressed (PRS) rats, which show abnormalities in the reward system and anxious/depressive-like behavior. Some of the hallmarks of PRS rats are known to be sex-dependent. We report that PRS enhanced and reduced milk chocolate-induced conditioned place preference in males and females, respectively. Male PRS rats also show increases in plasma dihydrotestosterone (DHT) levels and dopamine (DA) levels in the nucleus accumbens (NAc), and reductions in 5-hydroxytryptamine (5-HT) levels in the NAc and prefrontal cortex (PFC). In male rats, systemic treatment with the DHT-lowering drug finasteride reduced both milk chocolate preference and NAc DA levels. Female PRS rats showed lower plasma estradiol (E 2 ) levels and lower DA levels in the NAc, and 5-HT levels in the NAc and PFC. E 2 supplementation reversed the reduction in milk chocolate preference and PFC 5-HT levels. In the hypothalamus, PRS increased ERα and ERβ estrogen receptor and CARTP (cocaine-and-amphetamine receptor transcript peptide) mRNA levels in males, and 5-HT 2 C receptor mRNA levels in females. Changes were corrected by treatments with finasteride and E 2 , respectively. These new findings show that early life stress has a profound impact on hedonic sensitivity to high-palatable food via long-lasting changes in gonadal hormones. This paves the way to the development of hormonal strategies aimed at correcting abnormalities in the response to natural rewards. © 2015 Society for the Study of Addiction.
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Wierenga, Christina E; Ely, Alice; Bischoff-Grethe, Amanda; Bailer, Ursula F; Simmons, Alan N; Kaye, Walter H
2014-01-01
The primary defining characteristic of a diagnosis of an eating disorder (ED) is the "disturbance of eating or eating-related behavior that results in the altered consumption or absorption of food" (DSM V; American Psychiatric Association, 2013). There is a spectrum, ranging from those who severely restrict eating and become emaciated on one end to those who binge and overconsume, usually accompanied by some form of compensatory behaviors, on the other. How can we understand reasons for such extremes of food consummatory behaviors? Recent work on obesity and substance use disorders has identified behaviors and neural pathways that play a powerful role in human consummatory behaviors. That is, corticostriatal limbic and dorsal cognitive neural circuitry can make drugs and food rewarding, but also engage self-control mechanisms that may inhibit their use. Importantly, there is considerable evidence that alterations of these systems also occur in ED. This paper explores the hypothesis that an altered balance of reward and inhibition contributes to altered extremes of response to salient stimuli, such as food. We will review recent studies that show altered sensitivity to reward and punishment in ED, with evidence of altered activity in corticostriatal and insula processes with respect to monetary gains or losses, and tastes of palatable foods. We will also discuss evidence for a spectrum of extremes of inhibition and dysregulation behaviors in ED supported by studies suggesting that this is related to top-down self-control mechanisms. The lack of a mechanistic understanding of ED has thwarted efforts for evidence-based approaches to develop interventions. Understanding how ED behavior is encoded in neural circuits would provide a foundation for developing more specific and effective treatment approaches.
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Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K; Solstrand Dahlberg, Linda; Larsen, Anna L; Olaya Búcaro, Marcela; Gustafsson, Veronica P; Titova, Olga E; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J; Schiöth, Helgi B
2016-01-01
Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention.
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Olivo, Gaia; Wiemerslage, Lyle; Nilsson, Emil K.; Solstrand Dahlberg, Linda; Larsen, Anna L.; Olaya Búcaro, Marcela; Gustafsson, Veronica P.; Titova, Olga E.; Bandstein, Marcus; Larsson, Elna-Marie; Benedict, Christian; Brooks, Samantha J.; Schiöth, Helgi B.
2016-01-01
Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene are linked to obesity, but how these SNPs influence resting-state neural activation is unknown. Few brain-imaging studies have investigated the influence of obesity-related SNPs on neural activity, and no study has investigated resting-state connectivity patterns. We tested connectivity within three, main resting-state networks: default mode (DMN), sensorimotor (SMN), and salience network (SN) in 30 male participants, grouped based on genotype for the rs9939609 FTO SNP, as well as punishment and reward sensitivity measured by the Behavioral Inhibition (BIS) and Behavioral Activation System (BAS) questionnaires. Because obesity is associated with anomalies in both systems, we calculated a BIS/BAS ratio (BBr) accounting for features of both scores. A prominence of BIS over BAS (higher BBr) resulted in increased connectivity in frontal and paralimbic regions. These alterations were more evident in the obesity-associated AA genotype, where a high BBr was also associated with increased SN connectivity in dopaminergic circuitries, and in a subnetwork involved in somatosensory integration regarding food. Participants with AA genotype and high BBr, compared to corresponding participants in the TT genotype, also showed greater DMN connectivity in regions involved in the processing of food cues, and in the SMN for regions involved in visceral perception and reward-based learning. These findings suggest that neural connectivity patterns influence the sensitivity toward punishment and reward more closely in the AA carriers, predisposing them to developing obesity. Our work explains a complex interaction between genetics, neural patterns, and behavioral measures in determining the risk for obesity and may help develop individually-tailored strategies for obesity prevention. PMID:26924971
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The amount effect and marginal value.
Rachlin, Howard; Arfer, Kodi B; Safin, Vasiliy; Yen, Ming
2015-07-01
The amount effect of delay discounting (by which the value of larger reward amounts is discounted by delay at a lower rate than that of smaller amounts) strictly implies that value functions (value as a function of amount) are steeper at greater delays than they are at lesser delays. That is, the amount effect and the difference in value functions at different delays are actually a single empirical finding. Amount effects of delay discounting are typically found with choice experiments. Value functions for immediate rewards have been empirically obtained by direct judgment. (Value functions for delayed rewards have not been previously obtained.) The present experiment obtained value functions for both immediate and delayed rewards by direct judgment and found them to be steeper when the rewards were delayed--hence, finding an amount effect with delay discounting. © Society for the Experimental Analysis of Behavior.
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Cigarette craving is associated with blunted reward processing in nicotine-dependent smokers.
Peechatka, Alyssa L; Whitton, Alexis E; Farmer, Stacey L; Pizzagalli, Diego A; Janes, Amy C
2015-10-01
Dysfunctional reward processing leading to the undervaluation of non-drug rewards is hypothesized to play a crucial role in nicotine dependence. However, it is unclear if blunted reward responsivity and the desire to use nicotine are directly linked after a brief period of abstinence. Such an association would suggest that individuals with reduced reward responsivity may be at increased risk to experience nicotine craving. Reward function was evaluated with a probabilistic reward task (PRT), which measures reward responsivity to monetary incentives. To identify whether smoking status influenced reward function, PRT performance was compared between non-depressed, nicotine-dependent smokers and non-smokers. Within smokers, correlations were conducted to determine if blunted reward responsivity on the PRT was associated with increased nicotine craving. Time since last nicotine exposure was standardized to 4h for all smokers. Smokers and non-smokers did not differ in reward responsivity on the PRT. However, within smokers, a significant negative correlation was found between reward responsivity and intensity of nicotine craving. The current findings show that, among smokers, the intensity of nicotine craving is linked to lower sensitivity to non-drug rewards. This finding is in line with prior theories that suggest reward dysfunction in some clinical populations (e.g., depressive disorders, schizophrenia) may facilitate nicotine use. The current study expands on such theories by indicating that sub-clinical variations in reward function are related to motivation for nicotine use. Identifying smokers who show blunted sensitivity to non-drug rewards may help guide treatments aimed at mitigating the motivation to smoke. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress.
Vialou, Vincent; Thibault, Mackenzie; Kaska, Sophia; Cooper, Sarah; Gajewski, Paula; Eagle, Andrew; Mazei-Robison, Michelle; Nestler, Eric J; Robison, A J
2015-12-01
Major depressive disorder is thought to arise in part from dysfunction of the brain's "reward circuitry", consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FosB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FosB gene product expression (i.e., differential expression of full-length FosB, ΔFosB, and Δ2ΔFosB) in brain regions associated with depression--the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus--in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FosB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FosB isoform in the NAc, PFC, and hippocampus even 24 h following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFosB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FosB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Chester, David S; DeWall, C Nathan; Derefinko, Karen J; Estus, Steven; Lynam, Donald R; Peters, Jessica R; Jiang, Yang
2016-10-01
Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression's hedonically rewarding qualities.
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Byrne, Jamie E M; Murray, Greg
2017-01-01
A range of evidence suggests that human reward functioning is partly driven by the endogenous circadian system, generating 24-hour rhythms in behavioural measures of reward activation. Reward functioning is multifaceted but literature to date is largely limited to measures of self-reported positive mood states. The aim of this study was to advance the field by testing for hypothesised diurnal variation in previously unexplored components of psychological reward: 'wanting', liking, and learning using subjective and behavioural measures. Risky decision making (automatic Balloon Analogue Risk Task), affective responsivity to positive images (International Affective Pictures System), uncued self-reported discrete emotions, and learning-contingent reward (Iowa Gambling Task) were measured at 10.00 hours, 14.00 hours, and 19.00 hours in a counterbalanced repeated measures design with 50 healthy male participants (aged 18-30). As hypothesised, risky decision making (unconscious 'wanting') and ratings of arousal towards positive images (conscious wanting) exhibited a diurnal waveform with indices highest at 14.00 hours. No diurnal rhythm was observed for liking (pleasure ratings to positive images, discrete uncued positive emotions) or in a learning-contingent reward task. Findings reaffirm that diurnal variation in human reward functioning is most pronounced in the motivational 'wanting' components of reward.
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Oyama, Kei; Tateyama, Yukina; Hernádi, István; Tobler, Philippe N; Iijima, Toshio; Tsutsui, Ken-Ichiro
2015-11-01
To investigate how the striatum integrates sensory information with reward information for behavioral guidance, we recorded single-unit activity in the dorsal striatum of head-fixed rats participating in a probabilistic Pavlovian conditioning task with auditory conditioned stimuli (CSs) in which reward probability was fixed for each CS but parametrically varied across CSs. We found that the activity of many neurons was linearly correlated with the reward probability indicated by the CSs. The recorded neurons could be classified according to their firing patterns into functional subtypes coding reward probability in different forms such as stimulus value, reward expectation, and reward prediction error. These results suggest that several functional subgroups of dorsal striatal neurons represent different kinds of information formed through extensive prior exposure to CS-reward contingencies. Copyright © 2015 the American Physiological Society.
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Oyama, Kei; Tateyama, Yukina; Hernádi, István; Tobler, Philippe N.; Iijima, Toshio
2015-01-01
To investigate how the striatum integrates sensory information with reward information for behavioral guidance, we recorded single-unit activity in the dorsal striatum of head-fixed rats participating in a probabilistic Pavlovian conditioning task with auditory conditioned stimuli (CSs) in which reward probability was fixed for each CS but parametrically varied across CSs. We found that the activity of many neurons was linearly correlated with the reward probability indicated by the CSs. The recorded neurons could be classified according to their firing patterns into functional subtypes coding reward probability in different forms such as stimulus value, reward expectation, and reward prediction error. These results suggest that several functional subgroups of dorsal striatal neurons represent different kinds of information formed through extensive prior exposure to CS-reward contingencies. PMID:26378201
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Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity
Eisenstein, Sarah A.; Gredysa, Danuta M.; Antenor–Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M.; Black, Kevin J.; Perlmutter, Joel S.; Moerlein, Stephen M.; Hershey, Tamara
2015-01-01
Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans. PMID:26192187
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Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity.
Eisenstein, Sarah A; Gredysa, Danuta M; Antenor-Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M; Black, Kevin J; Perlmutter, Joel S; Moerlein, Stephen M; Hershey, Tamara
2015-01-01
Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans.
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Effects of motivation on reward and attentional networks: an fMRI study.
Ivanov, Iliyan; Liu, Xun; Clerkin, Suzanne; Schulz, Kurt; Friston, Karl; Newcorn, Jeffrey H; Fan, Jin
2012-11-01
Existing evidence suggests that reward and attentional networks function in concert and that activation in one system influences the other in a reciprocal fashion; however, the nature of these influences remains poorly understood. We therefore developed a three-component task to assess the interaction effects of reward anticipation and conflict resolution on the behavioral performance and the activation of brain reward and attentional systems. Sixteen healthy adult volunteers aged 21-45 years were scanned with functional magnetic resonance imaging (fMRI) while performing the task. A two-way repeated measures analysis of variance (ANOVA) with cue (reward vs. non-reward) and target (congruent vs. incongruent) as within-subjects factors was used to test for main and interaction effects. Neural responses to anticipation, conflict, and reward outcomes were tested. Behaviorally there were main effects of both reward cue and target congruency on reaction time. Neuroimaging results showed that reward anticipation and expected reward outcomes activated components of the attentional networks, including the inferior parietal and occipital cortices, whereas surprising non-rewards activated the frontoinsular cortex bilaterally and deactivated the ventral striatum. In turn, conflict activated a broad network associated with cognitive control and motor functions. Interaction effects showed decreased activity in the thalamus, anterior cingulated gyrus, and middle frontal gyrus bilaterally when difficult conflict trials (e.g., incongruent targets) were preceded by reward cues; in contrast, the ventral striatum and orbitofrontal cortex showed greater activation during congruent targets preceded by reward cues. These results suggest that reward anticipation is associated with lower activation in attentional networks, possibly due to increased processing efficiency, whereas more difficult, conflict trials are associated with lower activity in regions of the reward system, possibly because such trials are experienced as less rewarding.
