What cues do nurses use to predict aggression in people with acquired brain injury?

PubMed

Pryor, Julie

2005-04-01

There is a paucity of research on the frequent and repeated episodes of aggression and violence experienced by nurses when working with people who have an acquired brain injury. The purpose of this study was to bring this issue into focus by identifying the cues nurses use to predict aggression in people with acquired brain injury. Twenty-eight nurses from 10 different inpatient brain injury rehabilitation units in Australia participated in the study. Participants were interviewed using the Critical Decision Method on a one to one basis for up to one and one half hours on two consecutive days. Transcripts of the interviews were analysed using thematic analysis. Results revealed that nurses identified five groups of cues that predict aggression in a patient: (1) what a patient is saying; (2) changes in a patient's voice; (3) changes in a patient's face; (4) changes in a patient's behavior; and (5) a patient's emotions. Nurses reported using multiple cues to predict aggression and highlighted the importance of personal knowledge of the patient in conjunction with identified cues when predicting aggression. Nurses caring for patients with acquired brain injury can predict many episodes of aggression, though not all, by identifying cues from the patient.

Brain Monoamine Oxidase-A Activity Predicts Trait Aggression

PubMed Central

Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W.; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.

2008-01-01

The genetic deletion of monoamine oxidase A (MAO A, an enzyme which breaks down the monoamine neurotransmitters norepinephrine, serotonin and dopamine) produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, MIM 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in-vivo in healthy non-smoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the Multidimensional Personality Questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than a third of the variability. Since trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

RNAi therapeutics for brain cancer: current advancements in RNAi delivery strategies.

PubMed

Malhotra, Meenakshi; Toulouse, André; Godinho, Bruno M D C; Mc Carthy, David John; Cryan, John F; O'Driscoll, Caitriona M

2015-10-01

Malignant primary brain tumors are aggressive cancerous cells that invade the surrounding tissues of the central nervous system. The current treatment options for malignant brain tumors are limited due to the inability to cross the blood-brain barrier. The advancements in current research has identified and characterized certain molecular markers that are essential for tumor survival, progression, metastasis and angiogenesis. These molecular markers have served as therapeutic targets for the RNAi based therapies, which enable site-specific silencing of the gene responsible for tumor proliferation. However, to bring about therapeutic success, an efficient delivery carrier that can cross the blood-brain barrier and reach the targeted site is essential. The current review focuses on the potential of targeted, non-viral and viral particles containing RNAi therapeutic molecules as delivery strategies specifically for brain tumors.

Neuromodulation can reduce aggressive behavior elicited by violent video games.

PubMed

Riva, Paolo; Gabbiadini, Alessandro; Romero Lauro, Leonor J; Andrighetto, Luca; Volpato, Chiara; Bushman, Brad J

2017-04-01

Research has shown that exposure to violent media increases aggression. However, the neural underpinnings of violent-media-related aggression are poorly understood. Additionally, few experiments have tested hypotheses concerning how to reduce violent-media-related aggression. In this experiment, we focused on a brain area involved in the regulation of aggressive impulses-the right ventrolateral prefrontal cortex (rVLPFC). We tested the hypothesis that brain polarization through anodal transcranial direct current stimulation (tDCS) over rVLPFC reduces aggression related to violent video games. Participants (N = 79) were randomly assigned to play a violent or a nonviolent video game while receiving anodal or sham stimulation. Afterward, participants aggressed against an ostensible partner using the Taylor aggression paradigm (Taylor Journal of Personality, 35, 297-310, 1967), which measures both unprovoked and provoked aggression. Among those who received sham stimulation, unprovoked aggression was significantly higher for violent-game players than for nonviolent-game players. Among those who received anodal stimulation, unprovoked aggression did not differ for violent- and nonviolent-game players. Thus, anodal stimulation reduced unprovoked aggression in violent-game players. No significant effects were found for provoked aggression, suggesting tit-for-tat responding. This experiment sheds light on one possible neural underpinning of violent-media-related aggression-the rVLPFC, a brain area involved in regulating negative feelings and aggressive impulses.

Interplay between aggression, brain monoamines and fur color mutation in the American mink.

PubMed

Kulikov, A V; Bazhenova, E Y; Kulikova, E A; Fursenko, D V; Trapezova, L I; Terenina, E E; Mormede, P; Popova, N K; Trapezov, O V

2016-11-01

Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 ± 0.03) and tame (+3.5 ± 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive (-1.2 ± 0.1) and tame (+3.0 ± 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Clarifying relations between dispositional aggression and brain potential response: overlapping and distinct contributions of impulsivity and stress reactivity.

PubMed

Venables, Noah C; Patrick, Christopher J; Hall, Jason R; Bernat, Edward M

2011-03-01

Impulsive-aggressive individuals exhibit deficits in amplitude of the P3 brain potential response, however, it remains unclear how separable dispositional traits account for this association. The current study sought to clarify the basis of this association by examining contributions of trait impulsiveness and stress reactivity to the observed relationship between dispositional aggression and amplitude of the P3 brain potential response in a visual novelty-oddball procedure. A significant negative association was found between aggressiveness and amplitude of P3 response to both target and novel stimuli over frontal-central scalp sites. Impulsivity showed a parallel inverse relationship with P3 amplitude, attributable to its overlap with dispositional aggression. In contrast, stress reactivity did not exhibit a zero-order association with P3 amplitude, but modestly predicted P3 in a positive direction after accounting for its overlap with aggression. Results are discussed in terms of their implications for individual difference variables and brain processes underlying impulsive-aggressive behavior. Copyright © 2011 Elsevier B.V. All rights reserved.

Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results.

PubMed

Lyden, Hannah; Gimbel, Sarah I; Del Piero, Larissa; Tsai, A Bryna; Sachs, Matthew E; Kaplan, Jonas T; Margolin, Gayla; Saxbe, Darby

2016-01-01

Associations between brain structure and early adversity have been inconsistent in the literature. These inconsistencies may be partially due to methodological differences. Different methods of brain segmentation may produce different results, obscuring the relationship between early adversity and brain volume. Moreover, adolescence is a time of significant brain growth and certain brain areas have distinct rates of development, which may compromise the accuracy of automated segmentation approaches. In the current study, 23 adolescents participated in two waves of a longitudinal study. Family aggression was measured when the youths were 12 years old, and structural scans were acquired an average of 4 years later. Bilateral amygdalae and hippocampi were segmented using three different methods (manual tracing, FSL, and NeuroQuant). The segmentation estimates were compared, and linear regressions were run to assess the relationship between early family aggression exposure and all three volume segmentation estimates. Manual tracing results showed a positive relationship between family aggression and right amygdala volume, whereas FSL segmentation showed negative relationships between family aggression and both the left and right hippocampi. However, results indicate poor overlap between methods, and different associations were found between early family aggression exposure and brain volume depending on the segmentation method used.

Associations between Family Adversity and Brain Volume in Adolescence: Manual vs. Automated Brain Segmentation Yields Different Results

PubMed Central

Lyden, Hannah; Gimbel, Sarah I.; Del Piero, Larissa; Tsai, A. Bryna; Sachs, Matthew E.; Kaplan, Jonas T.; Margolin, Gayla; Saxbe, Darby

2016-01-01

Associations between brain structure and early adversity have been inconsistent in the literature. These inconsistencies may be partially due to methodological differences. Different methods of brain segmentation may produce different results, obscuring the relationship between early adversity and brain volume. Moreover, adolescence is a time of significant brain growth and certain brain areas have distinct rates of development, which may compromise the accuracy of automated segmentation approaches. In the current study, 23 adolescents participated in two waves of a longitudinal study. Family aggression was measured when the youths were 12 years old, and structural scans were acquired an average of 4 years later. Bilateral amygdalae and hippocampi were segmented using three different methods (manual tracing, FSL, and NeuroQuant). The segmentation estimates were compared, and linear regressions were run to assess the relationship between early family aggression exposure and all three volume segmentation estimates. Manual tracing results showed a positive relationship between family aggression and right amygdala volume, whereas FSL segmentation showed negative relationships between family aggression and both the left and right hippocampi. However, results indicate poor overlap between methods, and different associations were found between early family aggression exposure and brain volume depending on the segmentation method used. PMID:27656121

Brain Regions Influencing Implicit Violent Attitudes: A Lesion-Mapping Study.

PubMed

Cristofori, Irene; Zhong, Wanting; Mandoske, Valerie; Chau, Aileen; Krueger, Frank; Strenziok, Maren; Grafman, Jordan

2016-03-02

Increased aggression is common after traumatic brain injuries and may persist after cognitive recovery. Maladaptive aggression and violence are associated with dysfunction in the prefrontal and temporal cortex, but such dysfunctional behaviors are typically measured by explicit scales and history. However, it is well known that answers on explicit scales on sensitive topics--such as aggressive thoughts and behaviors--may not reveal true tendencies. Here, we investigated the neural basis of implicit attitudes toward aggression in humans using a modified version of the Implicit Association Task (IAT) with a unique sample of 112 Vietnam War veterans who suffered penetrating brain injury and 33 healthy controls who also served in combat in Vietnam but had no history of brain injury. We hypothesized that dorsolateral prefrontal cortex (dlPFC) lesions, due to the crucial role of the dlPFC in response inhibition, could influence performance on the IAT. In addition, we investigated the causal contribution of specific brain areas to implicit attitudes toward violence. We found a more positive implicit attitude toward aggression among individuals with lesions to the dlPFC and inferior posterior temporal cortex (ipTC). Furthermore, executive functions were critically involved in regulating implicit attitudes toward violence and aggression. Our findings complement existing evidence on the neural basis of explicit aggression centered on the ventromedial prefrontal cortex. These findings highlight that dlPFC and ipTC play a causal role in modulating implicit attitudes about violence and are crucially involved in the pathogenesis of aggressive behavior. Maladaptive aggression and violence can lead to interpersonal conflict and criminal behavior. Surprisingly little is known about implicit attitudes toward violence and aggression. Here, we used a range of techniques, including voxel-based lesion-symptom mapping, to examine the causal role of brain structures underpinning implicit attitudes toward aggression in a unique sample of combat veterans with traumatic brain injury. We found that damage to the dorsolateral prefrontal cortex (dlPFC) led to a more positive implicit attitude toward violence that under most normal situations would be considered inappropriate. These results suggest that treatments aimed at increasing cognitive control using cognitive behavioral therapies dependent on the intact dlPFC could treat aggressive and violent behavior. Copyright © 2016 the authors 0270-6474/16/362757-12$15.00/0.

The relationship between brain behavioral systems and the characteristics of the five factor model of personality with aggression among Iranian students.

PubMed

Komasi, Saeid; Saeidi, Mozhgan; Soroush, Ali; Zakiei, Ali

2016-07-01

Aggression is one of the negative components of emotion and it is usually considered to be the outcome of the activity of the Behavioral Inhibition and the Behavioral Activation System (BIS/BAS): components which can be considered as predisposing factors for personality differences. Therefore, the purpose of this study was to investigate the relationship between brain behavioral systems and the characteristics of the five factor model of personality with aggression among students. The present study has a correlation descriptive design. The research population included all of the Razi University students in the academic year of 2012-2013. The sampling was carried out with a random stratified method and 360 people (308 female and 52 male) were studied according to a table of Morgan. The study instruments were Buss and Perry Aggression Questionnaire, NEO Personality Inventory (Short Form), and Carver and White scale for BAS/BIS. Finally, SPSS20 was utilized to analyze the data using Pearson correlation, regression analysis, and canonical correlation. The data showed a significant positive relationship between the neurosis and agreeableness personality factors with aggression; but there is a significant negative relationship between the extroversion, openness, and conscientiousness personality factors with aggression. Furthermore, there is a significant positive relationship between all the components of brain behavioral systems (impulsivity, novelty seeking, sensitivity, tender) and aggression. The results of regression analysis indicated the personality characteristics and the brain behavioral systems which can predict 29 percent of the changes to aggression, simultaneously. According to a predictable level of aggressiveness by the personality characteristics and brain behavioral systems, it is possible to identify the personality characteristics and template patterns of brain behavioral systems for the students which be presented to them as a necessary training in order to control and manage of anger and aggression. © 2016 KUMS, All rights reserved.

MALDI Imaging Analysis of Neuropeptides in Africanized Honeybee (Apis mellifera) Brain: Effect of Aggressiveness.

PubMed

Pratavieira, Marcel; Menegasso, Anally Ribeiro da Silva; Esteves, Franciele Grego; Sato, Kenny Umino; Malaspina, Osmar; Palma, Mario Sérgio

2018-05-18

The aggressiveness in honeybees seems to be regulated by multiple genes, under the influence of different factors, such as polyethism of workers, environmental factors, and response to alarm pheromones, creating a series of behavioral responses. It is suspected that neuropeptides seem to be involved with the regulation of the aggressive behavior. The role of allatostatin and tachykinin-related neuropeptides in honeybee brain during the aggressive behavior is unknown; thus, worker honeybees were stimulated to attack and to sting leather targets hanged in front of the colonies. The aggressive individuals were collected and immediately frozen in liquid nitrogen; the heads were removed, and sliced at sagittal plan. The brain slices were submitted to MALDI-Spectral-Imaging analysis, and the results of the present study reported the processing of the precursors proteins into mature forms of the neuropeptides AmAST A (59-76) (AYTYVSEYKRLPVYNFGL-NH2), AmAST A (69-76) (LPVYNFGL-NH2), AmTRP (88 - 96) (APMGFQGMR-NH2), and AmTRP (254 - 262) (ARMGFHGMR-NH2), which apparently acted in different neuropils of honeybee brain, during the aggressive behavior, possibly playing the neuromodulation of different aspects of this complex behavior. These results were biologically validated performing aggressiveness-related behavioral assays, using young honeybee workers that received 1 ng of AmAST A (69-76) or AmTRP (88 - 96) via hemocele. The young workers that were not expected to be aggressive individuals, presented a complete series of the aggressive behaviors, in presence of the neuropeptides, corroborating the hypothesis that correlates the presence of mature AmASTs A and AmTRPs in honeybee brain with the aggressiveness of this insect.

A non-aggressive, highly efficient, enzymatic method for dissociation of human brain-tumors and brain-tissues to viable single-cells.

PubMed

Volovitz, Ilan; Shapira, Netanel; Ezer, Haim; Gafni, Aviv; Lustgarten, Merav; Alter, Tal; Ben-Horin, Idan; Barzilai, Ori; Shahar, Tal; Kanner, Andrew; Fried, Itzhak; Veshchev, Igor; Grossman, Rachel; Ram, Zvi

2016-06-01

Conducting research on the molecular biology, immunology, and physiology of brain tumors (BTs) and primary brain tissues requires the use of viably dissociated single cells. Inadequate methods for tissue dissociation generate considerable loss in the quantity of single cells produced and in the produced cells' viability. Improper dissociation may also demote the quality of data attained in functional and molecular assays due to the presence of large quantities cellular debris containing immune-activatory danger associated molecular patterns, and due to the increased quantities of degraded proteins and RNA. Over 40 resected BTs and non-tumorous brain tissue samples were dissociated into single cells by mechanical dissociation or by mechanical and enzymatic dissociation. The quality of dissociation was compared for all frequently used dissociation enzymes (collagenase, DNase, hyaluronidase, papain, dispase) and for neutral protease (NP) from Clostridium histolyticum. Single-cell-dissociated cell mixtures were evaluated for cellular viability and for the cell-mixture dissociation quality. Dissociation quality was graded by the quantity of subcellular debris, non-dissociated cell clumps, and DNA released from dead cells. Of all enzymes or enzyme combinations examined, NP (an enzyme previously not evaluated on brain tissues) produced dissociated cell mixtures with the highest mean cellular viability: 93 % in gliomas, 85 % in brain metastases, and 89 % in non-tumorous brain tissue. NP also produced cell mixtures with significantly less cellular debris than other enzymes tested. Dissociation using NP was non-aggressive over time-no changes in cell viability or dissociation quality were found when comparing 2-h dissociation at 37 °C to overnight dissociation at ambient temperature. The use of NP allows for the most effective dissociation of viable single cells from human BTs or brain tissue. Its non-aggressive dissociative capacity may enable ambient-temperature shipping of tumor pieces in multi-center clinical trials, meanwhile being dissociated. As clinical grade NP is commercially available it can be easily integrated into cell-therapy clinical trials in neuro-oncology. The high quality viable cells produced may enable investigators to conduct more consistent research by avoiding the experimental artifacts associated with the presence dead cells or cellular debris.

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Genetically defined fear-induced aggression: Focus on BDNF and its receptors.

PubMed

Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Kondaurova, Elena M; Popova, Nina K; Naumenko, Vladimir S

2018-05-02

Brain-derived neurotrophic factor (BDNF), its precursor proBDNF, BDNF pro-peptide, BDNF mRNA levels, as well as TrkB and p75 NTR receptors mRNA and protein levels, were studied in the brain of rats, selectively bred for more than 85 generations for either the high level or the lack of fear-induced aggressive behavior. Furthermore, we have found that rats of aggressive strain demonstrated both high level of aggression toward humans and increased amplitude of acoustic startle response compared to rats selectively bred for the lack of fear-induced aggression. Significant increase in the BDNF mRNA, mature BDNF and proBDNF protein levels in the raphe nuclei (RN), hippocampus (Hc), nucleus accumbens (NAcc), amygdala, striatum and hypothalamus (Ht) of aggressive rats was revealed. The BDNF/proBDNF ratio was significantly reduced in the Hc and NAcc of highly aggressive rats suggesting prevalence of the proBDNF in these structures. In the Hc and frontal cortex (FC) of aggressive rats, the level of the full-length TrkB (TrkB-FL) receptor form was decreased, whereas the truncated TrkB (TrkB-T) protein level was increased in the RN, FC, substantia nigra and Ht. The TrkB-FL/TrkB-T ratio was significantly decreased in highly aggressive rats suggesting TrkB-T is predominant in highly aggressive rats. The p75 NTR expression was slightly changed in majority of studied brain structures of aggressive rats. The data indicate the BDNF system in the brain of aggressive and nonaggressive animals is extremely different at all levels, from transcription to reception, suggesting significant role of BDNF system in the development of highly aggressive phenotype. Copyright © 2018 Elsevier B.V. All rights reserved.

Modelling verbal aggression, physical aggression and inappropriate sexual behaviour after acquired brain injury

PubMed Central

James, Andrew I. W.; Böhnke, Jan R.; Young, Andrew W.; Lewis, Gary J.

2015-01-01

Understanding the underpinnings of behavioural disturbances following brain injury is of considerable importance, but little at present is known about the relationships between different types of behavioural disturbances. Here, we take a novel approach to this issue by using confirmatory factor analysis to elucidate the architecture of verbal aggression, physical aggression and inappropriate sexual behaviour using systematic records made across an eight-week observation period for a large sample (n = 301) of individuals with a range of brain injuries. This approach offers a powerful test of the architecture of these behavioural disturbances by testing the fit between observed behaviours and different theoretical models. We chose models that reflected alternative theoretical perspectives based on generalized disinhibition (Model 1), a difference between aggression and inappropriate sexual behaviour (Model 2), or on the idea that verbal aggression, physical aggression and inappropriate sexual behaviour reflect broadly distinct but correlated clinical phenomena (Model 3). Model 3 provided the best fit to the data indicating that these behaviours can be viewed as distinct, but with substantial overlap. These data are important both for developing models concerning the architecture of behaviour as well as for clinical management in individuals with brain injury. PMID:26136449

Hospitalizations for critically ill children with traumatic brain injuries: a longitudinal analysis.

PubMed

Tilford, John M; Aitken, Mary E; Anand, K J S; Green, Jerril W; Goodman, Allen C; Parker, James G; Killingsworth, Jeffrey B; Fiser, Debra H; Adelson, P David

2005-09-01

This study examines the incidence, utilization of procedures, and outcomes for critically ill children hospitalized with traumatic brain injury over the period 1988-1999 to describe the benefits of improved treatment. Retrospective analysis of hospital discharges was conducted using data from the Health Care Cost and Utilization Project Nationwide Inpatient Sample that approximates a 20% sample of U.S. acute care hospitals. Hospital inpatient stays from all types of U.S. community hospitals. The study sample included all children aged 0-21 with a primary or secondary ICD-9-CM diagnosis code for traumatic brain injury and a procedure code for either endotracheal intubation or mechanical ventilation. None. Deaths occurring during hospitalization were used to calculate mortality rates. Use of intracranial pressure monitoring and surgical openings of the skull were investigated as markers for the aggressiveness of treatment. Patients were further classified by insurance status, household income, and hospital characteristics. Over the 12-yr study period, mortality rates decreased 8 percentage points whereas utilization of intracranial pressure monitoring increased by 11 percentage points. The trend toward more aggressive management of traumatic brain injury corresponded with improved hospital outcomes over time. Lack of insurance was associated with vastly worse outcomes. An estimated 6,437 children survived their traumatic brain injury hospitalization because of improved treatment, and 1,418 children died because of increased mortality risk associated with being uninsured. Improved treatment was valued at approximately dollar 17 billion, whereas acute care hospitalization costs increased by dollar 1.5 billion (in constant 2000 dollars). Increased mortality in uninsured children was associated with a dollar 3.76 billion loss in economic benefits. More aggressive management of pediatric traumatic brain injury appears to have contributed to reduced mortality rates over time and saved thousands of lives. Additional lives could be saved if mortality rates could be equalized between insured and uninsured children.

Aggression after traumatic brain injury: analysing socially desirable responses and the nature of aggressive traits.

PubMed

Dyer, Kevin F W; Bell, Rob; McCann, John; Rauch, Robert

2006-10-01

To compare patients with traumatic brain injury (TBI) with controls on sub-types of aggression and explore the role of social desirability. Quasi-experimental, matched-participants design. Sixty-nine participants were included in the study. The sample comprised a TBI group (n = 24), a spinal cord injury (SCI) group (n = 21) and an uninjured (UI) group of matched healthy volunteers (n = 24). Participants were given self-report measures of aggression, social desirability and impulsivity. Sixty-one independent 'other-raters' were nominated, who rated participant pre-morbid and post-morbid aggression. Using standardized norms, 25-39% of participants with TBI were classified as high average-very high on anger and 35-38% as high average-very high on verbal aggression. Other-raters rated participants with TBI as significantly higher on verbal aggression than SCI and UI participants. There were no differences between the groups on physical aggression. The TBI group also had higher levels of impulsivity than SCI and UI groups. Social desirability was a highly significant predictor of self-reported aggression for the entire sample. Impulsive verbal aggression and anger are the principal aggressive traits after brain injury. Physical aggression may present in extreme cases after TBI, but appears less prominent overall in this population. Social desirability, previously overlooked in research examining TBI aggression, emerged as an influential variable that should be considered in future TBI research.

Fronto-parietal regulation of media violence exposure in adolescents: a multi-method study

PubMed Central

Strenziok, Maren; Krueger, Frank; Deshpande, Gopikrishna; Lenroot, Rhoshel K.; van der Meer, Elke

2011-01-01

Adolescents spend a significant part of their leisure time watching TV programs and movies that portray violence. It is unknown, however, how the extent of violent media use and the severity of aggression displayed affect adolescents’ brain function. We investigated skin conductance responses, brain activation and functional brain connectivity to media violence in healthy adolescents. In an event-related functional magnetic resonance imaging experiment, subjects repeatedly viewed normed videos that displayed different degrees of aggressive behavior. We found a downward linear adaptation in skin conductance responses with increasing aggression and desensitization towards more aggressive videos. Our results further revealed adaptation in a fronto-parietal network including the left lateral orbitofrontal cortex (lOFC), right precuneus and bilateral inferior parietal lobules, again showing downward linear adaptations and desensitization towards more aggressive videos. Granger causality mapping analyses revealed attenuation in the left lOFC, indicating that activation during viewing aggressive media is driven by input from parietal regions that decreased over time, for more aggressive videos. We conclude that aggressive media activates an emotion–attention network that has the capability to blunt emotional responses through reduced attention with repeated viewing of aggressive media contents, which may restrict the linking of the consequences of aggression with an emotional response, and therefore potentially promotes aggressive attitudes and behavior. PMID:20934985

Brain mitochondrial bioenergetics change with rapid and prolonged shifts in aggression in the honey bee, Apis mellifera.

PubMed

Rittschof, Clare C; Vekaria, Hemendra J; Palmer, Joseph H; Sullivan, Patrick G

2018-04-25

Neuronal function demands high-level energy production, and as such, a decline in mitochondrial respiration characterizes brain injury and disease. A growing number of studies, however, link brain mitochondrial function to behavioral modulation in non-diseased contexts. In the honey bee, we show for the first time that an acute social interaction, which invokes an aggressive response, may also cause a rapid decline in brain mitochondrial bioenergetics. The degree and speed of this decline has only been previously observed in the context of brain injury. Furthermore, in the honey bee, age-related increases in aggressive tendency are associated with increased baseline brain mitochondrial respiration, as well as increased plasticity in response to metabolic fuel type in vitro Similarly, diet restriction and ketone body feeding, which commonly enhance mammalian brain mitochondrial function in vivo , cause increased aggression. Thus, even in normal behavioral contexts, brain mitochondria show a surprising degree of variation in function over both rapid and prolonged time scales, with age predicting both baseline function and plasticity in function. These results suggest that mitochondrial function is integral to modulating aggression-related neuronal signaling. We hypothesize that variation in function reflects mitochondrial calcium buffering activity, and that shifts in mitochondrial function signal to the neuronal soma to regulate gene expression and neural energetic state. Modulating brain energetic state is emerging as a critical component of the regulation of behavior in non-diseased contexts. © 2018. Published by The Company of Biologists Ltd.

[The aggressive child (author's transl)].

PubMed

Harbauer, H

1978-08-01

In children a "normal" aggressiveness should be distinguished from "hostile" and "inhibited" aggression; the latter usually become apparent as heteroaggressive or autoaggressive behaviour. Autoaggression is more common with younger children. Different hypotheses about the origin of aggressiveness are discussed. In the younger child nail biting, trichotillomania, rocking, an intensified phase of contrariness and enkopresis may have components of aggressiveness. In older children and adolescents dissocial forms of development, drug taking, attempted suicid, and anorexia nervosa may be parts of aggressive behaviour. Minimal brain dysfunction, autism, and postencephalitic syndromes predominate amongst organic alterations of the brain as causes for aggressive behaviour. Particularly the Lesch-Nyhan-syndrome, but equally the Cornelia de Lange-syndrome show autoaggressive tendencies.

Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse, human glioblastomas in the mouse brain in vivo

PubMed Central

Marin-Valencia, Isaac; Yang, Chendong; Mashimo, Tomoyuki; Cho, Steve; Baek, Hyeonman; Yang, Xiao-Li; Rajagopalan, Kartik N.; Maddie, Melissa; Vemireddy, Vamsidhara; Zhao, Zhenze; Cai, Ling; Good, Levi; Tu, Benjamin P.; Hatanpaa, Kimmo J.; Mickey, Bruce E.; Matés, José M.; Pascual, Juan M.; Maher, Elizabeth A.; Malloy, Craig R.; DeBerardinis, Ralph J.; Bachoo, Robert M.

2012-01-01

SUMMARY Dysregulated metabolism is a hallmark of cancer cell lines, but little is known about the fate of glucose and other nutrients in tumors growing in their native microenvironment. To study tumor metabolism in vivo, we used an orthotopic mouse model of primary human glioblastoma (GBM). We infused 13C-labeled nutrients into mice bearing three independent GBM lines, each with a distinct set of mutations. All three lines displayed glycolysis, as expected for aggressive tumors. They also displayed unexpected metabolic complexity, oxidizing glucose via pyruvate dehydrogenase and the citric acid cycle, and using glucose to supply anaplerosis and other biosynthetic activities. Comparing the tumors to surrounding brain revealed obvious metabolic differences, notably the accumulation of a large glutamine pool within the tumors. Many of these same activities were conserved in cells cultured ex vivo from the tumors. Thus GBM cells utilize mitochondrial glucose oxidation during aggressive tumor growth in vivo. PMID:22682223

NG2 expression in glioblastoma identifies an actively proliferating population with an aggressive molecular signature

PubMed Central

Al-Mayhani, M. Talal F.; Grenfell, Richard; Narita, Masashi; Piccirillo, Sara; Kenney-Herbert, Emma; Fawcett, James W.; Collins, V. Peter; Ichimura, Koichi; Watts, Colin

2011-01-01

Glioblastoma multiforme (GBM) is the most common type of primary brain tumor and a highly malignant and heterogeneous cancer. Current conventional therapies fail to eradicate or curb GBM cell growth. Hence, exploring the cellular and molecular basis of GBM cell growth is vital to develop novel therapeutic approaches. Neuroglia (NG)-2 is a transmembrane proteoglycan expressed by NG2+ progenitors and is strongly linked to cell proliferation in the normal brain. By using NG2 as a biomarker we identify a GBM cell population (GBM NG2+ cells) with robust proliferative, clonogenic, and tumorigenic capacity. We show that a significant proportion (mean 83%) of cells proliferating in the tumor mass express NG2 and that over 50% of GBM NG2+ cells are proliferating. Compared with the GBM NG2− cells from the same tumor, the GBM of NG2+ cells overexpress genes associated with aggressive tumorigenicity, including overexpression of Mitosis and Cell Cycling Module genes (e.g., MELK, CDC, MCM, E2F), which have been previously shown to correlate with poor survival in GBM. We also show that the coexpression pattern of NG2 with other glial progenitor markers in GBM does not recapitulate that described in the normal brain. The expression of NG2 by such an aggressive and actively cycling GBM population combined with its location on the cell surface identifies this cell population as a potential therapeutic target in a subset of patients with GBM. PMID:21798846

Ventromedial Hypothalamus and the Generation of Aggression

PubMed Central

Hashikawa, Yoshiko; Hashikawa, Koichi; Falkner, Annegret L.; Lin, Dayu

2017-01-01

Aggression is a costly behavior, sometimes with severe consequences including death. Yet aggression is prevalent across animal species ranging from insects to humans, demonstrating its essential role in the survival of individuals and groups. The question of how the brain decides when to generate this costly behavior has intrigued neuroscientists for over a century and has led to the identification of relevant neural substrates. Various lesion and electric stimulation experiments have revealed that the hypothalamus, an ancient structure situated deep in the brain, is essential for expressing aggressive behaviors. More recently, studies using precise circuit manipulation tools have identified a small subnucleus in the medial hypothalamus, the ventrolateral part of the ventromedial hypothalamus (VMHvl), as a key structure for driving both aggression and aggression-seeking behaviors. Here, we provide an updated summary of the evidence that supports a role of the VMHvl in aggressive behaviors. We will consider our recent findings detailing the physiological response properties of populations of VMHvl cells during aggressive behaviors and provide new understanding regarding the role of the VMHvl embedded within the larger whole-brain circuit for social sensation and action. PMID:29375329

Correlates and Prevalence of Aggression at Six Months and One Year After First-Time Traumatic Brain Injury.

PubMed

Roy, Durga; Vaishnavi, Sandeep; Han, Dingfen; Rao, Vani

2017-01-01

Few studies have examined clinical correlates of aggression after first-time traumatic brain injury (TBI) within the first year after injury. The authors aimed to identify the rates of aggression at 6 and 12 months post-TBI and establish clinical and demographic correlates. A total of 103 subjects with first-time TBI were seen within 12 months postinjury and evaluated for aggression. Post-TBI social functioning and new-onset depression (within 3 months of the TBI) may serve as particularly important predictors for aggression within the first year of TBI, as these factors may afford intervention and subsequent decreased risk of aggression.

Interaction of parenting experiences and brain structure in the prediction of depressive symptoms in adolescents.

PubMed

Yap, Marie B H; Whittle, Sarah; Yücel, Murat; Sheeber, Lisa; Pantelis, Christos; Simmons, Julian G; Allen, Nicholas B

2008-12-01

Although some evidence suggests that neuroanatomic abnormalities may confer risk for major depressive disorder, findings are inconsistent. One potential explanation for this is the moderating role of environmental context, with individuals differing in their biological sensitivity to context. To examine the influence of adverse parenting as an environmental moderator of the association between brain structure and depressive symptoms. Cross-sectional measurement of brain structure, adverse parenting, and depressive symptoms in early adolescents. General community. A total of 106 students aged 11 to 13 years (55 males [51%]), recruited from primary schools in Melbourne, Australia, and their mothers. Selection was based on affective temperament, aimed at producing a sample representing a broad range of risk for major depressive disorder. No participant evidenced current or past case-level depressive, substance use, or eating disorder. (1) Volumetric measures of adolescents' amygdala, hippocampus, and anterior cingulate cortex (ACC); (2) frequency of observed maternal aggressive behavior during a mother-adolescent conflict-resolution interaction; and (3) adolescent depressive symptoms. Boys with smaller right amygdalas reported more depressive symptoms. However, neither hippocampal volume nor asymmetry measures of limbic or paralimbic ACC were directly related to level of depressive symptoms. Importantly, frequency of maternal aggressive behaviors moderated the associations between both the amygdala and ACC, and adolescent symptoms. Particularly, in conditions of low levels of maternal aggressiveness, boys with larger right amygdalas, girls with smaller bilateral amygdalas, and both boys and girls with smaller left paralimbic ACC reported fewer symptoms. These findings help elucidate the complex relationships between brain structure, environmental factors, and depressive symptoms. Further longitudinal research is required to examine how these factors contribute to the onset of case-level disorder, but given that family context risk factors are modifiable, our findings do suggest the potential utility of targeted early parenting interventions.