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Gee, Dylan G; Fetcho, Robert N; Jing, Deqiang; Li, Anfei; Glatt, Charles E; Drysdale, Andrew T; Cohen, Alexandra O; Dellarco, Danielle V; Yang, Rui R; Dale, Anders M; Jernigan, Terry L; Lee, Francis S; Casey, B J
2016-04-19
Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3- to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxiety-related behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.
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Geste, Jean R; Pompilus, Marjory; Febo, Marcelo; Bruijnzeel, Adriaan W
2018-05-09
Methylenedioxypyrovalerone (MDPV) is an addictive synthetic drug with severe side effects. Previous studies have shown that MDPV has positive reinforcing properties. However, little is known about the effect of MDPV self-administration on the state of the brain reward system and the neuronal mechanisms by which MDPV mediates its effects. The goal of the present studies was to determine the effect of MDPV self-administration on reward function and the role of cholinergic neurotransmission in the reinforcing effects of MDPV. To study the effect of MDPV self-administration on the brain reward system, rats were prepared with intravenous catheters and intracranial self-stimulation electrodes (ICSS). For 10 days, the reward thresholds were assessed immediately before (23 h post prior session) and after 1 h of MDPV self-administration. The reward thresholds were decreased immediately after MDPV self-administration, which is indicative of a potentiation of brain reward function. The reward thresholds 23 h after MDPV intake gradually increased over time, which is indicative of anhedonia. Pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased the self-administration of MDPV and completely prevented the decrease in reward thresholds. A control study with palatable chocolate pellets showed that responding for a natural reinforcer does not affect the state of the brain reward system. Furthermore, mecamylamine did not affect responding for food pellets. In conclusion, the self-administration of MDPV potentiates reward function and nAChR blockade prevents the reward enhancing effects of MDPV self-administration. Preventing the MDPV-induced increase in cholinergic neurotransmission might be a safe approach to diminish MDPV abuse. Copyright © 2018. Published by Elsevier Ltd.
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Garland, Eric L.; Bryan, Craig J.; Nakamura, Yoshio; Froeliger, Brett; Howard, Matthew O.
2016-01-01
Rationale Prescription opioid misuse and high dose opioid use may result in allostatic dysregulation of hedonic brain circuitry, leading to reduced emotion regulation capacity. In particular, opioid misuse may blunt the ability to experience and upregulate positive affect from natural rewards. Objectives The purpose of this study was to examine associations between opioid use/misuse and autonomic indices of emotion regulation capability in a sample of chronic pain patients receiving prescription opioid pharmacotherapy. Methods Chronic pain patients taking long-term opioid analgesics (N = 40) completed an emotion regulation task while heart rate variability (HRV) was recorded, as well as self-report measures of opioid misuse, craving, pain severity, and emotional distress. Based on a validated cut-point on the Current Opioid Misuse Measure, participants were grouped as opioid misusers or non-misusers. Opioid misuse status and morphine equivalent daily dose (MEDD) were examined as predictors of HRV and self-reports of emotion regulation. Results Opioid misusers exhibited significantly less HRV during positive and negative emotion regulation, and significantly less positive affect, than non-misusers, after controlling for confounders including pain severity and emotional distress. MEDD was inversely associated with positive emotion regulation efficacy. Conclusion Findings implicate the presence of reward processing deficits among chronic pain patients with opioid-misusing behaviors, and opioid dosage was associated with deficient emotion regulation, suggesting the presence of compromised top-down cognitive control over bottom-up hedonic processes. Emotion regulation among opioid misusers may represent an important treatment target. PMID:27933366
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Ghane, Merage; Valdespino, Andrew; Coffman, Marika C.; Strege, Marlene V.; White, Susan W.; Ollendick, Thomas H.
2017-01-01
Abstract Social anxiety disorder (SAD) involves abnormalities in social motivation, which may be independent of well-documented differences in fear and arousal systems. Yet, the neurobiology underlying motivational difficulties in SAD is not well understood. The aim of the current study was to spatiotemporally dissociate reward circuitry dysfunction from alterations in fear and arousal-related neural activity during anticipation and notification of social and non-social reward and punishment. During fMRI acquisition, non-depressed adults with social anxiety disorder (SAD; N = 21) and age-, sex- and IQ-matched control subjects (N = 22) completed eight runs of an incentive delay task, alternating between social and monetary outcomes and interleaved in alternating order between gain and loss outcomes. Adults with SAD demonstrated significantly reduced neural activity in ventral striatum during the anticipation of positive but not negative social outcomes. No differences between the SAD and control groups were observed during anticipation of monetary gain or loss outcomes or during anticipation of negative social images. However, consistent with previous work, the SAD group demonstrated amygdala hyper-activity upon notification of negative social outcomes. Degraded anticipatory processing in bilateral ventral striatum in SAD was constrained exclusively to anticipation of positive social information and dissociable from the effects of negative social outcomes previously observed in the amygdala. Alterations in anticipation-related neural signals may represent a promising target for treatment that is not addressed by available evidence-based interventions, which focus primarily on fear extinction and habituation processes. PMID:27798252
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Clarke, Hannah F.; Robbins, Trevor W.; Roberts, Angela C.
2014-01-01
The ability to switch responding between two visual stimuli based on their changing relationship with reward is dependent on the orbitofrontal cortex (OFC). OFC lesions in humans, monkeys, and rats disrupt performance on a common test of this ability, the visual serial discrimination reversal task. This finding is of particular significance to our understanding of psychiatric disorders such as obsessive–compulsive disorder (OCD) and schizophrenia, in which behavioral inflexibility is a prominent symptom. Although OFC dysfunction can occur in these disorders, there is considerable evidence for more widespread dysfunction within frontostriatal and frontoamygdalar circuitry. Because the contribution of these subcortical structures to behavioral flexibility is poorly understood, the present study compared the effects of excitotoxic lesions of the medial striatum (MS), amygdala, and OFC in the marmoset monkey on performance of the serial reversal task. All monkeys were able to learn a novel stimulus–reward association but, compared with both control and amygdala-lesioned monkeys, those with MS or OFC lesions showed a perseverative impairment in their ability to reverse this association. However, whereas both MS and OFC groups showed insensitivity to negative feedback, only OFC-lesioned monkeys showed insensitivity to positive feedback. These findings suggest that, for different reasons, both the MS and OFC support behavioral flexibility after changes in reward contingencies, and are consistent with the hypothesis that striatal and OFC dysfunction can contribute to pathological perseveration. PMID:18945905
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Beitscher-Campbell, Harriet; Blum, Kenneth; Febo, Marcelo; Madigan, Margaret A; Giordano, John; Badgaiyan, Rajendra D; Braverman, Eric R; Dushaj, Kristina; Li, Mona; Gold, Mark S
2016-09-01
Background The reward deficiency syndrome hypothesis posits that genes are responsible for reward dependence and related behaviors. There is evidence that both bulimia and anorexia nervosa, especially in women, have been linked to a lifetime history of substance use disorder (SUD). There are difficulties in accepting food as an addiction similar to drugs; however, increasingly neuroimaging studies favor such an assertion. Case presentations We are reporting the evidence of comorbidity of eating disorders with SUD found within these case presentations. We show 50 case reports derived from two independent treatment centers in Florida that suggest the commonality between food and drug addictions. In an attempt to provide data from this cohort, many participants did not adequately respond to our questionnaire. Discussion We propose that dopamine agonist therapy may be of common benefit. Failure in the past may reside in too powerful D2 agonist activity leading to D2 receptor downregulation, while the new methodology may cause a reduction of "dopamine resistance" by inducing "dopamine homeostasis." While this is not a definitive study, it does provide some additional clinical evidence that these two addictions are not mutually exclusive. Conclusion Certainly, it is our position that there is an overlap between food- and drug-seeking behavior. We propose that the studies focused on an effort to produce natural activation of dopaminergic reward circuitry as a type of common therapy may certainly be reasonable. Additional research is warranted.
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Brain serotonergic circuitries
Charnay, Yves; Leger, Lucienne
2010-01-01
Brain serotonergic circuitries interact with other neurotransmitter systems on a multitude of different molecular levels. In humans, as in other mammalian species, serotonin (5-HT) plays a modulatory role in almost every physiological function. Furthermore, serotonergic dysfunction is thought to be implicated in several psychiatric and neurodegenerative disorders. We describe the neuroanatomy and neurochemistry of brain serotonergic circuitries. The contribution of emergent in vivo imaging methods to the regional localization of binding site receptors and certain aspects of their functional connectivity in correlation to behavior is also discussed. 5-HT cell bodies, mainly localized in the raphe nuclei, send axons to almost every brain region. It is argued that the specificity of the local chemocommunication between 5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT, the diversity of high-affinity membrane receptors, and their specific transduction modalities. PMID:21319493
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Graziane, Nicholas M; Neumann, Peter A; Dong, Yan
2018-01-01
The lateral habenula (LHb) regulates reward learning and controls the updating of reward-related information. Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine ex vivo and in vivo results for an overview of how drugs of abuse alter LHb function and how these functional alterations affect the ability to learn and update behavioral responses to hedonic external stimuli.
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Zhao, Weihua; Geng, Yayuan; Luo, Lizhu; Zhao, Zhiying; Ma, Xiaole; Xu, Lei; Yao, Shuxia; Kendrick, Keith M
2017-01-01
The neuropeptide oxytocin (OXT) can influence self-processing and may help motivate us to value the attributes of others in a more self-like manner by reducing medial prefrontal cortex (mPFC) responses. We do not know however whether this OXT effect extends to possessions. We tend to place a higher monetary value on specific objects that belong to us compared to others, known as the "endowment effect". In two double-blind, between-subject placebo (PLC) controlled experiments in subjects from a collectivist culture, we investigated the influence of intranasal OXT on the endowment effect, with the second study incorporating functional magnetic resonance imaging (fMRI). In the task, subjects decided whether to buy or sell their own or others' (mother/father/classmate/stranger) possessions at various prices. Both experiments demonstrated an endowment effect in the self-owned condition which extended to close others (mother/father) and OXT increased this for self and all other-owned items. This OXT effect was associated with reduced activity in the ventral mPFC (vmPFC) in the self-owned condition but increased in the mother-condition. For the classmate- and stranger-owned conditions OXT increased activity in the dorsal mPFC (dmPFC). Changes in vmPFC activation were associated with the size of the endowment effect for self- and mother-owned items. Functional connectivity between the dmPFC and ventral striatum (VStr) was reduced by OXT in self- and mother-owned conditions and between vmPFC and precuneus in the self-condition. Overall our results show that OXT enhances the endowment effect for both self- and other-owned items in Chinese subjects. This effect is associated with reduced mPFC activation in the self-condition but enhanced activation in all other-conditions and involves differential actions on both dorsal and ventral regions as well as functional connectivity with brain reward and other self-processing regions. Overall our findings suggest that OXT increases the perceived value of both self- and other-owned items by acting on neural circuitry involved in self-processing and reward.
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Zhao, Weihua; Geng, Yayuan; Luo, Lizhu; Zhao, Zhiying; Ma, Xiaole; Xu, Lei; Yao, Shuxia; Kendrick, Keith M.
2017-01-01
The neuropeptide oxytocin (OXT) can influence self-processing and may help motivate us to value the attributes of others in a more self-like manner by reducing medial prefrontal cortex (mPFC) responses. We do not know however whether this OXT effect extends to possessions. We tend to place a higher monetary value on specific objects that belong to us compared to others, known as the “endowment effect”. In two double-blind, between-subject placebo (PLC) controlled experiments in subjects from a collectivist culture, we investigated the influence of intranasal OXT on the endowment effect, with the second study incorporating functional magnetic resonance imaging (fMRI). In the task, subjects decided whether to buy or sell their own or others’ (mother/father/classmate/stranger) possessions at various prices. Both experiments demonstrated an endowment effect in the self-owned condition which extended to close others (mother/father) and OXT increased this for self and all other-owned items. This OXT effect was associated with reduced activity in the ventral mPFC (vmPFC) in the self-owned condition but increased in the mother-condition. For the classmate- and stranger-owned conditions OXT increased activity in the dorsal mPFC (dmPFC). Changes in vmPFC activation were associated with the size of the endowment effect for self- and mother-owned items. Functional connectivity between the dmPFC and ventral striatum (VStr) was reduced by OXT in self- and mother-owned conditions and between vmPFC and precuneus in the self-condition. Overall our results show that OXT enhances the endowment effect for both self- and other-owned items in Chinese subjects. This effect is associated with reduced mPFC activation in the self-condition but enhanced activation in all other-conditions and involves differential actions on both dorsal and ventral regions as well as functional connectivity with brain reward and other self-processing regions. Overall our findings suggest that OXT increases the perceived value of both self- and other-owned items by acting on neural circuitry involved in self-processing and reward. PMID:28588469
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Hasler, Brant P; Forbes, Erika E; Franzen, Peter L
2014-10-30
Human and animal studies indicate that reward function is modulated by the circadian clock that governs our daily sleep/wake rhythm. For example, a robust circadian rhythm exists in positive affect, which is lower in the morning hours and peaks in the afternoon. A handful of functional neuroimaging studies suggest that systematic diurnal variation exists in brain activity related to other functions, but no published human studies have examined daily variation in the neural processing of reward. In the present study, we attempt to advance this literature by using functional neuroimaging methods to examine time-of-day changes in the responsivity of the reward circuit. Using a within-person design and a functional magnetic resonance imaging (fMRI) monetary reward task, we compared morning and afternoon reward-related brain activation in a sample of healthy young adults within 24h. Region of interest analyses focused on the striatum, and we hypothesized greater reward activation in the afternoon, concordant with the circadian peak in positive affect. Results were consistent with our hypothesis. In addition, we counterbalanced the order of morning and afternoon scans in order to explore the short-term stability of the neural response. Whole-brain analyses showed a markedly higher reactivity to reward throughout the brain in the first scan relative to the second scan, consistent with habituation to the monetary reward stimuli. However, these effects did not appear to explain the time-of-day findings. In summary, we report the first preliminary evidence of circadian variation in the neural processing of reward. These findings have both methodological and theoretical implications. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
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Neurobiology of dysregulated motivational systems in drug addiction
Edwards, Scott; Koob, George F
2010-01-01
The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention. PMID:20563312
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Hasler, Brant P.; Casement, Melynda D.; Sitnick, Stephanie L.; Shaw, Daniel S.; Forbes, Erika E.
2017-01-01
Eveningness, a preference for later sleep-wake timing, is linked to altered reward function, which may explain a consistent association with substance abuse. Notably, the extant literature rests largely on cross-sectional data, yet both eveningness and reward function show developmental changes. We examined whether circadian preference during late adolescence predicted the neural response to reward two years later. A sample of 93 males reported circadian preference and completed a monetary reward fMRI paradigm at ages 20 and 22. Primary analyses examined longitudinal paths from circadian preference to medial prefrontal cortex (mPFC) and ventral striatal (VS) reward responses. We also explored whether reward responses mediated longitudinal associations between circadian preference and alcohol dependence, frequency of alcohol use, and/or frequency of cannabis use. Age 20 eveningness was positively associated with age 22 mPFC and VS responses to win, but not associated with age 22 reactivity to reward anticipation. Age 20 eveningness was indirectly related to age 22 alcohol dependence via age 22 mPFC response to win. Our findings provide novel evidence that altered reward-related brain function could underlie associations between eveningness and alcohol use problems. Eveningness may be an under-recognized but modifiable risk factor for reward-related problems such as mood and substance use disorders. PMID:28254633
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Lanza di Scalea, Teresa; Matthews, Karen A; Avis, Nancy E; Thurston, Rebecca C; Brown, Charlotte; Harlow, Sioban; Bromberger, Joyce T
2012-05-01
Little is known about the independent associations of reward and stress within specific roles with multiple measures of mental health in an ethnically diverse community sample of midlife women. The objective of this study is to examine if (1) role reward (within each role and across roles) contributes directly to mental health and buffers the negative impact of role stress and (2) associations among role occupancy, role stress, and role reward and mental health vary by race/ethnicity. With separate logistic regression analysis, we investigated cross-sectional relationships between role stress and role reward with presence/absence of high depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D≥16]), anxiety symptoms (feeling tense or nervous, irritable or grouchy, fearful for no reason, and heart pounding or racing total score≥4), or low social functioning (bottom 25th percentile of the Short-Form-36 [SF-36] social functioning subscale) in 2549 women participating in the third visit of the Study of Women's Health Across the Nation (SWAN), a longitudinal population-based study of menopause. High reward across roles attenuated the negative impact of role stress on social functioning but not on anxiety or depression. High reward marriage buffered the impact of marital stress on depression, and high reward mothering buffered the effect of maternal stress on depression and social functioning. Compared to Caucasians, Hispanics and Chinese with high stress across roles had better social functioning, and African American mothers had lower odds of high depressive symptoms. Role reward buffers the negative impact of stress on social functioning and depression, but not on anxiety. Minorities may respond to role stress by seeking social support.
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Lanza di Scalea, Teresa; Matthews, Karen A.; Avis, Nancy E.; Thurston, Rebecca C.; Brown, Charlotte; Harlow, Sioban
2012-01-01
Abstract Background Little is known about the independent associations of reward and stress within specific roles with multiple measures of mental health in an ethnically diverse community sample of midlife women. The objective of this study is to examine if (1) role reward (within each role and across roles) contributes directly to mental health and buffers the negative impact of role stress and (2) associations among role occupancy, role stress, and role reward and mental health vary by race/ethnicity. Methods With separate logistic regression analysis, we investigated cross-sectional relationships between role stress and role reward with presence/absence of high depressive symptoms (Center for Epidemiologic Studies Depression Scale [CES-D≥16]), anxiety symptoms (feeling tense or nervous, irritable or grouchy, fearful for no reason, and heart pounding or racing total score≥4), or low social functioning (bottom 25th percentile of the Short-Form-36 [SF-36] social functioning subscale) in 2549 women participating in the third visit of the Study of Women's Health Across the Nation (SWAN), a longitudinal population-based study of menopause. Results High reward across roles attenuated the negative impact of role stress on social functioning but not on anxiety or depression. High reward marriage buffered the impact of marital stress on depression, and high reward mothering buffered the effect of maternal stress on depression and social functioning. Compared to Caucasians, Hispanics and Chinese with high stress across roles had better social functioning, and African American mothers had lower odds of high depressive symptoms. Conclusions Role reward buffers the negative impact of stress on social functioning and depression, but not on anxiety. Minorities may respond to role stress by seeking social support. PMID:22360697
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Ventral pallidum roles in reward and motivation.
Smith, Kyle S; Tindell, Amy J; Aldridge, J Wayne; Berridge, Kent C
2009-01-23
In recent years the ventral pallidum has become a focus of great research interest as a mechanism of reward and incentive motivation. As a major output for limbic signals, the ventral pallidum was once associated primarily with motor functions rather than regarded as a reward structure in its own right. However, ample evidence now suggests that ventral pallidum function is a major mechanism of reward in the brain. We review data indicating that (1) an intact ventral pallidum is necessary for normal reward and motivation, (2) stimulated activation of ventral pallidum is sufficient to cause reward and motivation enhancements, and (3) activation patterns in ventral pallidum neurons specifically encode reward and motivation signals via phasic bursts of excitation to incentive and hedonic stimuli. We conclude that the ventral pallidum may serve as an important 'limbic final common pathway' for mesocorticolimbic processing of many rewards.
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Jacobs, Emily G; Weiss, Blair; Makris, Nikos; Whitfield-Gabrieli, Sue; Buka, Stephen L; Klibanski, Anne; Goldstein, Jill M
2017-05-01
Converging preclinical and human evidence indicates that the decline in ovarian estradiol production during the menopausal transition may play a mechanistic role in the neuronal changes that occur early in the aging process. Here, we present findings from a population-based fMRI study characterizing regional and network-level differences in working memory (WM) circuitry in midlife men and women (N = 142; age range 46-53), as a function of sex and reproductive stage. Reproductive histories and hormonal evaluations were used to determine menopausal status. Participants performed a verbal WM task during fMRI scanning. Results revealed robust differences in task-evoked responses in dorsolateral prefrontal cortex and hippocampus as a function of women's reproductive stage, despite minimal variance in chronological age. Sex differences in regional activity and functional connectivity that were pronounced between men and premenopausal women were diminished for postmenopausal women. Critically, analyzing data without regard to sex or reproductive status obscured group differences in the circuit-level neural strategies associated with successful working memory performance. These findings underscore the importance of reproductive age and hormonal status, over and above chronological age, for understanding sex differences in the aging of memory circuitry. Further, these findings suggest that early changes in working memory circuitry are evident decades before the age range typically targeted in cognitive aging studies. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Opioid pharmaceuticals and addiction: the issues, and research directions seeking solutions.
Walwyn, Wendy M; Miotto, Karen A; Evans, Christopher J
2010-05-01
There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies.
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Opioid pharmaceuticals and addiction: The issues, and research directions seeking solutions
Walwyn, Wendy M.; Miotto, Karen A.; Evans, Christopher J.
2011-01-01
There are few pharmaceuticals superior to opiates for the treatment of pain. However, with concerns of addiction, withdrawal and questionable efficacy for all types of pain, these compounds are far from a magical panacea for pain-relief. As it is unlikely that other classes of compounds will supersede the opioids in the very near future, it is important to both optimize current opioid therapies and curb the astounding diversion of opioids from their intended analgesic use to non-medical abuse. In optimizing opioid therapeutics it is necessary to enhance the clinical awareness of the benefits of treating pain and combine this with aggressive strategies to reduce diversion for non-medical use. At the heart of the issue of opioid misuse is the role of opioid systems in the reward circuitry, and the adaptive processes associated with repetitive opioid use that manifest during withdrawal. Emerging pharmacological insights of opioid receptors will be reviewed that provide future hope for developing opioid-based analgesics with reduced addictive properties and perhaps, reduced opponent processes. In addition, with the increased understanding of nociceptive circuitry and the molecules involved in transmitting pain, new therapeutic targets have become evident that may result in effective analgesics either alone or in combination with current opioid therapies. PMID:20188495
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A Biologically Inspired Computational Model of Basal Ganglia in Action Selection.
Baston, Chiara; Ursino, Mauro
2015-01-01
The basal ganglia (BG) are a subcortical structure implicated in action selection. The aim of this work is to present a new cognitive neuroscience model of the BG, which aspires to represent a parsimonious balance between simplicity and completeness. The model includes the 3 main pathways operating in the BG circuitry, that is, the direct (Go), indirect (NoGo), and hyperdirect pathways. The main original aspects, compared with previous models, are the use of a two-term Hebb rule to train synapses in the striatum, based exclusively on neuronal activity changes caused by dopamine peaks or dips, and the role of the cholinergic interneurons (affected by dopamine themselves) during learning. Some examples are displayed, concerning a few paradigmatic cases: action selection in basal conditions, action selection in the presence of a strong conflict (where the role of the hyperdirect pathway emerges), synapse changes induced by phasic dopamine, and learning new actions based on a previous history of rewards and punishments. Finally, some simulations show model working in conditions of altered dopamine levels, to illustrate pathological cases (dopamine depletion in parkinsonian subjects or dopamine hypermedication). Due to its parsimonious approach, the model may represent a straightforward tool to analyze BG functionality in behavioral experiments.
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Positive autobiographical memory retrieval reduces temporal discounting.
Lempert, Karolina M; Speer, Megan E; Delgado, Mauricio R; Phelps, Elizabeth A
2017-10-01
People generally prefer rewards sooner rather than later. This phenomenon, temporal discounting, underlies many societal problems, including addiction and obesity. One way to reduce temporal discounting is to imagine positive future experiences. Since there is overlap in the neural circuitry associated with imagining future experiences and remembering past events, here we investigate whether recalling positive memories can also promote more patient choice. We found that participants were more patient after retrieving positive autobiographical memories, but not when they recalled negative memories. Moreover, individuals were more impulsive after imagining novel positive scenes that were not related to their memories, showing that positive imagery alone does not drive this effect. Activity in the striatum and temporo parietal junction during memory retrieval predicted more patient choice, suggesting that to the extent that memory recall is rewarding and involves perspective-taking, it influences decision-making. Furthermore, representational similarity in the ventromedial prefrontal cortex between memory recall and decision phases correlated with the behavioral effect across participants. Thus, we have identified a novel manipulation for reducing temporal discounting-remembering the positive past-and have begun to characterize the psychological and neural mechanisms behind it. © The Author (2017). Published by Oxford University Press.
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The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.
Felger, Jennifer C
Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.
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The neurobiological and behavioral overlaps of nicotine and food addiction.
Criscitelli, Kristen; Avena, Nicole M
2016-11-01
Both cigarette smoking and obesity are significant public health concerns and are associated with increased risk of early mortality. It is well established that the mesolimbic dopamine pathway is an important component of the reward system within the brain and is implicated in the development of addiction. Indeed, nicotine and highly palatable foods are capable of altering dopamine release within this system, engendering addictive like responses in susceptible individuals. Although additional research is warranted, findings from animal and human literature have elucidated many of neuroadaptions that occur from exposure to nicotine and highly palatable foods, leading to a greater understanding of the underlying mechanisms contributing to these aberrant behaviors. In this review we present the findings taken from preclinical and clinical literature of the known effects of exposure to nicotine and highly palatable foods on the reward related circuitry within the brain. Further, we compare the neurobiological and behavioral overlaps between nicotine, highly palatable foods and obesity. Lastly, we examine the stigma associated with smoking, obesity and food addiction, and the consequences stigma has on the overall health and wellbeing of an individual. Copyright © 2016. Published by Elsevier Inc.
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Suboptimal foraging behavior: A new perspective on gambling
Addicott, Merideth A.; Pearson, John M.; Kaiser, Nicole; Platt, Michael L.; McClernon, F. Joseph
2015-01-01
Why do people gamble? Conventional views hold that gambling may be motivated by irrational beliefs, risk-seeking, impulsive temperament, or dysfunction within the same reward circuitry affected by drugs of abuse. An alternate, unexplored perspective is that gambling is an extension of natural foraging behavior to a financial environment. However, when these foraging algorithms are applied to stochastic gambling outcomes, undesirable results may occur. To test this hypothesis, we recruited participants based on their frequency of gambling – yearly (or less), monthly, and weekly – and investigated how gambling frequency related to irrational beliefs, risk-taking/impulsivity, and foraging behavior. We found that increased gambling frequency corresponded to greater gambling-related beliefs, more exploratory choices on an explore/exploit foraging task, and fewer points earned on a patchy foraging task. Gambling-related beliefs negatively related to performance on the patchy foraging task, indicating that individuals with more gambling-related cognitions tended to leave a patch too quickly. This indicates that frequent gamblers have reduced foraging ability to maximize rewards; however, gambling frequency- and by extension, poor foraging ability- was not related to risk-taking or impulsive behavior. These results suggest that gambling reflects the application of a dysfunctional foraging process to financial outcomes. PMID:26191945
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Suboptimal foraging behavior: a new perspective on gambling.