Tunicamycin inhibits progression of glioma cells through downregulation of the MEG-3-regulated wnt/β-catenin signaling pathway.

PubMed

Li, Xin; Xue, Lei; Peng, Qin

2018-06-01

Glioma is derived from the oncogenic transformation of brain and spinal cord glial cells, and is one of the most common primary brain tumors. Tunicamycin (TUN) can significantly inhibit glioma growth and aggressiveness by promoting apoptosis in glioma cells. The purpose of the present study was to investigate the effects of TUN on growth of glioma cells and examine the TUN-mediated signaling pathway. The inhibitory effects of TUN on apoptosis, growth, aggressiveness and cell cycle arrest of glioma tumor cells were determined by western blotting, reverse transcription-quantitative polymerase chain reaction, apoptotic assays and immunofluorescence. The results demonstrated that treatment with TUN suppressed growth, migration and invasion of glioma carcinoma cells. In addition, TUN treatment induced apoptosis of glioma cells through downregulation of Bcl-2 and P53 expression levels. Findings also indicated that TUN suppressed proliferation and arrested the glioma cells in the S phase of the cell cycle. Further analysis of the mechanisms of TUN demonstrated that TUN treatment upregulated the expression levels of maternally expressed gene (MEG)-3, wnt and β-catenin in glioma cells. Furthermore, knockdown of MEG-3 expression reversed the TUN-decreased wnt/β-catenin signaling pathway, which subsequently also reversed the TUN-inhibited growth and aggressiveness of glioma cells. In conclusion, the findings in the present study indicated that TUN treatment inhibited growth and aggressiveness through MEG-3-mediated wnt/β-catenin signaling, suggesting that TUN may be an efficient anticancer agent for the treatment of glioma.

Testosterone and aggressive behavior in man.

PubMed

Batrinos, Menelaos L

2012-01-01

Atavistic residues of aggressive behavior prevailing in animal life, determined by testosterone, remain attenuated in man and suppressed through familial and social inhibitions. However, it still manifests itself in various intensities and forms from; thoughts, anger, verbal aggressiveness, competition, dominance behavior, to physical violence. Testosterone plays a significant role in the arousal of these behavioral manifestations in the brain centers involved in aggression and on the development of the muscular system that enables their realization. There is evidence that testosterone levels are higher in individuals with aggressive behavior, such as prisoners who have committed violent crimes. Several field studies have also shown that testosterone levels increase during the aggressive phases of sports games. In more sensitive laboratory paradigms, it has been observed that participant's testosterone rises in the winners of; competitions, dominance trials or in confrontations with factitious opponents. Aggressive behavior arises in the brain through interplay between subcortical structures in the amygdala and the hypothalamus in which emotions are born and the prefrontal cognitive centers where emotions are perceived and controlled. The action of testosterone on the brain begins in the embryonic stage. Earlier in development at the DNA level, the number of CAG repeats in the androgen receptor gene seems to play a role in the expression of aggressive behavior. Neuroimaging techniques in adult males have shown that testosterone activates the amygdala enhancing its emotional activity and its resistance to prefrontal restraining control. This effect is opposed by the action of cortisol which facilitates prefrontal area cognitive control on impulsive tendencies aroused in the subcortical structures. The degree of impulsivity is regulated by serotonin inhibiting receptors, and with the intervention of this neurotransmitter the major agents of the neuroendocrine influence on the brain process of aggression forms a triad. Testosterone activates the subcortical areas of the brain to produce aggression, while cortisol and serotonin act antagonistically with testosterone to reduce its effects.

Transcriptional regulation of brain gene expression in response to a territorial intrusion

PubMed Central

Sanogo, Yibayiri O.; Band, Mark; Blatti, Charles; Sinha, Saurabh; Bell, Alison M.

2012-01-01

Aggressive behaviour associated with territorial defence is widespread and has fitness consequences. However, excess aggression can interfere with other important biological functions such as immunity and energy homeostasis. How the expression of complex behaviours such as aggression is regulated in the brain has long intrigued ethologists, but has only recently become amenable for molecular dissection in non-model organisms. We investigated the transcriptomic response to territorial intrusion in four brain regions in breeding male threespined sticklebacks using expression microarrays and quantitative polymerase chain reaction (qPCR). Each region of the brain had a distinct genomic response to a territorial challenge. We identified a set of genes that were upregulated in the diencephalon and downregulated in the cerebellum and the brain stem. Cis-regulatory network analysis suggested transcription factors that regulated or co-regulated genes that were consistently regulated in all brain regions and others that regulated gene expression in opposing directions across brain regions. Our results support the hypothesis that territorial animals respond to social challenges via transcriptional regulation of genes in different brain regions. Finally, we found a remarkably close association between gene expression and aggressive behaviour at the individual level. This study sheds light on the molecular mechanisms in the brain that underlie the response to social challenges. PMID:23097509

Psychophysiological correlates of aggression and violence: an integrative review.

PubMed

Patrick, Christopher J

2008-08-12

This paper reviews existing psychophysiological studies of aggression and violent behaviour including research employing autonomic, electrocortical and neuroimaging measures. Robust physiological correlates of persistent aggressive behaviour evident in this literature include low baseline heart rate, enhanced autonomic reactivity to stressful or aversive stimuli, enhanced EEG slow wave activity, reduced P300 brain potential response and indications from structural and functional neuroimaging studies of dysfunction in frontocortical and limbic brain regions that mediate emotional processing and regulation. The findings are interpreted within a conceptual framework that draws on two integrative models in the literature. The first is a recently developed hierarchical model of impulse control (externalizing) problems, in which various disinhibitory syndromes including aggressive and addictive behaviours of different kinds are seen as arising from common as well as distinctive aetiologic factors. This model represents an approach to organizing these various interrelated phenotypes and investigating their common and distinctive aetiologic substrates. The other is a neurobiological model that posits impairments in affective regulatory circuits in the brain as a key mechanism for impulsive aggressive behaviour. This model provides a perspective for integrating findings from studies employing different measures that have implicated varying brain structures and physiological systems in violent and aggressive behaviour.

Neural mechanisms of the rejection-aggression link.

PubMed

Chester, David S; Lynam, Donald R; Milich, Richard; DeWall, C Nathan

2018-05-01

Social rejection is a painful event that often increases aggression. However, the neural mechanisms of this rejection-aggression link remain unclear. A potential clue may be that rejected people often recruit the ventrolateral prefrontal cortex's (VLPFC) self-regulatory processes to manage the pain of rejection. Using functional MRI, we replicated previous links between rejection and activity in the brain's mentalizing network, social pain network and VLPFC. VLPFC recruitment during rejection was associated with greater activity in the brain's reward network (i.e. the ventral striatum) when individuals were given an opportunity to retaliate. This retaliation-related striatal response was associated with greater levels of retaliatory aggression. Dispositionally aggressive individuals exhibited less functional connectivity between the ventral striatum and the right VLPFC during aggression. This connectivity exerted a suppressing effect on dispositionally aggressive individuals' greater aggressive responses to rejection. These results help explain how the pain of rejection and reward of revenge motivate rejected people to behave aggressively.

Reactions to Media Violence: It’s in the Brain of the Beholder

PubMed Central

Alia-Klein, Nelly; Wang, Gene-Jack; Preston-Campbell, Rebecca N.; Moeller, Scott J.; Parvaz, Muhammad A.; Zhu, Wei; Jayne, Millard C.; Wong, Chris; Tomasi, Dardo; Goldstein, Rita Z.; Fowler, Joanna S.; Volkow, Nora D.

2014-01-01

Media portraying violence is part of daily exposures. The extent to which violent media exposure impacts brain and behavior has been debated. Yet there is not enough experimental data to inform this debate. We hypothesize that reaction to violent media is critically dependent on personality/trait differences between viewers, where those with the propensity for physical assault will respond to the media differently than controls. The source of the variability, we further hypothesize, is reflected in autonomic response and brain functioning that differentiate those with aggression tendencies from others. To test this hypothesis we pre-selected a group of aggressive individuals and non-aggressive controls from the normal healthy population; we documented brain, blood-pressure, and behavioral responses during resting baseline and while the groups were watching media violence and emotional media that did not portray violence. Positron Emission Tomography was used with [18F]fluoro-deoxyglucose (FDG) to image brain metabolic activity, a marker of brain function, during rest and during film viewing while blood-pressure and mood ratings were intermittently collected. Results pointed to robust resting baseline differences between groups. Aggressive individuals had lower relative glucose metabolism in the medial orbitofrontal cortex correlating with poor self-control and greater glucose metabolism in other regions of the default-mode network (DMN) where precuneus correlated with negative emotionality. These brain results were similar while watching the violent media, during which aggressive viewers reported being more Inspired and Determined and less Upset and Nervous, and also showed a progressive decline in systolic blood-pressure compared to controls. Furthermore, the blood-pressure and brain activation in orbitofrontal cortex and precuneus were differentially coupled between the groups. These results demonstrate that individual differences in trait aggression strongly couple with brain, behavioral, and autonomic reactivity to media violence which should factor into debates about the impact of media violence on the public. PMID:25208327

Reactions to media violence: it's in the brain of the beholder.

PubMed

Alia-Klein, Nelly; Wang, Gene-Jack; Preston-Campbell, Rebecca N; Moeller, Scott J; Parvaz, Muhammad A; Zhu, Wei; Jayne, Millard C; Wong, Chris; Tomasi, Dardo; Goldstein, Rita Z; Fowler, Joanna S; Volkow, Nora D

2014-01-01

Media portraying violence is part of daily exposures. The extent to which violent media exposure impacts brain and behavior has been debated. Yet there is not enough experimental data to inform this debate. We hypothesize that reaction to violent media is critically dependent on personality/trait differences between viewers, where those with the propensity for physical assault will respond to the media differently than controls. The source of the variability, we further hypothesize, is reflected in autonomic response and brain functioning that differentiate those with aggression tendencies from others. To test this hypothesis we pre-selected a group of aggressive individuals and non-aggressive controls from the normal healthy population; we documented brain, blood-pressure, and behavioral responses during resting baseline and while the groups were watching media violence and emotional media that did not portray violence. Positron Emission Tomography was used with [18F]fluoro-deoxyglucose (FDG) to image brain metabolic activity, a marker of brain function, during rest and during film viewing while blood-pressure and mood ratings were intermittently collected. Results pointed to robust resting baseline differences between groups. Aggressive individuals had lower relative glucose metabolism in the medial orbitofrontal cortex correlating with poor self-control and greater glucose metabolism in other regions of the default-mode network (DMN) where precuneus correlated with negative emotionality. These brain results were similar while watching the violent media, during which aggressive viewers reported being more Inspired and Determined and less Upset and Nervous, and also showed a progressive decline in systolic blood-pressure compared to controls. Furthermore, the blood-pressure and brain activation in orbitofrontal cortex and precuneus were differentially coupled between the groups. These results demonstrate that individual differences in trait aggression strongly couple with brain, behavioral, and autonomic reactivity to media violence which should factor into debates about the impact of media violence on the public.

Social instigation and repeated aggressive confrontations in male Swiss mice: analysis of plasma corticosterone, CRF and BDNF levels in limbic brain areas.

PubMed

Fortes, Paula Madeira; Albrechet-Souza, Lucas; Vasconcelos, Mailton; Ascoli, Bruna Maria; Menegolla, Ana Paula; de Almeida, Rosa Maria M

2017-01-01

Agonistic behaviors help to ensure survival, provide advantage in competition, and communicate social status. The resident-intruder paradigm, an animal model based on male intraspecific confrontations, can be an ethologically relevant tool to investigate the neurobiology of aggressive behavior. To examine behavioral and neurobiological mechanisms of aggressive behavior in male Swiss mice exposed to repeated confrontations in the resident intruder paradigm. Behavioral analysis was performed in association with measurements of plasma corticosterone of mice repeatedly exposed to a potential rival nearby, but inaccessible (social instigation), or to 10 sessions of social instigation followed by direct aggressive encounters. Moreover, corticotropin-releasing factor (CRF) and brain-derived neurotrophic factor (BNDF) were measured in the brain of these animals. Control mice were exposed to neither social instigation nor aggressive confrontations. Mice exposed to aggressive confrontations exhibited a similar pattern of species-typical aggressive and non-aggressive behaviors on the first and the last session. Moreover, in contrast to social instigation only, repeated aggressive confrontations promoted an increase in plasma corticosterone. After 10 aggressive confrontation sessions, mice presented a non-significant trend toward reducing hippocampal levels of CRF, which inversely correlated with plasma corticosterone levels. Conversely, repeated sessions of social instigation or aggressive confrontation did not alter BDNF concentrations at the prefrontal cortex and hippocampus. Exposure to repeated episodes of aggressive encounters did not promote habituation over time. Additionally, CRF seems to be involved in physiological responses to social stressors.

Relationships between symptomatology and SES-related factors in hyperkinetic/MBD boys.

PubMed

Paternite, C E; Loney, J; Langhorne, J E

1976-04-01

Relationships among symptomatology, socioeconomic status, and parenting styles were examined for 113 hyperkinetic/minimal brain dysfunction boys from intact families. Primary symptoms (e.g. hyperactivity) did not vary as a function of SES, but SES-related differences emerged for secondary symptoms (e.g., aggressive behavior, self-esteem deficits) and for parenting variables. Parenting variables were found to be better predictors of secondary symptoms than was SES. Implications for further research are offered.

Primary Central Nervous System Fibrosarcoma.

PubMed

Vinodh, V P; Harun, Rahmat; Sellamuthu, Pulivendhan; Kandasamy, Regunath

2017-08-01

We report a rare case of a young female with primary brain fibrosarcoma, and to the best of our knowledge, we believe that only <50 cases have been reported or described worldwide so far. Fibrosarcoma is a malignant neoplasm, in which histologically the predominant cells are fibroblasts that divide excessively without cellular control and they can invade local tissues or metastasize. Primary central nervous system fibrosarcomas are very aggressive neoplasms and generally have a poor prognosis. This tumor is either from sarcomatous transformation of a meningioma or arises de novo within the brain parenchyma. Our patient, a 48-year-old woman, who presented with progressive speech disorder over the period of 4 months, showed a left temporoparietal lesion with surrounding edema and local mass effect. Total surgical resection was achieved. Histopathology revealed classical fibrosarcoma features and secondary screening revealed no other distant lesion as diagnosis of primary brain fibrosarcoma was established. This case is deemed to be extremely rare because most reports claim that recurrence is within 6 months with poor prognosis; however, this patient is currently recurrence-free at 3 years. This would suggest of the possibility for a relook into this disease's course and recurrence rate when complete excision is achieved. Due to extreme rarity of these tumors, more comparative studies will be needed to improve the disease outcome.

Rapid effects of 17β-estradiol on aggressive behavior in songbirds: Environmental and genetic influences.

PubMed

Heimovics, Sarah A; Merritt, Jennifer R; Jalabert, Cecilia; Ma, Chunqi; Maney, Donna L; Soma, Kiran K

2018-04-24

17β-estradiol (E 2 ) has numerous rapid effects on the brain and behavior. This review focuses on the rapid effects of E 2 on aggression, an important social behavior, in songbirds. First, we highlight the contributions of studies on song sparrows, which reveal that seasonal changes in the environment profoundly influence the capacity of E 2 to rapidly alter aggressive behavior. E 2 administration to male song sparrows increases aggression within 20 min in the non-breeding season, but not in the breeding season. Furthermore, E 2 rapidly modulates several phosphoproteins in the song sparrow brain. In particular, E 2 rapidly affects pCREB in the medial preoptic nucleus, in the non-breeding season only. Second, we describe studies of the white-throated sparrow, which reveal how a genetic polymorphism may influence the rapid effects of E 2 on aggression. In this species, a chromosomal rearrangement that includes ESR1, which encodes estrogen receptor α (ERα), affects ERα expression in the brain and the ability of E 2 to rapidly promote aggression. Third, we summarize studies showing that aggressive interactions rapidly affect levels of E 2 and other steroids, both in the blood and in specific brain regions, and the emerging potential for steroid profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS). Such studies of songbirds demonstrate the value of an ethologically informed approach, in order to reveal how steroids act rapidly on the brain to alter naturally-occurring behavior. Copyright © 2018. Published by Elsevier Inc.

Staff-reported antecedents to aggression in a post-acute brain injury treatment programme: What are they and what implications do they have for treatment?

PubMed Central

Giles, Gordon Muir; Scott, Karen; Manchester, David

2013-01-01

Research in psychiatric settings has found that staff attribute the majority of inpatient aggression to immediate environmental stressors. We sought to determine if staff working with persons with brain injury-related severe and chronic impairment make similar causal attributions. If immediate environmental stressors precipitate the majority of aggressive incidents in this client group, it is possible an increased focus on the management of factors that initiate client aggression may be helpful. The research was conducted in a low-demand treatment programme for individuals with chronic cognitive impairment due to acquired brain injury. Over a six-week period, 63 staff and a research assistant reported on 508 aggressive incidents. Staff views as to the causes of client aggression were elicited within 72 hours of observing an aggressive incident. Staff descriptions of causes were categorised using qualitative methods and analysed both qualitatively and quantitatively. Aggression towards staff was predominantly preceded by (a) actions that interrupted or redirected a client behaviour, (b) an activity demand, or (c) a physical intrusion. The majority of aggressive incidents appeared hostile/angry in nature and were not considered by staff to be pre-meditated. Common treatment approaches can be usefully augmented by a renewed focus on interventions aimed at reducing antecedents that provoke aggression. Possible approaches for achieving this are considered. PMID:23782342

Staff-reported antecedents to aggression in a post-acute brain injury treatment programme: what are they and what implications do they have for treatment?

PubMed

Giles, Gordon Muir; Scott, Karen; Manchester, David

2013-01-01

Research in psychiatric settings has found that staff attribute the majority of in-patient aggression to immediate environmental stressors. We sought to determine if staff working with persons with brain injury-related severe and chronic impairment make similar causal attributions. If immediate environmental stressors precipitate the majority of aggressive incidents in this client group, it is possible an increased focus on the management of factors that initiate client aggression may be helpful. The research was conducted in a low-demand treatment programme for individuals with chronic cognitive impairment due to acquired brain injury. Over a six-week period, 63 staff and a research assistant reported on 508 aggressive incidents. Staff views as to the causes of client aggression were elicited within 72 hours of observing an aggressive incident. Staff descriptions of causes were categorised using qualitative methods and analysed both qualitatively and quantitatively. Aggression towards staff was predominantly preceded by (a) actions that interrupted or redirected a client behaviour, (b) an activity demand, or (c) a physical intrusion. The majority of aggressive incidents appeared hostile/angry in nature and were not considered by staff to be pre-meditated. Common treatment approaches can be usefully augmented by a renewed focus on interventions aimed at reducing antecedents that provoke aggression. Possible approaches for achieving this are considered.

Quetiapine modulates functional connectivity in brain aggression networks.

PubMed

Klasen, Martin; Zvyagintsev, Mikhail; Schwenzer, Michael; Mathiak, Krystyna A; Sarkheil, Pegah; Weber, René; Mathiak, Klaus

2013-07-15

Aggressive behavior is associated with dysfunctions in an affective regulation network encompassing amygdala and prefrontal areas such as orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC). In particular, prefrontal regions have been postulated to control amygdala activity by inhibitory projections, and this process may be disrupted in aggressive individuals. The atypical antipsychotic quetiapine successfully attenuates aggressive behavior in various disorders; the underlying neural processes, however, are unknown. A strengthened functional coupling in the prefrontal-amygdala system may account for these anti-aggressive effects. An inhibition of this network has been reported for virtual aggression in violent video games as well. However, there have been so far no in-vivo observations of pharmacological influences on corticolimbic projections during human aggressive behavior. In a double-blind, placebo-controlled study, quetiapine and placebo were administered for three successive days prior to an fMRI experiment. In this experiment, functional brain connectivity was assessed during virtual aggressive behavior in a violent video game and an aggression-free control task in a non-violent modification. Quetiapine increased the functional connectivity of ACC and DLPFC with the amygdala during virtual aggression, whereas OFC-amygdala coupling was attenuated. These effects were observed neither for placebo nor for the non-violent control. These results demonstrate for the first time a pharmacological modification of aggression-related human brain networks in a naturalistic setting. The violence-specific modulation of prefrontal-amygdala networks appears to control aggressive behavior and provides a neurobiological model for the anti-aggressive effects of quetiapine. Copyright © 2013 Elsevier Inc. All rights reserved.

Emotional Labour of Caregivers Confronted With Aggressive Brain-injured Patients.

PubMed

Huet, Magali; Dany, Lionel; Apostolidis, Thémistoklis

2018-06-01

Aggressive behaviours are common with people who have suffered brain injuries and induce difficult emotions among certified nursing assistants and medical-psychological assistants who take care of them. These caregivers carry out emotional labour whose content and strategies are little known. The study explores the emotional labour of certified nursing assistants and medical-psychological assistants faced with the aggressive behaviours of brain-injured patients. Semi-structured interviews were conducted with 37 caregivers. Interviews were analysed via a thematic content analysis. The analysis shows that the emotional labour of caregivers varies in accordance with the state of "consciousness" or "non-consciousness" that they attribute to the brain-injured patient with regard to this aggressive behaviour. This is a deep acting strategy. Moreover, caregivers shut off their emotions in order not to transmit them to the patient. This surface acting has the first objective for the caregiver of maintaining control of the situation and a second objective of protecting the patient emotionally and therefore of being perceived as a "good" caregiver. Emotional labour also meets a need to preserve the professional self-image and professional status negatively affected in the interaction with the aggressive brain-injured patient. Our study specifies the different strategies of the emotional labour of caregivers and their circumstances of use when they are confronted with aggressive behaviour by brain-injured patients. Targeted support for this emotional labour, such as training and practical analysis, is essential for the development of care practices promoting a caring relationship. Copyright © 2017 Elsevier Inc. All rights reserved.

Differences in brain circuitry for appetitive and reactive aggression as revealed by realistic auditory scripts

PubMed Central

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

Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse.

PubMed

Shelton, Laura M; Huysentruyt, Leanne C; Mukherjee, Purna; Seyfried, Thomas N

2010-07-23

GBM (glioblastoma multiforme) is the most aggressive and invasive form of primary human brain cancer. We recently developed a novel brain cancer model in the inbred VM mouse strain that shares several characteristics with human GBM. Using bioluminescence imaging, we tested the efficacy of CR (calorie restriction) for its ability to reduce tumour size and invasion. CR targets glycolysis and rapid tumour cell growth in part by lowering circulating glucose levels. The VM-M3 tumour cells were implanted intracerebrally in the syngeneic VM mouse host. Approx. 12-15 days post-implantation, brains were removed and both ipsilateral and contralateral hemispheres were imaged to measure bioluminescence of invading tumour cells. CR significantly reduced the invasion of tumour cells from the implanted ipsilateral hemisphere into the contralateral hemisphere. The total percentage of Ki-67-stained cells within the primary tumour and the total number of blood vessels was also significantly lower in the CR-treated mice than in the mice fed ad libitum, suggesting that CR is anti-proliferative and anti-angiogenic. Our findings indicate that the VM-M3 GBM model is a valuable tool for studying brain tumour cell invasion and for evaluating potential therapeutic approaches for managing invasive brain cancer. In addition, we show that CR can be effective in reducing malignant brain tumour growth and invasion.

Effects of a novel anti-aggressive agent upon two types of brain stimulated emotional behavior.

PubMed

Katz, R J; Thomas, E

1976-07-09

The effects of anti-aggressive agent Sch 12679 were evaluated upon stable baselines of rage and predation elicited by electrical stimulation of the hypothalamus in cats. Sch 12679 depressed approach and terminal aspects of both forms of attack. This is consistent with previous reports, and suggests the drug is effective in reducing many forms of aggression including brain stimulated emotional behavior.

Neural networks underlying trait aggression depend on MAOA gene alleles.

PubMed

Klasen, Martin; Wolf, Dhana; Eisner, Patrick D; Habel, Ute; Repple, Jonathan; Vernaleken, Ingo; Schlüter, Thorben; Eggermann, Thomas; Zerres, Klaus; Zepf, Florian D; Mathiak, Klaus

2018-03-01

Low expressing alleles of the MAOA gene (MAOA-L) have been associated with an increased risk for developing an aggressive personality. This suggests an MAOA-L-specific neurobiological vulnerability associated with trait aggression. The neural networks underlying this vulnerability are unknown. The present study investigated genotype-specific associations between resting state brain networks and trait aggression (Buss-Perry Aggression Questionnaire) in 82 healthy Caucasian males. Genotype influences on aggression-related networks were studied for intrinsic and seed-based brain connectivity. Intrinsic connectivity was higher in the ventromedial prefrontal cortex (VMPFC) of MAOA-L compared to high expressing allele (MAOA-H) carriers. Seed-based connectivity analyses revealed genotype differences in the functional involvement of this region. MAOA genotype modulated the relationship between trait aggression and VMPFC connectivity with supramarginal gyrus (SMG) and areas of the default mode network (DMN). Separate analyses for the two groups were performed to better understand how the genotype modulated the relationship between aggression and brain networks. They revealed a positive correlation between VMPFC connectivity and aggression in right angular gyrus (AG) and a negative correlation in right SMG in the MAOA-L group. No such effect emerged in the MAOA-H carriers. The results indicate a particular relevance of VMPFC for aggression in MAOA-L carriers; in specific, a detachment from the DMN along with a strengthened coupling to the AG seems to go along with lower trait aggression. MAOA-L carriers may thus depend on a synchronization of emotion regulation systems (VMPFC) with core areas of empathy (SMG) to prevent aggression.

I'm Still Me: Inspiration and Instruction from Individuals with Brain Cancer.

PubMed

Piderman, Katherine M; Egginton, Jason S; Ingram, Cory; Dose, Ann Marie; Yoder, Timothy J; Lovejoy, Laura A; Swanson, Spence W; Hogg, James T; Lapid, Maria I; Jatoi, Aminah; Remtema, Megan S; Tata, Beba S; Breitkopf, Carmen Radecki

2017-01-01

Individuals with brain cancer face many challenges, including threats to cognition, personality, and sensory and motor functioning. These can alter one's sense of identity and result in despair. Chaplain-led spiritual interviews were conducted with 19 patients with brain cancer as part of a larger spiritual legacy intervention called "Hear My Voice." The majority was female (58%), married (68%) and had aggressive/advanced tumors (63%). Participants were 22-68 years of age and expressed the following religious affiliations: Protestant (42%), Catholic (21%), Muslim (5%), and none (32%). Framework analysis was applied to reduce and understand the interview data. Primary codes were relationships with: God or the spiritual, others, and self. Brain cancer was reported to deepen and enrich patients' commitment to these relationships. Struggle and grief were also revealed. Results suggest the continued vitality, growth and generativity of these participants and provide insight for chaplains and others on the medical team.

Immunotherapy for the Treatment of Glioblastoma

PubMed Central

Thomas, Alissa A.; Ernstoff, Marc S.; Fadul, Camilo E.

2012-01-01

Glioblastoma, the most aggressive primary brain tumor, thrives in a microenvironment of relative immunosuppression within the relatively immune-privileged central nervous system. Despite treatments with surgery, radiation therapy, and chemotherapy, prognosis remains poor. The recent success of immunotherapy in the treatment of other cancers has renewed interest in vaccine therapy for the treatment of gliomas. In this article, we outline various immunotherapeutic strategies, review recent clinical trials data, and discuss the future of vaccine therapy for glioblastoma. PMID:22290259

Molecular Heterogeneity in Glioblastoma: Potential Clinical Implications

PubMed Central

Parker, Nicole Renee; Khong, Peter; Parkinson, Jonathon Fergus; Howell, Viive Maarika; Wheeler, Helen Ruth

2015-01-01

Glioblastomas, (grade 4 astrocytomas), are aggressive primary brain tumors characterized by histopathological heterogeneity. High-resolution sequencing technologies have shown that these tumors also feature significant inter-tumoral molecular heterogeneity. Molecular subtyping of these tumors has revealed several predictive and prognostic biomarkers. However, intra-tumoral heterogeneity may undermine the use of single biopsy analysis for determining tumor genotype and has implications for potential targeted therapies. The clinical relevance and theories of tumoral molecular heterogeneity in glioblastoma are discussed. PMID:25785247

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding

PubMed Central

Mc Mahon, Brenda; MacDonald Fisher, Patrick; Jensen, Peter Steen; Svarer, Claus; Moos Knudsen, Gitte

2016-01-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [11C]SB207145 for quantification of brain 5-HT4R binding. The Buss–Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. PMID:26772668

Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury

PubMed Central

Pardini, M.; Krueger, F.; Hodgkinson, C.; Raymont, V.; Ferrier, C.; Goldman, D.; Strenziok, M.; Guida, S.

2011-01-01

Objective: This study investigates the interaction between brain lesion location and monoamine oxidase A (MAO-A) in the genesis of aggression in patients with penetrating traumatic brain injury (PTBI). Methods: We enrolled 155 patients with PTBI and 42 controls drawn from the Vietnam Head Injury Study registry. Patients with PTBI were divided according to lesion localization (prefrontal cortex [PFC] vs non-PFC) and were genotyped for the MAO-A polymorphism linked to low and high transcriptional activity. Aggression was assessed with the aggression/agitation subscale of the Neuropsychiatric Inventory (NPI-a). Results: Patients with the highest levels of aggression preferentially presented lesions in PFC territories. A significant interaction between MAO-A transcriptional activity and lesion localization on aggression was revealed. In the control group, carriers of the low-activity allele demonstrated higher aggression than high-activity allele carriers. In the PFC lesion group, no significant differences in aggression were observed between carriers of the 2 MAO-A alleles, whereas in the non-PFC lesion group higher aggression was observed in the high-activity allele than in the low-activity allele carriers. Higher NPI-a scores were linked to more severe childhood psychological traumatic experiences and posttraumatic stress disorder symptomatology in the control and non-PFC lesion groups but not in the PFC lesion group. Conclusions: Lesion location and MAO-A genotype interact in mediating aggression in PTBI. Importantly, PFC integrity is necessary for modulation of aggressive behaviors by genetic susceptibilities and traumatic experiences. Potentially, lesion localization and MAO-A genotype data could be combined to develop risk-stratification algorithms and individualized treatments for aggression in PTBI. PMID:21422455

Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats.

PubMed

Calcagnoli, Federica; Meyer, Neele; de Boer, Sietse F; Althaus, Monika; Koolhaas, Jaap M

2014-04-01

Oxytocin (OXT) has been implicated in the regulation of social behaviors, including intermale offensive aggression. Recently, we showed that acute enhancement of brain OXT levels markedly suppressed offensive aggression and increased social exploration in resident rats confronted with an intruder in their home territory. Moreover, a different responsivity to the exogenous OXTergic manipulation was observed among individuals based on their baseline aggression. In this study we aimed at evaluating the behavioral response to chronically enhancing or attenuating central OXT levels, and at scrutinizing whether the trait-aggression moderates the treatment-induced behavioral changes. To this end, resident male wild-type Groningen rats were continuously (via osmotic minipumps) intracerebroventricularly infused with synthetic OXT or a selective OXT receptor (OXTR) antagonist for 7days. Changes in behavior were assessed performing a resident-intruder test before and at the end of the treatment period, as well as after 7days of withdrawal. Chronic infusion of OXT was found to selectively suppress aggression and enhance social exploration. Chronic blockage of OXTRs instead increased introductory aggressive behavior (i.e. lateral threat), yet without affecting the total duration of the aggression. The magnitude of the anti-aggressive changes correlated positively with the level of baseline aggression. Interestingly, OXT-induced behavioral changes persisted 7days after cessation of the treatment. In conclusion, these findings provide further evidence that enhanced functional activity of the central OXTergic system decreases social offensive aggression while it increases social explorative behavior. The data also indicate that chronically enhancing brain OXT levels may cause enduring anti-aggressive and pro-social explorative behavioral effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Honey bee aggression supports a link between gene regulation and behavioral evolution.