Addicott, Merideth A; Pearson, John M; Kaiser, Nicole; Platt, Michael L; McClernon, F Joseph
2015-10-01
Why do people gamble? Conventional views hold that gambling may be motivated by irrational beliefs, risk-seeking, impulsive temperament, or dysfunction within the same reward circuitry affected by drugs of abuse. An alternate, unexplored perspective is that gambling is an extension of natural foraging behavior to a financial environment. However, when these foraging algorithms are applied to stochastic gambling outcomes, undesirable results may occur. To test this hypothesis, we recruited participants based on their frequency of gambling-yearly (or less), monthly, and weekly-and investigated how gambling frequency related to irrational beliefs, risk-taking/impulsivity, and foraging behavior. We found that increased gambling frequency corresponded to greater gambling-related beliefs, more exploratory choices on an explore/exploit foraging task, and fewer points earned on a Patchy Foraging Task. Gambling-related beliefs negatively related to performance on the Patchy Foraging Task, indicating that individuals with more gambling-related cognitions tended to leave a patch too quickly. This indicates that frequent gamblers have reduced foraging ability to maximize rewards; however, gambling frequency -and by extension, poor foraging ability- was not related to risk-taking or impulsive behavior. These results suggest that gambling reflects the application of a dysfunctional foraging process to financial outcomes. (c) 2015 APA, all rights reserved).
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Juárez-Morales, José L; Martinez-De Luna, Reyna I; Zuber, Michael E; Roberts, Alan; Lewis, Katharine E
2017-09-01
A correctly functioning spinal cord is crucial for locomotion and communication between body and brain but there are fundamental gaps in our knowledge of how spinal neuronal circuitry is established and functions. To understand the genetic program that regulates specification and functions of this circuitry, we need to connect neuronal molecular phenotypes with physiological analyses. Studies using Xenopus laevis tadpoles have increased our understanding of spinal cord neuronal physiology and function, particularly in locomotor circuitry. However, the X. laevis tetraploid genome and long generation time make it difficult to investigate how neurons are specified. The opacity of X. laevis embryos also makes it hard to connect functional classes of neurons and the genes that they express. We demonstrate here that Tol2 transgenic constructs using zebrafish enhancers that drive expression in specific zebrafish spinal neurons label equivalent neurons in X. laevis and that the incorporation of a Gal4:UAS amplification cassette enables cells to be observed in live X. laevis tadpoles. This technique should enable the molecular phenotypes, morphologies and physiologies of distinct X. laevis spinal neurons to be examined together in vivo. We have used an islet1 enhancer to label Rohon-Beard sensory neurons and evx enhancers to identify V0v neurons, for the first time, in X. laevis spinal cord. Our work demonstrates the homology of spinal cord circuitry in zebrafish and X. laevis, suggesting that future work could combine their relative strengths to elucidate a more complete picture of how vertebrate spinal cord neurons are specified, and function to generate behavior. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1007-1020, 2017. © 2017 Wiley Periodicals, Inc.
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Differential reward network functional connectivity in cannabis dependent and non-dependent users☆
Filbey, Francesca M.; Dunlop, Joseph
2015-01-01
Background Emergent studies show that similar to other substances of abuse, cue-reactivity to cannabis is also associated with neural response in the brain’s reward pathway (Filbey et al., 2009). However, the inter-relatedness of brain regions during cue-reactivity in cannabis users remains unknown. Methods In this study, we conducted a series of investigations to determine functional connectivity during cue-reactivity in 71 cannabis users. First, we used psychophysiological interaction (PPI) analysis to examine coherent neural response to cannabis cues. Second, we evaluated whether these patterns of network functional connectivity differentiated dependent and non-dependent users. Finally, as an exploratory analysis, we determined the directionality of these connections via Granger connectivity analyses. Results PPI analyses showed reward network functional connectivity with the nucleus accumbens (NAc) seed region during cue exposure. Between-group contrasts found differential effects of dependence status. Dependent users (N = 31) had greater functional connectivity with amygdala and anterior cingulate gyrus (ACG) seeds while the non-dependent users (N = 24) had greater functional connectivity with the NAc, orbitofrontal cortex (OFC) and hippocampus seeds. Granger analyses showed that hippocampal and ACG activation preceded neural response in reward areas. Conclusions Both PPI and Granger analyses demonstrated strong functional coherence in reward regions during exposure to cannabis cues in current cannabis users. Functional connectivity (but not regional activation) in the reward network differentiated dependent from non-dependent cannabis users. Our findings suggest that repeated cannabis exposure causes observable changes in functional connectivity in the reward network and should be considered in intervention strategies. PMID:24838032
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Saturation of subjective reward magnitude as a function of current and pulse frequency.
Simmons, J M; Gallistel, C R
1994-02-01
In rats with electrodes in the medial forebrain bundle, the upper portion of the function relating the experienced magnitude of the reward to pulse frequency was determined at currents ranging from 100 to 1,000 microA. The pulse frequency required to produce an asymptotic level of reward was inversely proportional to current except at the lowest currents and highest pulse frequencies. At a given current, the subjective reward magnitude functions decelerated to an asymptote over an interval in which the pulse frequency doubled or tripled. The asymptotic level of reward was approximately constant for currents between 200 and 1,000 microA but declined substantially at currents at or below 100 microA and pulse frequencies at or above 250 to 400 pulses per second. The results are consistent with the hypothesis that the magnitude of the experienced reward depends only on the number of action potentials generated by the train of pulses in the bundle of reward-relevant axons.
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Orbitofrontal reward sensitivity and impulsivity in adult attention deficit hyperactivity disorder.
Wilbertz, Gregor; van Elst, Ludger Tebartz; Delgado, Mauricio R; Maier, Simon; Feige, Bernd; Philipsen, Alexandra; Blechert, Jens
2012-03-01
Impulsivity symptoms of adult attention deficit hyperactivity disorder (ADHD) such as increased risk taking have been linked with impaired reward processing. Previous studies have focused on reward anticipation or on rewarded executive functioning tasks and have described a striatal hyporesponsiveness and orbitofrontal alterations in adult and adolescent ADHD. Passive reward delivery and its link to behavioral impulsivity are less well understood. To study this crucial aspect of reward processing we used functional magnetic resonance imaging (fMRI) combined with electrodermal assessment in male and female adult ADHD patients (N=28) and matched healthy control participants (N=28) during delivery of monetary and non-monetary rewards. Further, two behavioral tasks assessed risky decision making (game of dice task) and delay discounting. Results indicated that both groups activated ventral and dorsal striatum and the medial orbitofrontal cortex (mOFC) in response to high-incentive (i.e. monetary) rewards. A similar, albeit less strong activation pattern was found for low-incentive (i.e. non-monetary) rewards. Group differences emerged when comparing high and low incentive rewards directly: activation in the mOFC coded for the motivational change in reward delivery in healthy controls, but not ADHD patients. Additionally, this dysfunctional mOFC activity in patients correlated with risky decision making and delay discounting and was paralleled by physiological arousal. Together, these results suggest that the mOFC codes reward value and type in healthy individuals whereas this function is deficient in ADHD. The brain-behavior correlations suggest that this deficit might be related to behavioral impulsivity. Reward value processing difficulties in ADHD should be considered when assessing reward anticipation and emotional learning in research and applied settings. Copyright © 2011 Elsevier Inc. All rights reserved.
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Holsen, Laura M; Lawson, Elizabeth A; Blum, Justine; Ko, Eunice; Makris, Nikos; Fazeli, Pouneh K; Klibanski, Anne; Goldstein, Jill M
2012-09-01
Previous studies have provided evidence of food motivation circuitry dysfunction in individuals with anorexia nervosa. However, methodological limitations present challenges to the development of a cohesive neurobiological model of anorexia nervosa. Our goal was to investigate the neural circuitry of appetite dysregulation across states of hunger and satiety in active and weight-restored phases of anorexia nervosa using robust methodology to advance our understanding of potential neural circuitry abnormalities related to hedonic and nonhedonic state and trait. We scanned women with active anorexia nervosa, weight-restored women with anorexia nervosa and healthy-weight controls on a 3-T Siemens magnetic resonance scanner while they viewed images of high- and low-calorie foods and objects before (premeal) and after (postmeal) eating a 400 kcal meal. We enrolled 12 women with active disease, 10 weight-restored women with anorexia nervosa and 11 controls in our study. Compared with controls, both weight-restored women and those with active disease demonstrated hypoactivity premeal in the hypothalamus, amygdala and anterior insula in response to high-calorie foods (v. objects). Postmeal, hypoactivation in the anterior insula persisted in women with active disease. Percent signal change in the anterior insula was positively correlated with food stimuli ratings and hedonic and nonhedonic appetite ratings in controls, but not women with active disease. Our findings are limited by a relatively small sample size, which prevented the use of an analysis of variance model and exploration of interaction effects, although our substantial effect sizes of between-group differences suggest adequate power for our statistical analysis approach. Participants taking psychotropic medications were included. Our data provide evidence of potential state and trait hypoactivations in food motivation regions involved in the assessment of food's reward value and integration of these with interoceptive signalling of one's internal state of well-being, with important relations between brain activity and homeostatic and hedonic aspects of appetite. Our findings give novel evidence of disruption in neurobiological circuits and stress the importance of examining both state and trait characteristics in the investigation of brain phenotypes in individuals with anorexia nervosa.
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Gene Expression Changes in the Motor Cortex Mediating Motor Skill Learning
Cheung, Vincent C. K.; DeBoer, Caroline; Hanson, Elizabeth; Tunesi, Marta; D'Onofrio, Mara; Arisi, Ivan; Brandi, Rossella; Cattaneo, Antonino; Goosens, Ki A.
2013-01-01
The primary motor cortex (M1) supports motor skill learning, yet little is known about the genes that contribute to motor cortical plasticity. Such knowledge could identify candidate molecules whose targeting might enable a new understanding of motor cortical functions, and provide new drug targets for the treatment of diseases which impair motor function, such as ischemic stroke. Here, we assess changes in the motor-cortical transcriptome across different stages of motor skill acquisition. Adult rats were trained on a gradually acquired appetitive reach and grasp task that required different strategies for successful pellet retrieval, or a sham version of the task in which the rats received pellet reward without needing to develop the reach and grasp skill. Tissue was harvested from the forelimb motor-cortical area either before training commenced, prior to the initial rise in task performance, or at peak performance. Differential classes of gene expression were observed at the time point immediately preceding motor task improvement. Functional clustering revealed that gene expression changes were related to the synapse, development, intracellular signaling, and the fibroblast growth factor (FGF) family, with many modulated genes known to regulate synaptic plasticity, synaptogenesis, and cytoskeletal dynamics. The modulated expression of synaptic genes likely reflects ongoing network reorganization from commencement of training till the point of task improvement, suggesting that motor performance improves only after sufficient modifications in the cortical circuitry have accumulated. The regulated FGF-related genes may together contribute to M1 remodeling through their roles in synaptic growth and maturation. PMID:23637843
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Koziol, Leonard F; Budding, Deborah Ely; Chidekel, Dana
2010-12-01
Current cortico-centric models of cognition lack a cohesive neuroanatomic framework that sufficiently considers overlapping levels of function, from "pathological" through "normal" to "gifted" or exceptional ability. While most cognitive theories presume an evolutionary context, few actively consider the process of adaptation, including concepts of neurodevelopment. Further, the frequent co-occurrence of "gifted" and "pathological" function is difficult to explain from a cortico-centric point of view. This comprehensive review paper proposes a framework that includes the brain's vertical organization and considers "giftedness" from an evolutionary and neurodevelopmental vantage point. We begin by discussing the current cortico-centric model of cognition and its relationship to intelligence. We then review an integrated, dual-tiered model of cognition that better explains the process of adaptation by simultaneously allowing for both stimulus-based processing and higher-order cognitive control. We consider the role of the basal ganglia within this model, particularly in relation to reward circuitry and instrumental learning. We review the important role of white matter tracts in relation to speed of adaptation and development of behavioral mastery. We examine the cerebellum's critical role in behavioral refinement and in cognitive and behavioral automation, particularly in relation to expertise and giftedness. We conclude this integrated model of brain function by considering the savant syndrome, which we believe is best understood within the context of a dual-tiered model of cognition that allows for automaticity in adaptation as well as higher-order executive control.
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Knight, Emily J; Testini, Paola; Min, Hoon-Ki; Gibson, William S; Gorny, Krzysztof R; Favazza, Christopher P; Felmlee, Joel P; Kim, Inyong; Welker, Kirk M; Clayton, Daniel A; Klassen, Bryan T; Chang, Su-youne; Lee, Kendall H
2015-06-01
To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. clinicaltrials.gov Identifier: NCT01809613. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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Ventral Pallidum Roles in Reward and Motivation
Smith, Kyle S.; Tindell, Amy J.; Aldridge, J. Wayne; Berridge, Kent C.
2008-01-01
In recent years the ventral pallidum has become a focus of great research interest as a mechanism of reward and incentive motivation. As a major output for limbic signals, the ventral pallidum was once associated primarily with motor functions rather than regarded as a reward structure in its own right. However, ample evidence now suggests that ventral pallidum function is a major mechanism of reward in the brain. We review data indicating that 1) an intact ventral pallidum is necessary for normal reward and motivation, 2) stimulated activation of ventral pallidum is sufficient to cause reward and motivation enhancements, and 3) activation patterns in ventral pallidum neurons specifically encode reward and motivation signals via phasic bursts of excitation to incentive and hedonic stimuli. We conclude that the ventral pallidum may serve as an important ‘limbic final common pathway’ for mesocorticolimbic processing of many rewards. PMID:18955088
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Response effort discounts the subjective value of rewards.
Nishiyama, Ryoji
2014-09-01
Factors associated with obtaining a reward, such as a temporal delay in receiving the reward, can influence the subjective value of the reward. Cognitive as well as physical response effort is also known to influence choice behaviors. The present study used hypothetical situations to assess whether response effort affects the subjective value of rewards. The results demonstrated that increasing response effort increases the amount of money that participants are willing to forgo to avoid engaging in work. An exponential as well as hyperbolic function provided a good fit for such discounting. The findings suggest that response effort discounts the subjective value of a reward as a function of its amount. Copyright © 2014 Elsevier B.V. All rights reserved.
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Amotivation in schizophrenia: integrated assessment with behavioral, clinical, and imaging measures.
Wolf, Daniel H; Satterthwaite, Theodore D; Kantrowitz, Jacob J; Katchmar, Natalie; Vandekar, Lillie; Elliott, Mark A; Ruparel, Kosha
2014-11-01
Motivational deficits play a central role in disability caused by schizophrenia and constitute a major unmet therapeutic need. Negative symptoms have previously been linked to hypofunction in ventral striatum (VS), a core component of brain motivation circuitry. However, it remains unclear to what extent this relationship holds for specific negative symptoms such as amotivation, and this question has not been addressed with integrated behavioral, clinical, and imaging measures. Here, 41 individuals with schizophrenia and 37 controls performed a brief, computerized progressive ratio task (PRT) that quantifies effort exerted in pursuit of monetary reward. Clinical amotivation was assessed using the recently validated Clinical Assessment Interview for Negative Symptoms (CAINS). VS function was probed during functional magnetic resonance imaging using a monetary guessing paradigm. We found that individuals with schizophrenia had diminished motivation as measured by the PRT, which significantly and selectively related to clinical amotivation as measured by the CAINS. Critically, lower PRT motivation in schizophrenia was also dimensionally related to VS hypofunction. Our results demonstrate robust dimensional associations between behavioral amotivation, clinical amotivation, and VS hypofunction in schizophrenia. Integrating behavioral measures such as the PRT will facilitate translational efforts to identify biomarkers of amotivation and to assess response to novel therapeutic interventions. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Dopamine in the medial amygdala network mediates human bonding.
Atzil, Shir; Touroutoglou, Alexandra; Rudy, Tali; Salcedo, Stephanie; Feldman, Ruth; Hooker, Jacob M; Dickerson, Bradford C; Catana, Ciprian; Barrett, Lisa Feldman
2017-02-28
Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.
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Review of thalamocortical resting-state fMRI studies in schizophrenia
Giraldo-Chica, Monica; Woodward, Neil D.
2017-01-01
Brain circuitry underlying cognition, emotion, and perception is abnormal in schizophrenia. There is considerable evidence that the neuropathology of schizophrenia includes the thalamus, a key hub of cortical-subcortical circuitry and an important regulator of cortical activity. However, the thalamus is a heterogeneous structure composed of several nuclei with distinct inputs and cortical connections. Limitations of conventional neuroimaging methods and conflicting findings from post-mortem investigations have made it difficult to determine if thalamic pathology in schizophrenia is widespread or limited to specific thalamocortical circuits. Resting-state fMRI has proven invaluable for understanding the large-scale functional organization of the brain and investigating neural circuitry relevant to psychiatric disorders. This article summarizes resting-state fMRI investigations of thalamocortical functional connectivity in schizophrenia. Particular attention is paid to the course, diagnostic specificity, and clinical correlates of thalamocortical network dysfunction. PMID:27531067
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Technologies for imaging neural activity in large volumes
Ji, Na; Freeman, Jeremy; Smith, Spencer L.
2017-01-01
Neural circuitry has evolved to form distributed networks that act dynamically across large volumes. Collecting data from individual planes, conventional microscopy cannot sample circuitry across large volumes at the temporal resolution relevant to neural circuit function and behaviors. Here, we review emerging technologies for rapid volume imaging of neural circuitry. We focus on two critical challenges: the inertia of optical systems, which limits image speed, and aberrations, which restrict the image volume. Optical sampling time must be long enough to ensure high-fidelity measurements, but optimized sampling strategies and point spread function engineering can facilitate rapid volume imaging of neural activity within this constraint. We also discuss new computational strategies for the processing and analysis of volume imaging data of increasing size and complexity. Together, optical and computational advances are providing a broader view of neural circuit dynamics, and help elucidate how brain regions work in concert to support behavior. PMID:27571194
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Richter, Anja; Gruber, Oliver
2018-02-01
It is argued that the mesolimbic system has a more general function in processing all salient events, including and extending beyond rewards. Saliency was defined as an event that is unexpected due to its frequency of occurrence and elicits an attentional-behavioral switch. Using functional magnetic resonance imaging (fMRI), signals were measured in response to the modulation of salience of rewarding and nonrewarding events during a reward-based decision making task, the so called desire-reason dilemma paradigm (DRD). Replicating previous findings, both frequent and infrequent, and therefore salient, reward stimuli elicited reliable activation of the ventral tegmental area (VTA) and ventral striatum (vStr). When immediate reward desiring contradicted the superordinate task-goal, we found an increased activation of the VTA and vStr when the salient reward stimuli were presented compared to the nonsalient reward stimuli, indicating a boosting of activation in these brain regions. Furthermore, we found a significantly increased functional connectivity between the VTA and vStr, confirming the boosting of vStr activation via VTA input. Moreover, saliency per se without a reward association led to an increased activation of brain regions in the mesolimbic reward system as well as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate cortex (ACC). Finally, findings uncovered multiple increased functional interactions between cortical saliency-processing brain areas and the VTA and vStr underlying detection and processing of salient events and adaptive decision making. © 2017 Wiley Periodicals, Inc.
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The human cerebellum: a review of physiologic neuroanatomy.
Roostaei, Tina; Nazeri, Arash; Sahraian, Mohammad Ali; Minagar, Alireza
2014-11-01
The cerebellum resides in the posterior cranial fossa dorsal to the brainstem and has diverse connections to the cerebrum, brain stem, and spinal cord. It is anatomically and physiologically divided into distinct functional compartments and is composed of highly regular arrays of neuronal units, each sharing the same basic cerebellar microcircuitry. Its circuitry is critically involved in motor control and motor learning, and its role in nonmotor cognitive and affective functions is becoming increasingly recognized. This article describes the cerebellar gross and histologic neuroanatomy in relation to its function, and the relevance of cerebellar circuitry and firing patterns to motor learning. Copyright © 2014 Elsevier Inc. All rights reserved.
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Immaturities in Reward Processing and Its Influence on Inhibitory Control in Adolescence
Terwilliger, R.; Teslovich, T.; Velanova, K.; Luna, B.
2010-01-01
The nature of immature reward processing and the influence of rewards on basic elements of cognitive control during adolescence are currently not well understood. Here, during functional magnetic resonance imaging, healthy adolescents and adults performed a modified antisaccade task in which trial-by-trial reward contingencies were manipulated. The use of a novel fast, event-related design enabled developmental differences in brain function underlying temporally distinct stages of reward processing and response inhibition to be assessed. Reward trials compared with neutral trials resulted in faster correct inhibitory responses across ages and in fewer inhibitory errors in adolescents. During reward trials, the blood oxygen level–dependent signal was attenuated in the ventral striatum in adolescents during cue assessment, then overactive during response preparation, suggesting limitations during adolescence in reward assessment and heightened reactivity in anticipation of reward compared with adults. Importantly, heightened activity in the frontal cortex along the precentral sulcus was also observed in adolescents during reward-trial response preparation, suggesting reward modulation of oculomotor control regions supporting correct inhibitory responding. Collectively, this work characterizes specific immaturities in adolescent brain systems that support reward processing and describes the influence of reward on inhibitory control. In sum, our findings suggest mechanisms that may underlie adolescents’ vulnerability to poor decision-making and risk-taking behavior. PMID:19875675
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Video game training and the reward system.
Lorenz, Robert C; Gleich, Tobias; Gallinat, Jürgen; Kühn, Simone
2015-01-01
Video games contain elaborate reinforcement and reward schedules that have the potential to maximize motivation. Neuroimaging studies suggest that video games might have an influence on the reward system. However, it is not clear whether reward-related properties represent a precondition, which biases an individual toward playing video games, or if these changes are the result of playing video games. Therefore, we conducted a longitudinal study to explore reward-related functional predictors in relation to video gaming experience as well as functional changes in the brain in response to video game training. Fifty healthy participants were randomly assigned to a video game training (TG) or control group (CG). Before and after training/control period, functional magnetic resonance imaging (fMRI) was conducted using a non-video game related reward task. At pretest, both groups showed strongest activation in ventral striatum (VS) during reward anticipation. At posttest, the TG showed very similar VS activity compared to pretest. In the CG, the VS activity was significantly attenuated. This longitudinal study revealed that video game training may preserve reward responsiveness in the VS in a retest situation over time. We suggest that video games are able to keep striatal responses to reward flexible, a mechanism which might be of critical value for applications such as therapeutic cognitive training.
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Video game training and the reward system
Lorenz, Robert C.; Gleich, Tobias; Gallinat, Jürgen; Kühn, Simone
2015-01-01
Video games contain elaborate reinforcement and reward schedules that have the potential to maximize motivation. Neuroimaging studies suggest that video games might have an influence on the reward system. However, it is not clear whether reward-related properties represent a precondition, which biases an individual toward playing video games, or if these changes are the result of playing video games. Therefore, we conducted a longitudinal study to explore reward-related functional predictors in relation to video gaming experience as well as functional changes in the brain in response to video game training. Fifty healthy participants were randomly assigned to a video game training (TG) or control group (CG). Before and after training/control period, functional magnetic resonance imaging (fMRI) was conducted using a non-video game related reward task. At pretest, both groups showed strongest activation in ventral striatum (VS) during reward anticipation. At posttest, the TG showed very similar VS activity compared to pretest. In the CG, the VS activity was significantly attenuated. This longitudinal study revealed that video game training may preserve reward responsiveness in the VS in a retest situation over time. We suggest that video games are able to keep striatal responses to reward flexible, a mechanism which might be of critical value for applications such as therapeutic cognitive training. PMID:25698962
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Suboptimal choice in rats: incentive salience attribution promotes maladaptive decision-making
Chow, Jonathan J; Smith, Aaron P; Wilson, A George; Zentall, Thomas R; Beckmann, Joshua S
2016-01-01
Stimuli that are more predictive of subsequent reward also function as better conditioned reinforcers. Moreover, stimuli attributed with incentive salience function as more robust conditioned reinforcers. Some theories have suggested that conditioned reinforcement plays an important role in promoting suboptimal choice behavior, like gambling. The present experiments examined how different stimuli, those attributed with incentive salience versus those without, can function in tandem with stimulus-reward predictive utility to promote maladaptive decision-making in rats. One group of rats had lights associated with goal-tracking as the reward-predictive stimuli and another had levers associated with sign-tracking as the reward-predictive stimuli. All rats were first trained on a choice procedure in which the expected value across both alternatives was equivalent but differed in their stimulus-reward predictive utility. Next, the expected value across both alternatives was systematically changed so that the alternative with greater stimulus-reward predictive utility was suboptimal in regard to primary reinforcement. The results demonstrate that in order to obtain suboptimal choice behavior, incentive salience alongside strong stimulus-reward predictive utility may be necessary; thus, maladaptive decision-making can be driven more by the value attributed to stimuli imbued with incentive salience that reliably predict a reward rather than the reward itself. PMID:27993692
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Suboptimal choice in rats: Incentive salience attribution promotes maladaptive decision-making.
Chow, Jonathan J; Smith, Aaron P; Wilson, A George; Zentall, Thomas R; Beckmann, Joshua S
2017-03-01
Stimuli that are more predictive of subsequent reward also function as better conditioned reinforcers. Moreover, stimuli attributed with incentive salience function as more robust conditioned reinforcers. Some theories have suggested that conditioned reinforcement plays an important role in promoting suboptimal choice behavior, like gambling. The present experiments examined how different stimuli, those attributed with incentive salience versus those without, can function in tandem with stimulus-reward predictive utility to promote maladaptive decision-making in rats. One group of rats had lights associated with goal-tracking as the reward-predictive stimuli and another had levers associated with sign-tracking as the reward-predictive stimuli. All rats were first trained on a choice procedure in which the expected value across both alternatives was equivalent but differed in their stimulus-reward predictive utility. Next, the expected value across both alternatives was systematically changed so that the alternative with greater stimulus-reward predictive utility was suboptimal in regard to primary reinforcement. The results demonstrate that in order to obtain suboptimal choice behavior, incentive salience alongside strong stimulus-reward predictive utility may be necessary; thus, maladaptive decision-making can be driven more by the value attributed to stimuli imbued with incentive salience that reliably predict a reward rather than the reward itself. Copyright © 2016 Elsevier B.V. All rights reserved.