PubMed

Alaux, Cédric; Sinha, Saurabh; Hasadsri, Linda; Hunt, Greg J; Guzmán-Novoa, Ernesto; DeGrandi-Hoffman, Gloria; Uribe-Rubio, José Luis; Southey, Bruce R; Rodriguez-Zas, Sandra; Robinson, Gene E

2009-09-08

A prominent theory states that animal phenotypes arise by evolutionary changes in gene regulation, but the extent to which this theory holds true for behavioral evolution is not known. Because "nature and nurture" are now understood to involve hereditary and environmental influences on gene expression, we studied whether environmental influences on a behavioral phenotype, i.e., aggression, could have evolved into inherited differences via changes in gene expression. Here, with microarray analysis of honey bees, we show that aggression-related genes with inherited patterns of brain expression are also environmentally regulated. There were expression differences in the brain for hundreds of genes between the highly aggressive Africanized honey bee compared with European honey bee (EHB) subspecies. Similar results were obtained for EHB in response to exposure to alarm pheromone (which provokes aggression) and when comparing old and young bees (aggressive tendencies increase with age). There was significant overlap of the gene lists generated from these three microarray experiments. Moreover, there was statistical enrichment of several of the same cis regulatory motifs in promoters of genes on all three gene lists. Aggression shows a remarkably robust brain molecular signature regardless of whether it occurs because of inherited, age-related, or environmental (social) factors. It appears that one element in the evolution of different degrees of aggressive behavior in honey bees involved changes in regulation of genes that mediate the response to alarm pheromone.

Antisecretory Factor-mediated Inhibition of Cell Volume Dynamics Produces Anti-tumor Activity in Glioblastoma. | Office of Cancer Genomics

Cancer.gov

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma multiforme (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays anti-secretory effects in animals and patients.

The Relations of Self-Reported Aggression to Alexithymia, Depression, and Anxiety After Traumatic Brain Injury.

PubMed

Neumann, Dawn; Malec, James F; Hammond, Flora M

To compare self-reported aggression in people with and without traumatic brain injury (TBI) and examine the relations of aggression to alexithymia (poor emotional insight), depression, and anxiety. Rehabilitation hospital. Forty-six adults with moderate to severe TBI who were at least 3 months postinjury; 49 healthy controls (HCs); groups were frequency matched for age and gender. Cross-sectional study using a quasi-experimental design. Aggression (Buss-Perry Aggression Questionnaire); alexithymia (Toronto Alexithymia Scale-20); depression (Patient Health Questionnaire-9); and trait anxiety (State-Trait Anxiety Inventory). Participants with TBI had significantly higher aggression scores than HCs. For participants with TBI, 34.2% of the adjusted variance of aggression was significantly explained by alexithymia, depression, and anxiety; alexithymia accounted for the largest unique portion of the variance in this model (16.2%). Alexithymia, depression, and anxiety explained 46% of the adjusted variance of aggression in HCs; in contrast to participants with TBI, depression was the largest unique contributor to aggression (15.9%). This was the first empirical study showing that poor emotional insight (alexithymia) significantly contributes to aggression after TBI. This relation, and the potential clinical implications it may have for the treatment of aggression, warrants further investigation.

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

PubMed

da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

2016-04-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

The effect of observers on behavior and the brain during aggressive encounters

PubMed Central

Desjardins, Julie K.; Becker, Lisa; Fernald, Russell D.

2015-01-01

What effect does an audience have on an animal’s behavior and where is this influence registered in the brain? To answer these questions, we analyzed male cichlid fish fighting in the presence of audiences of various compositions and measured expression of immediate early genes in the brain as a proxy for neural activity. We hypothesized their behavior would change depending on who was watching them. We measured behavioral responses from both the “watchers” and the “watched” during aggressive encounters and found that males fighting in the presence of an audience were more aggressive than males fighting without an audience. Depending on the nature of the audience, immediate early gene expression in key brain nuclei was differentially influenced. Both when an audience of larger males watched fighting males, and when they were watching larger males fighting, nuclei in the brain considered homologous with mammalian nuclei known to be associated with anxiety showed increased activity. When males were in the presence of any audience or when males saw any other males fighting, nuclei in the brain known to be involved in reproduction and aggression were differentially activated relative to control animals. In all cases, there was a close relationship between patterns of brain gene expression between fighters and observers. This suggests that the network of brain regions known as the social behavior network, common across vertebrates, are activated not only in association with the expression of social behavior but also by the reception of social information. PMID:26097004

[Lorenz was right, or does aggressive energy accumulate?].

PubMed

Kudriavtseva, N N

2004-06-01

Evidence supporting the fact that inherited mechanisms of regulation of aggressive behavior as a result of a repeated experience of aggression ending in victories are transformed into pathological mechanisms based on accumulation of neurochemical shifts in the brain, enhancing aggressiveness, and forming aggressive motivation in aggressive winners. This confirms the concept by Lorenz on the existence of a mechanism (but not instinct) of a spontaneous accumulation of aggressive energy that needs a discharge and formation of permanent attraction to manifestation of aggression.

Neural mediators of the intergenerational transmission of family aggression

PubMed Central

Saxbe, Darby; Del Piero, Larissa Borofsky; Immordino-Yang, Mary Helen; Kaplan, Jonas Todd; Margolin, Gayla

2015-01-01

Youth exposed to family aggression may become more aggressive themselves, but the mechanisms of intergenerational transmission are understudied. In a longitudinal study, we found that adolescents’ reduced neural activation when rating their parents’ emotions, assessed via magnetic resonance imaging, mediated the association between parents’ past aggression and adolescents’ subsequent aggressive behavior toward parents. A subsample of 21 youth, drawn from the larger study, underwent magnetic resonance imaging scanning proximate to the second of two assessments of the family environment. At Time 1 (when youth were on average 15.51 years old) we measured parents’ aggressive marital and parent–child conflict behaviors, and at Time 2 (≈2 years later), we measured youth aggression directed toward parents. Youth from more aggressive families showed relatively less activation to parent stimuli in brain areas associated with salience and socioemotional processing, including the insula and limbic structures. Activation patterns in these same areas were also associated with youths’ subsequent parent-directed aggression. The association between parents’ aggression and youths’ subsequent parent-directed aggression was statistically mediated by signal change coefficients in the insula, right amygdala, thalamus, and putamen. These signal change coefficients were also positively associated with scores on a mentalizing measure. Hypoarousal of the emotional brain to family stimuli may support the intergenerational transmission of family aggression. PMID:26073067

Brain serotonin transporter density and aggression in abstinent methamphetamine abusers.

PubMed

Sekine, Yoshimoto; Ouchi, Yasuomi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Futatsubashi, Masami; Okada, Hiroyuki; Minabe, Yoshio; Suzuki, Katsuaki; Iwata, Yasuhide; Tsuchiya, Kenji J; Tsukada, Hideo; Iyo, Masaomi; Mori, Norio

2006-01-01

In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. Case-control analysis. A hospital research center. Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([(11)C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [(11)C](+)McN-5652 distribution volume. Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

Aggression in Women: Behavior, Brain and Hormones

PubMed Central

Denson, Thomas F.; O’Dean, Siobhan M.; Blake, Khandis R.; Beames, Joanne R.

2018-01-01

We review the literature on aggression in women with an emphasis on laboratory experimentation and hormonal and brain mechanisms. Women tend to engage in more indirect forms of aggression (e.g., spreading rumors) than other types of aggression. In laboratory studies, women are less aggressive than men, but provocation attenuates this difference. In the real world, women are just as likely to aggress against their romantic partner as men are, but men cause more serious physical and psychological harm. A very small minority of women are also sexually violent. Women are susceptible to alcohol-related aggression, but this type of aggression may be limited to women high in trait aggression. Fear of being harmed is a robust inhibitor of direct aggression in women. There are too few studies and most are underpowered to detect unique neural mechanisms associated with aggression in women. Testosterone shows the same small, positive relationship with aggression in women as in men. The role of cortisol is unclear, although some evidence suggests that women who are high in testosterone and low in cortisol show heightened aggression. Under some circumstances, oxytocin may increase aggression by enhancing reactivity to provocation and simultaneously lowering perceptions of danger that normally inhibit many women from retaliating. There is some evidence that high levels of estradiol and progesterone are associated with low levels of aggression. We highlight that more gender-specific theory-driven hypothesis testing is needed with larger samples of women and aggression paradigms relevant to women. PMID:29770113

Aggression in Women: Behavior, Brain and Hormones.

PubMed

Denson, Thomas F; O'Dean, Siobhan M; Blake, Khandis R; Beames, Joanne R

2018-01-01

We review the literature on aggression in women with an emphasis on laboratory experimentation and hormonal and brain mechanisms. Women tend to engage in more indirect forms of aggression (e.g., spreading rumors) than other types of aggression. In laboratory studies, women are less aggressive than men, but provocation attenuates this difference. In the real world, women are just as likely to aggress against their romantic partner as men are, but men cause more serious physical and psychological harm. A very small minority of women are also sexually violent. Women are susceptible to alcohol-related aggression, but this type of aggression may be limited to women high in trait aggression. Fear of being harmed is a robust inhibitor of direct aggression in women. There are too few studies and most are underpowered to detect unique neural mechanisms associated with aggression in women. Testosterone shows the same small, positive relationship with aggression in women as in men. The role of cortisol is unclear, although some evidence suggests that women who are high in testosterone and low in cortisol show heightened aggression. Under some circumstances, oxytocin may increase aggression by enhancing reactivity to provocation and simultaneously lowering perceptions of danger that normally inhibit many women from retaliating. There is some evidence that high levels of estradiol and progesterone are associated with low levels of aggression. We highlight that more gender-specific theory-driven hypothesis testing is needed with larger samples of women and aggression paradigms relevant to women.

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour.

PubMed

Lesch, Klaus-Peter; Araragi, Naozumi; Waider, Jonas; van den Hove, Daniel; Gutknecht, Lise

2012-09-05

Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.

Structural Magnetic Resonance Imaging Correlates of Aggression in Psychosis: A Systematic Review and Effect Size Analysis.

PubMed

Widmayer, Sonja; Sowislo, Julia F; Jungfer, Hermann A; Borgwardt, Stefan; Lang, Undine E; Stieglitz, Rolf D; Huber, Christian G

2018-01-01

Background: Aggression in psychoses is of high clinical importance, and volumetric MRI techniques have been used to explore its structural brain correlates. Methods: We conducted a systematic review searching EMBASE, ScienceDirect, and PsycINFO through September 2017 using thesauri representing aggression, psychosis, and brain imaging. We calculated effect sizes for each study and mean Hedge's g for whole brain (WB) volume. Methodological quality was established using the PRISMA checklist (PROSPERO: CRD42014014461). Results: Our sample consisted of 12 studies with 470 patients and 155 healthy controls (HC). After subtracting subjects due to cohort overlaps, 314 patients and 96 HC remained. Qualitative analyses showed lower volumes of WB, prefrontal regions, temporal lobe, hippocampus, thalamus and cerebellum, and higher volumes of lateral ventricles, amygdala, and putamen in violent vs. non-violent people with schizophrenia. In quantitative analyses, violent persons with schizophrenia exhibited a significantly lower WB volume than HC ( p = 0.004), and also lower than non-violent persons with schizophrenia ( p = 0.007). Conclusions: We reviewed evidence for differences in brain volume correlates of aggression in persons with schizophrenia. Our results point toward a reduced whole brain volume in violent as opposed to non-violent persons with schizophrenia. However, considerable sample overlap in the literature, lack of reporting of potential confounding variables, and missing research on affective psychoses limit our explanatory power. To permit stronger conclusions, further studies evaluating structural correlates of aggression in psychotic disorders are needed.

Relational Aggression: The Voices of Primary School Learners

ERIC Educational Resources Information Center

Botha, Johan

2014-01-01

The aim of this research was to explore and describe primary school learners' experiences of relational aggression at school. This was done within a qualitative research design with a phenomenological approach. In order to give a voice to primary school learners' lived experiences of relational aggression, 25 individual interviews were conducted…

Glioblastoma: new therapeutic strategies to address cellular and genomic complexity

PubMed Central

Cai, Xue; Sughrue, Michael E.

2018-01-01

Glioblastoma (GBM) is the most invasive and devastating primary brain tumor with a median overall survival rate about 18 months with aggressive multimodality therapy. Its unique characteristics of heterogeneity, invasion, clonal populations maintaining stem cell-like cells and recurrence, have limited responses to a variety of therapeutic approaches, and have made GBM the most difficult brain cancer to treat. A great effort and progress has been made to reveal promising molecular mechanisms to target therapeutically. Especially with the emerging of new technologies, the mechanisms underlying the pathology of GBM are becoming more clear. The purpose of this review is to summarize the current knowledge of molecular mechanisms of GBM and highlight the novel strategies and concepts for the treatment of GBM. PMID:29507709

Brain Tumor’s Radioresistance: The Neighborhood Helps | Center for Cancer Research

Cancer.gov

Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. The primary treatment for GBM is radiation therapy. Unfortunately, while some patients initially respond, the vast majority of GBM patients fail radiotherapy, and the tumor usually grows back within two years. To gain a better understanding of the biological basis for GBM resistance to radiation, researchers initially studied GBM cell lines in vitro. In recent years, the focus has been on so-called tumor stem-like cells (TSCs), which are thought to be responsible for driving and maintaining tumor growth. To the researchers’ surprise, TSCs grown in vitro did not have the same ability to resist radiation as TSCs in the GBM tumors.

Prefrontal brain asymmetry and aggression in imprisoned violent offenders.

PubMed

Keune, Philipp M; van der Heiden, Linda; Várkuti, Bálint; Konicar, Lilian; Veit, Ralf; Birbaumer, Niels

2012-05-02

Anterior brain asymmetry, assessed through the alpha and beta band in resting-state electroencephalogram (EEG) is associated with approach-related behavioral dispositions, particularly with aggression in the general population. To date, the association between frontal asymmetry and aggression has not been examined in highly aggressive groups. We examined the topographic characteristics of alpha and beta activity, the relation of both asymmetry metrics to trait aggression, and whether alpha asymmetry was extreme in anterior regions according to clinical standards in a group of imprisoned violent offenders. As expected, these individuals were characterized by stronger right than left-hemispheric alpha activity, which was putatively extreme in anterior regions in one third of the cases. We also report that in line with observations made in the general population, aggression was associated with stronger right-frontal alpha activity in these violent individuals. This suggests that frontal alpha asymmetry, as a correlate of trait aggression, might be utilizable as an outcome measure in studies which assess the effects of anti-aggressiveness training in violent offenders. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Gibbon Aggression During Introductions: An International Survey.

PubMed

Harl, Heather; Stevens, Lisa; Margulis, Susan W; Petersen, Jay

2016-01-01

Little is known regarding the prevalence of aggression seen during introductions of captive gibbons (Hylobatidae). In this study, an online survey was developed to quantify and collect contextual details regarding the frequency and types of aggression seen during introductions of captive gibbons (Hylobatidae). Nineteen percent of institutions (17 institutions) reported observing aggression, and 6 of these institutions recorded multiple instances of aggression, though a vast majority of these cases resulted in mild injuries or none at all. The female was the primary aggressor in 23% of cases, the male was the primary aggressor in 58% of cases, and both were the primary aggressor in 1 case. Although these aggressive interactions were often not associated with a known cause, 27% of cases were associated with food displacement. In most cases, management changes, including trying new pairings, greatly reduced situational aggression, suggesting that individual personalities may play a factor in aggression. These data begin to explain the extent of aggression observed in captive gibbons; future studies will address possible correlations with aggression and introduction techniques.

The effect of observers on behavior and the brain during aggressive encounters.

PubMed

Desjardins, Julie K; Becker, Lisa; Fernald, Russell D

2015-10-01

What effect does an audience have on an animal's behavior and where is this influence registered in the brain? To answer these questions, we analyzed male cichlid fish fighting in the presence of audiences of various compositions and measured expression of immediate early genes in the brain as a proxy for neural activity. We hypothesized their behavior would change depending on who was watching them. We measured behavioral responses from both the "watchers" and the "watched" during aggressive encounters and found that males fighting in the presence of an audience were more aggressive than males fighting without an audience. Depending on the nature of the audience, immediate early gene expression in key brain nuclei was differentially influenced. Both when an audience of larger males watched fighting males, and when they were watching larger males fighting, nuclei in the brain considered homologous with mammalian nuclei known to be associated with anxiety showed increased activity. When males were in the presence of any audience or when males saw any other males fighting, nuclei in the brain known to be involved in reproduction and aggression were differentially activated relative to control animals. In all cases, there was a close relationship between patterns of brain gene expression between fighters and observers. This suggests that the network of brain regions known as the social behavior network, common across vertebrates, are activated not only in association with the expression of social behavior but also by the reception of social information. Copyright © 2015 Elsevier B.V. All rights reserved.

Disruption of behavior and brain metabolism in artificially reared rats.

PubMed

Aguirre-Benítez, Elsa L; Porras, Mercedes G; Parra, Leticia; González-Ríos, Jacquelina; Garduño-Torres, Dafne F; Albores-García, Damaris; Avendaño, Arturo; Ávila-Rodríguez, Miguel A; Melo, Angel I; Jiménez-Estrada, Ismael; Mendoza-Garrido, Ma Eugenia; Toriz, César; Diaz, Daniel; Ibarra-Coronado, Elizabeth; Mendoza-Ángeles, Karina; Hernández-Falcón, Jesús

2017-12-01

Early adverse life stress has been associated to behavioral disorders that can manifest as inappropriate or aggressive responses to social challenges. In this study, we analyzed the effects of artificial rearing on the open field and burial behavioral tests and on GFAP, c-Fos immunoreactivity, and glucose metabolism measured in anxiety-related brain areas. Artificial rearing of male rats was performed by supplying artificial milk through a cheek cannula and tactile stimulation, mimicking the mother's licking to rat pups from the fourth postnatal day until weaning. Tactile stimulation was applied twice a day, at morning and at night, by means of a camel brush on the rat anogenital area. As compared to mother reared rats, greater aggressiveness, and boldness, stereotyped behavior (burial conduct) was observed in artificially reared rats which occurred in parallel to a reduction of GFAP immunoreactivity in somatosensory cortex, c-Fos immunoreactivity at the amygdala and primary somatosensory cortex, and lower metabolism in amygdala (as measured by 2-deoxi-2-[ 18 fluoro]-d-glucose uptake, assessed by microPET imaging). These results could suggest that tactile and/or chemical stimuli from the mother and littermates carry relevant information for the proper development of the central nervous system, particularly in brain areas involved with emotions and social relationships of the rat. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1413-1429, 2017. © 2017 Wiley Periodicals, Inc.

The Process and Regulatory Components of Inflammation in Brain Oncogenesis

PubMed Central

Mostofa, A.G.M.; Punganuru, Surendra R.; Madala, Hanumantha Rao; Al-Obaide, Mohammad; Srivenugopal, Kalkunte S.

2017-01-01

Central nervous system tumors comprising the primary cancers and brain metastases remain the most lethal neoplasms and challenging to treat. Substantial evidence points to a paramount role for inflammation in the pathology leading to gliomagenesis, malignant progression and tumor aggressiveness in the central nervous system (CNS) microenvironment. This review summarizes the salient contributions of oxidative stress, interleukins, tumor necrosis factor-α(TNF-α), cyclooxygenases, and transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and the associated cross-talks to the inflammatory signaling in CNS cancers. The roles of reactive astrocytes, tumor associated microglia and macrophages, metabolic alterations, microsatellite instability, O6-methylguanine DNA methyltransferase (MGMT) DNA repair and epigenetic alterations mediated by the isocitrate dehydrogenase 1 (IDH1) mutations have been discussed. The inflammatory pathways with relevance to the brain cancer treatments have been highlighted. PMID:28346397

A Testosterone-Related Structural Brain Phenotype Predicts Aggressive Behavior From Childhood to Adulthood

PubMed Central

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N.; Hudziak, James J; Ducharme, Simon

2015-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6 to 22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. PMID:26431805

A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood.

PubMed

Nguyen, Tuong-Vi; McCracken, James T; Albaugh, Matthew D; Botteron, Kelly N; Hudziak, James J; Ducharme, Simon

2016-01-01

Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood. Copyright © 2015 Elsevier Ltd. All rights reserved.

Observed Measures of Negative Parenting Predict Brain Development during Adolescence.

PubMed

Whittle, Sarah; Vijayakumar, Nandita; Dennison, Meg; Schwartz, Orli; Simmons, Julian G; Sheeber, Lisa; Allen, Nicholas B

2016-01-01

Limited attention has been directed toward the influence of non-abusive parenting behaviour on brain structure in adolescents. It has been suggested that environmental influences during this period are likely to impact the way that the brain develops over time. The aim of this study was to investigate the association between aggressive and positive parenting behaviors on brain development from early to late adolescence, and in turn, psychological and academic functioning during late adolescence, using a multi-wave longitudinal design. Three hundred and sixty seven magnetic resonance imaging (MRI) scans were obtained over three time points from 166 adolescents (11-20 years). At the first time point, observed measures of maternal aggressive and positive behaviors were obtained. At the final time point, measures of psychological and academic functioning were obtained. Results indicated that a higher frequency of maternal aggressive behavior was associated with alterations in the development of right superior frontal and lateral parietal cortical thickness, and of nucleus accumbens volume, in males. Development of the superior frontal cortex in males mediated the relationship between maternal aggressive behaviour and measures of late adolescent functioning. We suggest that our results support an association between negative parenting and adolescent functioning, which may be mediated by immature or delayed brain maturation.

Observed Measures of Negative Parenting Predict Brain Development during Adolescence

PubMed Central

Whittle, Sarah; Vijayakumar, Nandita; Dennison, Meg; Schwartz, Orli; Simmons, Julian G.; Sheeber, Lisa; Allen, Nicholas B.

2016-01-01

Limited attention has been directed toward the influence of non-abusive parenting behaviour on brain structure in adolescents. It has been suggested that environmental influences during this period are likely to impact the way that the brain develops over time. The aim of this study was to investigate the association between aggressive and positive parenting behaviors on brain development from early to late adolescence, and in turn, psychological and academic functioning during late adolescence, using a multi-wave longitudinal design. Three hundred and sixty seven magnetic resonance imaging (MRI) scans were obtained over three time points from 166 adolescents (11–20 years). At the first time point, observed measures of maternal aggressive and positive behaviors were obtained. At the final time point, measures of psychological and academic functioning were obtained. Results indicated that a higher frequency of maternal aggressive behavior was associated with alterations in the development of right superior frontal and lateral parietal cortical thickness, and of nucleus accumbens volume, in males. Development of the superior frontal cortex in males mediated the relationship between maternal aggressive behaviour and measures of late adolescent functioning. We suggest that our results support an association between negative parenting and adolescent functioning, which may be mediated by immature or delayed brain maturation. PMID:26824348

TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

PubMed Central

Brabetz, Sebastian; Schmidt, Christin; Groebner, Susanne N.; Mack, Norman; Seker-Cin, Huriye; Jones, David T.W.; Chavez, Lukas; Milde, Till; Witt, Olaf; Leary, Sarah E.; Li, Xiao-Nan; Wechsler-Reya, Robert J.; Olson, James M.; Pfister, Stefan M.; Kool, Marcel

2017-01-01

Abstract Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies for children with malignant brain tumors.

Serotonin (5-HT) augmentation reduces provoked aggression associated with primary psychopathy traits.

PubMed

Fanning, Jennifer R; Berman, Mitchell E; Guillot, Casey R; Marsic, Angelika; McCloskey, Michael S

2014-06-01

Psychopathy has long been associated with aggressive behavior; however, the neurochemical underpinnings of this relationship are poorly understood. Serotonin (5-HT) neurotransmitter system abnormalities have been associated with provoked aggression in general. In addition, 5-HT dysregulation has been linked to empathy, a trait that is lacking in individuals who score high on primary psychopathy. The purpose of this study was to determine if 5-HT modulates the relationship between psychopathic traits and aggression. Participants (N = 47) completed a self-report measure of psychopathy and were then administered either 40 mg paroxetine (acutely augmenting 5-HT) or placebo. Aggression was assessed during a competitive reaction-time game in which electric shocks were exchanged with an increasingly provocative fictitious opponent. Results indicated that primary psychopathy (but not secondary psychopathy) was related to aggressive responding to provocation. Moreover, 5-HT augmentation attenuated this effect, supporting the notion that aggressive responding associated with primary psychopathic traits may be due in part to 5-HT dysregulation.

Long-Term Survival of a Patient with Brainstem and Recurrent Brain Metastasis from Stage IV Nonsmall Cell Lung Cancer Treated with Multiple Gamma Knife Radiosurgeries and Craniotomies: A Case Report and Review of the Literature

PubMed Central

Lamm, Andrew F.; Elaimy, Ameer L.; Mackay, Alexander R.; Fairbanks, Robert K.; Demakas, John J.; Cooke, Barton S.; Lee, Christopher M.; Taylor, Blake S.; Lamoreaux, Wayne T.

2012-01-01

The prognosis of patients diagnosed with stage IV nonsmall cell lung cancer that have brain and brainstem metastasis is very poor, with less than a third surviving a year past their initial date of diagnosis. We present the rare case of a 57-year-old man who is a long-term survivor of brainstem and recurrent brain metastasis, after aggressive treatment. He is now five and a half years out from diagnosis and continues to live a highly functional life without evidence of disease. Four separate Gamma Knife stereotactic radiosurgeries in conjunction with two craniotomies were utilized since his initial diagnosis to treat recurrent brain metastasis while chemoradiation therapy and thoracic surgery were used to treat his primary disease in the right upper lung. In his situation, Gamma Knife radiosurgery proved to be a valuable, safe, and effective tool for the treatment of multiply recurrent brain metastases within critical normal structures. PMID:23056973

Keys to successful organ procurement: An experience-based review of clinical practices at a high-performing health-care organization

PubMed Central

Wojda, Thomas R.; Stawicki, Stanislaw P.; Yandle, Kathy P.; Bleil, Maria; Axelband, Jennifer; Wilde-Onia, Rebecca; Thomas, Peter G.; Cipolla, James; Hoff, William S.; Shultz, Jill

2017-01-01

Organ procurement (OP) from donors after brain death and circulatory death represents the primary source of transplanted organs. Despite favorable laws and regulations, OP continues to face challenges for a number of reasons, including institutional, personal, and societal barriers. This focused review presents some of the key components of a successful OP program at a large, high-performing regional health network. This review focuses on effective team approaches, aggressive resuscitative strategies, optimal communication, family support, and community outreach efforts. PMID:28660162

Neural Correlates of Affect Processing and Aggression in Methamphetamine Dependence

PubMed Central

Payer, Doris E.; Lieberman, Matthew D.; London, Edythe D.

2012-01-01

Context Methamphetamine abuse is associated with high rates of aggression, but few studies have addressed the contributing neurobiological factors. Objective To quantify aggression, investigate function of the amygdala and prefrontal cortex, and assess relationships between brain function and behavior in methamphetamine-dependent individuals. Design In a case-control study, aggression and brain activation were compared between methamphetamine-dependent and control participants. Setting Participants were recruited from the general community to an academic research center. Participants Thirty-nine methamphetamine-dependent volunteers (16 women) who were abstinent for 7 to 10 days and 37 drug-free control volunteers (18 women) participated in the study; subsets completed self-report and behavioral measures. Functional magnetic resonance imaging (fMRI) was performed on 25 methamphetamine-dependent and 23 control participants. Main outcome measures We measured self-reported and perpetrated aggression, and self-reported alexithymia. Brain activation was assessed using fMRI during visual processing of facial affect (affect matching), and symbolic processing (affect labeling), the latter representing an incidental form of emotion regulation. Results Methamphetamine-dependent participants self-reported more aggression and alexithymia than control participants and escalated perpetrated aggression more following provocation. Alexithymia scores correlated with measures of aggression. During affect matching, fMRI showed no differences between groups in amygdala activation, but found lower activation in methamphetamine-dependent than control participants in bilateral ventral inferior frontal gyrus. During affect labeling, participants recruited dorsal inferior frontal gyrus and exhibited decreased amygdala activity, consistent with successful emotion regulation; there was no group difference in this effect. The magnitude of decrease in amygdala activity during affect labeling correlated inversely with self-reported aggression in control participants, and perpetrated aggression in all participants. Ventral inferior frontal gyrus activation correlated inversely with alexithymia in control participants. Conclusions Contrary to the hypotheses, methamphetamine-dependent individuals may successfully regulate emotions through incidental means (affect labeling). Instead, low ventral inferior frontal gyrus activity may contribute to heightened aggression by limiting emotional insight. PMID:21041607

Neuropharmacology of brain-stimulation-evoked aggression.

PubMed

Siegel, A; Roeling, T A; Gregg, T R; Kruk, M R

1999-01-01

Evidence is reviewed concerning the brain areas and neurotransmitters involved in aggressive behavior in the cat and rodent. In the cat, two distinct neural circuits involving the hypothalamus and PAG subserve two different kinds of aggression: defensive rage and predatory (quiet-biting) attack. The roles played by the neurotransmitters serotonin, GABA, glutamate, opioids, cholecystokinin, substance P, norepinephrine, dopamine, and acetylcholine in the modulation and expression of aggression are discussed. For the rat, a single area, largely coincident with the intermediate hypothalamic area, is crucial for the expression of attack; variations in the rat attack response in natural settings are due largely to environmental variables. Experimental evidence emphasizing the roles of serotonin and GABA in modulating hypothalamically evoked attack in the rat is discussed. It is concluded that significant progress has been made concerning our knowledge of the circuitry underlying the neural basis of aggression. Although new and important insights have been made concerning neurotransmitter regulation of aggressive behavior, wide gaps in our knowledge remain.

In the eye of the beholder: individual differences in reward-drive modulate early frontocentral ERPs to angry faces.

PubMed

Bediou, Benoit; Eimer, Martin; d'Amato, Thierry; Hauk, Olaf; Calder, Andrew J

2009-02-01

Individual differences in reward-drive have been associated with increased attention toward facial signals of aggression, heightened experience of anger and vulnerability to display aggressive behaviour. Recent fMRI research suggests that these effects rely on reduced ventromedial prefrontal (and increased amygdala) response to aggressive facial displays compared with neutral and sad expressions in subjects scoring high on reward-drive. However, nothing is known about the timing of this modulation. Using event-related potentials (ERPs), we provide the first evidence that greater proneness to display hostile and aggressive behaviour (measured by high scores on the reward-drive) is associated with a reduced midline frontocentral response to aggressive faces within 200-300ms. In addition to confirming a particular interaction between anger processing and aggression related personality traits in ventromedial prefrontal brain regions, our study brings a first indication of when their interaction occurs in the brain, strengthening results from previous classical as well as functional connectivity fMRI studies.

Brain arginine vasotocin and isotocin in breeding female three-spined sticklebacks (Gasterosteus aculeatus): the presence of male and egg deposition.

PubMed

Kulczykowska, Ewa; Kleszczyńska, Agnieszka

2014-08-01

Arginine vasotocin (AVT) and isotocin (IT) are fish hypothalamic nonapeptides involved in numerous social and reproductive behaviors. Vasotocinergic and isotocinergic fibers project to different brain areas where peptides act as neurotransmitters and/or neuromodulators. In this study, we measured whole brain levels of bioactive AVT and IT in breeding females of three-spined stickleback (Gasterosteus aculeatus) when they were kept with: (i) courting nest-owners, (ii) courting males that did not build the nest, (iii) non-courting males, and (iv) alone. Only some of the females kept with courting nest-owners deposited eggs. The highest and similar brain AVT levels were in those of females that did not deposit eggs, regardless of whether they were kept with non-courting or courting male, having the nest or not. The highest IT levels were in females that did not deposit eggs but only in those kept with courting male. We suggest that production of AVT in females' brain is stimulated by the presence of male in close proximity, irrespective of whether or not it displays courting behavior, but that of IT is stimulated by male courtship proxies. Moreover, presence of courting or non-courting male that stimulate IT or/and AVT producing neurones may be decisive for final oocyte maturation or egg deposition, because brain levels of both nonapeptides decrease after egg deposition. Similar AVT levels in brains of aggressive and non-aggressive individuals and lack of correlation between brain IT levels and aggressive behavior of females suggest that the nonapeptides are not related to females aggressiveness in three-spined sticklebacks. Copyright © 2014. Published by Elsevier Inc.

Stress-induced changes in brain serotonergic activity, plasma cortisol and aggressive behavior in Arctic charr (Salvelinus alpinus) is counteracted by L-DOPA.

PubMed

Höglund, E; Kolm, N; Winberg, S

2001-10-01

Arctic charr (Salvelinus alpinus) were tested for aggressive behavior using intruder tests, before and after 2 days of dyadic social interaction. Following social interaction, half of the dominant and half of the subordinate fish were given L-DOPA (10 mg/kg, orally), whereas the remaining dominant and subordinate fish were given vehicle. One hour following drug treatment, the fish were tested for aggressive behavior again in a third and final intruder test, after which blood plasma and brain tissue were sampled for analysis of plasma cortisol concentrations and brain levels of monoamines and monoamine metabolites. Subordinate fish showed a reduction in the number of attacks launched against the intruder, as well as an increase in attack latency, as compared to prior to dyadic social interactions. Social subordination also resulted in an elevation of brain serotonergic activity. Fish receiving L-DOPA prior to the final intruder test showed shorter attack latency than vehicle controls. Drug treatment was a stressful experience and vehicle controls showed elevated plasma cortisol levels and longer attack latency as compared to before treatment. L-DOPA-treated fish showed lower plasma levels of cortisol and lower serotonergic activity in certain brain areas than vehicle controls. These results suggest that L-DOPA counteracts the stress-induced inhibition of aggressive behavior, and at the same time inhibits stress-induced effects on brain serotonergic activity and plasma cortisol concentrations.

Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

PubMed Central

Cases, Olivier; Grimsby, Joseph; Gaspar, Patricia; Chen, Kevin; Pournin, Sandrine; Müller, Ulrike; Aguet, Michel; Babinet, Charles; Shih, Jean Chen; De Maeyer, Edward

2010-01-01

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males. PMID:7792602

Psychopathy and instrumental aggression: Evolutionary, neurobiological, and legal perspectives.

PubMed

Glenn, Andrea L; Raine, Adrian

2009-01-01

In the study of aggression, psychopathy represents a disorder that is of particular interest because it often involves aggression which is premeditated, emotionless, and instrumental in nature; this is especially true for more serious types of offenses. Such instrumental aggression is aimed at achieving a goal (e.g., to obtain resources such as money, or to gain status). Unlike the primarily reactive aggression observed in other disorders, psychopaths appear to engage in aggressive acts for the purpose of benefiting themselves. This is especially interesting in light of arguments that psychopathy may represent an alternative life-history strategy that is evolutionarily adaptive; behaviors such as aggression, risk-taking, manipulation, and promiscuous sexual behavior observed in psychopathy may be means by which psychopaths gain advantage over others. Recent neurobiological research supports the idea that abnormalities in brain regions key to emotion and morality may allow psychopaths to pursue such a strategy-psychopaths may not experience the social emotions such as empathy, guilt, and remorse that typically discourage instrumentally aggressive acts, and may even experience pleasure when committing these acts. Findings from brain imaging studies of psychopaths may have important implications for the law.

NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression

PubMed Central

Bortolato, Marco; Godar, Sean C.; Melis, Miriam; Soggiu, Alessio; Roncada, Paola; Casu, Angelo; Flore, Giovanna; Chen, Kevin; Frau, Roberto; Urbani, Andrea; Castelli, M. Paola; Devoto, Paola; Shih, Jean C.

2012-01-01

Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25–6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality. PMID:22723698

NMDARs mediate the role of monoamine oxidase A in pathological aggression.

PubMed

Bortolato, Marco; Godar, Sean C; Melis, Miriam; Soggiu, Alessio; Roncada, Paola; Casu, Angelo; Flore, Giovanna; Chen, Kevin; Frau, Roberto; Urbani, Andrea; Castelli, M Paola; Devoto, Paola; Shih, Jean C

2012-06-20

Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality.

Neurogenetics of Aggressive Behavior – Studies in Rodents

PubMed Central

Takahashi, Aki; Miczek, Klaus A.

2014-01-01

Aggressive behavior is observed in many animal species, such as insects, fish, lizards, frogs, and most mammals including humans. This wide range of conservation underscores the importance of aggressive behavior in the animals’ survival and fitness, and the likely heritability of this behavior. Although typical patterns of aggressive behavior differ between species, there are several concordances in the neurobiology of aggression among rodents, primates, and humans. Studies with rodent models may eventually help us to understand the neurogenetic architecture of aggression in humans. However, it is important to recognize the difference between the ecological and ethological significance of aggressive behavior (species-typical aggression) and maladaptive violence (escalated aggression) when applying the findings of aggression research using animal models to human or veterinary medicine. Well-studied rodent models for aggressive behavior in the laboratory setting include the mouse (Mus musculus), rat (Rattus norvegicus), hamster (Mesocricetus auratus), and prairie vole (Microtus ochrogaster). The neural circuits of rodent aggression have been gradually elucidated by several techniques e.g. immunohistochemistry of immediate-early gene (c-Fos) expression, intracranial drug microinjection, in vivo microdialysis, and optogenetics techniques. Also, evidence accumulated from the analysis of gene-knockout mice shows the involvement of several genes in aggression. Here we review the brain circuits that have been implicated in aggression, such as the hypothalamus, prefrontal cortex (PFC), dorsal raphe nucleus (DRN), nucleus accumbens (NAc), and olfactory system. We then discuss the roles of glutamate and γ-aminobutyric acid (GABA), major inhibitory and excitatory amino acids in the brain, as well as their receptors, in controlling aggressive behavior, focusing mainly on recent findings. At the end of this chapter, we discuss how genes can be identified that underlie individual differences in aggression, using the so-called forward genetics approach. PMID:24318936

Violence-related content in video game may lead to functional connectivity changes in brain networks as revealed by fMRI-ICA in young men.

PubMed

Zvyagintsev, M; Klasen, M; Weber, R; Sarkheil, P; Esposito, F; Mathiak, K A; Schwenzer, M; Mathiak, K

2016-04-21

In violent video games, players engage in virtual aggressive behaviors. Exposure to virtual aggressive behavior induces short-term changes in players' behavior. In a previous study, a violence-related version of the racing game "Carmageddon TDR2000" increased aggressive affects, cognitions, and behaviors compared to its non-violence-related version. This study investigates the differences in neural network activity during the playing of both versions of the video game. Functional magnetic resonance imaging (fMRI) recorded ongoing brain activity of 18 young men playing the violence-related and the non-violence-related version of the video game Carmageddon. Image time series were decomposed into functional connectivity (FC) patterns using independent component analysis (ICA) and template-matching yielded a mapping to established functional brain networks. The FC patterns revealed a decrease in connectivity within 6 brain networks during the violence-related compared to the non-violence-related condition: three sensory-motor networks, the reward network, the default mode network (DMN), and the right-lateralized frontoparietal network. Playing violent racing games may change functional brain connectivity, in particular and even after controlling for event frequency, in the reward network and the DMN. These changes may underlie the short-term increase of aggressive affects, cognitions, and behaviors as observed after playing violent video games. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

PubMed

Kondaurova, Elena M; Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2016-09-01

Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested. Copyright © 2016 Elsevier B.V. All rights reserved.

Estrogenic encounters: How interactions between aromatase and the environment modulate aggression

PubMed Central

Trainor, Brian C.; Kyomen, Helen H.; Marler, Catherine A.

2007-01-01

Initial investigations into the mechanistic basis of aggression focused on the role of testosterone (T) and a variety of studies on non-human animals found that elevated T levels promote aggression. However, many correlational studies have not detected a significant association between aggression and peripheral T levels. One reason for this inconsistency may be due to differential metabolism of T within the brain, in particular, the conversion of T to estrogen by aromatase. Thus, differences in aromatase enzyme activity, estrogen receptor expression, and related cofactors may have important effects on how steroids affect aggressive behavior. Hormone manipulation studies conducted in a wide variety of species indicate that estrogens modulate aggression. There is also growing evidence that social experience has important effects on the production of estrogen within the brain, and some cases can not be explained by androgenic regulation of aromatase. Such changes in central aromatase activity may play an important role in determining how social experiences affect the probability of whether an individual engages in aggressive behavior. Although studies have been conducted in many taxa, there has been relatively little integration between literatures examining aggression in different species. In this review, we compare and contrast studies examining aggression in birds, mammals, and humans. By taking an integrative approach to our review, we consider mechanisms that could explain species differences in how estrogen modulates aggression. PMID:16376420

Effects of problem-solving interventions on aggressive behaviours among primary school pupils in Ibadan, Nigeria.

PubMed

Abdulmalik, Jibril; Ani, Cornelius; Ajuwon, Ademola J; Omigbodun, Olayinka

2016-01-01

Aggressive patterns of behavior often start early in childhood, and tend to remain stable into adulthood. The negative consequences include poor academic performance, disciplinary problems and encounters with the juvenile justice system. Early school intervention programs can alter this trajectory for aggressive children. However, there are no studies evaluating the feasibility of such interventions in Africa. This study therefore, assessed the effect of group-based problem-solving interventions on aggressive behaviors among primary school pupils in Ibadan, Nigeria. This was an intervention study with treatment and wait-list control groups. Two public primary schools in Ibadan Nigeria were randomly allocated to an intervention group and a waiting list control group. Teachers rated male Primary five pupils in the two schools on aggressive behaviors and the top 20 highest scorers in each school were selected. Pupils in the intervention school received 6 twice-weekly sessions of group-based intervention, which included problem-solving skills, calming techniques and attribution retraining. Outcome measures were; teacher rated aggressive behaviour (TRAB), self-rated aggression scale (SRAS), strengths and difficulties questionnaire (SDQ), attitude towards aggression questionnaire (ATAQ), and social cognition and attribution scale (SCAS). The participants were aged 12 years (SD = 1.2, range 9-14 years). Both groups had similar socio-demographic backgrounds and baseline measures of aggressive behaviors. Controlling for baseline scores, the intervention group had significantly lower scores on TRAB and SRAS 1-week post intervention with large Cohen's effect sizes of 1.2 and 0.9 respectively. The other outcome measures were not significantly different between the groups post-intervention. Group-based problem solving intervention for aggressive behaviors among primary school students showed significant reductions in both teachers' and students' rated aggressive behaviours with large effect sizes. However, this was a small exploratory trial whose findings may not be generalizable, but it demonstrates that psychological interventions for children with high levels of aggressive behaviour are feasible and potentially effective in Nigeria.

Aggression behaviour induced by oral administration of the Janus-kinase inhibitor tofacitinib, but not oclacitinib, under stressful conditions.

PubMed

Fukuyama, Tomoki; Tschernig, Thomas; Qi, Yulin; Volmer, Dietrich A; Bäumer, Wolfgang

2015-10-05

Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour. Copyright © 2015 Elsevier B.V. All rights reserved.

Sequential social experiences interact to modulate aggression but not brain gene expression in the honey bee (Apis mellifera).

PubMed

Rittschof, Clare C

2017-01-01

In highly structured societies, individuals behave flexibly and cooperatively in order to achieve a particular group-level outcome. However, even in social species, environmental inputs can have long lasting effects on individual behavior, and variable experiences can even result in consistent individual differences and constrained behavioral flexibility. Despite the fact that such constraints on behavior could have implications for behavioral optimization at the social group level, few studies have explored how social experiences accumulate over time, and the mechanistic basis of these effects. In the current study, I evaluate how sequential social experiences affect individual and group level aggressive phenotypes, and individual brain gene expression, in the highly social honey bee ( Apis mellifera ). To do this, I combine a whole colony chronic predator disturbance treatment with a lab-based manipulation of social group composition. Compared to the undisturbed control, chronically disturbed individuals show lower aggression levels overall, but also enhanced behavioral flexibility in the second, lab-based social context. Disturbed bees display aggression levels that decline with increasing numbers of more aggressive, undisturbed group members. However, group level aggressive phenotypes are similar regardless of the behavioral tendencies of the individuals that make up the group, suggesting a combination of underlying behavioral tendency and negative social feedback influences the aggressive behaviors displayed, particularly in the case of disturbed individuals. An analysis of brain gene expression showed that aggression related biomarker genes reflect an individual's disturbance history, but not subsequent social group experience or behavioral outcomes. In highly social animals with collective behavioral phenotypes, social context may mask underlying variation in individual behavioral tendencies. Moreover, gene expression patterns may reflect behavioral tendency, while behavioral outcomes are further regulated by social cues perceived in real-time.

Deep-brain stimulation for aggressive and disruptive behavior.

PubMed

Franzini, Angelo; Broggi, Giovanni; Cordella, Roberto; Dones, Ivano; Messina, Giuseppe

2013-01-01

To describe our institutional experience with deep-brain stimulation (DBS) used in the treatment of aggressive and disruptive behavior refractory to conservative treatment. With stereotactic methodology and under general anesthesia, seven patients (from 2002 to 2010) were given DBS in the posterior hypothalamic region, bilaterally, and with the aid of intraoperative microrecording. Six of seven patients presented a clear reduction in the aggression and disruptive bouts, with subsequent simplification of familiar management. DBS of the posterior hypothalamic region could be an effective treatment for patients affected by mental retardation in whom disruptive and drug-refractory aggressive behavior coexists. Although several experimental data are available on this target, further studies are necessary to confirm the long-term efficacy and safety of this procedure. Copyright © 2013. Published by Elsevier Inc.

Inhibition of Y-box binding protein-1 slows the growth of glioblastoma multiforme and sensitizes to temozolomide independent O6-methylguanine-DNA methyltransferase.

PubMed

Gao, Yuanyuan; Fotovati, Abbas; Lee, Cathy; Wang, Michelle; Cote, Gilbert; Guns, Emma; Toyota, Brian; Faury, Damien; Jabado, Nada; Dunn, Sandra E

2009-12-01

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor where <3% of newly diagnosed cases in the patients will survive >5 years. In adults, GBM is the most common type of brain tumor. It is rarer in children, where it constitutes approximately 15% of all brain tumors diagnosed. These tumors are often invasive, making surgical resection difficult. Further, they can be refractory to current therapies such as temozolomide. The current dogma is that temozolomide resistance rests on the expression of O6-methylguanine-DNA methyltransferase (MGMT) because it cleaves methylated DNA adducts formed by the drug. Our laboratory recently reported that another drug resistance gene known as the Y-box binding protein-1 (YB-1) is highly expressed in primary GBM but not in normal brain tissues based on the evaluation of primary tumors. We therefore questioned whether GBM depend on YB-1 for growth and/or response to temozolomide. Herein, we report that YB-1 inhibition reduced tumor cell invasion and growth in monolayer as well as in soft agar. Moreover, blocking this protein ultimately delayed tumor onset in mice. Importantly, inhibiting YB-1 enhanced temozolomide sensitivity in a manner that was independent of MGMT in models of adult and pediatric GBM. In conclusion, inhibiting YB-1 may be a novel way to improve the treatment of GBM.

Who's flying the plane: serotonin levels, aggression and free will.

PubMed

Siegel, Allan; Douard, John

2011-01-01

The present paper addresses the philosophical problem raised by current causal neurochemical models of impulsive violence and aggression: to what extent can we hold violent criminal offenders responsible for their conduct if that conduct is the result of deterministic biochemical processes in the brain. This question is currently receiving a great deal of attention among neuroscientists, legal scholars and philosophers. We examine our current knowledge of neuroscience to assess the possible roles of deterministic factors which induce impulsive aggression, and the extent to which this behavior can be controlled by neural conditioning mechanisms. Neural conditioning mechanisms, we suggest, may underlie what we consider the basis of responsible (though not necessarily moral) behavior: the capacity to give and take reasons. The models we first examine are based in part upon the role played by the neurotransmitter, serotonin, in the regulation of violence and aggression. Collectively, these results would appear to argue in favor of the view that low brain serotonin levels induce impulsive aggression which overrides mechanisms related to rational decision making processes. We next present an account of responsibility as based on the capacity to exercise a certain kind of reason-responsive control over one's conduct. The problem with such accounts of responsibility, however, is that they fail to specify a neurobiological realization of such mechanisms of control. We present a neurobiological, and weakly determinist, framework for understanding how persons can exercise guidance control over their conduct. This framework is based upon classical conditioning of neurons in the prefrontal cortex that allow for a decision making mechanism that provides for prefrontal cortical control of the sites in the brain which express aggressive behavior that include the hypothalamus and midbrain periaqueductal gray. The authors support the view that, in many circumstances, neural conditioning mechanisms provide the basis for the control of human aggression in spite of the presence of brain serotonin levels that might otherwise favor the expression of impulsive aggressive behavior. Indeed if those neural conditioning mechanisms underlie the human capacity to exercise control, they may be the neural realization of reason-responsiveness generally. Copyright © 2010 Elsevier Ltd. All rights reserved.

Who's flying the plane: Serotonin levels, aggression and free will

PubMed Central

Siegel, Allan; Douard, John

2010-01-01

The present paper addresses the philosophical problem raised by current causal neurochemical models of impulsive violence and aggression: to what extent can we hold violent criminal offenders responsible for their conduct if that conduct is the result of deterministic biochemical processes in the brain. This question is currently receiving a great deal of attention among neuroscientists, legal scholars and philosophers. We examine our current knowledge of neuroscience to assess the possible roles of deterministic factors which induce impulsive aggression, and the extent to which this behavior can be controlled by neural conditioning mechanisms. Neural conditioning mechanisms, we suggest, may underlie what we consider the basis of responsible (though not necessarily moral) behavior: the capacity to give and take reasons. The models we first examine are based in part upon the role played by the neurotransmitter, serotonin, in the regulation of violence and aggression. Collectively, these results would appear to argue in favor of the view that low brain serotonin levels induce impulsive aggression which overrides mechanisms related to rational decision making processes. We next present an account of responsibility as based on the capacity to exercise a certain kind of reason-responsive control over one's conduct. The problem with such accounts of responsibility, however, is that they fail to specify a neurobiological realization of such mechanisms of control. We present a neurobiological, and weakly determinist, framework for understanding how persons can exercise guidance control over their conduct. This framework is based upon classical conditioning of neurons in the prefrontal cortex that allow for a decision making mechanism that provides for prefrontal cortical control of the sites in the brain which express aggressive behavior that include the hypothalamus and midbrain periaqueductal gray. The authors support the view that, in many circumstances, neural conditioning mechanisms provide the basis for the control of human aggression in spite of the presence of brain serotonin levels that might otherwise favor the expression of impulsive aggressive behavior. Indeed if those neural conditioning mechanisms underlie the human capacity to exercise control, they may be the neural realization of reason-responsiveness generally. PMID:21112635

The orthotopic xenotransplant of human glioblastoma successfully recapitulates glioblastoma-microenvironment interactions in a non-immunosuppressed mouse model.

PubMed

Garcia, Celina; Dubois, Luiz Gustavo; Xavier, Anna Lenice; Geraldo, Luiz Henrique; da Fonseca, Anna Carolina Carvalho; Correia, Ana Helena; Meirelles, Fernanda; Ventura, Grasiella; Romão, Luciana; Canedo, Nathalie Henriques Silva; de Souza, Jorge Marcondes; de Menezes, João Ricardo Lacerda; Moura-Neto, Vivaldo; Tovar-Moll, Fernanda; Lima, Flavia Regina Souza

2014-12-08

Glioblastoma (GBM) is the most common primary brain tumor and the most aggressive glial tumor. This tumor is highly heterogeneous, angiogenic, and insensitive to radio- and chemotherapy. Here we have investigated the progression of GBM produced by the injection of human GBM cells into the brain parenchyma of immunocompetent mice. Xenotransplanted animals were submitted to magnetic resonance imaging (MRI) and histopathological analyses. Our data show that two weeks after injection, the produced tumor presents histopathological characteristics recommended by World Health Organization for the diagnosis of GBM in humans. The tumor was able to produce reactive gliosis in the adjacent parenchyma, angiogenesis, an intense recruitment of macrophage and microglial cells, and presence of necrosis regions. Besides, MRI showed that tumor mass had enhanced contrast, suggesting a blood-brain barrier disruption. This study demonstrated that the xenografted tumor in mouse brain parenchyma develops in a very similar manner to those found in patients affected by GBM and can be used to better understand the biology of GBM as well as testing potential therapies.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

PubMed

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal

PubMed Central

Hildebrandt, Tom; Heywood, Ashley; Wesley, Daniel; Schulz, Kurt

2018-01-01

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances. PMID:29651261

Brain imaging before primary lung cancer resection: a controversial topic.

PubMed

Hudson, Zoe; Internullo, Eveline; Edey, Anthony; Laurence, Isabel; Bianchi, Davide; Addeo, Alfredo

2017-01-01

International and national recommendations for brain imaging in patients planned to undergo potentially curative resection of non-small-cell lung cancer (NSCLC) are variably implemented throughout the United Kingdom [Hudson BJ, Crawford MB, and Curtin J et al (2015) Brain imaging in lung cancer patients without symptoms of brain metastases: a national survey of current practice in England Clin Radiol https://doi.org/10.1016/j.crad.2015.02.007]. However, the recommendations are not based on high-quality evidence and do not take into account cost implications and local resources. Our aim was to determine local practice based on historic outcomes in this patient cohort. This retrospective study took place in a regional thoracic surgical centre in the United Kingdom. Pathology records for all patients who had undergone lung resection with curative intent during the time period January 2012-December 2014 were analysed in October 2015. Electronic pathology and radiology reports were accessed for each patient and data collected about their histological findings, TNM stage, resection margins, and the presence of brain metastases on either pre-operative or post-operative imaging. From the dates given on imaging, we calculated the number of days post-resection that the brain metastases were detected. 585 patients were identified who had undergone resection of their lung cancer. Of these, 471 had accessible electronic radiology records to assess for the radiological evidence of brain metastases. When their electronic records were evaluated, 25/471 (5.3%) patients had radiological evidence of brain metastasis. Of these, five patients had been diagnosed with a brain metastasis at initial presentation and had undergone primary resection of the brain metastasis followed by resection of the lung primary. One patient had been diagnosed with both a primary lung and a primary bowel adenocarcinoma; on review of the case, it was felt that the brain metastasis was more likely to have originated from the bowel cancer. One had been clinically diagnosed with a cerebral abscess while the radiology had been reported as showing a metastatic deposit. Of the remaining 18/471 (3.8%) patients who presented with brain metastases after their surgical resection, 12 patients had adenocarcinoma, four patients had squamous cell carcinoma, one had basaloid, and one had large-cell neuroendocrine. The mean number of days post-resection that the brain metastases were identified was 371 days, range 14-1032 days, median 295 days (date of metastases not available for two patients). The rate of brain metastases identified in this study was similar to previous studies. This would suggest that preoperative staging of the central nervous system may change the management pathway in a small group of patients. However, for this group of patients, the change would be significant either sparing them non-curative surgery or allowing aggressive management of oligometastatic disease. Therefore, we would recommend pre-operative brain imaging with MRI for all patients undergoing potentially curative lung resection.

Cell-type-specific role of ΔFosB in nucleus accumbens in modulating inter-male aggression.

PubMed

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.

Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres

NASA Astrophysics Data System (ADS)

Jain, Anjana; Betancur, Martha; Patel, Gaurangkumar D.; Valmikinathan, Chandra M.; Mukhatyar, Vivek J.; Vakharia, Ajit; Pai, S. Balakrishna; Brahma, Barunashish; MacDonald, Tobey J.; Bellamkonda, Ravi V.

2014-03-01

Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.

Winning territorial disputes selectively enhances androgen sensitivity in neural pathways related to motivation and social aggression.

PubMed

Fuxjager, Matthew J; Forbes-Lorman, Robin M; Coss, Dylan J; Auger, Catherine J; Auger, Anthony P; Marler, Catherine A

2010-07-06

Winning aggressive disputes can enhance future fighting ability and the desire to seek out additional contests. In some instances, these effects are long lasting and vary in response to the physical location of a fight. Thus, in principle, winning aggressive encounters may cause long-term and context-dependent changes to brain areas that control the output of antagonistic behavior or the motivation to fight (or both). We examined this issue in the territorial California mouse (Peromyscus californicus) because males of this species are more likely to win fights after accruing victories in their home territory but not after accruing victories in unfamiliar locations. Using immunocytochemistry and real-time quantitative PCR, we found that winning fights either at home or away increases the expression of androgen receptors (AR) in the medial anterior bed nucleus of the stria terminalis, a key brain area that controls social aggression. We also found that AR expression in brain regions that mediate motivation and reward, nucleus accumbens (NAcc) and ventral tegmental area (VTA), increases only in response to fights in the home territory. These effects of winning were likely exclusive to the neural androgenic system because they have no detectible impact on the expression of progestin receptors. Finally, we demonstrated that the observed changes in androgen sensitivity in the NAcc and VTA are positively associated with the ability to win aggressive contests. Thus, winning fights can change brain phenotype in a manner that likely promotes future victory and possibly primes neural circuits that motivate individuals to fight.

Genetic dissection of intermale aggressive behavior in BALB/cJ and A/J mice.

PubMed

Dow, H C; Kreibich, A S; Kaercher, K A; Sankoorikal, G M V; Pauley, E D; Lohoff, F W; Ferraro, T N; Li, H; Brodkin, E S

2011-02-01

Aggressive behaviors are disabling, treatment refractory, and sometimes lethal symptoms of several neuropsychiatric disorders. However, currently available treatments for patients are inadequate, and the underlying genetics and neurobiology of aggression is only beginning to be elucidated. Inbred mouse strains are useful for identifying genomic regions, and ultimately the relevant gene variants (alleles) in these regions, that affect mammalian aggressive behaviors, which, in turn, may help to identify neurobiological pathways that mediate aggression. The BALB/cJ inbred mouse strain exhibits relatively high levels of intermale aggressive behaviors and shows multiple brain and behavioral phenotypes relevant to neuropsychiatric syndromes associated with aggression. The A/J strain shows very low levels of aggression. We hypothesized that a cross between BALB/cJ and A/J inbred strains would reveal genomic loci that influence the tendency to initiate intermale aggressive behavior. To identify such loci, we conducted a genomewide scan in an F2 population of 660 male mice bred from BALB/cJ and A/J inbred mouse strains. Three significant loci on chromosomes 5, 10 and 15 that influence aggression were identified. The chromosome 5 and 15 loci are completely novel, and the chromosome 10 locus overlaps an aggression locus mapped in our previous study that used NZB/B1NJ and A/J as progenitor strains. Haplotype analysis of BALB/cJ, NZB/B1NJ and A/J strains showed three positional candidate genes in the chromosome 10 locus. Future studies involving fine genetic mapping of these loci as well as additional candidate gene analysis may lead to an improved biological understanding of mammalian aggressive behaviors. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Brain Serotonin Receptors and Transporters: Initiation vs. Termination of Escalated Aggression

PubMed Central

Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

2013-01-01

Rationale Recent findings have shown a complexly regulated 5-HT system as it is linked to different kinds of aggression. Objective We focus on (1) phasic and tonic changes of 5-HT and (2) state and trait of aggression, and emphasize the different receptor subtypes, their role in specific brain regions, feed-back regulation and modulation by other amines, acids and peptides. Results New pharmacological tools differentiate the first three 5-HT receptor families and their modulation by GABA, glutamate and CRF. Activation of 5-HT1A, 5-HT1B and 5-HT2A/2C receptors in mesocorticolimbic areas, reduce species-typical and other aggressive behaviors. In contrast, agonists at 5-HT1A and 5-HT1B receptors in the medial prefrontal cortex or septal area can increase aggressive behavior under specific conditions. Activation of serotonin transporters reduce mainly pathological aggression. Genetic analyses of aggressive individuals have identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g., Neuropeptide Y, αCaMKII, NOS, BDNF). Dysfunction in genes for MAOA escalates pathological aggression in rodents and humans, particularly in interaction with specific experiences. Conclusions Feedback to autoreceptors of the 5-HT1 family and modulation via heteroreceptors are important in the expression of aggressive behavior. Tonic increase of the 5-HT2 family expression may cause escalated aggression, whereas the phasic increase of 5-HT2 receptors inhibits aggressive behaviors. Polymorphisms in the genes of 5-HT transporters or rate-limiting synthetic and metabolic enzymes of 5-HT modulate aggression, often requiring interaction with the rearing environment. PMID:20938650

DEVELOPMENTAL AND WITHDRAWAL EFFECTS OF ADOLESCENT AAS EXPOSURE ON THE GLUTAMATERGIC SYSTEM IN HAMSTERS

PubMed Central

Carrillo, Maria; Ricci, Lesley A.; Melloni, Richard H.

2011-01-01

In the Syrian hamster (Mesocricetus auratus) glutamate activity has been implicated in the modulation of adolescent anabolic-androgenic steroid (AAS)-induced aggression. The current study investigated the time course of adolescent AAS-induced neurodevelopmental and withdrawal effects on the glutamatergic system and examined whether these changes paralleled those of adolescent AAS-induced aggression. Glutamate activity in brain areas comprising the aggression circuit in hamsters and aggression were examined following 1, 2, 3 and 4 weeks of AAS treatment or 1, 2, 3 and 4 weeks following the cessation of AAS exposure. In these studies glutamate activity was examined using vesicular glutamate transporter 2 (VGLUT2). The onset of aggression was observed following 2 weeks exposure to AAS and continued to increase showing maximal aggression levels after 4 weeks of AAS treatment. This aggressive phenotype was detected after 2 weeks of withdrawal from AAS. The time-course of AAS-induced changes in latero anterior hypothalamus (LAH)-VGLUT2 closely paralleled increases in aggression. Increases in LAH-VGLUT2 were first detected in animals exposed to AAS for 2 weeks and were maintained up to 3 weeks following the cessation of AAS treatment. AAS treatment also produced developmental and long-term alterations in VGLUT2 expression within other aggression areas. However, AAS-induced changes in glutamate activity within these regions did not coincide with changes in aggression. Together, these data indicate that adolescent AAS treatment leads to alterations in the glutamatergic system in brain areas implicated in aggression control, yet only alterations in LAH-glutamate parallel the time course of AAS-induced changes in the aggressive phenotype. PMID:21500881

Neuromodulation of Nestmate Recognition Decisions by Pavement Ants.

PubMed

Bubak, Andrew N; Yaeger, Jazmine D W; Renner, Kenneth J; Swallow, John G; Greene, Michael J

2016-01-01

Ant colonies are distributed systems that are regulated in a non-hierarchical manner. Without a central authority, individuals inform their decisions by comparing information in local cues to a set of inherent behavioral rules. Individual behavioral decisions collectively change colony behavior and lead to self-organization capable of solving complex problems such as the decision to engage in aggressive societal conflicts with neighbors. Despite the relevance to colony fitness, the mechanisms that drive individual decisions leading to cooperative behavior are not well understood. Here we show how sensory information, both tactile and chemical, and social context-isolation, nestmate interaction, or fighting non-nestmates-affects brain monoamine levels in pavement ants (Tetramorium caespitum). Our results provide evidence that changes in octopamine and serotonin in the brains of individuals are sufficient to alter the decision by pavement ants to be aggressive towards non-nestmate ants whereas increased brain levels of dopamine correlate to physical fighting. We propose a model in which the changes in brain states of many workers collectively lead to the self-organization of societal aggression between neighboring colonies of pavement ants.

Neuromodulation of Nestmate Recognition Decisions by Pavement Ants

PubMed Central

Bubak, Andrew N.; Yaeger, Jazmine D. W.; Renner, Kenneth J.; Swallow, John G.; Greene, Michael J.

2016-01-01

Ant colonies are distributed systems that are regulated in a non-hierarchical manner. Without a central authority, individuals inform their decisions by comparing information in local cues to a set of inherent behavioral rules. Individual behavioral decisions collectively change colony behavior and lead to self-organization capable of solving complex problems such as the decision to engage in aggressive societal conflicts with neighbors. Despite the relevance to colony fitness, the mechanisms that drive individual decisions leading to cooperative behavior are not well understood. Here we show how sensory information, both tactile and chemical, and social context—isolation, nestmate interaction, or fighting non-nestmates—affects brain monoamine levels in pavement ants (Tetramorium caespitum). Our results provide evidence that changes in octopamine and serotonin in the brains of individuals are sufficient to alter the decision by pavement ants to be aggressive towards non-nestmate ants whereas increased brain levels of dopamine correlate to physical fighting. We propose a model in which the changes in brain states of many workers collectively lead to the self-organization of societal aggression between neighboring colonies of pavement ants. PMID:27846261

Brain structures and neurotransmitters regulating aggression in cats: implications for human aggression.

PubMed

Gregg, T R; Siegel, A

2001-01-01

1. Violence and aggression are major public health problems. 2. The authors have used techniques of electrical brain stimulation, anatomical-immunohistochemical techniques, and behavioral pharmacology to investigate the neural systems and circuits underlying aggressive behavior in the cat. 3. The medial hypothalamus and midbrain periaqueductal gray are the most important structures mediating defensive rage behavior, and the perifornical lateral hypothalamus clearly mediates predatory attack behavior. The hippocampus, amygdala, bed nucleus of the stria terminalis, septal area, cingulate gyrus, and prefrontal cortex project to these structures directly or indirectly and thus can modulate the intensity of attack and rage. 4. Evidence suggests that several neurotransmitters facilitate defensive rage within the PAG and medial hypothalamus, including glutamate, Substance P, and cholecystokinin, and that opioid peptides suppress it; these effects usually depend on the subtype of receptor that is activated. 5. A key recent discovery was a GABAergic projection that may underlie the often-observed reciprocally inhibitory relationship between these two forms of aggression. 6. Recently, Substance P has come under scrutiny as a possible key neurotransmitter involved in defensive rage, and the mechanism by which it plays a role in aggression and rage is under investigation. 7. It is hoped that this line of research will provide a better understanding of the neural mechanisms and substrates regulating aggression and rage and thus establish a rational basis for treatment of disorders associated with these forms of aggression.

Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

PubMed

Soloff, Paul; White, Richard; Diwadkar, Vaibhav A

2014-06-30

Impulsivity and aggressiveness are trait dispositions associated with the vulnerability to suicidal behavior across diagnoses. They are associated with structural and functional abnormalities in brain networks involved in regulation of mood, impulse and behavior. They are also core characteristics of borderline personality disorder (BPD), a disorder defined, in part, by recurrent suicidal behavior. We assessed the relationships between personality traits, brain structure and lethality of suicide attempts in 51 BPD attempters using multiple regression analyses on structural MRI data. BPD was diagnosed by the Diagnostic Interview for Borderline Patients-revised, impulsivity by the Barratt Impulsiveness Scale (BIS), aggression by the Brown-Goodwin Lifetime History of Aggression (LHA), and high lethality by a score of 4 or more on the Lethality Rating Scale (LRS). Sixteen High Lethality attempters were compared to 35 Low Lethality attempters, with no significant differences noted in gender, co-morbidity, childhood abuse, BIS or LHA scores. Degree of medical lethality (LRS) was negatively related to gray matter volumes across multiple fronto-temporal-limbic regions. Effects of impulsivity and aggression on gray matter volumes discriminated High from Low Lethality attempters and differed markedly within lethality groups. Lethality of suicide attempts in BPD may be related to the mediation of these personality traits by specific neural networks. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

What are the disruptive symptoms of behavioral disorders after traumatic brain injury? A systematic review leading to recommendations for good practices.

PubMed

Stéfan, Angélique; Mathé, Jean-François

2016-02-01

Behavioral disorders are major sequelae of severe traumatic brain injury. Before considering care management of these disorders, and in the absence of a precise definition for TBI-related behavioral disorder, it is essential to refine, according to the data from the literature, incidence, prevalence, predictive factors of commonly admitted disruptive symptoms. Systematic review of the literature targeting epidemiological data related to behavioral disorders after traumatic brain injury in order to elaborate good practice recommendations according to the methodology established by the French High Authority for Health. Two hundred and ninety-nine articles were identified. The responsibility of traumatic brain injury (TBI) in the onset of behavioral disorders is unequivocal. Globally, behavioral disorders are twice more frequent after TBI than orthopedic trauma without TBI (Masson et al., 1996). These disorders are classified into disruptive primary behaviors by excess (agitation 11-70%, aggression 25-39%, irritability 29-71%, alcohol abuse 7-26% drug abuse 2-20%), disruptive primary behaviors by default (apathy 20-71%), affective disorders - anxiety - psychosis (depression 12-76%, anxiety 0.8-24,5%, posttraumatic stress 11-18%, obsessive-compulsive disorders 1.2-30%, psychosis 0.7%), suicide attempts and suicide 1%. The improvement of care management for behavioral disorders goes through a first step of defining a common terminology. Four categories of posttraumatic behavioral clinical symptoms are defined: disruptive primary behaviors by excess, by default, affective disorders-psychosis-anxiety, suicide attempts and suicide. All these symptoms yield a higher prevalence than in the general population. They impact all of life's domains and are sustainable over time. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Neurobiological factors in aggressive behavior.

PubMed

Garza-Treviño, E S

1994-07-01

The author's aim was to review literature in the neurosciences and psychiatric clinical research reports about biological factors in aggression and the pathophysiological mechanisms that accompany aggression in neuropsychiatric syndromes. Studies were located through computer searches of relevant experimental reports and review articles mainly from the last 25 years. Several studies using neuroimaging and neurophysiological and neuropathological research techniques have identified lesions in the limbic structures, temporal lobes, and frontal lobes of the brain in abnormally aggressive individuals. Several reports have associated deficiency or dysregulation of serotonin with homicidal, suicidal, and impulsive behavior. However, few studies have focused on polypeptides or second messenger systems, although abnormalities in these systems have been reported in patients with neuropsychiatric syndromes who have shown aggressive behavior. Even fewer studies focus on the correlation of brain structures and metabolic markers. The understanding of aggressive behavior in psychiatric patients is fragmented. Some explanations are speculative and extrapolated to clinical psychiatric syndromes from experimental data on the neurophysiology of cats, rats, and other mammals. Identification of biochemical markers that can be used in predicting patients' response to pharmacological interventions may be the next step in developing more rational treatment of violent patients.

Oxytocin-Induced Changes in Monoamine Level in Symmetric Brain Structures of Isolated Aggressive C57Bl/6 Mice.

PubMed

Karpova, I V; Mikheev, V V; Marysheva, V V; Bychkov, E R; Proshin, S N

2016-03-01

Changes in activity of monoaminergic systems of the left and right brain hemispheres after administration of saline and oxytocin were studied in male C57Bl/6 mice subjected to social isolation. The concentrations of dopamine, norepinephrine, serotonin, and their metabolites dihydroxyphenylacetic, homovanillic, and 5-hydroxyindoleacetic acids were measured in the cerebral cortex, hippocampus, olfactory tubercle, and striatum of the left and right brain hemispheres by HPLC. In isolated aggressive males treated intranasally with saline, the content of serotonin and 5-hydroxyindoleacetic acid was significantly higher in the right hippocampus. Oxytocin reduces aggression caused by long-term social isolation, but has no absolute ability to suppress this type of behavior. Oxytocin reduced dopamine content in the left cortex and serotonin content in the right hippocampus and left striatum. Furthermore, oxytocin evened the revealed asymmetry in serotonin and 5-hydroxyindoleacetic acid concentrations in the hippocampus. At the same time, asymmetry in dopamine concentration appeared in the cortex with predominance of this transmitter in the right hemisphere. The data are discussed in the context of lateralization of neurotransmitter systems responsible for intraspecific aggression caused by long-term social isolation.

Wiring Pathways to Replace Aggression

ERIC Educational Resources Information Center

Bath, Howard

2006-01-01

The previous article in this series introduced the triune brain, the three components of which handle specialized life tasks. The survival brain, or brain stem, directs automatic physiological functions, such as heartbeat and breathing, and mobilizes fight/flight behaviour in times of threat. The emotional (or limbic) brain activates positive or…

Effects of an Online Rational Emotive Curriculum on Primary School Students' Tendencies for Online and Real-World Aggression

ERIC Educational Resources Information Center

Liu, Eric Zhi-Feng; Ho, H. C.; Song, Y. J.

2011-01-01

This study investigated the relationship between online and real-world aggressive behavior among primary school students as well as the effects of an online rational emotive curriculum on reducing the tendency of students to display aggression online and in the real-world. We developed an online information literacy course integrated with rational…

C1473G polymorphism in mouse tph2 gene is linked to tryptophan hydroxylase-2 activity in the brain, intermale aggression, and depressive-like behavior in the forced swim test.

PubMed

Osipova, Daria V; Kulikov, Alexander V; Popova, Nina K

2009-04-01

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of brain serotonin synthesis. The C1473G polymorphism in the mouse tryptophan hydroxylase-2 gene affects the enzyme's activity. In the present study, we investigated the linkage between the C1473G polymorphism, enzyme activity in the brain, and behavior in the forced swim, intermale aggression, and open field tests using mice of the C57BL/6 (C/C) and CC57BR/Mv (G/G) strains and the B6-1473C (C/C) and B6-1473G (G/G) lines created by three successive backcrossings on C57BL/6. Mice of the CC57BR/Mv strain had decreased brain enzyme activity, aggression intensity, and immobility in the forced swim test, but increased locomotor activity and time spent in the central part of the open field arena compared with animals of the C57BL/6 strain. Mice of the B6-1473G line homozygous for the 1473G allele had lower TPH2 activity in the brain, aggression intensity, and immobility time in the forced swim test compared with animals of the B6-1473C line homozygous for the 1473C allele. No differences were found between the B6-1473G and B6-1473C mice in locomotor activity and time spent in the central part of the arena in the open field test. Thus, the C1473G polymorphism is involved in the determination of TPH2 activity and is linked to aggression intensity and forced-swim immobility in mice. At the same time, the polymorphism does not affect locomotion and anxiety-related behavior in the open field test. The B6-1473C and B6-1473G mice represent a valuable experimental model for investigating molecular mechanisms of serotonin-related behavior.

In vivo magnetic resonance imaging investigating the development of experimental brain metastases due to triple negative breast cancer.

PubMed

Hamilton, Amanda M; Foster, Paula J

2017-02-01

Triple negative breast cancer (TNBC), when associated with poor outcome, is aggressive in nature with a high incidence of brain metastasis and the shortest median overall patient survival after brain metastasis development compared to all other breast cancer subtypes. As therapies that control primary cancer and extracranial metastatic sites improve, the incidence of brain metastases is increasing and the management of patients with breast cancer brain metastases continues to be a significant clinical challenge. Mouse models have been developed to permit in depth evaluation of breast cancer metastasis to the brain. In this study, we compare the efficiency and metastatic potential of two experimental mouse models of TNBC. Longitudinal MRI analysis and end point histology were used to quantify initial cell arrest as well as the number and volume of metastases that developed in mouse brain over time. We showed significant differences in MRI appearance, tumor progression and model efficiency between the syngeneic 4T1-BR5 model and the xenogeneic 231-BR model. Since TNBC does not respond to many standard breast cancer treatments and TNBC brain metastases lack effective targeted therapies, these preclinical TNBC models represent invaluable tools for the assessment of novel systemic therapeutic approaches. Further pursuits of therapeutics designed to bypass the blood tumor barrier and permit access to the brain parenchyma and metastatic cells within the brain will be paramount in the fight to control and treat lethal metastatic cancer.

CRMP2 Phosphorylation Drives Glioblastoma Cell Proliferation.

PubMed

Moutal, Aubin; Villa, Lex Salas; Yeon, Seul Ki; Householder, Kyle T; Park, Ki Duk; Sirianni, Rachael W; Khanna, Rajesh

2018-05-01

Glioblastoma (GBM) is an aggressive primary brain tumor. The rapid growth and the privileged provenance of the tumor within the brain contribute to its aggressivity and poor therapeutic targeting. A poor prognostic factor in glioblastoma is the deletion or mutation of the Nf1 gene. This gene codes for the protein neurofibromin, a tumor suppressor gene that is known to interact with the collapsin response mediator protein 2 (CRMP2). CRMP2 expression and elevated expression of nuclear phosphorylated CRMP2 have recently been implicated in cancer progression. The CRMP2-neurofibromin interaction protects CRMP2 from its phosphorylation by cyclin-dependent kinase 5 (Cdk5), an event linked to cancer progression. In three human glioblastoma cell lines (GL15, A172, and U87), we observed an inverse correlation between neurofibromin expression and CRMP2 phosphorylation levels. Glioblastoma cell proliferation was dependent on CRMP2 expression and phosphorylation by Cdk5 and glycogen synthase kinase 3 beta (GSK3β). The CRMP2 phosphorylation inhibitor (S)-lacosamide reduces, in a concentration-dependent manner, glioblastoma cell proliferation and induced apoptosis in all three GBM cell lines tested. Since (S)-lacosamide is bioavailable in the brain, we tested its utility in an in vivo orthotopic model of GBM using GL261-LucNeo glioma cells. (S)-lacosamide decreased tumor size, as measured via in vivo bioluminescence imaging, by ~54% compared to vehicle control. Our results introduce CRMP2 expression and phosphorylation as a novel player in GBM proliferation and survival, which is enhanced by loss of Nf1.

No consistent relationship of glioblastoma incidence and cytomegalovirus seropositivity in whites, blacks, and Hispanics.

PubMed

Lehrer, Steven; Green, Sheryl; Ramanathan, Lakshmi; Rosenzweig, Kenneth; Labombardi, Vincent

2012-03-01

Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Recently, evidence for a viral cause has been postulated, possibly cytomegalovirus (CMV). In one report, 80% of patients with newly diagnosed glioblastoma multiforme had detectable cytomegalovirus DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus. However, another study reported that five glioblastoma patients showed no circulating CMV detected either with RT-PCR or blood culture. We utilized Cytomegalovirus Seroprevalence in the United States data from the National Health and Nutrition Examination Surveys, 1988-2004. Glioblastoma Incidence Rates 2004-2008 by race and gender are from Cancer of the Brain and Other Nervous System - SEER Stat Fact Sheets (http://seer.cancer.gov/statfacts/html/brain.html). Statistical significance was determined from published 95% confidence intervals. CMV seroprevalence rates are not consistently related to glioblastoma incidence rates. CMV seroprevalence is significantly lower in whites than in blacks or Hispanics (Mexican Americans), while glioblastoma incidence is higher. However, both CMV seroprevalence and glioblastoma incidence are higher in Hispanics than in blacks. CMV seroprevalence rates are significantly higher in women, 55.5% (53.3-57.7, mean ± 95% CI) than men, 45.2% (42.4-48.0), although glioblastoma is more common in men. A possible CMV-glioblastoma association cannot be readily substantiated with CMV seropositivity rates.

Influences of Gender, Religion, Dietary Patterns, and Mixed-sex Education on Aggressiveness in Children: A Sociodemographic Study in Municipal Primary Schools of South Delhi.

PubMed

Jain, Khushbu; Sharma, Schweta; Prajna, Samani Chaitanya; Jain, Viney

2018-01-01

Increasing antisocial and violent behaviors in adolescents and young adults present serious challenges for public health. Children with persistent high levels of aggressiveness are often associated with developing conduct disorders later in life. Early detection of highly aggressive children and sociodemographic risk-modifying factors are important for developing effective preventive strategies. The present study was undertaken to assess levels of aggressiveness for detecting highly aggressive children in sample populations of primary school children in an urban setting and determine significant biosociocultural risk-modifying factors in this scenario. The study was conducted during August-September, 2015 in 5 primary schools of South Delhi Municipal Corporation. Sociodemographic data on 2080 students were collected. Overall aggressiveness scores (OA-Scores) were estimated using a self-report questionnaire in Hindi. Categorizing students according to their OA-Scores, the data revealed that highly aggressive children constituted 4.3% of the study population. Analysis showed significant influence of (a) gender: boys displayed higher levels of aggressiveness compared to girls; (b) dietary pattern: omnivores showed higher aggressiveness than vegetarians; and (c) school environment: boys in mixed-sex (coeducational) schools displayed lower aggressiveness than from single-sex schools. Statistically significant influences of religion (Hindu/Muslim) and family type (joint/nuclear) on aggressiveness profiles were not noticeable. Vegetarian diets and mixed-sex education act as protective factors in the development of aggressiveness in children, especially among boys. Extending investigations to populations differing in geography and cultural backgrounds are warranted to verify present results.

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development.

PubMed

Ziermans, T; Dumontheil, I; Roggeman, C; Peyrard-Janvid, M; Matsson, H; Kere, J; Klingberg, T

2012-02-28

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene-brain-behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ~6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.

Aggression and violence against primary care physicians—a nationwide questionnaire survey.

PubMed

Vorderwülbecke, Florian; Feistle, Maximilian; Mehring, Michael; Schneider, Antonius; Linde, Klaus

2015-03-06

International studies show that aggressive behavior against primary care physicians is not an uncommon occurrence. There has been no systematic study to date of the nature and frequency of such occurrences in Germany. A four-page questionnaire was sent to a nationwide random sample of 1500 primary care physicians. It contained questions about the type, frequency, severity, and site of aggressive behavior against the physician. 831 (59%) of 1408 correctly delivered questionnaires could be included in the analysis. 91% of the respondents (95% confidence interval [CI], 89%-93%) said they had been the object of aggressive behavior at some time in their career as a primary care physician, 73% (95% CI, 70%-76%) in the previous 12 months. Severe aggression or violence had been experienced by 23% (95% CI, 20%-25%) in their entire career and 11% (95% CI, 8%-13%) in the previous year. The vast majority of respondents said they felt safe in their offices. 66% of female and 34% of male respondents said they did not feel safe making house visits while on on-call duty. The frequency and extent of aggression and violence against primary care physicians in Germany is comparable to those reported by international studies. Strategies for dealing with this problem should be developed. In particular, the issue of safety on emergency call needs to be addressed.

Early Childhood Education Teachers' Strategies Use in Order to Prevent Aggressive Behaviors in Classes: The Case of Turkey

ERIC Educational Resources Information Center

Derman, Meral Taner

2017-01-01

The aim of this research is to investigate the aggression types observed in class environment in preschool and primary schools and the strategies that teachers use in order to prevent aggressive behaviors in classes by variables like gender, seniority and socioeconomic level. 118 preschool teachers and 176 primary school teachers, a total of 294…

[Immunotherapy in brain tumors].

PubMed

De Carli, Emilie; Delion, Matthieu; Rousseau, Audrey

2017-02-01

Diffuse gliomas represent the most common primary central nervous system (CNS) tumors in adults and children alike. Glioblastoma is the most frequent and malignant form of diffuse glioma with a median overall survival of 15 months despite aggressive treatments. New therapeutic approaches are needed to prolong survival in this always fatal disease. The CNS has been considered for a long time as an immune privileged organ, in part because of the existence of the blood-brain barrier. Nonetheless, immunotherapy is a novel approach in the therapeutic management of glioma patients, which has shown promising results in several clinical trials, especially in the adult population. Vaccination, with or without dendritic cells, blockade of the immune checkpoints, and adoptive T cell transfer are the most studied modalities of diffuse glioma immunotherapy. The future most likely resides in combinatorial approaches, with administration of conventional treatments (surgery, radiochemotherapy) and immunotherapy following yet to determine schedules. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Brain self-regulation in criminal psychopaths.

PubMed

Konicar, Lilian; Veit, Ralf; Eisenbarth, Hedwig; Barth, Beatrix; Tonin, Paolo; Strehl, Ute; Birbaumer, Niels

2015-03-24

Psychopathic individuals are characterized by impaired affective processing, impulsivity, sensation-seeking, poor planning skills and heightened aggressiveness with poor self-regulation. Based on brain self-regulation studies using neurofeedback of Slow Cortical Potentials (SCPs) in disorders associated with a dysregulation of cortical activity thresholds and evidence of deficient cortical functioning in psychopathy, a neurobiological approach seems to be promising in the treatment of psychopathy. The results of our intensive brain regulation intervention demonstrate, that psychopathic offenders are able to gain control of their brain excitability over fronto-central brain areas. After SCP self-regulation training, we observed reduced aggression, impulsivity and behavioral approach tendencies, as well as improvements in behavioral-inhibition and increased cortical sensitivity for error-processing. This study demonstrates improvements on the neurophysiological, behavioral and subjective level in severe psychopathic offenders after SCP-neurofeedback training and could constitute a novel neurobiologically-based treatment for a seemingly change-resistant group of criminal psychopaths.

Trait and state patterns of basolateral amygdala connectivity at rest are related to endogenous testosterone and aggression in healthy young women.

PubMed

Buades-Rotger, Macià; Engelke, Christin; Krämer, Ulrike M

2018-05-09

The steroid hormone testosterone (T) has been suggested to influence reactive aggression upon its action on the basolateral amygdala (BLA), a key brain region for threat detection. However, it is unclear whether T modulates resting-state functional connectivity (rsFC) of the BLA, and whether this predicts subsequent aggressive behavior. Aggressive interactions themselves, which often induce changes in T concentrations, could further alter BLA rsFC, but this too remains untested. Here we investigated the effect of endogenous T on rsFC of the BLA at baseline as well as after an aggressive encounter, and whether this was related to behavioral aggression in healthy young women (n = 39). Pre-scan T was negatively correlated with basal rsFC between BLA and left superior temporal gyrus (STG; p < .001, p < .05 Family-Wise Error [FWE] cluster-level corrected), which in turn was associated with increased aggression (r = .37, p = .020). BLA-STG coupling at rest might thus underlie hostile readiness in low-T women. In addition, connectivity between the BLA and the right superior parietal lobule (SPL), a brain region involved in higher-order perceptual processes, was reduced in aggressive participants (p < .001, p < .05 FWE cluster-level corrected). On the other hand, post-task increases in rsFC between BLA and medial orbitofrontal cortex (mOFC) were linked to reduced aggression (r = -.36, p = .023), consistent with the established notion that the mOFC regulates amygdala activity in order to curb aggressive impulses. Finally, competition-induced changes in T were associated with increased coupling between the BLA and the right lateral OFC (p < .001, p < .05 FWE cluster-level corrected), but this effect was unrelated to aggression. We thus identified connectivity patterns that prospectively predict aggression in women, and showed how aggressive interactions in turn impact these neural systems.

Multi-disciplinary management for patients with oligometastases to the brain: results of a 5 year cohort study.

PubMed

Maclean, Jillian; Fersht, Naomi; Singhera, Mausam; Mulholland, Paul; McKee, Orla; Kitchen, Neil; Short, Susan C

2013-06-27

The incidence of oligometastases to the brain in good performance status patients is increasing due to improvements in systemic therapy and MRI screening, but specific management pathways are often lacking. We established a multi-disciplinary brain metastases clinic with specific referral guidelines and standard follow-up for good prognosis patients with the view that improving the process of care may improve outcomes. We evaluated patient demographic and outcome data for patients first seen between February 2007 and November 2011. The clinic was feasible to run and referrals were appropriate. 87% of patients referred received a localised therapy during their treatment course. 114 patients were seen and patient numbers increased during the 5 years that the clinic has been running as relationships between clinicians were developed. Median follow-up for those still alive was 23.1 months (6.1-79.1 months). Primary treatments were: surgery alone 52%, surgery plus whole brain radiotherapy (WBRT) 9%, radiosurgery 14%, WBRT alone 23%, supportive care 2%. 43% received subsequent treatment for brain metastases. 25%, 11% and 15% respectively developed local neurological progression only, new brain metastases only or both. Median overall survival following brain metastases diagnosis was 16.0 months (range 1-79.1 months). Breast (32%) and NSCLC (26%) were the most common primary tumours with median survivals of 26 and 16.9 months respectively (HR 0.6, p=0.07). Overall one year survival was 55% and two year survival 31.5%. 85 patients died of whom 37 (44%) had a neurological death. Careful patient selection and multi-disciplinary management identifies a subset of patients with oligometastatic brain disease who benefit from aggressive local treatment. A dedicated joint neurosurgical/ neuro-oncology clinic for such patients is feasible and effective. It also offers the opportunity to better define management strategies and further research in this field. Consideration should be given to defining specific management pathways for these patients within general oncology practice.

OPTOGENETICS, SEX AND VIOLENCE IN THE BRAIN: IMPLICATIONS FOR PSYCHIATRY

PubMed Central

Anderson, David J.

2012-01-01

Pathological aggression, and the inability to control aggressive impulses, takes a tremendous toll on society. Yet aggression is a normal component of the innate behavior repertoire of most vertebrate animal species, as well as of many invertebrates. Progress in understanding the etiology of disorders of aggressive behavior, whether genetic or environmental in nature, therefore requires an understanding of the brain circuitry that controls normal aggression. Efforts to understand this circuitry at the level of specific neuronal populations have been constrained by the limited resolution of classical methodologies, such as electrical stimulation and electrolytic lesion. The availability of new, genetically based tools for mapping and manipulating neural circuits at the level of specific, genetically defined neuronal subtypes provides an opportunity to investigate the functional organization of aggression circuitry with cellular resolution. However these technologies are optimally applied in the mouse, where there has been surprisingly little traditional work on the functional neuroanatomy of aggression. Here we discuss recent, initial efforts to apply optogenetics and other state-of-the-art methods to the dissection of aggression circuitry in the mouse. We find, surprisingly, that neurons necessary and sufficient for inter-male aggression are located within the ventrolateral subdivision of the ventromedial hypothalamic nucleus (VMHvl), a structure traditionally associated with reproductive behavior. These neurons are intermingled with neurons activated during male-female mating, with ~20% overlap between the populations. We discuss the significance of these findings with respect to neuroethological and neuroanatomical perspectives on the functional organization of innate behaviors, and their potential implications for psychiatry. PMID:22209636

Neurotensin inversely modulates maternal aggression

PubMed Central

Gammie, Stephen C.; D’Anna, Kimberly L.; Gerstein, Hilary; Stevenson, Sharon A.

2008-01-01

Neurotensin (NT) is a versatile neuropeptide involved in analgesia, hypothermia, and schizophrenia. Although NT is released from and acts upon brain regions involved in social behaviors, it has not been linked to a social behavior. We previously selected mice for high maternal aggression (maternal defense), an important social behavior that protects offspring, and found significantly lower NT expression in the CNS of highly protective females. Our current study directly tested NT’s role in maternal defense. Intracerebroventricular (icv) injections of NT significantly impaired defense in terms of time aggressive and number of attacks at all doses tested (0.05, 0.1, 1.0, and 3.0 μg). Other maternal behaviors, including pup retrieval, were unaltered following NT injections (0.05 μg) relative to vehicle, suggesting specificity of NT action on defense. Further, icv injections of the NT receptor 1 (NT1) antagonist, SR 48692 (30 μg), significantly elevated maternal aggression in terms of time aggressive and attack number. To understand where NT may regulate aggression, we examined Fos following injection of either 0.1 μg NT or vehicle. 13 of 26 brain regions examined exhibited significant Fos increases with NT, including regions expressing NT1 and previously implicated in maternal aggression, such as lateral septum, bed nucleus of stria terminalis, paraventricular nucleus, and central amygdala. Together, our results indicate that NT inversely regulates maternal aggression and provide the first direct evidence that lowering of NT signaling can be a mechanism for maternal aggression. To our knowledge, this is the first study to directly link NT to a social behavior. PMID:19118604

Reduced prefrontal and increased subcortical brain functioning assessed using positron emission tomography in predatory and affective murderers.

PubMed

Raine, A; Meloy, J R; Bihrle, S; Stoddard, J; LaCasse, L; Buchsbaum, M S

1998-01-01

There appear to be no brain imaging studies investigating which brain mechanisms subserve affective, impulsive violence versus planned, predatory violence. It was hypothesized that affectively violent offenders would have lower prefrontal activity, higher subcortical activity, and reduced prefrontal/subcortical ratios relative to controls, while predatory violent offenders would show relatively normal brain functioning. Glucose metabolism was assessed using positron emission tomography in 41 comparisons, 15 predatory murderers, and nine affective murderers in left and right hemisphere prefrontal (medial and lateral) and subcortical (amygdala, midbrain, hippocampus, and thalamus) regions. Affective murderers relative to comparisons had lower left and right prefrontal functioning, higher right hemisphere subcortical functioning, and lower right hemisphere prefrontal/subcortical ratios. In contrast, predatory murderers had prefrontal functioning that was more equivalent to comparisons, while also having excessively high right subcortical activity. Results support the hypothesis that emotional, unplanned impulsive murderers are less able to regulate and control aggressive impulses generated from subcortical structures due to deficient prefrontal regulation. It is hypothesized that excessive subcortical activity predisposes to aggressive behaviour, but that while predatory murderers have sufficiently good prefrontal functioning to regulate these aggressive impulses, the affective murderers lack such prefrontal control over emotion regulation.

Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study.

PubMed

Pan, Wei; Gao, Xuemei; Shi, Shuo; Liu, Fuqu; Li, Chao

2017-01-01

A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI). We used the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify spontaneous brain activity. The results showed there is no significant difference in ALFF, or fALFF, between violent video game group and the control part, indicating that long time exposure to violent video games won't significantly influence spontaneous brain activity, especially the core brain regions such as execution control, moral judgment and short-term memory. This implies the adverse impact of violent video games is exaggerated.

Spontaneous Brain Activity Did Not Show the Effect of Violent Video Games on Aggression: A Resting-State fMRI Study

PubMed Central

Pan, Wei; Gao, Xuemei; Shi, Shuo; Liu, Fuqu; Li, Chao

2018-01-01

A great many of empirical researches have proved that longtime exposure to violent video game can lead to a series of negative effects. Although research has focused on the neural basis of the correlation between violent video game and aggression, little is known whether the spontaneous brain activity is associated with violent video game exposure. To address this question, we measured the spontaneous brain activity using resting-state functional magnetic resonance imaging (fMRI). We used the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify spontaneous brain activity. The results showed there is no significant difference in ALFF, or fALFF, between violent video game group and the control part, indicating that long time exposure to violent video games won’t significantly influence spontaneous brain activity, especially the core brain regions such as execution control, moral judgment and short-term memory. This implies the adverse impact of violent video games is exaggerated. PMID:29375416

Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation.

PubMed

Skidmore, F M; Drago, V; Foster, P; Schmalfuss, I M; Heilman, K M; Streiff, R R

2008-04-01

Hereditary aceruloplasminaemia is a disorder of iron metabolism that is characterised by iron accumulation in the brain and other visceral organs. In previously reported cases, individuals with the disorder were noted to have evidence of iron accumulation in the brain. Oral chelating agents have not been used in neurological diseases of iron metabolism. A 54-year-old woman who presented with ataxia, lower extremity spasticity and chorea was evaluated for evidence of the source of neurological dysfunction. Blood studies revealed no detectable ceruloplasmin. Marked iron overload was defined by a liver biopsy, which showed a variegated pattern consistent with a primary cause of iron overload. Review of MRI scans showed progressive brain atrophy without visible iron accumulation occurring over a 5-year period. The history suggested that neurodegeneration was coincident with aggressive oral iron replacement. Oral chelation improved many symptoms. Our findings in this patient suggest that disorders of iron transport such as aceruloplasminaemia can be a cause of neurological symptoms such as chorea and cognitive decline, as well as progressive neurodegeneration in the absence of visible iron on MRI scans. We found that oral iron chelation was effective at improving symptoms.

Is aggressive treatment of traumatic brain injury cost-effective?

PubMed

Whitmore, Robert G; Thawani, Jayesh P; Grady, M Sean; Levine, Joshua M; Sanborn, Matthew R; Stein, Sherman C

2012-05-01

The object of this study was to determine whether aggressive treatment of severe traumatic brain injury (TBI), including invasive intracranial monitoring and decompressive craniectomy, is cost-effective. A decision-analytical model was created to compare costs, outcomes, and cost-effectiveness of 3 strategies for treating a patient with severe TBI. The aggressive-care approach is compared with "routine care," in which Brain Trauma Foundation guidelines are not followed. A "comfort care" category, in which a single day in the ICU is followed by routine floor care, is included for comparison only. Probabilities of each treatment resulting in various Glasgow Outcome Scale (GOS) scores were obtained from the literature. The GOS scores were converted to quality-adjusted life years (QALYs), based on expected longevity and calculated quality of life associated with each GOS category. Estimated direct (acute and long-term medical care) and indirect (loss of productivity) costs were calculated from the perspective of society. Sensitivity analyses employed a 2D Monte Carlo simulation of 1000 trials, each with 1000 patients. The model was also used to estimate these values for patients 40, 60, and 80 years of age. For the average 20-year-old, aggressive care yields 11.7 (± 1.6 [SD]) QALYs, compared with routine care (10.0 ± 1.5 QALYs). This difference is highly significant (p < 0.0001). Although the differences in effectiveness between the 2 strategies diminish with advancing age, aggressive care remains significantly better at all ages. When all costs are considered, aggressive care is also significantly less costly than routine care ($1,264,000 ± $118,000 vs $1,361,000 ± $107,000) for the average 20-year-old. Aggressive care remains significantly less costly until age 80, at which age it costs more than routine care. However, even in the 80-year-old, aggressive care is likely the more cost-effective approach. Comfort care is associated with poorer outcomes at all ages and with higher costs for all groups except 80-year-olds. When all the costs of severe TBI are considered, aggressive treatment is a cost-effective option, even for older patients. Comfort care for severe TBI is associated with poor outcomes and high costs, and should be reserved for situations in which aggressive approaches have failed or testing suggests such treatment is futile.

Narcissism, Perceived Social Status, and Social Cognition and Their Influence on Aggression

ERIC Educational Resources Information Center

Gumpel, Thomas P.; Wiesenthal, Vered; Söderberg, Patrik

2015-01-01

This study had three primary goals: to explore the relationship between narcissism, participant roles, and aggression; to examine the role of gender as a moderating influence on narcissism-based aggression; and to examine how these variables work together to influence aggressive outcomes in a sample of aggressive middle and high school students.…

Aggression is associated with greater subsequent alcohol consumption: A shared neural basis in the ventral striatum.

PubMed

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.

Unravelling the neurophysiological basis of aggression in a fish model

PubMed Central

2010-01-01

Background Aggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate. Results Substantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo-pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors. Conclusions Thus, through an integrated approach, combining gene expression profiling, behavioural analyses, and pharmacological manipulations, we identified candidate genes and pathways that appear to play significant roles in regulating aggression in fish. Many of these are novel for non-mammalian systems. We further present a validated system for advancing our understanding of the mechanistic underpinnings of complex behaviours using a fish model. PMID:20846403

Quantitative proteomic analysis reveals effects of epidermal growth factor receptor (EGFR) on invasion-promoting proteins secreted by glioblastoma cells.