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Sweitzer, Maggie M; Geier, Charles F; Joel, Danielle L; McGurrin, Patrick; Denlinger, Rachel L; Forbes, Erika E; Donny, Eric C
2014-11-01
Theories of addiction suggest that chronic smoking may be associated with both hypersensitivity to smoking and related cues and hyposensitivity to alternative reinforcers. However, neural responses to smoking and nonsmoking rewards are rarely evaluated within the same paradigm, leaving the extent to which both processes operate simultaneously uncertain. Behavioral evidence and theoretical models suggest that dysregulated reward processing may be more pronounced during deprivation from nicotine, but neuroimaging evidence on the effects of deprivation on reward processing is limited. The current study examined the impact of deprivation from smoking on neural processing of both smoking and monetary rewards. Two separate functional magnetic resonance imaging scans were performed in 38 daily smokers, one after smoking without restriction and one following 24 hours of abstinence. A rewarded guessing task was conducted during each scan to evaluate striatal blood oxygen level-dependent response during anticipation of both smoking and monetary rewards. A significant reward type by abstinence interaction was observed in the bilateral caudate and medial prefrontal cortex during reward anticipation. The blood oxygen level-dependent response to anticipation of smoking reward was significantly higher and anticipation of monetary rewards was significantly lower during abstinence compared with nonabstinence. Attenuation of monetary reward-related activation during abstinence was significantly correlated with abstinence-induced increases in craving and withdrawal. These results provide the first direct evidence of dissociated effects of smoking versus monetary rewards as a function of abstinence. The findings suggest an important neural pathway that may underlie the choice to smoke in lieu of alternative reinforcement during a quit attempt. © 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.
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Olino, Thomas M.; McMakin, Dana L.; Dahl, Ronald E.; Ryan, Neal D.; Silk, Jennifer S.; Birmaher, Boris; Axelson, David A.; Forbes, Erika E.
2011-01-01
Major Depressive Disorder (MDD) in adolescents is characterized by alterations in positive emotions and reward processing. Recent investigations using functional magnetic resonance imaging (fMRI) find depression-related differences in reward anticipation. However, it is unknown whether feedback influences subsequent reward anticipation, which may highlight the context of reward processing. Ten youth with MDD and sixteen youth with no history of MDD completed an fMRI assessment using a reward task. Reward anticipation was indexed by blood oxygen level dependent signal change in the striatum following winning; losing; non-winning; and non-losing outcomes. A significant interaction between diagnostic status and outcome condition predicted reward anticipation in the caudate. Decomposition of the interaction indicated that following winning outcomes, depressed youth demonstrated reduced reward anticipation relative to healthy youth. However, no significant differences between depressed and healthy youth were found after other outcomes. Reward anticipation is altered following winning outcomes. This finding has implications for understanding the developmental pathophysiology of MDD and suggests specific contexts where altered motivational system functioning may play a role in maintaining depression. PMID:22079656
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Trost, Sarah; Diekhof, Esther K; Mohr, Holger; Vieker, Henning; Krämer, Bernd; Wolf, Claudia; Keil, Maria; Dechent, Peter; Binder, Elisabeth B; Gruber, Oliver
2016-10-01
Recent genome-wide association studies have identified MAD1L1 (mitotic arrest deficient-like 1) as a susceptibility gene for bipolar disorder and schizophrenia. The minor allele of the single-nucleotide polymorphism (SNP) rs11764590 in MAD1L1 was associated with bipolar disorder. Both diseases, bipolar disorder and schizophrenia, are linked to functional alterations in the reward system. We aimed at investigating possible effects of the MAD1L1 rs11764590 risk allele on reward systems functioning in healthy adults. A large homogenous sample of 224 young (aged 18-31 years) participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All participants performed the 'Desire-Reason Dilemma' paradigm investigating the neural correlates that underlie reward processing and active reward dismissal in favor of a long-term goal. We found significant hypoactivations of the ventral tegmental area (VTA), the bilateral striatum and bilateral frontal and parietal cortices in response to conditioned reward stimuli in the risk allele carriers compared with major allele carriers. In the dilemma situation, functional connectivity between prefrontal brain regions and the ventral striatum was significantly diminished in the risk allele carriers. Healthy risk allele carriers showed a significant deficit of their bottom-up response to conditioned reward stimuli in the bilateral VTA and striatum. Furthermore, functional connectivity between the ventral striatum and prefrontal areas exerting top-down control on the mesolimbic reward system was reduced in this group. Similar alterations in reward processing and disturbances of prefrontal control mechanisms on mesolimbic brain circuits have also been reported in bipolar disorder and schizophrenia. Together, these findings suggest the existence of an intermediate phenotype associated with MAD1L1.
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Neural Sensitivity to Absolute and Relative Anticipated Reward in Adolescents
Vaidya, Jatin G.; Knutson, Brian; O'Leary, Daniel S.; Block, Robert I.; Magnotta, Vincent
2013-01-01
Adolescence is associated with a dramatic increase in risky and impulsive behaviors that have been attributed to developmental differences in neural processing of rewards. In the present study, we sought to identify age differences in anticipation of absolute and relative rewards. To do so, we modified a commonly used monetary incentive delay (MID) task in order to examine brain activity to relative anticipated reward value (neural sensitivity to the value of a reward as a function of other available rewards). This design also made it possible to examine developmental differences in brain activation to absolute anticipated reward magnitude (the degree to which neural activity increases with increasing reward magnitude). While undergoing fMRI, 18 adolescents and 18 adult participants were presented with cues associated with different reward magnitudes. After the cue, participants responded to a target to win money on that trial. Presentation of cues was blocked such that two reward cues associated with $.20, $1.00, or $5.00 were in play on a given block. Thus, the relative value of the $1.00 reward varied depending on whether it was paired with a smaller or larger reward. Reflecting age differences in neural responses to relative anticipated reward (i.e., reference dependent processing), adults, but not adolescents, demonstrated greater activity to a $1 reward when it was the larger of the two available rewards. Adults also demonstrated a more linear increase in ventral striatal activity as a function of increasing absolute reward magnitude compared to adolescents. Additionally, reduced ventral striatal sensitivity to absolute anticipated reward (i.e., the difference in activity to medium versus small rewards) correlated with higher levels of trait Impulsivity. Thus, ventral striatal activity in anticipation of absolute and relative rewards develops with age. Absolute reward processing is also linked to individual differences in Impulsivity. PMID:23544046
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Modeling the effect of reward amount on probability discounting.
Myerson, Joel; Green, Leonard; Morris, Joshua
2011-03-01
The present study with college students examined the effect of amount on the discounting of probabilistic monetary rewards. A hyperboloid function accurately described the discounting of hypothetical rewards ranging in amount from $20 to $10,000,000. The degree of discounting increased continuously with amount of probabilistic reward. This effect of amount was not due to changes in the rate parameter of the discounting function, but rather was due to increases in the exponent. These results stand in contrast to those observed with the discounting of delayed monetary rewards, in which the degree of discounting decreases with reward amount due to amount-dependent decreases in the rate parameter. Taken together, this pattern of results suggests that delay and probability discounting reflect different underlying mechanisms. That is, the fact that the exponent in the delay discounting function is independent of amount is consistent with a psychophysical scaling interpretation, whereas the finding that the exponent of the probability-discounting function is amount-dependent is inconsistent with such an interpretation. Instead, the present results are consistent with the idea that the probability-discounting function is itself the product of a value function and a weighting function. This idea was first suggested by Kahneman and Tversky (1979), although their prospect theory does not predict amount effects like those observed. The effect of amount on probability discounting was parsimoniously incorporated into our hyperboloid discounting function by assuming that the exponent was proportional to the amount raised to a power. The amount-dependent exponent of the probability-discounting function may be viewed as reflecting the effect of amount on the weighting of the probability with which the reward will be received.
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Hopper, James W; Pitman, Roger K; Su, Zhaohui; Heyman, Gene M; Lasko, Natasha B; Macklin, Michael L; Orr, Scott P; Lukas, Scott E; Elman, Igor
2008-08-01
Posttraumatic stress disorder (PTSD) may be associated with dysfunctional reward processing. The present study assessed for such dysfunction in both the expectancy and outcome phases of reward processing. Male Vietnam veterans with (n=15) and without (n=11) combat-related PTSD were administered a wheel of fortune-type gambling task. Self-reported ratings of expectancy and satisfaction were collected respectively before and after each experience of monetary gain or loss. PTSD participants reported both lower expectancy of reward and lower satisfaction with reward when it was received. The latter result was manifest in a failure of PTSD participants to show the greater satisfaction that normally accompanies rewards received under conditions of low expectancy. These results suggest reward function impairment in PTSD related to expectancy, satisfaction, and the expectancy-satisfaction relationship.
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Pan, Pedro Mario; Sato, João R; Salum, Giovanni A; Rohde, Luis A; Gadelha, Ary; Zugman, Andre; Mari, Jair; Jackowski, Andrea; Picon, Felipe; Miguel, Eurípedes C; Pine, Daniel S; Leibenluft, Ellen; Bressan, Rodrigo A; Stringaris, Argyris
2017-11-01
Previous studies have implicated aberrant reward processing in the pathogenesis of adolescent depression. However, no study has used functional connectivity within a distributed reward network, assessed using resting-state functional MRI (fMRI), to predict the onset of depression in adolescents. This study used reward network-based functional connectivity at baseline to predict depressive disorder at follow-up in a community sample of adolescents. A total of 637 children 6-12 years old underwent resting-state fMRI. Discovery and replication analyses tested intrinsic functional connectivity (iFC) among nodes of a putative reward network. Logistic regression tested whether striatal node strength, a measure of reward-related iFC, predicted onset of a depressive disorder at 3-year follow-up. Further analyses investigated the specificity of this prediction. Increased left ventral striatum node strength predicted increased risk for future depressive disorder (odds ratio=1.54, 95% CI=1.09-2.18), even after excluding participants who had depressive disorders at baseline (odds ratio=1.52, 95% CI=1.05-2.20). Among 11 reward-network nodes, only the left ventral striatum significantly predicted depression. Striatal node strength did not predict other common adolescent psychopathology, such as anxiety, attention deficit hyperactivity disorder, and substance use. Aberrant ventral striatum functional connectivity specifically predicts future risk for depressive disorder. This finding further emphasizes the need to understand how brain reward networks contribute to youth depression.
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Functional dysconnectivity of corticostriatal circuitry as a risk phenotype for psychosis.
Fornito, Alex; Harrison, Ben J; Goodby, Emmeline; Dean, Anna; Ooi, Cinly; Nathan, Pradeep J; Lennox, Belinda R; Jones, Peter B; Suckling, John; Bullmore, Edward T
2013-11-01
Dysregulation of corticostriatal circuitry has long been thought to be critical in the etiology of psychotic disorders, although the differential roles played by dorsal and ventral systems in mediating risk for psychosis have been contentious. To use resting-state functional magnetic resonance imaging to characterize disease-related, risk-related, and symptom-related changes of corticostriatal functional circuitry in patients with first-episode psychosis and their unaffected first-degree relatives. This case-control cross-sectional study was conducted at a specialist early psychosis clinic, GlaxoSmithKline Clinical Unit, and magnetic resonance imaging facility. Nineteen patients with first-episode psychosis, 25 of their unaffected first-degree relatives, and 26 healthy control subjects were included in this study. Voxelwise statistical parametric maps testing differences in the strength of functional connectivity between 6 striatal seed regions of interest (3 caudate and 3 putamen) per hemisphere and all other brain regions. Disease-related changes, reflecting differences between patients and control subjects, involved widespread dysregulation of corticostriatal systems characterized most prominently by a dorsal-to-ventral gradient of hypoconnectivity to hyperconnectivity between striatal and prefrontal regions. A similar gradient was evident in comparisons between relatives and control subjects, identifying it as a genetically inherited risk phenotype. In patients, functional connectivity in risk-affected and disease-affected dorsal frontostriatal circuitry correlated with the severity of both positive and negative symptoms. First-episode psychosis is associated with pronounced dysregulation of corticostriatal systems, characterized most prominently by hypoconnectivity of dorsal and hyperconnectivity of ventral frontostriatal circuits. These changes correlate with symptom severity and are also apparent in unaffected first-degree relatives, suggesting that they represent a putative risk phenotype for psychotic illness.
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Stress and reward processing in bipolar disorder: a functional magnetic resonance imaging study.
Berghorst, Lisa H; Kumar, Poornima; Greve, Doug N; Deckersbach, Thilo; Ongur, Dost; Dutra, Sunny J; Pizzagalli, Diego A
2016-11-01
A link between negative life stress and the onset of mood episodes in bipolar disorder (BD) has been established, but processes underlying such a link remain unclear. Growing evidence suggests that stress can negatively affect reward processing and related neurobiological substrates, indicating that a dysregulated reward system may provide a partial explanation. The aim of this study was to test the impact of stress on reward-related neural functioning in BD. Thirteen euthymic or mildly depressed individuals with BD and 15 controls performed a Monetary Incentive Delay (MID) task while undergoing functional magnetic resonance imaging during no-stress and stress (negative psychosocial stressor involving poor performance feedback and threat of monetary deductions) conditions. In hypothesis-driven region-of-interest analyses, a significant group-by-condition interaction emerged in the amygdala during reward anticipation. Relative to controls, while anticipating a potential reward, subjects with BD were characterized by amygdalar hyperactivation in the no-stress condition but hypoactivation during stress. Moreover, relative to controls, subjects with BD had significantly larger amygdala volumes. After controlling for structural differences, the effects of stress on amygdalar function remained, whereas groups no longer differed during the no-stress condition. During reward consumption, a group-by-condition interaction emerged in the putamen due to increased putamen activation in response to rewards in participants with BD during stress, but an opposite pattern in controls. Overall, findings highlight possible impairments in using reward-predicting cues to adaptively engage in goal-directed actions in BD, combined with stress-induced hypersensitivity to reward consumption. Potential clinical implications are discussed. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Sharma, Anup; Wolf, Daniel H; Ciric, Rastko; Kable, Joseph W; Moore, Tyler M; Vandekar, Simon N; Katchmar, Natalie; Daldal, Aylin; Ruparel, Kosha; Davatzikos, Christos; Elliott, Mark A; Calkins, Monica E; Shinohara, Russell T; Bassett, Danielle S; Satterthwaite, Theodore D
2017-07-01
Anhedonia is central to multiple psychiatric disorders and causes substantial disability. A dimensional conceptualization posits that anhedonia severity is related to a transdiagnostic continuum of reward deficits in specific neural networks. Previous functional connectivity studies related to anhedonia have focused on case-control comparisons in specific disorders, using region-specific seed-based analyses. Here, the authors explore the entire functional connectome in relation to reward responsivity across a population of adults with heterogeneous psychopathology. In a sample of 225 adults from five diagnostic groups (major depressive disorder, N=32; bipolar disorder, N=50; schizophrenia, N=51; psychosis risk, N=39; and healthy control subjects, N=53), the authors conducted a connectome-wide analysis examining the relationship between a dimensional measure of reward responsivity (the reward sensitivity subscale of the Behavioral Activation Scale) and resting-state functional connectivity using multivariate distance-based matrix regression. The authors identified foci of dysconnectivity associated with reward responsivity in the nucleus accumbens, the default mode network, and the cingulo-opercular network. Follow-up analyses revealed dysconnectivity among specific large-scale functional networks and their connectivity with the nucleus accumbens. Reward deficits were associated with decreased connectivity between the nucleus accumbens and the default mode network and increased connectivity between the nucleus accumbens and the cingulo-opercular network. In addition, impaired reward responsivity was associated with default mode network hyperconnectivity and diminished connectivity between the default mode network and the cingulo-opercular network. These results emphasize the centrality of the nucleus accumbens in the pathophysiology of reward deficits and suggest that dissociable patterns of connectivity among large-scale networks are critical to the neurobiology of reward dysfunction across clinical diagnostic categories.
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Workload-Based Automated Interface Mode Selection
2012-03-22
Process . . . . . . . . . . . . . . . . . . . . . 31 3.5.10 Agent Reward Function . . . . . . . . . . . . . . . . 31 3.5.11 Accelerated Learning... Strategies . . . . . . . . . . . . 31 4. Experimental Methodology . . . . . . . . . . . . . . . . . . . . . . . . 33 4.1 System Engineering Methodology...26 5. Agent state function. . . . . . . . . . . . . . . . . . . . . . . . . . . 28 6. Agent reward function
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Shigemune, Yayoi; Tsukiura, Takashi; Kambara, Toshimune; Kawashima, Ryuta
2014-05-01
The motivation of getting rewards or avoiding punishments reinforces learning behaviors. Although the neural mechanisms underlying the effect of rewards on episodic memory have been demonstrated, there is little evidence of the effect of punishments on this memory. Our functional magnetic resonance imaging (fMRI) study investigated the effects of monetary rewards and punishments on activation during the encoding of source memories. During encoding, participants memorized words (item) and locations of presented words (source) under 3 conditions (Reward, Punishment, and Control). During retrieval, participants retrieved item and source memories of the words and were rewarded or penalized according to their performance. Source memories encoded with rewards or punishments were remembered better than those without such encoding. fMRI data demonstrated that the ventral tegmental area and substantia nigra and nucleus accumbens activations reflected both the processes of reward and punishment, whereas insular activation increased as a linear function of punishment. Activation in the hippocampus and parahippocampal cortex predicted subsequent retrieval success of source memories. Additionally, correlations between these reward/punishment-related regions and the hippocampus were significant. The successful encoding of source memories could be enhanced by punishments and rewards, and interactions between reward/punishment-related regions and memory-related regions could contribute to memory enhancement by reward and/or punishment.
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Shigemune, Yayoi; Tsukiura, Takashi; Kambara, Toshimune; Kawashima, Ryuta
2014-01-01
The motivation of getting rewards or avoiding punishments reinforces learning behaviors. Although the neural mechanisms underlying the effect of rewards on episodic memory have been demonstrated, there is little evidence of the effect of punishments on this memory. Our functional magnetic resonance imaging (fMRI) study investigated the effects of monetary rewards and punishments on activation during the encoding of source memories. During encoding, participants memorized words (item) and locations of presented words (source) under 3 conditions (Reward, Punishment, and Control). During retrieval, participants retrieved item and source memories of the words and were rewarded or penalized according to their performance. Source memories encoded with rewards or punishments were remembered better than those without such encoding. fMRI data demonstrated that the ventral tegmental area and substantia nigra and nucleus accumbens activations reflected both the processes of reward and punishment, whereas insular activation increased as a linear function of punishment. Activation in the hippocampus and parahippocampal cortex predicted subsequent retrieval success of source memories. Additionally, correlations between these reward/punishment-related regions and the hippocampus were significant. The successful encoding of source memories could be enhanced by punishments and rewards, and interactions between reward/punishment-related regions and memory-related regions could contribute to memory enhancement by reward and/or punishment. PMID:23314939
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Neuroimaging in attention-deficit hyperactivity disorder: beyond the frontostriatal circuitry.
Cherkasova, Mariya V; Hechtman, Lily
2009-10-01
To review the findings of structural and functional neuroimaging studies in attention-deficit hyperactivity disorder (ADHD), with a focus on abnormalities reported in brain regions that lie outside the frontostriatal circuitry, which is currently believed to play a central role in the pathophysiology of ADHD. Relevant publications were found primarily by searching the MEDLINE and PubMed databases using the keywords ADHD and the abbreviations of magnetic resonance imaging (MRI), functional MRI, positron emission tomography, and single photon emission computed tomography. The reference lists of the articles found through the databases were then reviewed for the purpose of finding additional articles. There is now substantial evidence of structural and functional alterations in regions outside the frontostriatal circuitry in ADHD, most notably in the cerebellum and the parietal lobes. Although there is compelling evidence suggesting that frontostriatal dysfunction may be central to the pathophysiology of ADHD, the neuroimaging findings point to distributed neural substrates rather than a single one. More research is needed to elucidate the nature of contributions of nonfrontostriatal regions to the pathophysiology of ADHD.
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Forbes, Erika E; Ryan, Neal D; Phillips, Mary L; Manuck, Stephen B; Worthman, Carol M; Moyles, Donna L; Tarr, Jill A; Sciarrillo, Samantha R; Dahl, Ronald E
2010-02-01
Changes in reward-related behavior are an important component of normal adolescent affective development. Understanding the neural underpinnings of these normative changes creates a foundation for investigating adolescence as a period of vulnerability to affective disorders, substance use disorders, and health problems. Studies of reward-related brain function have revealed conflicting findings regarding developmental change in the reactivity of the striatum and medial prefrontal cortex (mPFC) and have not considered puberty. The current study focused on puberty-specific changes in brain function and their association with mood. A sample of 77 healthy adolescents (26 pre-/early pubertal, 51 mid-/late pubertal) recruited in a narrow age range (mean = 11.94 years, SD = 0.75) were assessed for sexual maturation and circulating testosterone, completed a functional magnetic resonance imaging (fMRI) guessing task with monetary reward, and underwent experience sampling of mood in natural environments. For comparison, 19 healthy adults completed the fMRI assessment. Adolescents with more advanced pubertal maturation exhibited less striatal and more mPFC reactivity during reward outcome than similarly aged adolescents with less advanced maturation. Testosterone was positively correlated with striatal reactivity in boys during reward anticipation and negatively correlated with striatal reactivity in girls and boys during reward outcome. Striatal reactivity was positively correlated with real-world subjective positive affect and negatively correlated with depressive symptoms. mPFC reactivity was positively correlated with depressive symptoms. Reward-related brain function changes with puberty and is associated with adolescents' positive affect and depressive symptoms. Increased reward-seeking behavior at this developmental point could serve to compensate for these changes.
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Reward-related brain function and sleep in pre/early pubertal and mid/late pubertal adolescents.
Holm, Stephanie M; Forbes, Erika E; Ryan, Neal D; Phillips, Mary L; Tarr, Jill A; Dahl, Ronald E
2009-10-01
The onset of adolescence is a time of dramatic changes, including changes in sleep, and a time of new health concerns related to increases in risk-taking, sensation seeking, depression, substance use, and accidents. As part of a larger study examining puberty-specific changes in adolescents' reward-related brain function, the current article focuses on the relationship between functional neuroimaging measures of reward and measures of sleep. A total of 58 healthy participants 11-13 years of age completed a functional magnetic resonance imaging scan using a guessing task with monetary rewards and 4 days of at-home actigraphy and self-reported sleep ratings. Sleep variables included actigraph measures of mean weekend minutes asleep, sleep onset time, and sleep offset time, as well as self-reported sleep quality. During reward anticipation, less activation in the caudate (part of the ventral striatum) was associated with fewer minutes asleep, later sleep onset time, and lower sleep quality. During reward outcome, less caudate activation was associated with later sleep onset time, earlier sleep offset time, and lower sleep quality. It has been hypothesized that adolescents' low reactivity in reward-related brain areas could lead to compensatory increases in reward-driven behavior. This study's findings suggest that sleep could contribute to such behavior. Because decreased sleep has been associated with risky behavior and negative mood, these findings raise concerns about a negative spiral whereby the effects of puberty and sleep deprivation may have synergistic effects on reward processing, contributing to adolescent behavioral and emotional health problems.
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Reward-Based Spatial Learning in Teens With Bulimia Nervosa
Cyr, Marilyn; Wang, Zhishun; Tau, Gregory Z.; Zhao, Guihu; Friedl, Eve; Stefan, Mihaela; Terranova, Kate; Marsh, Rachel
2016-01-01
Objective To assess the functioning of mesolimbic and fronto-striatal areas involved in reward-based spatial learning in teenaged girls with bulimia nervosa (BN) that might be involved in the development and maintenance of maladaptive behaviors characteristic of the disorder. Method We compared functional magnetic resonance imaging blood oxygen level dependent response in 27 adolescent girls with BN to that of 27 healthy, age-matched control participants during a reward-based learning task that required learning to use extra-maze cues to navigate a virtual 8-arm radial maze to find hidden rewards. We compared groups in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudo-randomly to experimentally prevent learning. Results Both groups learned to navigate the maze to find hidden rewards, but group differences in brain activity associated with maze navigation and reward processing were detected in fronto-striatal regions and right anterior hippocampus. Unlike healthy adolescents, those with BN did not engage right inferior frontal gyrus during maze navigation, activated right anterior hippocampus during the receipt of unexpected rewards (control condition), and deactivated left superior frontal gyrus and right anterior hippocampus during expected reward receipt (learning condition). These patterns of hippocampal activation in the control condition were significantly associated with the frequency of binge-eating episodes. Conclusion Adolescents with BN displayed abnormal functioning of anterior hippocampus and fronto-striatal regions during reward-based spatial learning. These findings suggest that an imbalance in control and reward circuits may arise early in the course of BN. Clinical trial registration information An fMRI Study of Self-regulation in Adolescents With Bulimia Nervosa; https://clinicaltrials.gov/ct2/show/NCT00345943; NCT00345943. PMID:27806864
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Opel, Nils; Redlich, Ronny; Grotegerd, Dominik; Dohm, Katharina; Haupenthal, Cordula; Heindel, Walter; Kugel, Harald; Arolt, Volker; Dannlowski, Udo
2015-06-01
Obesity has been characterized by alterations in brain structure and function associated with emotion processing and regulation. Particularly, aberrations in food-related reward processing have been frequently demonstrated in obese subjects. However, it remains unclear whether reward-associated functional aberrations in obesity are specific for food-related stimuli or represent a general deficit in reward processing, extending to other stimulus domains. Given the crucial role of rewarding effects in the development of obesity and the ongoing discussion on overlapping neurobiological traits of obesity and psychiatric disorders such as depression and substance-related disorders, this study aimed to investigate the possibility of altered reward processing in obese subjects to occur in the absence of food-related stimuli during a monetary reward condition. Twenty-nine healthy obese subjects (body mass index >30) and 29 healthy, age-, and sex-matched control subjects of normal weight underwent functional MRI during a frequently used card guessing paradigm. A Group × Condition (win vs. loss) ANOVA was conducted to investigate differences between obese and normal-weight subjects. We found significant Group × Condition interaction effects in brain areas involved in emotion regulation and reward processing including the insula, the striatum, and the orbitofrontal cortex (OFC). This interaction was predominantly driven by a significant increase in blood oxygenation level dependent (BOLD) response in obese individuals while experiencing reward. Enhanced neural activation in obesity during reward processing seems to be apparent even in the absence of food-related stimuli and, thus, might point to generalized dysfunctions in reward-related brain circuits in obese individuals. © 2015 Wiley Periodicals, Inc.
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Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia.