PubMed

Sangar, Vineet; Funk, Cory C; Kusebauch, Ulrike; Campbell, David S; Moritz, Robert L; Price, Nathan D

2014-10-01

Glioblastoma multiforme is a highly invasive and aggressive brain tumor with an invariably poor prognosis. The overexpression of epidermal growth factor receptor (EGFR) is a primary influencer of invasion and proliferation in tumor cells and the constitutively active EGFRvIII mutant, found in 30-65% of Glioblastoma multiforme, confers more aggressive invasion. To better understand how EGFR contributes to tumor aggressiveness, we investigated the effect of EGFR on the secreted levels of 65 rationally selected proteins involved in invasion. We employed selected reaction monitoring targeted mass spectrometry using stable isotope labeled internal peptide standards to quantity proteins in the secretome from five GBM (U87) isogenic cell lines in which EGFR, EGFRvIII, and/or PTEN were expressed. Our results show that cell lines with EGFR overexpression and constitutive EGFRvIII expression differ remarkably in the expression profiles for both secreted and intracellular signaling proteins, and alterations in EGFR signaling result in reproducible changes in concentrations of secreted proteins. Furthermore, the EGFRvIII-expressing mutant cell line secretes the majority of the selected invasion-promoting proteins at higher levels than other cell lines tested. Additionally, the intracellular and extracellular protein measurements indicate elevated oxidative stress in the EGFRvIII-expressing cell line. In conclusion, the results of our study demonstrate that EGFR signaling has a significant effect on the levels of secreted invasion-promoting proteins, likely contributing to the aggressiveness of Glioblastoma multiforme. Further characterization of these proteins may provide candidates for new therapeutic strategies and targets as well as biomarkers for this aggressive disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Signals that regulate the oncogenic fate of neural stem cells and progenitors

PubMed Central

Swartling, Fredrik J.; Bolin, Sara; Phillips, Joanna J.; Persson, Anders I.

2013-01-01

Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors. PMID:23376224

Maternal nurturing is dependent on her innate anxiety: the behavioral roles of brain oxytocin and vasopressin.

PubMed

Bosch, Oliver J

2011-02-01

The maternal brain undergoes remarkable physiological and behavioral changes in the peripartum period to meet the demands of the offspring. Here, the brain neuropeptides oxytocin and vasopressin, together with prolactin, play important roles. These neuropeptides are critically involved in the regulation of maternal behavior. Furthermore, reduced anxiety in lactation is another adaptation of the maternal brain. Therefore, a link between maternal behavior and maternal anxiety has been repeatedly postulated. This is supported by our studies in rats bred for high (HAB) and low (LAB) anxiety-related behavior. While female HAB rats become less anxious in lactation, their anxiety level is still four times higher compared with LAB dams. Interestingly, HAB dams display an intense and protective mothering style including increased arched back nursing and pup retrieval whereas LAB dams display only low levels of maternal care. The amount of maternal care directed towards the pups correlates with the mother's innate anxiety. In addition to differences in maternal care, HAB dams are also more protective as they show heightened aggression against a virgin intruder compared with the less aggressive LAB dams. The level of maternal aggression correlates with both their innate anxiety level as well as with the release of oxytocin and vasopressin in hypothalamic and limbic brain areas. Importantly, manipulations of the brain oxytocin and vasopressin systems alter maternal behavior and - depending on the brain region - can also alter the dam's anxiety. Thus, the mother's innate anxiety determines her maternal performance and oxytocin and vasopressin are involved in both parameters. Copyright © 2010 Elsevier Inc. All rights reserved.

[Aggressions towards Primary Health Care Workers in Madrid, Spain, 2011-2012].

PubMed

Rincón-Del Toro, Teresa; Villanueva-Guerra, Adela; Rodríguez-Barrientos, Ricardo; Polentinos-Castro, Elena; Torijano-Castillo, Mª José; de Castro-Monteiro, Emilia; Escrivá de Romaní de Gregorio, Blanca; Barba Calderón, Margarita; de Frías Redondo, María Soledad; Alejo Brú, Nury; Blanco Morales, Concepción; Vázquez Pinilla, Margarita; Besora Altés, Cristina; Heras-Mosteiro, Julio; Infantes Rodríguez, Juan Ángel; Bustamante Fernández, Pilar; de Blas Salvador, Victorina

2016-10-25

The number of aggressions towards health care professionals has risen over the past few years. There are no previous studies in primary care covering an entire region and to all professional categories. The aim of this study was to characterize aggressions in Primary Care in the Community of Madrid. Multicenter cross-sectional study. Analysis of a Registration System that reports any type of aggression suffered by Primary Care workers, in the Community of Madrid. The study variables included sociodemographic characteristics of the aggressor and the victim, the type of aggression (verbal or physical abuse), its causes and consequences. We described median, intercuartilic range and frequencies. Logistic regression was performed calculating odds ratio and their 95% confidence intervals. 1,157 assaults were reported, 53.07% suffered by doctors. Physical assault occurred in 4.7% of the cases. The main reason was dissatisfaction with the care (36.1%). The non-medical staff showed less risk of being physically assaulted (OR: 0.38; CI95%: 0.17-0.86). The perpetrator profile was male (56.8%), aged between 31-40 (26.8%) years. Health care victim profile was female (84%), aged between 45-60 years. 10% of professionals reported some form of aggression, 5,9% of aggression were submitted to court. The risk of assault is higher in health personnel, particularly physicians. There were significant differences by gender and age, both in the profile of the aggressor and the victim.

Cytomegalovirus infection in early childhood may be protective against glioblastoma multiforme, while later infection is a risk factor.

PubMed

Lehrer, Steven

2012-05-01

Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. Recently, evidence for a viral cause has been postulated, possibly cytomegalovirus (CMV). In one report, 80% of patients with newly diagnosed glioblastoma multiforme had detectable cytomegalovirus DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus. However, another study reported that five glioblastoma patients showed no circulating CMV detected either with RT-PCR or blood culture. But CMV could still be a factor in the genesis of glioblastoma multiforme, if age at infection is taken into account, since the incidence of both glioblastoma multiforme and CMV infection are inversely related to socioeconomic status. CMV infection in early childhood, more common in lower socioeconomic groups, may be protective against glioblastoma multiforme, whereas CMV infection in later childhood or adulthood may be a risk factor for glioblastoma. If so, glioblastoma multiforme occurrence would resemble paralytic polio, where low socioeconomic status, poor hygiene and early infection are protective. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dexamethasone Alleviates Tumor-Associated Brain Damage and Angiogenesis

PubMed Central

Fan, Zheng; Sehm, Tina; Rauh, Manfred; Buchfelder, Michael

2014-01-01

Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc −; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage. PMID:24714627

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development

PubMed Central

Ziermans, T; Dumontheil, I; Roggeman, C; Peyrard-Janvid, M; Matsson, H; Kere, J; Klingberg, T

2012-01-01

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene–brain–behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ∼6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development. PMID:22832821

Status Struggles: Network Centrality and Gender Segregation in Same- and Cross-Gender Aggression

ERIC Educational Resources Information Center

Faris, Robert; Felmlee, Diane

2011-01-01

Literature on aggression often suggests that individual deficiencies, such as social incompetence, psychological difficulties, or troublesome home environments, are responsible for aggressive behavior. In this article, by contrast, we examine aggression from a social network perspective, arguing that social network centrality, our primary measure…

Behavior Management for Children and Adolescents with Acquired Brain Injury

ERIC Educational Resources Information Center

Slifer, Keith J.; Amari, Adrianna

2009-01-01

Behavioral problems such as disinhibition, irritability, restlessness, distractibility, and aggression are common after acquired brain injury (ABI). The persistence and severity of these problems impair the brain-injured individual's reintegration into family, school, and community life. Since the early 1980s, behavior analysis and therapy have…

Attributional bias and reactive aggression.

PubMed

Hudley, C; Friday, J

1996-01-01

This article looks at a cognitive behavioral intervention designed to reduce minority youths' (Latino and African-American boys) levels of reactive peer-directed aggression. The BrainPower Program trains aggressive boys to recognize accidental causation in ambiguous interactions with peers. The objective of this research is to evaluate the effectiveness of this attribution retraining program in reducing levels of reactive, peer-directed aggression. This research hypothesizes that aggressive young boys' tendency to attribute hostile intentions to others in ambiguous social interactions causes display of inappropriate, peer-directed aggression. A reduction in attributional bias should produce a decrease in reactive physical and verbal aggression directed toward peers. A 12-session, attributional intervention has been designed to reduce aggressive students' tendency to infer hostile intentions in peers following ambiguous peer provocations. The program trains boys to (1) accurately perceive and categorize the available social cues in interactions with peers, (2) attribute negative outcomes of ambiguous causality to accidental or uncontrollable causes, and (3) generate behaviors appropriate to these retrained attributions. African-American and Latino male elementary-school students (N = 384), in grades four-six, served as subjects in one of three groups: experimental attribution retraining program, attention training, and no-attention control group. Three broad categories of outcome data were collected: teacher and administrator reports of behavior, independent observations of behavior, and self-reports from participating students. Process measures to assess implementation fidelity include videotaped training sessions, observations of intervention sessions, student attendance records, and weekly team meetings. The baseline data indicated that students who were evenly distributed across the four sites were not significantly different on the baseline indicators: student cognitions, teacher perceptions of behavior, and student suspension rates. Substantial evidence has shown that aggressive boys tend to attribute hostile intentions to peers, often resulting in inappropriate retaliatory aggression. The BrainPower Program was designed to determine whether psychoeducational strategies in a school context are effective in reducing attributional bias and whether such reductions significantly reduce aggressive behavior.

Sex differences in aggression among children of low and high gender inequality backgrounds: a comparison of gender role and sexual selection theories.

PubMed

Nivette, Amy E; Eisner, Manuel; Malti, Tina; Ribeaud, Denis

2014-01-01

It is well understood in aggression research that males tend to exhibit higher levels of physical aggression than females. Yet there are still a number of gaps in our understanding of variation in sex differences in children's aggression, particularly in contexts outside North America. A key assumption of social role theory is that sex differences vary according to gender polarization, whereas sexual selection theory accords variation to the ecological environment that consequently affects male competition [Archer, J. (2009). Behavioral and Brain Sciences, 32, 249-311; Kenrick, D., & Griskevicious, V. (2009). More holes in social roles [Comment]. Behavioral and Brain Sciences, 32, 283-285]. In the present paper, we explore these contradicting theoretical frameworks by examining data from a longitudinal study of a culturally diverse sample of 863 children at ages 7-13 in Zurich, Switzerland. Making use of the large proportion of children from highly diverse immigrant background we compare the size of the sex difference in aggression between children whose parents were born in countries with low and with high levels of gender inequality. The results show that sex differences in aggression are generally larger among children with parents from high gender inequality backgrounds. However, this effect is small in comparison to the direct effect of a child's biological sex. We discuss implications for future research on sex differences in children's aggression. © 2014 Wiley Periodicals, Inc.

Effects of Early Serotonin Programming on Fear Response, Memory and Aggression

USDA-ARS?s Scientific Manuscript database

The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter development of serotonergic circuitry, altering behaviors mediated by 5-HT signaling, including memory, fear and aggression. The present study was desi...

Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors

PubMed Central

Mastorakos, Panagiotis; Zhang, Clark; Song, Eric; Kim, Young Eun; Park, Hee Won; Berry, Sneha; Choi, Won Kyu; Hanes, Justin; Suk, Jung Soo

2018-01-01

The discovery of powerful genetic targets has spurred clinical development of gene therapy approaches to treat patients with malignant brain tumors. However, lack of success in the clinic has been attributed to the inability of conventional gene vectors to achieve gene transfer throughout highly disseminated primary brain tumors. Here, we demonstrate ex vivo that small nanocomplexes composed of DNA condensed by a blend of biodegradable polymer, poly(β-amino ester) (PBAE), with PBAE conjugated with 5 kDa polyethylene glycol (PEG) molecules (PBAE-PEG) rapidly penetrate healthy brain parenchyma and orthotopic brain tumor tissues in rats. Rapid diffusion of these DNA-loaded nanocomplexes observed in fresh tissues ex vivo demonstrated that they avoided adhesive trapping in the brain owing to their dense PEG coating, which was critical to achieving widespread transgene expression throughout orthotopic rat brain tumors in vivo following administration by convection enhanced delivery. Transgene expression with the PBAE/PBAE-PEG blended nanocomplexes (DNA-loaded brain-penetrating nanocomplexes, or DNA-BPN) was uniform throughout the tumor core compared to nanocomplexes composed of DNA with PBAE only (DNA-loaded conventional nanocomplexes, or DNA-CN), and transgene expression reached beyond the tumor edge, where infiltrative cancer cells are found, only for the DNA-BPN formulation. Finally, DNA-BPN loaded with anti-cancer plasmid DNA provided significantly enhanced survival compared to the same plasmid DNA loaded in DNA-CN in two aggressive orthotopic brain tumor models in rats. These findings underscore the importance of achieving widespread delivery of therapeutic nucleic acids within brain tumors and provide a promising new delivery platform for localized gene therapy in the brain. PMID:28694032

[Palliative care in Primary Care: presentation of a case].

PubMed

Álvarez-Cordovés, M M; Mirpuri-Mirpuri, P G; Gonzalez-Losada, J; Chávez-Díaz, B

2013-10-01

We present a case of a patient diagnosed with glioblastoma multiforme refractory to treatment. Glioblastoma multiforme is the most common primary brain tumour and unfortunately the most aggressive, with an estimated mortality of about 90% in the first year after diagnosis. In our case the patient had reached a stage of life where quality of life was importsnt, with palliative care being the only recourse. The family is the mainstay in the provision of care of terminally ill patients, and without their active participation it would be difficult to achieve the objectives in patient care. We must also consider the family of the terminally ill in our care aim, as its members will experience a series of changes that will affect multiple areas where we should take action. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

Anabolic androgenic steroids differentially affect social behaviors in adolescent and adult male Syrian hamsters

PubMed Central

Salas-Ramirez, Kaliris Y.; Montalto, Pamela R.; Sisk, Cheryl L.

2010-01-01

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone used by over half a million adolescents in the United States for their tissue-building potency and performance-enhancing effects. AAS also affect behavior, including reports of heightened aggression and changes in sexual libido. The expression of sexual and aggressive behaviors is a function of complex interactions among hormones, social context, and the brain, which is extensively remodeled during adolescence. Thus, AAS may have different consequences on behavior during adolescence and adulthood. Using a rodent model, these studies directly compared the effects of AAS on the expression of male sexual and aggressive behaviors in adolescents and adults. Male Syrian hamsters were injected daily for 14 days with either vehicle or an AAS cocktail containing testosterone cypionate (2 mg/kg), nandrolone decanoate (2 mg/kg), and boldenone undecylenate (1 mg/kg), either during adolescence (27–41 days of age) or in adulthood (63–77 days of age). The day after the last injection, males were tested for either sexual behavior with a receptive female or agonistic behavior with a male intruder. Adolescent males treated with AAS showed significant increases in sexual and aggressive behaviors relative to vehicle-treated adolescents. In contrast, AAS-treated adults showed significantly lower levels of sexual behavior compared with vehicle-treated adults and did not show heightened aggression. Thus, adolescents, but not adults, displayed significantly higher behavioral responses to AAS, suggesting that the still-developing adolescent brain is more vulnerable than the adult brain to the adverse consequences of AAS on the nervous system and behavior. PMID:18201704

Sex-role reversal is reflected in the brain of African black coucals (Centropus grillii).

PubMed

Voigt, Cornelia; Goymann, Wolfgang

2007-10-01

In most bird species males compete over access to females and have elevated circulating androgen levels when they establish and defend a breeding territory or guard a mate. Testosterone is involved in the regulation of territorial aggression and sexual display in males. In few bird species the traditional sex-roles are reversed and females are highly aggressive and compete over access to males. Such species represent excellent models to study the hormonal modulation of aggressive behavior in females. Plasma sex steroid concentrations in sex-role reversed species follow the patterns of birds with "traditional" sex-roles. The neural mechanisms modulating endocrine secretion and hormone-behavior interactions in sex-role reversed birds are currently unknown. We investigated the sex differences in the mRNA expression of androgen receptors, estrogen receptor alpha, and aromatase in two brain nuclei involved in reproductive and aggressive behavior in the black coucal, the nucleus taeniae and the bed nucleus of the stria terminalis. In the bed nucleus there were no sex differences in the receptor or aromatase expression. In the nucleus taeniae, however, we show for the first time, that females have a higher mRNA expression of androgen receptors than males. These results suggest that the expression of agonistic and courtship behavior in females does not depend on elevated blood hormone levels, but may be regulated via increased steroid hormone sensitivity in particular target areas in the brain. Hence, aggression in females and males may indeed be modulated by the same hormones, but regulated at different levels of the neuroendocrine cascade. 2007 Wiley Periodicals, Inc.

Molecular mechanisms and the conflict between courtship and aggression in three-spined sticklebacks.

PubMed

Sanogo, Yibayiri O; Bell, Alison M

2016-09-01

In nature, animals often face conflicting demands. For example, breeding males must attract a mate but at the same time be ready to defend against rivals. The molecular mechanisms by which the brain resolves behavioural trade-offs are largely unknown. In this study, we compared the brain transcriptional responses of territorial male three-spined sticklebacks to a mating opportunity with a female and to a territorial challenge by a rival male. We focused on the diencephalon and the cerebellum, two regions of the brain implicated in courtship and aggression. There was a set of genes that were differentially expressed in response to both a courtship opportunity and a territorial challenge. Closer inspection of the direction of regulation revealed that genes that were downregulated in response to a courtship opportunity were upregulated in response to a territorial challenge and vice versa. Our study reveals some of the potential molecular mechanisms underlying behavioural trade-offs between sex and aggression, along with a possible solution to the conflict via social context-dependent gene regulation. © 2016 John Wiley & Sons Ltd.

Social determinants of aggression in a sample of Chinese primary school children.

PubMed

Ekblad, S

1986-05-01

The aim of the present study was to relate children's aggression levels to social determinants of interest (i.e., child-rearing measures, day-care attendance, peer group influence, and TV-watching) in a sample of Chinese children in the People's Republic of China. A sample of 290 primary school students (155 boys and 135 girls, mean age 10.3) in grade four in Beijing were investigated using the Multi-Faceted Aggression Inventory. The children's parents were asked about child-rearing measures and day-care experience for the child. Teachers rated the children's aggression, school achievement level, and membership in the Young Pioneers. Despite acknowledged limitations, the findings in this study gave evidence that according to a person-environment interaction perspective, the Chinese children's individual differences in aggression were influenced by the restricted environment. As aggressive behaviour is undesired and suppressed in the Chinese culture in and outside the home, the Chinese children seemed to show lower levels and less variation of aggression behaviour than children in permissive environments (e.g., Sweden). However, when analysing sex differences in aggression environmental influences alone might not explain the differences.

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Sykes, Catherine E; Shah, Mrudang M; Francescutti, Dina M; Rosenberg, David R; Thomas, David M; Kuhn, Donald M

2012-06-01

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Identifying aggressive prostate cancer foci using a DNA methylation classifier.

PubMed

Mundbjerg, Kamilla; Chopra, Sameer; Alemozaffar, Mehrdad; Duymich, Christopher; Lakshminarasimhan, Ranjani; Nichols, Peter W; Aron, Manju; Siegmund, Kimberly D; Ukimura, Osamu; Aron, Monish; Stern, Mariana; Gill, Parkash; Carpten, John D; Ørntoft, Torben F; Sørensen, Karina D; Weisenberger, Daniel J; Jones, Peter A; Duddalwar, Vinay; Gill, Inderbir; Liang, Gangning

2017-01-12

Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

Chemosensory danger detection in the human brain: Body odor communicating aggression modulates limbic system activation.

PubMed

Mutic, Smiljana; Brünner, Yvonne F; Rodriguez-Raecke, Rea; Wiesmann, Martin; Freiherr, Jessica

2017-05-01

Although the sense of smell is involved in numerous survival functions, the processing of body odor emitted by dangerous individuals is far from understood. The aim of the study was to explore how human fight chemosignals communicating aggression can alter brain activation related to an attentional bias and danger detection. While the anterior cingulate cortex (ACC) was seen involved in processing threat-related emotional information, danger detection and error evaluation, it still remains unknown whether human chemosignals communicating aggression can potentially modulate this activation. In the fMRI experiment, healthy male and female normosmic odor recipients (n=18) completed a higher-order processing task (emotional Stroop task with the word categories anger, anxiety, happiness and neutral) while exposed to aggression and exercise chemosignals (collected from a different group of healthy male donors; n=16). Our results provide first evidence that aggression chemosignals induce a time-sensitive attentional bias in chemosensory danger detection and modulate limbic system activation. During exposure to aggression chemosignals compared to exercise chemosignals, functional imaging data indicates an enhancement of thalamus, hypothalamus and insula activation (p<.05, FWE-corrected). Together with the thalamus, the ACC was seen activated in response to threat-related words (p<.001). Chemosensory priming and habituation to body odor signals are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

NASA Astrophysics Data System (ADS)

Davis, Shaun M.; Thomas, Amanda L.; Nomie, Krystle J.; Huang, Longwen; Dierick, Herman A.

2014-02-01

Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

Aggression, the Prequel: Preventing the Need

ERIC Educational Resources Information Center

Gartrell, Dan

2011-01-01

An authority on neuroscience (the study of the structure and functioning of the brain) and human relationships, Daniel Siegel (2001) begins his classic work, "The Developing Mind: How Relationships and the Brain Interact to Shape Who We Are," with a basic concept: the brain is an open system that physically changes throughout life in response to…

Developmental effects of aggressive behavior in male adolescents assessed with structural and functional brain imaging

PubMed Central

Strenziok, Maren; Krueger, Frank; Heinecke, Armin; Lenroot, Rhoshel K.; Knutson, Kristine M.; van der Meer, Elke

2011-01-01

Aggressive behavior is common during adolescence. Although aggression-related functional changes in the ventromedial prefrontal cortex (vmPFC) and frontopolar cortex (FPC) have been reported in adults, the neural correlates of aggressive behavior in adolescents, particularly in the context of structural neurodevelopment, are obscure. We used functional and structural magnetic resonance imaging (MRI) to measure the blood oxygenation level-depended signal and cortical thickness. In a block-designed experiment, 14–17-year old adolescents imagined aggressive and non-aggressive interactions with a peer. We show reduced vmPFC activation associated with imagined aggressive behavior as well as enhanced aggression-related activation and cortical thinning in the FPC with increasing age. Changes in FPC activation were also associated with judgments of the severity of aggressive acts. Reduced vmPFC activation was associated with greater aggression indicating its normal function is to exert inhibitory control over aggressive impulses. Concurrent FPC activation likely reflects foresight of harmful consequences that result from aggressive acts. The correlation of age-dependent activation changes and cortical thinning demonstrates ongoing maturation of the FPC during adolescence towards a refinement of social and cognitive information processing that can potentially facilitate mature social behavior in aggressive contexts. PMID:19770220

Pharmacology and pharmacogenetics of pediatric ADHD with associated aggression: a review.

PubMed

Patel, Bianca D; Barzman, Drew H

2013-12-01

Attention deficit hyperactivity disorder (ADHD) is often associated with symptoms of aggression in children and adolescents. Clinically, this is complex because aggression can be from hyperactivity and impulsivity, or could be a distinct symptom from a comorbid diagnosis. Past research has recommended first treating the primary disorder of ADHD. Stimulants are the most common treatment for pediatric ADHD, which can be helpful in decreasing aggressive behaviors. Alpha-adrenergic agonists and atomoxetine (ATX) are non-stimulant medications for ADHD and aggression, but more research is necessary to compare these drugs to stimulants. If aggressive symptoms do not improve from treating the primary disorder, aggression can be treated separately. Risperidone, lithium, valproic acid, clonidine, and guanfacine have shown positive results in reducing aggression, but studies including children with aggression and ADHD are limited. The variability in treatment tolerability in patients has stimulated research in pharmacogenetics for ADHD. Although this field is still emerging, research has found evidence supporting a link between the response rate of methylphenidate and the dopamine transporter (DAT1) and a link between the metabolism rate of atomoxetine and hepatic cytochrome 450 isozymes. Pharmacogenetics may be relevant to ADHD and associated aggression. Further research in pharmacogenetics will strive to identify patterns of genetic variations that can tailor individual treatments.

Peace Education's Effects on Aggression: A Mixed Method Study

ERIC Educational Resources Information Center

Sagkal, Ali Serdar; Turnuklu, Abbas; Totan, Tarik

2016-01-01

Problem Statement: Literature reviews clearly document that students still show a tendency to use violence in resolving interpersonal conflicts in school. Results from various research conducted in Turkey suggest that violence, aggression, and bullying behaviors are still rampant in the primary and high schools. Studies conducted in primary and…

Intimate Partner Aggression Perpetrated and Sustained by Male Afghanistan, Iraq, and Vietnam Veterans with and without Posttraumatic Stress Disorder

ERIC Educational Resources Information Center

Teten, Andra L.; Schumacher, Julie A.; Taft, Casey T.; Stanley, Melinda A.; Kent, Thomas A.; Bailey, Sara D.; Dunn, Nancy Jo; White, Donna L.

2010-01-01

Veterans with posttraumatic stress disorder (PTSD) consistently evidence higher rates of intimate partner aggression perpetration than veterans without PTSD, but most studies have examined rates of aggression among Vietnam veterans several years after their deployment. The primary aim of this study was to examine partner aggression among male…

The nature of human aggression.

PubMed

Archer, John

2009-01-01

Human aggression is viewed from four explanatory perspectives, derived from the ethological tradition. The first consists of its adaptive value, which can be seen throughout the animal kingdom, involving resource competition and protection of the self and offspring, which has been viewed from a cost-benefit perspective. The second concerns the phylogenetic origin of aggression, which in humans involves brain mechanisms that are associated with anger and inhibition, the emotional expression of anger, and how aggressive actions are manifest. The third concerns the origin of aggression in development and its subsequent modification through experience. An evolutionary approach to development yields conclusions that are contrary to the influential social learning perspective, notably that physical aggression occurs early in life, and its subsequent development is characterized by learned inhibition. The fourth explanation concerns the motivational mechanisms controlling aggression: approached from an evolutionary background, these mechanisms range from the inflexible reflex-like responses to those incorporating rational decision-making.

Seizure frequency reduction after posteromedial hypothalamus deep brain stimulation in drug-resistant epilepsy associated with intractable aggressive behavior.

PubMed

Benedetti-Isaac, Juan C; Torres-Zambrano, Martin; Vargas-Toscano, Andres; Perea-Castro, Esther; Alcalá-Cerra, Gabriel; Furlanetti, Luciano L; Reithmeier, Thomas; Tierney, Travis S; Anastasopoulos, Constantin; Fonoff, Erich T; Contreras Lopez, William Omar

2015-07-01

The aim of this study was to analyze the impact of deep brain stimulation (DBS) of the posteromedial hypothalamus (pHyp) on seizure frequency in patients with drug-resistant epilepsy (DRE) associated with intractable aggressive behavior (IAB). Data were collected retrospectively from nine patients, who received bilateral stereotactic pHyp-DBS for the treatment of medically intractable aggressive behavior, focusing on five patients who also had DRE. All patients were treated at the Colombian Center and Foundation of Epilepsy and Neurological Diseases-FIRE (Chapter of the International Bureau for Epilepsy), in Cartagena de Indias, Colombia from 2010 to 2014. Each case was evaluated previously by the institutional ethical committee, assessing the impact of aggressive behavior on the patient's family and social life, the humanitarian aspects of preserving the safety and physical integrity of caregivers, and the need to prevent self-harm. Epilepsy improvement was measured by a monthly seizure reduction percentage, comparing preoperative state and outcome. Additional response to epilepsy was defined by reduction of the antiepileptic drugs (AEDs). Aggressive behavior response was measured using the Overt Aggression Scale (OAS). All the patients with DRE associated with IAB presented a significant decrease of the rate of epileptic seizures after up to 4 years follow-up, achieving a general 89.6% average seizure reduction from the state before the surgery. Aggressiveness was significantly controlled, with evident improvement in the OAS, enhancing the quality of life of patients and families. In well-selected patients, DBS of the pHyp seems to be a safe and effective procedure for treatment of DRE associated with refractory aggressive behavior. Larger and prospective series are needed to define the pHyp as a target for DRE in different contexts. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Do sex reversal procedures differentially affect agonistic behaviors and sex steroid levels depending on the sexual genotype in Nile tilapia?

PubMed

Gennotte, Vincent; Akonkwa, Balagizi; Mélard, Charles; Denoël, Mathieu; Cornil, Charlotte A; Rougeot, Carole

2017-04-01

In Nile tilapia Oreochromis niloticus, phenotypic males and females with different sexual genotypes (XX, XY, YY) have particular behavioral and physiological traits. Compared to natural XX females and XY males, XY and YY females and XX males expressed higher level of aggressiveness that could be related to higher levels of 17β-estradiol and 11-ketotestosterone, respectively. Our results suggest that the presence of a Y chromosome increases aggressiveness in females. However, since the same relationship between aggressiveness and the Y chromosome is not observed in males, we can hypothesize that the differences in aggressiveness are not directly dependent on the genotype but on the sex reversal procedures applied on young fry during their sexual differentiation to produce these breeders. These hormonal treatments could have permanently modified the development of the brain and consequently influenced the behavior of adults independently of their genotype. In both hypotheses (genotype or sex reversal influence), the causes of behavioral modifications have to be searched in an early modification of the brain sexual differentiation. © 2017 Wiley Periodicals, Inc.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PubMed

Van Swearingen, Amanda E D; Siegel, Marni B; Deal, Allison M; Sambade, Maria J; Hoyle, Alan; Hayes, D Neil; Jo, Heejoon; Little, Paul; Dees, Elizabeth Claire; Muss, Hyman; Jolly, Trevor; Zagar, Timothy M; Patel, Nirali; Miller, C Ryan; Parker, Joel S; Smith, J Keith; Fisher, Julie; Shah, Nikita; Nabell, Lisle; Nanda, Rita; Dillon, Patrick; Abramson, Vandana; Carey, Lisa A; Anders, Carey K

2018-06-25

HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. (NCT01305941).

Combined targeting of PDK1 and EGFR triggers regression of glioblastoma by reversing the Warburg effect.

PubMed

Velpula, Kiran Kumar; Bhasin, Arnima; Asuthkar, Swapna; Tsung, Andrew J

2013-12-15

Glioblastoma multiforme is the most aggressive primary brain tumor in adults. Overexpression of the EGF receptor (EGFR) is recognized as a widespread oncogenic signature in glioblastoma multiforme, but the complexity of its contributions is not fully understood, nor the most effective ways to leverage anti-EGFR therapy in this setting. Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria (OXPHOS), a phenomenon termed the Warburg effect, which is a general feature of oncogenesis. In this study, we report that hypoxia drives expression of the pyruvate dehydrogenase kinase (PDK1) and EGFR along with the hypoxia-inducing factor (HIF)-1α in human glioblastoma multiforme cells. PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation, initiating a feed-forward loop that can sustain malignant progression. RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1α expression, shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation. In clinical specimens of glioblastoma multiforme, we found that immunohistochemical expression of PDK1, EGFR, and HIF-1α were elevated in glioblastoma multiforme specimens when compared with normal brain tissues. Collectively, our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme. ©2013 AACR.

Reactive and proactive aggression as meaningful distinctions at the variable and person level in primary school-aged children.

PubMed

Carroll, Annemaree; McCarthy, Molly; Houghton, Stephen; Sanders O'Connor, Emma; Zadow, Corinne

2018-04-24

Reactive and proactive aggression is a dichotomous classification of aggression in adults and children. This distinction has been supported by a number of variable-based and factor analytic studies. Due to high inter-correlations, however, the reactive-proactive aggression distinction may not be entirely useful for understanding how group or individual aggressive behavior varies in children and adolescents. Drawing on a sample of primary school-aged children (N = 242) aged 7-12 years, this study sought to determine whether reactive and proactive aggression could be distinguished at the variable-level and the person-level in children. Exploratory Factor Analysis of data from an aggression instrument measuring both functions and forms of aggression, found a two-factor construct of aggression constituted by a reactive and proactive aggression factor. A person-based analysis was then conducted after classifying children according to the presence of reactive and/or proactive aggression. Discriminant function analysis was used to discern whether classifications on the basis of aggression function produced meaningful distinctions in terms of antisocial traits and emotional valence and intensity measures. Two functions were identified which distinguished children with different combinations of reactive and proactive aggression. Reactive-only aggressive children were defined primarily by high levels of impulsivity, while proactive-only children were defined primarily by higher levels of antisocial traits. Children high in both types of aggression exhibited both the presence of antisocial traits and impulsivity. Contrary to recent findings, this suggests that differences in aggression functions remain meaningful at the person level in children. Implications for interventions are discussed. © 2018 Wiley Periodicals, Inc.