Richter, Anja; Petrovic, Aleksandra; Diekhof, Esther K; Trost, Sarah; Wolter, Sarah; Gruber, Oliver
2015-12-01
Schizophrenia is characterized by substantial dysfunctions of reward processing, leading to detrimental consequences for decision-making. The neurotransmitter dopamine is responsible for the transmission of reward signals and also known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), sixteen medicated patients with schizophrenia and sixteen healthy controls performed the 'desire-reason dilemma' (DRD) paradigm. This paradigm allowed us to directly investigate reward-related brain activations depending on the interaction of bottom-up and top-down mechanisms, when a previously conditioned reward stimulus had to be rejected to achieve a superordinate long-term goal. Both patients and controls showed significant activations in the mesolimbic reward system. In patients with schizophrenia, however, we found a significant hyperactivation of the left ventral striatum (vStr) when they were allowed to accept the conditioned reward stimuli, and a reduced top-down regulation of activation in the ventral striatum (vStr) and ventral tegmental area (VTA) while having to reject the immediate reward to pursue the superordinate task-goal. Moreover, while healthy subjects exhibited a negative functional coupling of the vStr with both the anteroventral prefrontal cortex (avPFC) and the ventromedial prefrontal cortex (VMPFC) in the dilemma situation, this functional coupling was significantly impaired in the patient group. These findings provide evidence for an increased ventral striatal activation to reward stimuli and an impaired top-down control of reward signals by prefrontal brain regions in schizophrenia. Copyright © 2015 Elsevier Ltd. All rights reserved.
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Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals
Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF
2013-01-01
Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926
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Instant transformation of learned repulsion into motivational "wanting".
Robinson, Mike J F; Berridge, Kent C
2013-02-18
Learned cues for pleasant reward often elicit desire, which, in addicts, may become compulsive. According to the dominant view in addiction neuroscience and reinforcement modeling, such desires are the simple products of learning, coming from a past association with reward outcome. We demonstrate that cravings are more than merely the products of accumulated pleasure memories-even a repulsive learned cue for unpleasantness can become suddenly desired via the activation of mesocorticolimbic circuitry. Rats learned repulsion toward a Pavlovian cue (a briefly-inserted metal lever) that always predicted an unpleasant Dead Sea saltiness sensation. Yet, upon first reencounter in a novel sodium-depletion state to promote mesocorticolimbic reactivity (reflected by elevated Fos activation in ventral tegmentum, nucleus accumbens, ventral pallidum, and the orbitofrontal prefrontal cortex), the learned cue was instantly transformed into an attractive and powerful motivational magnet. Rats jumped and gnawed on the suddenly attractive Pavlovian lever cue, despite never having tasted intense saltiness as anything other than disgusting. Instant desire transformation of a learned cue contradicts views that Pavlovian desires are essentially based on previously learned values (e.g., prediction error or temporal difference models). Instead desire is recomputed at reencounter by integrating Pavlovian information with the current brain/physiological state. This powerful brain transformation reverses strong learned revulsion into avid attraction. When applied to addiction, related mesocorticolimbic transformations (e.g., drugs or neural sensitization) of cues for already-pleasant drug experiences could create even more intense cravings. This cue/state transformation helps define what it means to say that addiction hijacks brain limbic circuits of natural reward. Copyright © 2013 Elsevier Ltd. All rights reserved.
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A Richey, John; Ghane, Merage; Valdespino, Andrew; Coffman, Marika C; Strege, Marlene V; White, Susan W; Ollendick, Thomas H
2017-01-01
Social anxiety disorder (SAD) involves abnormalities in social motivation, which may be independent of well-documented differences in fear and arousal systems. Yet, the neurobiology underlying motivational difficulties in SAD is not well understood. The aim of the current study was to spatiotemporally dissociate reward circuitry dysfunction from alterations in fear and arousal-related neural activity during anticipation and notification of social and non-social reward and punishment. During fMRI acquisition, non-depressed adults with social anxiety disorder (SAD; N = 21) and age-, sex- and IQ-matched control subjects (N = 22) completed eight runs of an incentive delay task, alternating between social and monetary outcomes and interleaved in alternating order between gain and loss outcomes. Adults with SAD demonstrated significantly reduced neural activity in ventral striatum during the anticipation of positive but not negative social outcomes. No differences between the SAD and control groups were observed during anticipation of monetary gain or loss outcomes or during anticipation of negative social images. However, consistent with previous work, the SAD group demonstrated amygdala hyper-activity upon notification of negative social outcomes. Degraded anticipatory processing in bilateral ventral striatum in SAD was constrained exclusively to anticipation of positive social information and dissociable from the effects of negative social outcomes previously observed in the amygdala. Alterations in anticipation-related neural signals may represent a promising target for treatment that is not addressed by available evidence-based interventions, which focus primarily on fear extinction and habituation processes. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.
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Intragastric nutrient infusion reduces motivation for food in male and female rats.
Maske, Calyn B; Loney, Gregory C; Lilly, Nicole; Terrill, Sarah J; Williams, Diana L
2018-03-13
The idea that gut-derived satiation signals influence food reward has recently gained traction, but this hypothesis is largely based on studies focused on neural circuitry, not the peripherally released signals. Here, we directly tested the hypothesis that intragastric (IG) nutrient infusion can suppress motivation for food. In a series of experiments, IG sucrose infusion (15 kcal) significantly and reliably reduced operant responding for a sucrose reward on a progressive ratio (PR) schedule. Moreover, food deprivation for 24 h before the test session did not prevent the suppressive effect of nutrients. The suppressive effect of IG sucrose on fixed ratio 5 (FR5) operant responding was also assessed as a comparison. The effect of IG nutrients to reduce motivation was not limited to sucrose; IG Ensure infusion (9.3 kcal) also significantly reduced PR operant responding for sucrose pellets. To verify that these effects are not secondary to the osmotic challenge of concentrated nutrients, we tested IG infusion of non-caloric saline solutions equiosmolar to 40% sucrose or Ensure, and found no effect. Finally, we focused on glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) as candidate mediators for the effect of IG nutrients. Pretreatment with Exendin-9, a GLP-1R antagonist, delivered IP, significantly attenuated the ability of IG nutrients to suppress PR responding and breakpoint in males, but not females, whereas pretreatment with Devazepide, a CCKA receptor antagonist, failed to do so in both sexes. Together, these data support the idea that nutrient-induced satiation signals influence food reward, and may implicate GLP-1 in this process.
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Abnormal Reward System Activation in Mania
Abler, Birgit; Greenhouse, Ian; Ongur, Dost; Walter, Henrik; Heckers, Stephan
2008-01-01
Transmission of reward signals is a function of dopamine, a neurotransmitter known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), we investigated how expectation and receipt of monetary rewards modulate brain activation in patients with bipolar mania and schizophrenia. We studied 12 acutely manic patients with a history of bipolar disorder, 12 patients with a current episode of schizoaffective disorder or schizophrenia and 12 healthy subjects. All patients were treated with dopamine antagonists at the time of the study. Subjects performed a delayed incentive paradigm with monetary reward in the scanner that allowed for investigating effects of expectation, receipt, and omission of rewards. Patients with schizophrenia and healthy control subjects showed the expected activation of dopaminergic brain areas, that is, ventral tegmentum activation upon expectation of monetary rewards and nucleus accumbens activation during receipt vs omission of rewards. In manic patients, however, we did not find a similar pattern of brain activation and the differential signal in the nucleus accumbens upon receipt vs omission of rewards was significantly lower compared to the healthy control subjects. Our findings provide evidence for abnormal function of the dopamine system during receipt or omission of expected rewards in bipolar disorder. These deficits in prediction error processing in acute mania may help to explain symptoms of disinhibition and abnormal goal pursuit regulation. PMID:17987058
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Reward salience and risk aversion underlie differential ACC activity in substance dependence
Alexander, William H.; Fukunaga, Rena; Finn, Peter; Brown, Joshua W.
2015-01-01
The medial prefrontal cortex, especially the dorsal anterior cingulate cortex (ACC), has long been implicated in cognitive control and error processing. Although the association between ACC and behavior has been established, it is less clear how ACC contributes to dysfunctional behavior such as substance dependence. Evidence from neuroimaging studies investigating ACC function in substance users is mixed, with some studies showing disengagement of ACC in substance dependent individuals (SDs), while others show increased ACC activity related to substance use. In this study, we investigate ACC function in SDs and healthy individuals performing a change signal task for monetary rewards. Using a priori predictions derived from a recent computational model of ACC, we find that ACC activity differs between SDs and controls in factors related to reward salience and risk aversion between SDs and healthy individuals. Quantitative fits of a computational model to fMRI data reveal significant differences in best fit parameters for reward salience and risk preferences. Specifically, the ACC in SDs shows greater risk aversion, defined as concavity in the utility function, and greater attention to rewards relative to reward omission. Furthermore, across participants risk aversion and reward salience are positively correlated. The results clarify the role that ACC plays in both the reduced sensitivity to omitted rewards and greater reward valuation in SDs. Clinical implications of applying computational modeling in psychiatry are also discussed. PMID:26106528
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Reward salience and risk aversion underlie differential ACC activity in substance dependence.
Alexander, William H; Fukunaga, Rena; Finn, Peter; Brown, Joshua W
2015-01-01
The medial prefrontal cortex, especially the dorsal anterior cingulate cortex (ACC), has long been implicated in cognitive control and error processing. Although the association between ACC and behavior has been established, it is less clear how ACC contributes to dysfunctional behavior such as substance dependence. Evidence from neuroimaging studies investigating ACC function in substance users is mixed, with some studies showing disengagement of ACC in substance dependent individuals (SDs), while others show increased ACC activity related to substance use. In this study, we investigate ACC function in SDs and healthy individuals performing a change signal task for monetary rewards. Using a priori predictions derived from a recent computational model of ACC, we find that ACC activity differs between SDs and controls in factors related to reward salience and risk aversion between SDs and healthy individuals. Quantitative fits of a computational model to fMRI data reveal significant differences in best fit parameters for reward salience and risk preferences. Specifically, the ACC in SDs shows greater risk aversion, defined as concavity in the utility function, and greater attention to rewards relative to reward omission. Furthermore, across participants risk aversion and reward salience are positively correlated. The results clarify the role that ACC plays in both the reduced sensitivity to omitted rewards and greater reward valuation in SDs. Clinical implications of applying computational modeling in psychiatry are also discussed.
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Sleep and metabolism: role of hypothalamic neuronal circuitry.
Rolls, Asya; Schaich Borg, Jana; de Lecea, Luis
2010-10-01
Sleep and metabolism are intertwined physiologically and behaviorally, but the neural systems underlying their coordination are still poorly understood. The hypothalamus is likely to play a major role in the regulation sleep, metabolism, and their interaction. And increasing evidence suggests that hypocretin cells in the lateral hypothalamus may provide particularly important contributions. Here we review: 1) direct interactions between biological arousal and metabolic systems in the hypothalamus, and 2) indirect interactions between these two systems mediated by stress or reward, emphasizing the role of hypocretins. An increased understanding of the mechanisms underlying these interactions may provide novel approaches for the treatment of patients with sleep disorders and obesity, as well as suggest new therapeutic strategies for symptoms of aging, stress, or addiction. Copyright © 2010. Published by Elsevier Ltd.
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Discounting of Delayed Food Rewards in Pigeons and Rats: Is There a Magnitude Effect
ERIC Educational Resources Information Center
Green, Leonard; Myerson, Joel; Holt, Daniel D.; Slavin, John R.; Estle, Sara J.
2004-01-01
Temporal discounting refers to the decrease in the present, subjective value of a reward as the time to its receipt increases. Results from humans have shown that a hyperbola-like function describes the form of the discounting function when choices involve hypothetical monetary rewards. In addition, magnitude effects have been reported in which…
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The rat's not for turning: Dissociating the psychological components of cognitive inflexibility☆
Nilsson, Simon R.O.; Alsiö, Johan; Somerville, Elizabeth M.; Clifton, Peter G.
2015-01-01
Executive function is commonly assessed by assays of cognitive flexibility such as reversal learning and attentional set-shifting. Disrupted performance in these assays, apparent in many neuropsychiatric disorders, is frequently interpreted as inability to overcome prior associations with reward. However, non-rewarded or irrelevant associations may be of considerable importance in both discrimination learning and cognitive flexibility. Non-rewarded associations can have greater influence on choice behaviour than rewarded associations in discrimination learning. Pathology-related deficits in cognitive flexibility can produce selective disruptions to both the processing of irrelevant associations and associations with reward. Genetic and pharmacological animal models demonstrate that modulation of reversal learning may result from alterations in either rewarded or non-rewarded associations. Successful performance in assays of cognitive flexibility can therefore depend on a combination of rewarded, non-rewarded, and irrelevant associations derived from previous learning, accounting for some inconsistencies observed in the literature. Taking this combination into account may increase the validity of animal models and may also reveal pathology-specific differences in problem solving and executive function. PMID:26112128
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Post-learning hippocampal dynamics promote preferential retention of rewarding events
Gruber, Matthias J.; Ritchey, Maureen; Wang, Shao-Fang; Doss, Manoj K.; Ranganath, Charan
2016-01-01
Reward motivation is known to modulate memory encoding, and this effect depends on interactions between the substantia nigra/ ventral tegmental area complex (SN/VTA) and the hippocampus. It is unknown, however, whether these interactions influence offline neural activity in the human brain that is thought to promote memory consolidation. Here, we used functional magnetic resonance imaging (fMRI) to test the effect of reward motivation on post-learning neural dynamics and subsequent memory for objects that were learned in high- or low-reward motivation contexts. We found that post-learning increases in resting-state functional connectivity between the SN/VTA and hippocampus predicted preferential retention of objects that were learned in high-reward contexts. In addition, multivariate pattern classification revealed that hippocampal representations of high-reward contexts were preferentially reactivated during post-learning rest, and the number of hippocampal reactivations was predictive of preferential retention of items learned in high-reward contexts. These findings indicate that reward motivation alters offline post-learning dynamics between the SN/VTA and hippocampus, providing novel evidence for a potential mechanism by which reward could influence memory consolidation. PMID:26875624