P1 interneurons promote a persistent internal state that enhances inter-male aggression in Drosophila

PubMed Central

Hoopfer, Eric D; Jung, Yonil; Inagaki, Hidehiko K; Rubin, Gerald M; Anderson, David J

2015-01-01

How brains are hardwired to produce aggressive behavior, and how aggression circuits are related to those that mediate courtship, is not well understood. A large-scale screen for aggression-promoting neurons in Drosophila identified several independent hits that enhanced both inter-male aggression and courtship. Genetic intersections revealed that 8-10 P1 interneurons, previously thought to exclusively control male courtship, were sufficient to promote fighting. Optogenetic experiments indicated that P1 activation could promote aggression at a threshold below that required for wing extension. P1 activation in the absence of wing extension triggered persistent aggression via an internal state that could endure for minutes. High-frequency P1 activation promoted wing extension and suppressed aggression during photostimulation, whereas aggression resumed and wing extension was inhibited following photostimulation offset. Thus, P1 neuron activation promotes a latent, internal state that facilitates aggression and courtship, and controls the overt expression of these social behaviors in a threshold-dependent, inverse manner. DOI: http://dx.doi.org/10.7554/eLife.11346.001 PMID:26714106

The pleasure of revenge: retaliatory aggression arises from a neural imbalance toward reward

PubMed Central

DeWall, C. Nathan

2016-01-01

Most of daily life hums along peacefully but provocations tip the balance toward aggression. Negative feelings are often invoked to explain why people lash out after an insult. Yet people might retaliate because provocation makes aggression hedonically rewarding. To test this alternative hypothesis, 69 participants underwent functional neuroimaging while they completed a behavioral aggression task that repeatedly manipulated whether aggression was preceded by an instance of provocation or not. After provocation, greater activity in the nucleus accumbens (NAcc) (a brain region reliably associated with reward) during aggressive decisions predicted louder noise blasts administered in retaliation. Greater NAcc activation was also associated with participants’ history of real-world violence. Functional connectivity between the NAcc and a regulatory region in the lateral prefrontal cortex related to lower retaliatory aggression. These findings suggest that provocation tips the neural balance towards hedonic reward, which fosters retaliatory aggression. Although such pleasure of inflicting pain may promote retaliatory aggression, self-regulatory processes can keep such aggressive urges at bay. Implications for theory and violence reduction are discussed. PMID:26117504

New approach to neurorehabilitation: cranial nerve noninvasive neuromodulation (CN-NINM) technology

NASA Astrophysics Data System (ADS)

Danilov, Yuri P.; Tyler, Mitchel E.; Kaczmarek, Kurt A.; Skinner, Kimberley L.

2014-06-01

Cranial Nerve NonInvasive NeuroModulation (CN-NINM) is a primary and complementary multi-targeted rehabilitation therapy that appears to initiate the recovery of multiple damaged or suppressed brain functions affected by neurological disorders. It is deployable as a simple, home-based device (portable neuromodulation stimulator, or PoNSTM) and training regimen following initial patient training in an outpatient clinic. It may be easily combined with many existing rehabilitation therapies, and may reduce or eliminate the need for more aggressive invasive procedures or possibly decrease total medication intake. CN-NINM uses sequenced patterns of electrical stimulation on the tongue. Our hypothesis is that CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal (CN-V), and facial (CN-VII). This stimulation excites a natural flow of neural impulses to the brainstem (pons varolli and medulla), and cerebellum, to effect changes in the function of these targeted brain structures, extending to corresponding nuclei of the brainstem. CN-NINM represents a synthesis of a new noninvasive brain stimulation technique with applications in physical medicine, cognitive, and affective neurosciences. Our new stimulation method appears promising for treatment of a full spectrum of movement disorders, and for both attention and memory dysfunction associated with traumatic brain injury.

[Functional neuroimaging in the study of aggressive behaviour in patients with schizophrenia].

PubMed

Garciá-Martí, Gracián; Martí-Bonmatí, Luis; Aguilar, Eduardo J; Sanz-Requena, Roberto; Alberich-Bayarri, Ángel; Bonmatí, Ana; Sanjuán, Julio

2013-02-16

Although aggressive behaviours are not always very highly prevalent in schizophrenia, their occurrence does represent a significant problem for patients and those around them. Although neuroimaging studies have made it possible to further our knowledge of the biology of these behaviours, there is still a notable degree of clinical heterogeneity in the study samples that makes it difficult to obtain conclusive results that can be compared with each other. To determine whether there are variations in the brain activity, as measured with functional magnetic resonance imaging, of a homogenous group of patients with schizophrenia and aggressive behaviour. The sample consisted of 32 patients with refractory schizophrenia and auditory hallucinations selected for the study. The subjects were submitted to a functional magnetic resonance imaging examination using an auditory paradigm with emotional stimulation, while the degree of aggressiveness was measured by means of the Brief Psychiatric Rating Scale. Significant correlations were found between functional activation and the degree of aggressiveness, which show focal hyperactivations in patients with a greater association to violent behaviours. The areas identified were located in the left hippocampus (p < 0.003, corrected) and in the right medial frontal gyrus (p < 0.004, corrected). This study determines the association between the degree of aggressiveness and certain regions in the brain that are responsible for cognitive and emotional processing in a phenotypically very homogenous group of patients with chronic auditory hallucinations and schizophrenia. This alteration of the neuronal circuits can favour loss in the processes involved in empathy and sensitivity, thus favouring the appearance of aggressive behaviours.

Maternal depression in childhood and aggression in young adulthood: evidence for mediation by offspring amygdala-hippocampal volume ratio.

PubMed

Gilliam, Mary; Forbes, Erika E; Gianaros, Peter J; Erickson, Kirk I; Brennan, Lauretta M; Shaw, Daniel S

2015-10-01

There is abundant evidence that offspring of depressed mothers are at increased risk for persistent behavior problems related to emotion regulation, but the mechanisms by which offspring incur this risk are not entirely clear. Early adverse caregiving experiences have been associated with structural alterations in the amygdala and hippocampus, which parallel findings of cortical regions altered in adults with behavior problems related to emotion regulation. This study examined whether exposure to maternal depression during childhood might predict increased aggression and/or depression in early adulthood, and whether offspring amygdala:hippocampal volume ratio might mediate this relationship. Participants were 258 mothers and sons at socioeconomic risk for behavior problems. Sons' trajectories of exposure to maternal depression were generated from eight reports collected prospectively from offspring ages 18 months to 10 years. Offspring brain structure, aggression, and depression were assessed at age 20 (n = 170). Persistent, moderately high trajectories of maternal depression during childhood predicted increased aggression in adult offspring. In contrast, stable and very elevated trajectories of maternal depression during childhood predicted depression in adult offspring. Increased amygdala: hippocampal volume ratios at age 20 were significantly associated with concurrently increased aggression, but not depression, in adult offspring. Offspring amygdala: hippocampal volume ratio mediated the relationship found between trajectories of moderately elevated maternal depression during childhood and aggression in adult offspring. Alterations in the relative size of brain structures implicated in emotion regulation may be one mechanism by which offspring of depressed mothers incur increased risk for the development of aggression. © 2014 Association for Child and Adolescent Mental Health.

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [11C] Harmine Positron Emission Tomography Study

PubMed Central

Kolla, Nathan J; Matthews, Brittany; Wilson, Alan A; Houle, Sylvain; Michael Bagby, R; Links, Paul; Simpson, Alexander I; Hussain, Amina; Meyer, Jeffrey H

2015-01-01

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [11C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=−0.50 to −0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity. PMID:26081301

Lower Monoamine Oxidase-A Total Distribution Volume in Impulsive and Violent Male Offenders with Antisocial Personality Disorder and High Psychopathic Traits: An [(11)C] Harmine Positron Emission Tomography Study.

PubMed

Kolla, Nathan J; Matthews, Brittany; Wilson, Alan A; Houle, Sylvain; Bagby, R Michael; Links, Paul; Simpson, Alexander I; Hussain, Amina; Meyer, Jeffrey H

2015-10-01

Antisocial personality disorder (ASPD) often presents with highly impulsive, violent behavior, and pathological changes in the orbitofrontal cortex (OFC) and ventral striatum (VS) are implicated. Several compelling reasons support a relationship between low monoamine oxidase-A (MAO-A), an enzyme that regulates neurotransmitters, and ASPD. These include MAO-A knockout models in rodents evidencing impulsive aggression and positron emission tomography (PET) studies of healthy subjects reporting associations between low brain MAO-A levels and greater impulsivity or aggression. However, a fundamental gap in the literature is that it is unknown whether brain MAO-A levels are low in more severe, clinical disorders of impulsivity, such as ASPD. To address this issue, we applied [(11)C] harmine PET to measure MAO-A total distribution volume (MAO-A VT), an index of MAO-A density, in 18 male ASPD participants and 18 age- and sex-matched controls. OFC and VS MAO-A VT were lower in ASPD compared with controls (multivariate analysis of variance (MANOVA): F2,33=6.8, P=0.003; OFC and VS MAO-A VT each lower by 19%). Similar effects were observed in other brain regions: prefrontal cortex, anterior cingulate cortex, dorsal putamen, thalamus, hippocampus, and midbrain (MANOVA: F7,28=2.7, P=0.029). In ASPD, VS MAO-A VT was consistently negatively correlated with self-report and behavioral measures of impulsivity (r=-0.50 to -0.52, all P-values<0.05). This study is the first to demonstrate lower brain MAO-A levels in ASPD. Our results support an important extension of preclinical models of impulsive aggression into a human disorder marked by pathological aggression and impulsivity.

In vivo detection of acute intracellular acidification in glioblastoma multiforme following a single dose of cariporide.

PubMed

Albatany, Mohammed; Li, Alex; Meakin, Susan; Bartha, Robert

2018-05-10

Glioblastoma is an aggressive brain cancer that is very difficult to treat. Clinically, it is important to be able to distinguish aggressive from non-aggressive brain tumors. Previous studies have shown that some drugs can induce a rapid change in intracellular pH that could help to identify aggressive cancer. The sodium proton exchanger (NHE1) plays a significant role in maintaining pH balance in the tumor microenvironment. Cariporide is a sodium proton exchange inhibitor that is well tolerated by humans in cardiac applications. We hypothesized that cariporide could selectively acidify brain tumors. The purpose of this study was to determine whether amine/amide concentration-independent detection (AACID) chemical exchange saturation transfer (CEST) MRI measurement of tumor pH i could detect acidification after cariporide injection. Using a 9.4T MRI scanner, CEST spectra were acquired in six mice approximately 14 days after implanting 10 5 U87 human glioblastoma multiforme cells in the brain, before and after administration of cariporide (dose: 6 mg/kg) by intraperitoneal injection. Three additional mice were studied as controls and received only vehicle injection (DMSO + PBS). Repeated measures t test was used to examine changes in tumor and contralateral tissue regions of interest. Two hours after cariporide injection, there was a significant 0.12 ± 0.03 increase in tumor AACID value corresponding to a 0.48 decrease in pH i and no change in AACID value in contralateral tissue. A small but significant increase of 0.04 ± 0.017 in tumor AACID value was also observed following vehicle injection. This study demonstrates that acute CEST MRI contrast changes, indicative of intracellular acidification, after administration of cariporide could help localize glioblastoma.

Aggression, science, and law: The origins framework. Introduction.

PubMed

Victoroff, Jeff

2009-01-01

Human societies have formalized instincts for compliance with reciprocal altruism in laws that sanction some aggression and not other aggression. Neuroscience makes steady advances toward measurements of various aspects of brain function pertinent to the aggressive behaviors that laws are designed to regulate. Consciousness, free will, rationality, intent, reality testing, empathy, moral reasoning, and capacity for self-control are somewhat subject to empirical assessment. The question becomes: how should law accommodate the wealth of information regarding these elements of mind that the science of aggression increasingly makes available? This essay discusses the evolutionary purpose of aggression, the evolutionary purpose of law, the problematic assumptions of the mens rea doctrine, and the prospects for applying the neuroscience of aggression toward the goal of equal justice for unequal minds. Nine other essays are introduced, demonstrating how each of them fits into the framework of the permanent debate about neuroscience and justice. It is concluded that advances in the science of human aggression will have vital, but biologically limited, impact on the provision of justice.

Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking.

PubMed

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.

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles.

PubMed

Blanco, Víctor M; Chu, Zhengtao; LaSance, Kathleen; Gray, Brian D; Pak, Koon Yan; Rider, Therese; Greis, Kenneth D; Qi, Xiaoyang

2016-05-31

Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

The Identification of Teasing among Students as an Indispensable Step towards Reducing Verbal Aggression in Schools

ERIC Educational Resources Information Center

Psunder, Mateja

2010-01-01

Surveys have confirmed the ubiquity of aggression in schools, and verbal aggression is not an exception. The identification of teasing as a frequent form of verbal aggression is an indispensable step towards diminishing it. The purpose of this study was to investigate teasing among primary school students in Slovenia. The research showed that…

Transcriptional Analysis of Aggressiveness and Heterogeneity across Grades of Astrocytomas

PubMed Central

Wang, Chunjing; Funk, Cory C.; Eddy, James A.; Price, Nathan D.

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades and hopefully can contribute towards improvements in diagnosis and therapy choices. Our results also identify a number of testable hypotheses relating to astrocytoma etiology that may prove helpful in developing much-needed biomarkers for earlier disease detection. PMID:24146911

Transcriptional analysis of aggressiveness and heterogeneity across grades of astrocytomas.

PubMed

Wang, Chunjing; Funk, Cory C; Eddy, James A; Price, Nathan D

2013-01-01

Astrocytoma is the most common glioma, accounting for half of all primary brain and spinal cord tumors. Late detection and the aggressive nature of high-grade astrocytomas contribute to high mortality rates. Though many studies identify candidate biomarkers using high-throughput transcriptomic profiling to stratify grades and subtypes, few have resulted in clinically actionable results. This shortcoming can be attributed, in part, to pronounced lab effects that reduce signature robustness and varied individual gene expression among patients with the same tumor. We addressed these issues by uniformly preprocessing publicly available transcriptomic data, comprising 306 tumor samples from three astrocytoma grades (Grade 2, 3, and 4) and 30 non-tumor samples (normal brain as control tissues). Utilizing Differential Rank Conservation (DIRAC), a network-based classification approach, we examined the global and individual patterns of network regulation across tumor grades. Additionally, we applied gene-based approaches to identify genes whose expression changed consistently with increasing tumor grade and evaluated their robustness across multiple studies using statistical sampling. Applying DIRAC, we observed a global trend of greater network dysregulation with increasing tumor aggressiveness. Individual networks displaying greater differences in regulation between adjacent grades play well-known roles in calcium/PKC, EGF, and transcription signaling. Interestingly, many of the 90 individual genes found to monotonically increase or decrease with astrocytoma grade are implicated in cancer-affected processes such as calcium signaling, mitochondrial metabolism, and apoptosis. The fact that specific genes monotonically increase or decrease with increasing astrocytoma grade may reflect shared oncogenic mechanisms among phenotypically similar tumors. This work presents statistically significant results that enable better characterization of different human astrocytoma grades and hopefully can contribute towards improvements in diagnosis and therapy choices. Our results also identify a number of testable hypotheses relating to astrocytoma etiology that may prove helpful in developing much-needed biomarkers for earlier disease detection.

76 FR 40381 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-08

... applications. Breakthrough Immunotherapy for Brain Cancer: Epidermal Growth Factor Receptor Variant III... receptor variant III (EGFRvIII) to use as a promising immunotherapy for aggressive brain cancer... immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen. Cancer...

Sex differences in structural brain asymmetry predict overt aggression in early adolescents.

PubMed

Visser, Troy A W; Ohan, Jeneva L; Whittle, Sarah; Yücel, Murat; Simmons, Julian G; Allen, Nicholas B

2014-04-01

The devastating social, emotional and economic consequences of human aggression are laid bare nightly on newscasts around the world. Aggression is principally mediated by neural circuitry comprising multiple areas of the prefrontal cortex and limbic system, including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), amygdala and hippocampus. A striking characteristic of these regions is their structural asymmetry about the midline (i.e. left vs right hemisphere). Variations in these asymmetries have been linked to clinical disorders characterized by aggression and the rate of aggressive behavior in psychiatric patients. Here, we show for the first time that structural asymmetries in prefrontal cortical areas are also linked to aggression in a normal population of early adolescents. Our findings indicate a relationship between parent reports of aggressive behavior in adolescents and structural asymmetries in the limbic and paralimbic ACC and OFC, and moreover, that this relationship varies by sex. Furthermore, while there was no relationship between aggression and structural asymmetries in the amygdala or hippocampus, hippocampal volumes did predict aggression in females. Taken together, the results suggest that structural asymmetries in the prefrontal cortex may influence human aggression, and that the anatomical basis of aggression varies substantially by sex.

To flock or fight: Neurochemical signatures of divergent life histories in sparrows

PubMed Central

Goodson, James L.; Wilson, Leah C.; Schrock, Sara E.

2012-01-01

Many bird species exhibit dramatic seasonal switches between territoriality and flocking, but whereas neuroendocrine mechanisms of territorial aggression have been extensively studied, those of seasonal flocking are unknown. We collected brains in spring and winter from male field sparrows (Spizella pusilla), which seasonally flock, and male song sparrows (Melospiza melodia), which are territorial year-round in much of their range. Spring collections were preceded by field-based assessments of aggression. Tissue series were immunofluorescently multilabeled for vasotocin, mesotocin (MT), corticotropin-releasing hormone (CRH), vasoactive intestinal polypeptide, tyrosine hydroxylase, and aromatase, and labeling densities were measured in many socially relevant brain areas. Extensive seasonal differences are shared by both species. Many measures correlate significantly with both individual and species differences in aggression, likely reflecting evolved mechanisms that differentiate the less aggressive field sparrow from the more aggressive song sparrow. Winter-specific species differences include a substantial increase of MT and CRH immunoreactivity in the dorsal lateral septum (LS) and medial amygdala of field sparrows but not song sparrows. These species differences likely relate to flocking rather than the suppression of winter aggression in field sparrows, because similar winter differences were found for two other emberizids that are not territorial in winter—dark-eyed juncos (Junco hyemalis), which seasonally flock, and eastern towhees (Pipilo erythropthalmus), which do not flock. MT signaling in the dorsal LS is also associated with year-round species differences in grouping in estrildid finches, suggesting that common mechanisms are targeted during the evolution of different life histories. PMID:22723363

Orally active vasopressin V1a receptor antagonist, SRX251, selectively blocks aggressive behavior.

PubMed

Ferris, Craig F; Lu, Shi-Fang; Messenger, Tara; Guillon, Christophe D; Heindel, Ned; Miller, Marvin; Koppel, Gary; Robert Bruns, F; Simon, Neal G

2006-02-01

Arginine vasopressin functions as a neurochemical signal in the brain to affect social behavior. There is an expanding literature from animal and human studies showing that vasopressin, through the vasopressin 1A receptor (V1A), can stimulate aggressive behavior. Using a novel monocylic beta lactam platform, a series of orally active vasopressin V1a antagonists was developed with high affinity for the human receptor. SRX251 was chosen from this series of V1a antagonists to screen for effects on serenic activity in a resident-intruder model of offensive aggression. Resident, male Syrian golden hamsters were given oral doses of SRX251 or intraperitoneal Manning compound, a selective V1a receptor antagonist with reduced brain penetrance, at doses of 0.2 microg, 20 microg, 2 mg/kg or vehicle. When tested 90-120 min later, SRX251, but not Manning compound, caused a significant dose-dependent reduction in offensive aggression toward intruders as measured by latency to bite and number of bites. The reduction in aggression persisted for over 6 h and was no longer present 12 h post treatment. SRX251 did not alter the amount of time the resident investigated the intruder, olfactory communication, general motor activity, or sexual motivation. These data corroborate previous studies showing a role for vasopressin neurotransmission in aggression and suggest that V1a receptor antagonists may be used to treat interpersonal violence co-occurring with such illness as ADHD, autism, bipolar disorder, and substance abuse.

To flock or fight: neurochemical signatures of divergent life histories in sparrows.

PubMed

Goodson, James L; Wilson, Leah C; Schrock, Sara E

2012-06-26

Many bird species exhibit dramatic seasonal switches between territoriality and flocking, but whereas neuroendocrine mechanisms of territorial aggression have been extensively studied, those of seasonal flocking are unknown. We collected brains in spring and winter from male field sparrows (Spizella pusilla), which seasonally flock, and male song sparrows (Melospiza melodia), which are territorial year-round in much of their range. Spring collections were preceded by field-based assessments of aggression. Tissue series were immunofluorescently multilabeled for vasotocin, mesotocin (MT), corticotropin-releasing hormone (CRH), vasoactive intestinal polypeptide, tyrosine hydroxylase, and aromatase, and labeling densities were measured in many socially relevant brain areas. Extensive seasonal differences are shared by both species. Many measures correlate significantly with both individual and species differences in aggression, likely reflecting evolved mechanisms that differentiate the less aggressive field sparrow from the more aggressive song sparrow. Winter-specific species differences include a substantial increase of MT and CRH immunoreactivity in the dorsal lateral septum (LS) and medial amygdala of field sparrows but not song sparrows. These species differences likely relate to flocking rather than the suppression of winter aggression in field sparrows, because similar winter differences were found for two other emberizids that are not territorial in winter--dark-eyed juncos (Junco hyemalis), which seasonally flock, and eastern towhees (Pipilo erythropthalmus), which do not flock. MT signaling in the dorsal LS is also associated with year-round species differences in grouping in estrildid finches, suggesting that common mechanisms are targeted during the evolution of different life histories.

Social Isolation Co-opts Fear and Aggression Circuits.

PubMed

Rodriguez-Romaguera, Jose; Stuber, Garret D

2018-05-17

Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses. Copyright © 2018. Published by Elsevier Inc.

Effects of environmental enrichment on growth, aggressive behaviour and brain monoamines of gilthead seabream Sparus aurata reared under different social conditions.

PubMed

Batzina, Alkisti; Dalla, Christina; Papadopoulou-Daifoti, Zeta; Karakatsouli, Nafsika

2014-03-01

The presence of blue or red-brown substrate on the tank bottom has been previously reported as an efficient means of environmental enrichment for gilthead seabream. The present study aimed to investigate whether this enrichment is still beneficial when gilthead seabream is reared under different social conditions (i.e. a lower 4.9 kg m(-3) and a higher 9.7 kg m(-3) density). Water exchange was adjusted according to fish biomass to exclude density effects on water quality. In the enriched tanks single-colour glass gravel was used as substrate (blue and red-brown substrate, or BS and RBS respectively), while control tanks had no gravel. Growth, aggressive behaviour and size distribution results indicated that the lower density created a less favourable social environment. In both densities studied, BS enhanced growth, suppressed aggression and reduced brain serotonergic activity. In the condition of intense social interactions (i.e. the lower density) BS also reduced brain dopaminergic activity. These results along with the negative correlations observed between brain monoamines and fish body mass, indicated that substrate and density effects are socially-induced. However, there may be several biotic and/or abiotic factors interfering with substrate effects that should be investigated before the practical use of a substrate in land-based intensive aquaculture. Copyright © 2013 Elsevier Inc. All rights reserved.

[Effect of sodium valproate on aggressive behavior of male mice with various aggression experience].

PubMed

Smagin, D A; Bondar', N P; Kudriavtseva, N N

2010-01-01

Sector of Social Behavior Neurogenetics, Institute of Cytology and Genetics, Siberian Branch, Effects of sodium valproate on the aggressive behavior of male mice with 2- and 20-day positive fighting experience have been studied. It is established that valproate administered in a singe dose of 100 mg/kg has no effect on the behavior of male mice with a 2-day experience of aggression. The treatment of mice with 300 mg/kg of valproate significantly decreased the level of aggressive motivation and the percentage of animals demonstrating attacks and threats. In male mice with a 20-day experience of aggression, valproate decreased the time of hostile behavior in a dose-dependent manner. Valproate in a single dose of 300 mg/kg significantly decreased the level of aggressive motivation, but also produced a toxic effect, whereby 73% of aggressive males demonstrated long-term immobility and 45% exhibited movement abnormalities (falls) upon the treatment. It is suggested that changes in the brain neurochemical activity, which are caused by a prolonged experience of aggression, modify the effects of sodium valproate.

Low Dose of Doxorubicin Potentiates the Effect of Temozolomide in Glioblastoma Cells.

PubMed

Villodre, Emilly Schlee; Kipper, Franciele Cristina; Silva, Andrew Oliveira; Lenz, Guido; Lopez, Patrícia Luciana da Costa

2018-05-01

Glioblastoma (GBM) is an aggressive brain tumor with temozolomide (TMZ)-based chemotherapy as the main therapeutic strategy. Doxorubicin (DOX) is not used in gliomas due to its low bioavailability in the brain; however, new delivery strategies and low doses may be effective in the long term, especially as part of a drug cocktail. Our aim was to evaluate the chronic effects of low doses of DOX and TMZ in GBM. Human U87-ATCC cells and a primary GBM culture were chronically treated with TMZ (5 μM) and DOX (1 and 10 nM) alone or combined. DOX resulted in a reduction in the number of cells over a period of 35 days and delayed the cell regrowth. In addition, DOX induced cell senescence and reduced tumor sphere formation and the proportion of NANOG- and OCT4-positive cells after 7 days. Low doses of TMZ potentiated the effects of DOX on senescence and sphere formation. This combined response using low doses of DOX may pave the way for its use in glioma therapy, with new technologies to overcome its low blood-brain barrier permeability.

The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

PubMed Central

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-01-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

Effective treatment of glioblastoma requires crossing the blood–brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine

PubMed Central

Kim, Sang-Soo; Harford, Joe B.; Pirollo, Kathleen F.; Chang, Esther H.

2015-01-01

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood–brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review. PMID:26116770

Sexual selection predicts brain structure in dragon lizards.

PubMed

Hoops, D; Ullmann, J F P; Janke, A L; Vidal-Garcia, M; Stait-Gardner, T; Dwihapsari, Y; Merkling, T; Price, W S; Endler, J A; Whiting, M J; Keogh, J S

2017-02-01

Phenotypic traits such as ornaments and armaments are generally shaped by sexual selection, which often favours larger and more elaborate males compared to females. But can sexual selection also influence the brain? Previous studies in vertebrates report contradictory results with no consistent pattern between variation in brain structure and the strength of sexual selection. We hypothesize that sexual selection will act in a consistent way on two vertebrate brain regions that directly regulate sexual behaviour: the medial preoptic nucleus (MPON) and the ventromedial hypothalamic nucleus (VMN). The MPON regulates male reproductive behaviour whereas the VMN regulates female reproductive behaviour and is also involved in male aggression. To test our hypothesis, we used high-resolution magnetic resonance imaging combined with traditional histology of brains in 14 dragon lizard species of the genus Ctenophorus that vary in the strength of precopulatory sexual selection. Males belonging to species that experience greater sexual selection had a larger MPON and a smaller VMN. Conversely, females did not show any patterns of variation in these brain regions. As the volumes of both these regions also correlated with brain volume (BV) in our models, we tested whether they show the same pattern of evolution in response to changes in BV and found that the do. Therefore, we show that the primary brain nuclei underlying reproductive behaviour in vertebrates can evolve in a mosaic fashion, differently between males and females, likely in response to sexual selection, and that these same regions are simultaneously evolving in concert in relation to overall brain size. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation

PubMed Central

Blake, Sophia M; Stricker, Stefan H; Halavach, Hanna; Poetsch, Anna R; Cresswell, George; Kelly, Gavin; Kanu, Nnennaya; Marino, Silvia; Luscombe, Nicholas M; Pollard, Steven M; Behrens, Axel

2016-01-01

Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors. DOI: http://dx.doi.org/10.7554/eLife.08711.001 PMID:26984279

Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence.

PubMed

Baysan, Mehmet; Woolard, Kevin; Cam, Margaret C; Zhang, Wei; Song, Hua; Kotliarova, Svetlana; Balamatsias, Demosthenes; Linkous, Amanda; Ahn, Susie; Walling, Jennifer; Belova, Galina I; Fine, Howard A

2017-11-15

Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets. © 2017 UICC.

A case of oculo-cerebral B-cell lymphoma in a cat.

PubMed

Giordano, Cristina; Giudice, Chiara; Bellino, Claudio; Borrelli, Antonio; D'Angelo, Antonio; Gianella, Paola

2013-01-01

To describe a case of a cat with primary B-cell lymphoma affecting the eye and brain and which shared features similar to oculo-cerebral lymphoma in humans. A 13-year-old castrated male Persian cat presented with clinical signs of anterior uveitis and increased intraocular pressure (IOP) in the left eye (OS). A complete diagnostic work-up was declined, and left-eye enucleation was performed. The globe was submitted for histopathology. One week after surgery, the cat became inappetent, hypothermic, and aggressive. Euthanasia was requested by the owner, and a necropsy was permitted.   Histopathology of the enucleated globe revealed an extensive neoplastic infiltration consistent with large-cell lymphoma, affecting the anterior uvea, neuroretina and optic nerve. At necropsy, all organs were unremarkable except for the brain, where there was a neoplastic cell population consistent with that described in the left eye, infiltrated and expanded meninges, and perivascular spaces. Immunohistochemically, the neoplastic cells were positive for B-cell marker (CD20) and negative for T-cell marker (CD3). Histology and immunophenotyping suggested a diagnosis of primary central nervous system and ocular large B-cell lymphoma. The lymphoma in this cat resembled oculo-cerebral lymphoma in humans, sharing similar clinical features and histopathological findings, including the perivascular pattern of neoplastic cell infiltration. To the best of the authors' knowledge, this is the first description of a primary oculo-cerebral B-cell lymphoma in a cat. © 2012 American College of Veterinary Ophthalmologists.

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek's disease

USDA-ARS?s Scientific Manuscript database

Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. The serotonergic system m...

Differential serotonergic mediation of aggression in roosters selected for resistance and susceptibility to Marek’s disease

USDA-ARS?s Scientific Manuscript database

1. Serotonin (5-HT) is a primary regulating neurotransmitter involved in aggressive and impulsive behaviors in mammals and birds. Previous studies have also demonstrated the function of serotonergic system in regulating aggression is affected by both genetic and environmental factors. 2. Our obje...

Psychopathy and Indirect Aggression: The Roles of Cortisol, Sex, and Type of Psychopathy

ERIC Educational Resources Information Center

Vaillancourt, Tracy; Sunderani, Shafik

2011-01-01

Salivary cortisol was examined in relation to indirect aggression and primary psychopathy (i.e., cold affect and interpersonal manipulation) and secondary psychopathy (i.e., criminal tendencies and erratic lifestyle) in a sample of 154 undergraduate students. Results revealed that although psychopathy and indirect aggression were strongly…

Student Aggression: Prevention, Management, and Replacement Training.

ERIC Educational Resources Information Center

Goldstein, Arnold P.; And Others

American society is violent, a fact which is well-reflected in schools. This book, designed specifically for school personnel, presents the primary techniques currently being employed by educators to prevent, manage, and replace student aggression. The volume opens with a description of the origins of aggressive behavior and offers some…

Sweetened Blood Cools Hot Tempers: Physiological Self-Control and Aggression

PubMed Central

DeWall, C. Nathan; Deckman, Timothy; Gailliot, Matthew T.; Bushman, Brad J.

2014-01-01

Aggressive and violent behaviors are restrained by self-control. Self-control consumes a lot of glucose in the brain, suggesting that low glucose and poor glucose metabolism are linked to aggression and violence. Four studies tested this hypothesis. Study 1 found that participants who consumed a glucose beverage behaved less aggressively than did participants who consumed a placebo beverage. Study 2 found an indirect relationship between diabetes (a disorder marked by low glucose levels and poor glucose metabolism) and aggressiveness through low self-control. Study 3 found that states with high diabetes rates also had high violent crime rates. Study 4 found that countries with high rates of glucose-6-phosphate dehydrogenase deficiency (a metabolic disorder related to low glucose levels) also had higher killings rates, both war related and non-war related. All four studies suggest that a spoonful of sugar helps aggressive and violent behaviors go down. PMID:21064166

Modulation of Fgfr1a signaling in zebrafish reveals a genetic basis for the aggression-boldness syndrome.

PubMed

Norton, William H J; Stumpenhorst, Katharina; Faus-Kessler, Theresa; Folchert, Anja; Rohner, Nicolas; Harris, Matthew P; Callebert, Jacques; Bally-Cuif, Laure

2011-09-28

Behavioral syndromes are suites of two or more behaviors that correlate across environmental contexts. The aggression-boldness syndrome links aggression, boldness, and exploratory activity in a novel environment. Although aggression-boldness has been described in many animals, the mechanism linking its behavioral components is not known. Here we show that mutation of the gene encoding fibroblast growth factor receptor 1a (fgfr1a) simultaneously increases aggression, boldness, and exploration in adult zebrafish. We demonstrate that altered Fgf signaling also results in reduced brain histamine levels in mutants. Pharmacological increase of histamine signaling is sufficient to rescue the behavioral phenotype of fgfr1a mutants. Together, we show that a single genetic locus can underlie the aggression-boldness behavioral syndrome. We also identify one of the neurotransmitter pathways that may mediate clustering of these behaviors.

Asymmetry in the dorsolateral prefrontal cortex and aggressive behavior: a continuous theta-burst magnetic stimulation study.

PubMed

Perach-Barzilay, N; Tauber, A; Klein, E; Chistyakov, A; Ne'eman, R; Shamay-Tsoory, S G

2013-01-01

Aggressive behavior is aimed at causing damage or pain to another individual. Aggression has been associated with structural and functional deficits in numerous brain areas, including the dorsolateral region of the prefrontal cortex (DLPFC), typically related to inhibition and impulse control. In this study, we used inhibitory continuous theta-burst magnetic stimulation (cTBS) to explore the role of the right and left DLPFC in aggression. Sixteen healthy right-handed volunteers underwent two sessions involving random, real and sham, right and left DLPFC stimulations. These sessions were followed by the Social Orientation Paradigm (SOP), a monetary task that was specially designed to assess participants' aggressive tendencies by measuring the patterns of their reactive aggression (a response to a perceived provocation) and proactive aggression (an aggressive act with goal-oriented purposes). Results indicate that using cTBS to target the left DLPFC was associated with a greater increase in aggressive responses than right DLPFC stimulation. This pattern of results was found for both reactive and proactive types of aggressive reactions. It is concluded that DLPFC asymmetry is involved in modulating reactive and proactive aggression. Our results are in line with recent studies suggesting that the left DLPFC plays a major role in aggressive behavior.

Neural correlates of proactive and reactive aggression in adolescent twins.

PubMed

Yang, Yaling; Joshi, Shantanu H; Jahanshad, Neda; Thompson, Paul M; Baker, Laura A

2017-05-01

Verbal and physical aggression begin early in life and steadily decline thereafter in normal development. As a result, elevated aggressive behavior in adolescence may signal atypical development and greater vulnerability for negative mental and health outcomes. Converging evidence suggests that brain disturbances in regions involved in impulse control, emotional regulation, and sensation seeking may contribute to heightened aggression. However, little is known regarding the neural mechanisms underlying subtypes of aggression (i.e., proactive and reactive aggression) and whether they differ between males and females. Using a sample of 106 14-year-old adolescent twins, this study found that striatal enlargement was associated with both proactive and reactive aggression. We also found that volumetric alterations in several frontal regions including smaller middle frontal and larger orbitofrontal cortex were correlated with higher levels of aggression in adolescent twins. In addition, cortical thickness analysis showed that thickness alterations in many overlapping regions including middle frontal, superior frontal, and anterior cingulate cortex and temporal regions were associated with aggression in adolescent twins. Results support the involvement of fronto-limbic-striatal circuit in the etiology of aggression during adolescence. Aggr. Behav. 43:230-240, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design.

PubMed

Devanand, D P; Strickler, Jesse G; Huey, Edward D; Crocco, Elizabeth; Forester, Brent P; Husain, Mustafa M; Vahia, Ipsit V; Andrews, Howard; Wall, Melanie M; Pelton, Gregory H

2018-05-31

Symptoms of agitation, aggression, and psychosis frequently occur in patients with Alzheimer's disease (AD). These symptoms are distressing to patients and caregivers, often lead to institutionalization, are associated with increased mortality, and are very difficult to treat. Lithium is an established treatment for bipolar and other psychotic disorders in which agitation can occur. The Lit-AD study is the first randomized, double-blind, placebo-controlled trial to assess the efficacy of lithium treatment for symptoms of agitation or aggression, with or without psychosis, in older adults diagnosed with AD. Patients are randomly assigned to low dose (150-600 mg) lithium or placebo, targeting a blood level of 0.2-0.6 mmol/L, stratified by the presence/absence of psychotic symptoms. The study duration for each patient is 12 weeks. The primary study outcome is change in the agitation/aggression domain score on the Neuropsychiatric Inventory (NPI) over the study period. The secondary outcome is improvement in neuropsychiatric symptoms defined as a 30% decrease in a NPI core score that combines agitation/aggression and psychosis domain scores. The Treatment Emergent Symptom Scale (TESS) is used to assess somatic side effects. Other exploratory analyses examine the associations between improvement on lithium and indices shown to be associated with response to lithium in bipolar disorder: serum brain-derived neurotrophic factor (BDNF) levels, a SNP in intron 1 of the ACCN1 gene, and variation at the 7q11.2 gene locus. If lithium demonstrates efficacy in this Phase II pilot trial, a Phase III study will be developed to establish its clinical utility in these patients. ClinicalTrials.gov Identifier NCT02129348. Copyright © 2018. Published by Elsevier Inc.

An investigation of the mechanism underlying teacher aggression: Testing I3 theory and the General Aggression Model.

PubMed

Montuoro, Paul; Mainhard, Tim

2017-12-01

Considerable research has investigated the deleterious effects of teachers responding aggressively to students who misbehave, but the mechanism underlying this dysfunctional behaviour remains unknown. This study investigated whether the mechanism underlying teacher aggression follows I 3 theory or General Aggression Model (GAM) metatheory of human aggression. I 3 theory explains exceptional, catastrophic events of human aggression, whereas the GAM explains common human aggression behaviours. A total of 249 Australian teachers participated in this study, including 142 primary school teachers (Mdn [age] = 35-39 years; Mdn [years teaching] = 10-14 years; 84% female) and 107 secondary school teachers (Mdn [age] = 45-49 years; Mdn [years teaching] = 15-19 years; 65% female). Participants completed four online self-report questionnaires, which assessed caregiving responsiveness, trait self-control, misbehaviour provocation, and teacher aggression. Analyses revealed that the GAM most accurately captures the mechanism underlying teacher aggression, with lower caregiving responsiveness appearing to indirectly lead to teacher aggression via higher misbehaviour provocation and lower trait self-control in serial, controlling for gender, age, years teaching, and current role (primary, secondary). This study indicates that teacher aggression proceeds from 'the person in the situation'. Specifically, lower caregiving responsiveness appears to negatively shape a teacher's affective, cognitive, and arousal states, which influence how they perceive and interpret student misbehaviour. These internal states, in turn, appear to negatively influence appraisal and decision processes, leading to immediate appraisal and impulsive actions. These results raise the possibility that teacher aggression is a form of countertransference. © 2017 The British Psychological Society.

Gene Expression of Serotonin and Dopamine Receptors and Monoamine Oxidase-A in the Brain of Dominant and Subordinate Pubertal Pigs Fed a ß-Adrenoreceptor Agonist

USDA-ARS?s Scientific Manuscript database

Aggression is a major source of social stress and injuries, negatively affecting the health and well-being of those involved in the fight. The serotonergic and dopaminergic systems are widely implicated in aggression regulation in several animal species, but information on molecular mechanisms media...

Explosive, Oppositional, and Aggressive Behavior in Children with Autism Compared to Other Clinical Disorders and Typical Children

ERIC Educational Resources Information Center

Mayes, Susan Dickerson; Calhoun, Susan L.; Aggarwal, Richa; Baker, Courtney; Mathapati, Santoshkumar; Anderson, Robert; Petersen, Christopher

2012-01-01

Maternal ratings of explosiveness, opposition, and aggression were analyzed in 1609 children 6-16 years of age. Behavior problems were common in autism, ADHD-Combined type, and depression, whereas children with ADHD-Inattentive type, anxiety disorder, and acquired brain injury did not differ from typical controls. More than 40% of children with…

Functional and clinical neuroanatomy of morality.

PubMed

Fumagalli, Manuela; Priori, Alberto

2012-07-01

Morality is among the most sophisticated features of human judgement, behaviour and, ultimately, mind. An individual who behaves immorally may violate ethical rules and civil rights, and may threaten others' individual liberty, sometimes becoming violent and aggressive. In recent years, neuroscience has shown a growing interest in human morality, and has advanced our understanding of the cognitive and emotional processes involved in moral decisions, their anatomical substrates and the neurology of abnormal moral behaviour. In this article, we review research findings that have provided a key insight into the functional and clinical neuroanatomy of the brain areas involved in normal and abnormal moral behaviour. The 'moral brain' consists of a large functional network including both cortical and subcortical anatomical structures. Because morality is a complex process, some of these brain structures share their neural circuits with those controlling other behavioural processes, such as emotions and theory of mind. Among the anatomical structures implicated in morality are the frontal, temporal and cingulate cortices. The prefrontal cortex regulates activity in subcortical emotional centres, planning and supervising moral decisions, and when its functionality is altered may lead to impulsive aggression. The temporal lobe is involved in theory of mind and its dysfunction is often implicated in violent psychopathy. The cingulate cortex mediates the conflict between the emotional and the rational components of moral reasoning. Other important structures contributing to moral behaviour include the subcortical nuclei such as the amygdala, hippocampus and basal ganglia. Brain areas participating in moral processing can be influenced also by genetic, endocrine and environmental factors. Hormones can modulate moral behaviour through their effects on the brain. Finally, genetic polymorphisms can predispose to aggressivity and violence, arguing for a genetic-based predisposition to morality. Because abnormal moral behaviour can arise from both functional and structural brain abnormalities that should be diagnosed and treated, the neurology of moral behaviour has potential implications for clinical practice and raises ethical concerns. Last, since research has developed several neuromodulation techniques to improve brain dysfunction (deep brain stimulation, transcranial magnetic stimulation and transcranial direct current stimulation), knowing more about the 'moral brain' might help to develop novel therapeutic strategies for neurologically based abnormal moral behaviour.

Aggression differentially modulates brain responses to fearful and angry faces: an exploratory study.

PubMed

Lu, Hui; Wang, Yu; Xu, Shuang; Wang, Yifeng; Zhang, Ruiping; Li, Tsingan

2015-08-19

Aggression is reported to modulate neural responses to the threatening information. However, whether aggression can modulate neural response to different kinds of threatening facial expressions (angry and fearful expressions) remains unknown. Thus, event-related potentials were measured in individuals (13 high aggressive, 12 low aggressive) exposed to neutral, angry, and fearful facial expressions while performing a frame-distinguishing task, irrespective of the emotional valence of the expressions. Highly aggressive participants showed no distinct neural responses between the three facial expressions. In addition, compared with individuals with low aggression, highly aggressive individuals showed a decreased frontocentral response to fearful faces within 250-300 ms and to angry faces within 400-500 ms of exposure. These results indicate that fearful faces represent a more threatening signal requiring a quick cognitive response during the early stage of facial processing, whereas angry faces elicit a stronger response during the later processing stage because of its eminent emotional significance. The present results represent the first known evidence that aggression is associated with different neural responses to fearful and angry faces. By exploring the distinct temporal responses to fearful and angry faces modulated by aggression, this study more precisely characterizes the cognitive characteristics of aggressive individuals. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

The Role of the Lateral Hypothalamus in Violent Intraspecific Aggression—The Glucocorticoid Deficit Hypothesis

PubMed Central

Haller, József

2018-01-01

This review argues for a central role of the lateral hypothalamus in those deviant forms of aggression, which result from chronic glucocorticoid deficiency. Currently, this nucleus is considered a key region of the mechanisms that control predatory aggression. However, recent findings demonstrate that it is strongly activated by aggression in subjects with a chronically downregulated hypothalamus-pituitary-adrenocortical (HPA) axis; moreover, this activation is causally involved in the emergence of violent aggression. The review has two parts. In the first part, we review human findings demonstrating that under certain conditions, strong stressors downregulate the HPA-axis on the long run, and that the resulting glucocorticoid deficiency is associated with violent aggression including aggressive delinquency and aggression-related psychopathologies. The second part addresses neural mechanisms in animals. We show that the experimental downregulation of HPA-axis function elicits violent aggression in rodents, and the activation of the brain circuitry that originally subserves predatory aggression accompanies this change. The lateral hypothalamus is not only an integral part of this circuitry, but can elicit deviant and violent forms of aggression. Finally, we formulate a hypothesis on the pathway that connects unfavorable social conditions to violent aggression via the neural circuitry that includes the lateral hypothalamus.

Right Anterior Cingulate Cortical Thickness and Bilateral Striatal Volume Correlate with CBCL Aggressive Behavior Scores in Healthy Children

PubMed Central

Ducharme, Simon; Hudziak, James J; Botteron, Kelly N; Ganjavi, Hooman; Lepage, Claude; Collins, D Louis; Albaugh, Matthew D.; Evans, Alan C; Karama, Sherif

2011-01-01

Background The anterior cingulate cortex (ACC), orbito-frontal cortex (OFC) and basal ganglia have been implicated in pathological aggression. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children. Methods Data from 193 representative 6–18 year-old healthy children were obtained from the NIH MRI Study of Normal Brain Development after a blinded quality control (1). Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist (CBCL). AGG scores were regressed against cortical thickness and basal ganglia volumes using first and second-order linear models while controlling for age, gender, scanner site and total brain volume. ‘Gender by AGG’ interactions were analyzed. Results There were positive associations between bilateral striatal volumes and AGG scores (right: r=0.238, p=0.001; left: r=0.188, p=0.01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second-order linear model (p<0.05, corrected). High AGG scores were associated with a relatively thin right ACC cortex. An ‘AGG by gender’ interaction trend was found in bilateral OFC and ACC associations with AGG scores. Conclusion This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender specific patterns of association in OFC/ACC grey matter. These results may guide research on oppositional-defiant and conduct disorders. PMID:21531391

Right anterior cingulate cortical thickness and bilateral striatal volume correlate with child behavior checklist aggressive behavior scores in healthy children.

PubMed

Ducharme, Simon; Hudziak, James J; Botteron, Kelly N; Ganjavi, Hooman; Lepage, Claude; Collins, D Louis; Albaugh, Matthew D; Evans, Alan C; Karama, Sherif

2011-08-01

The anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and basal ganglia have been implicated in pathological aggression. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children. Data from 193 representative 6- to 18-year-old healthy children were obtained from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development after a blinded quality control. Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist. AGG scores were regressed against cortical thickness and basal ganglia volumes using first- and second-order linear models while controlling for age, gender, scanner site, and total brain volume. Gender by AGG interactions were analyzed. There were positive associations between bilateral striatal volumes and AGG scores (right: r = .238, p = .001; left: r = .188, p = .01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second-order linear model (p < .05, corrected). High AGG scores were associated with a relatively thin right ACC cortex. An AGG by gender interaction trend was found in bilateral OFC and ACC associations with AGG scores. This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender-specific patterns of association in OFC/ACC gray matter. These results may guide research on oppositional-defiant and conduct disorders. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder

PubMed Central

Best, Mary; Williams, J. Michael; Coccaro, Emil F.

2002-01-01

Humans with lesions to the orbital/medial prefrontal cortex and interconnected areas display impulsive aggressive behavior. To examine further the relationship between impulsive aggression and orbital/medial prefrontal dysfunction, we measured the behavioral performance of psychiatric patients with a disorder characterized by impulsive aggression, Intermittent Explosive Disorder (IED). Presently, no evidence exists for a localized brain lesion in IED subjects. However, on the basis of the location of brain lesions that produce acquired impulsive aggression, we hypothesized that IED subjects would exhibit test performance similar to patients with lesions to the orbital/medial prefrontal cortex. Subjects with IED and controls were administered three tests sensitive to lesions of the orbital/medial prefrontal circuit: the Iowa Gambling Task, facial emotion recognition, and odor identification, and two control tests of working memory. On the gambling task, IED subjects continued to make disadvantageous decisions throughout the 100 trials, whereas controls learned to avoid disadvantageous decisions. On the facial recognition test, IED subjects were impaired at recognizing “anger,” “disgust,” and “surprise,” and they were biased to label neutral faces with “disgust” and “fear.” On odor identification, IED subjects were mildly anosmic and were impaired relative to controls. However, on the working memory control tests, both groups performed similarly. Across tests, the performance of IED subjects resembles the performance of patients with orbital/medial prefrontal lesions in previous studies. These results extend the link between dysfunction of the orbital/medial prefrontal circuit and impulsive aggressive behavior. PMID:12034876

Rare Aggressive Behavior of MDM2-Amplified Retroperitoneal Dedifferentiated Liposarcoma, with Brain, Lung and Subcutaneous Metastases.

PubMed

Ben Salha, Imen; Zaidi, Shane; Noujaim, Jonathan; Miah, Aisha B; Fisher, Cyril; Jones, Robin L; Thway, Khin

2016-09-05

Dedifferentiated liposarcoma (DDL) is a histologically pleomorphic sarcoma, traditionally defined as well-differentiated liposarcoma with abrupt transition to high grade, non-lipogenic sarcoma. It can occur as part of recurrent well-differentiated liposarcoma, or may arise de novo . DDL most frequently occurs within the retroperitoneum, and while it is prone to local recurrence, it usually has a lower rate of metastasis than other pleomorphic sarcomas. We describe a case of retroperitoneal dedifferentiated liposarcoma in a 63-year-old male, who showed MDM2 amplification with fluorescence in situ hybridization, which displayed unusually aggressive behavior, with brain, lung and subcutaneous soft tissue metastases. As previous reports of metastatic liposarcoma have largely grouped DDL in with other (genetically and clinically distinct) liposarcoma subtypes, we highlight and discuss the rare occurrence of brain metastasis in MDM2 -amplified retroperitoneal liposarcoma.

Impulsive Aggression as a Comorbidity of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents

PubMed Central

Amann, Birgit H.

2016-01-01

Abstract Objective: This article examines the characteristics of impulsive aggression (IA) as a comorbidity in children and adolescents with attention-deficit/hyperactivity disorder (ADHD), focusing on its incidence, impact on ADHD outcomes, need for timely intervention, and limitations of current treatment practices. Methods: Relevant literature was retrieved with electronic searches in PubMed and PsycINFO using the search strategy of “ADHD OR attention deficit hyperactivity disorder” AND “impulsive aggression OR reactive aggression OR hostile aggression OR overt aggression” AND “pediatric OR childhood OR children OR pre-adolescent OR adolescent” with separate searches using review OR clinical trial as search limits. Key articles published before the 2007 Expert Consensus Report on IA were identified using citation analysis. Results: More than 50% of preadolescents with ADHD combined subtype reportedly display clinically significant aggression, with impulsive aggression being the predominant subtype. Impulsive aggression is strongly predictive of a highly unfavorable developmental trajectory characterized by the potential for persistent ADHD, increasing psychosocial burden, accumulating comorbidities, serious lifelong functional deficits across a broad range of domains, delinquency/criminality, and adult antisocial behavior. Impulsive aggression, which triggers peer rejection and a vicious cycle of escalating dysfunction, may be a key factor in unfavorable psychosocial outcomes attributed to ADHD. Because severe aggressive behavior does not remit in many children when treated with primary ADHD therapy (i.e., stimulants and behavioral therapy), a common practice is to add medication of a different class to specifically target aggressive behavior. Conclusions: Impulsive aggression in children and adolescents with ADHD is a serious clinical and public health problem. Although adjunctive therapy with an aggression-targeted agent is widely recommended when aggressive behaviors do not remit with primary ADHD therapy, empirical evidence does not currently support the use of any specific agent. Randomized controlled trials are needed to identify aggression-targeted agents with favorable benefit–risk profiles. PMID:26744906

GBM skin metastasis: a case report and review of the literature

PubMed Central

Lewis, Gary D; Rivera, Andreana L; Tremont-Lukats, Ivo W; Ballester-Fuentes, Leomar Y; Zhang, Yi Jonathan; Teh, Bin S

2017-01-01

Glioblastoma (GBM) is the most common type of malignant tumor found in the brain, and acts very aggressively by quickly and diffusely infiltrating the surrounding brain parenchyma. Despite its aggressive nature, GBM is rarely found to spread extracranially and develop distant metastases. The most common sites of these rare metastases are the lungs, pleura and cervical lymph nodes. There are also a few case reports of skin metastasis. We present the clinical, imaging and pathologic features of a case of a GBM with metastasis to the soft tissue scar and skin near the original craniotomy site. In addition, we discuss the details of this case in the context of the previously reported literature. PMID:28718312

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells.

PubMed

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O'Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H M

2017-03-07

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer.

Anti-GD2-ch14.18/CHO coated nanoparticles mediate glioblastoma (GBM)-specific delivery of the aromatase inhibitor, Letrozole, reducing proliferation, migration and chemoresistance in patient-derived GBM tumor cells

PubMed Central

Tivnan, Amanda; Heilinger, Tatjana; Ramsey, Joanne M; O’Connor, Gemma; Pokorny, Jenny L; Sarkaria, Jann N; Stringer, Brett W; Day, Bryan W; Boyd, Andrew W; Kim, Ella L; Lode, Holger N; Cryan, Sally-Ann; Prehn, Jochen H.M

2017-01-01

Aromatase is a critical enzyme in the irreversible conversion of androgens to oestrogens, with inhibition used clinically in hormone-dependent malignancies. We tested the hypothesis that targeted aromatase inhibition in an aggressive brain cancer called glioblastoma (GBM) may represent a new treatment strategy. In this study, aromatase inhibition was achieved using third generation inhibitor, Letrozole, encapsulated within the core of biodegradable poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs). PLGA-NPs were conjugated to human/mouse chimeric anti-GD2 antibody ch14.18/CHO, enabling specific targeting of GD2-positive GBM cells. Treatment of primary and recurrent patient-derived GBM cells with free-Letrozole (0.1 μM) led to significant decrease in cell proliferation and migration; in addition to reduced spheroid formation. Anti-GD2-ch14.18/CHO-NPs displayed specific targeting of GBM cells in colorectal-glioblastoma co-culture, with subsequent reduction in GBM cell numbers when treated with anti-GD2-ch14.18-PLGA-Let-NPs in combination with temozolomide. As miR-191 is an estrogen responsive microRNA, its expression, fluctuation and role in Letrozole treated GBM cells was evaluated, where treatment with premiR-191 was capable of rescuing the reduced proliferative phenotype induced by aromatase inhibitor. The repurposing and targeted delivery of Letrozole for the treatment of GBM, with the potential role of miR-191 identified, provides novel avenues for target assessment in this aggressive brain cancer. PMID:28178667

Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation.

PubMed

Garzon-Muvdi, Tomas; Schiapparelli, Paula; ap Rhys, Colette; Guerrero-Cazares, Hugo; Smith, Christopher; Kim, Deok-Ho; Kone, Lyonell; Farber, Harrison; Lee, Danielle Y; An, Steven S; Levchenko, Andre; Quiñones-Hinojosa, Alfredo

2012-01-01

Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.

Unusual Asymptomatic Fluorodeoxyglucose Avid Pheochromocytoma in a Case of Myxoid Liposarcoma of the Extremity on 18-F Fluorodeoxyglucose Positron Emission Tomography-computed Tomography.

PubMed

Shivdasani, Divya; Singh, Natasha; Pereira, Melvika; Zade, Anand

2017-01-01

Sarcomas are a heterogeneous group of rare tumors and arise either from soft tissue or from bone. Soft-tissue sarcomas (STSs) initially metastasize to the lungs. Metastases to extrapulmonary sites such as liver, brain, and soft tissue distant from primary tumor usually develop later. However, cases with isolated adrenal metastasis without disseminated disease have been reported in literature. We present a case of primary myxoid liposarcoma of the lower limb, in which staging 18 -F fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan detected a suspicious FDG avid adrenal lesion which eventually on resection was diagnosed as asymptomatic pheochromocytoma. Pheochromocytomas have been reported to demonstrate FDG uptake mimicking metastasis. Hence, while interpreting FDG PET-CT scans in the context of STSs, both the extrapulmonary metastatic potential of aggressive histological subtypes of sarcoma and rare possibility of FDG avid coexistent benign tumor should be taken into consideration.

Video media-induced aggressiveness in children.

PubMed

Cardwell, Michael Steven

2013-09-01

Transmission of aggressive behaviors to children through modeling by adults has long been a commonly held psychological concept; however, with the advent of technological innovations during the last 30 years, video media-television, movies, video games, and the Internet-has become the primary model for transmitting aggressiveness to children. This review explores the acquisition of aggressive behaviors by children through modeling behaviors in violent video media. The impact of aggressive behaviors on the child, the family, and society is addressed. Suggestive action plans to curb this societal ill are presented.

Neural Correlates of Aggressive Behavior in Real Time: a Review of fMRI Studies of Laboratory Reactive Aggression

PubMed Central

Keedy, Sarah; Berman, Mitchell E.; Lee, Royce; Coccaro, Emil F.

2017-01-01

Purpose of review Aggressive behavior has adaptive value in many natural environments; however, it places substantial burden and costs on human society. For this reason, there has long been interest in understanding the neurobiological basis of aggression. This interest, and the flourishing of neuroimaging research in general, has spurred the development of a large and growing scientific literature on the topic. As a result, a neural circuit model of aggressive behavior has emerged that implicates interconnected brain regions that are involved in emotional reactivity, emotion regulation, and cognitive control. Recent findings Recently, behavioral paradigms that simulate provocative interactions have been adapted to neuroimaging protocols, providing an opportunity to directly probe the involvement of neural circuits in an aggressive interaction. Here we review neuroimaging studies of simulated aggressive interactions in research volunteers. We focus on studies that use a well-validated laboratory paradigm for reactive physical aggression and examine the neural correlates of provocation, retaliation, and evaluating punishment of an opponent. Summary Overall, the studies reviewed support the involvement of neural circuits that support emotional reactivity, emotion regulation, and cognitive control in aggressive behavior. Based on a synthesis of this literature, future research directions are discussed. PMID:29607288

New study tests the safety and efficacy of combination therapy in adults with astrocytoma and glioblastoma | Center for Cancer Research

Cancer.gov

A two-part clinical trial of a multikinase inhibitor plus chemotherapy in patients with two types of brain tumors is enrolling in Bethesda, MD. The study will be open to patients with anaplastic astrocytoma, an uncommon malignant brain tumor that develops from star-shaped brain cells called astrocytes and glioblastoma, the most common and aggressive form of astrocytoma. Learn

Serotonergic outcome, stress and sexual steroid hormones, and growth in a South American cichlid fish fed with an L-tryptophan enriched diet.

PubMed

Morandini, Leonel; Ramallo, Martín Roberto; Moreira, Renata Guimarães; Höcht, Christian; Somoza, Gustavo Manuel; Silva, Ana; Pandolfi, Matías

2015-11-01

Reared animals for edible or ornamental purposes are frequently exposed to high aggression and stressful situations. These factors generally arise from conspecifics in densely breeding conditions. In vertebrates, serotonin (5-HT) has been postulated as a key neuromodulator and neurotransmitter involved in aggression and stress. The essential amino acid L-tryptophan (trp) is crucial for the synthesis of 5-HT, and so, leaves a gateway for indirectly augmenting brain 5-HT levels by means of a trp-enriched diet. The cichlid fish Cichlasoma dimerus, locally known as chanchita, is an autochthonous, potentially ornamental species and a fruitful laboratory model which behavior and reproduction has been studied over the last 15years. It presents complex social hierarchies, and great asymmetries between subordinate and dominant animals in respect to aggression, stress, and reproductive chance. The first aim of this work was to perform a morphological description of chanchita's brain serotonergic system, in both males and females. Then, we evaluated the effects of a trp-supplemented diet, given during 4weeks, on brain serotonergic activity, stress and sexual steroid hormones, and growth in isolated specimens. Results showed that chanchita's brain serotonergic system is composed of several populations of neurons located in three main areas: pretectum, hypothalamus and raphe, with no clear differences between males and females at a morphological level. Animals fed with trp-enriched diets exhibited higher forebrain serotonergic activity and a significant reduction in their relative cortisol levels, with no effects on sexual steroid plasma levels or growth parameters. Thus, this study points to food trp enrichment as a "neurodietary'' method for elevating brain serotonergic activity and decreasing stress, without affecting growth or sex steroid hormone levels. Copyright © 2015 Elsevier Inc. All rights reserved.

The frontal lobe and aggression

PubMed Central

Séguin, Jean R.

2014-01-01

Frontal lesions often lead to psychosocial problems. It is not surprising that frontal lobe dysfunctions have been proposed to underlie antisocial behaviour in individuals without apparent lesions. However, physical aggression and violence have never been systematically related to acquired lesions. Whereas, traditional neuropsychological testing identifies problems in cognitive and emotional information processing, recent brain-imaging studies have revealed both the frontal structural and functional underpinnings of antisocial behaviour. Careful characterization of antisocial behaviour subtypes seems to indicate that cognitive-neuropsychological function is systematically poor in physical aggression and hyperactivity. Recent refinements point to biological and genetic moderators of that association. PMID:24976846

Characteristics of aggression in a German psychiatric hospital and predictors of patients at risk.

PubMed

Ketelsen, R; Zechert, C; Driessen, M; Schulz, M

2007-02-01

This study investigated the aggressive behaviour of all mentally ill patients within a whole psychiatric hospital with a catchment area of 325 000 inhabitants over a 1-year period (i) to assess the 1-year prevalence and characteristics of aggressive episodes and index inpatients, and (ii) to identify predictors of patients at risk by a multivariate approach. Staff Observation of Aggression Scale was used to assess aggressive behaviour. Characteristics of index inpatients were compared with those of non-index inpatients. Logistic regression analysis was applied to identify risk factors. A total of 171 out of 2210 admitted patients (7.7%) exhibited 441 aggressive incidents (1.7 incidents per bed per year). Logistic regression analyses revealed as major risk factors of aggression: diagnoses (organic brain syndromes OR = 3.6, schizophrenia OR = 2.9), poor psychosocial living conditions (OR = 2.2), and critical behaviour leading to involuntary admission (OR = 3.3). Predictors of aggressive behaviour can be useful to identify inpatients at risk. Nevertheless, additional situational determinants have to be recognized. Training for professionals should include preventive and de-escalating strategies to reduce the incidence of aggressive behaviour in psychiatric hospitals. The application of de-escalating interventions prior to admission might be effective in preventing aggressive behaviour during inpatient treatment especially for patients with severe mental disorders.

Role of Serotonin and Dopamine System Interactions in the Neurobiology of Impulsive Aggression and its Comorbidity with other Clinical Disorders

PubMed Central

Seo, Dongju; Patrick, Christopher J.; Kennealy, Patrick J.

2008-01-01

Impulsive aggression is characterized by an inability to regulate affect as well as aggressive impulses, and is highly comorbid with other mental disorders including depression, suicidal behavior, and substance abuse. In an effort to elucidate the neurobiological underpinnings of impulsive aggression and to help account for its connections with these other disorders, this paper reviews relevant biochemical, brain imaging, and genetic studies. The review suggests that dysfunctional interactions between serotonin and dopamine systems in the prefrontal cortex may be an important mechanism underlying the link between impulsive aggression and its comorbid disorders. Specifically, serotonin hypofunction may represent a biochemical trait that predisposes individuals to impulsive aggression, with dopamine hyperfunction contributing in an additive fashion to the serotonergic deficit. The current paper proposes a modified diathesis-stress model of impulsive aggression in which the underlying biological diathesis may be deficient serotonergic function in the ventral prefrontal cortex. This underlying disposition can be manifested behaviorally as impulsive aggression towards oneself and others, and as depression under precipitating life stressors. Substance abuse associated with impulsive aggression is understood in the context of dopamine dysregulation resulting from serotonergic deficiency. Also discussed are future research directions in the neurobiology of impulsive aggression and its comorbid disorders. PMID:19802333

Developmental trajectories of aggressive behavior in children from ages 8 to 10: The role of sex and hormones.

PubMed

Azurmendi, Aitziber; Pascual-Sagastizabal, Eider; Vergara, Ana I; Muñoz, Jose M; Braza, Paloma; Carreras, Rosario; Braza, Francisco; Sánchez-Martín, José R

2016-01-01

This study explored the developmental trajectory of aggressive behavior from age 8 to age 10 in school-aged children, taking into account possible sex differences, as well as the involvement of certain hormones. Participants were 90 children (49 boys and 41 girls) from four schools. At the beginning of the study, the children were 8-year old and were in 3rd grade of primary school. The second data collection phase was carried out two years later (at age 10) when the children were in 5th grade (primary). Their aggressive behavior was measured by the Direct and Indirect Aggression Scale, an instrument which uses peer rating. Hormone levels, testosterone, cortisol and estradiol were analyzed using an enzymoimmunoassay technique in saliva samples. The results revealed a difference in aggressive behavior between the ages of 8 and 10, in boys only, who were found to be more aggressive at age 10. A regression analysis revealed that cortisol and estradiol contributed to explaining the changes observed in aggressive behavior in boys. Boys whose cortisol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior increased most during the same timeframe. Moreover, boys whose estradiol levels rose most between the ages of 8 and 10 were also those whose aggressive behavior decreased most during the same timeframe. Our results highlight the importance of studying aggressive behavior from a longitudinal perspective, taking into account sex differences and biological measures. © 2015 Wiley Periodicals, Inc.

Lateralisation of aggressive displays in a tephritid fly

NASA Astrophysics Data System (ADS)

Benelli, Giovanni; Donati, Elisa; Romano, Donato; Stefanini, Cesare; Messing, Russell H.; Canale, Angelo

2015-02-01

Lateralisation (i.e. different functional and/or structural specialisations of the left and right sides of the brain) of aggression has been examined in several vertebrate species, while evidence for invertebrates is scarce. In this study, we investigated lateralisation of aggressive displays (boxing with forelegs and wing strikes) in the Mediterranean fruit fly, Ceratitis capitata. We attempted to answer the following questions: (1) do medflies show lateralisation of aggressive displays at the population-level; (2) are there sex differences in lateralisation of aggressive displays; and (3) does lateralisation of aggression enhance fighting success? Results showed left-biased population-level lateralisation of aggressive displays, with no consistent differences among sexes. In both male-male and female-female conflicts, aggressive behaviours performed with left body parts led to greater fighting success than those performed with right body parts. As we found left-biased preferential use of body parts for both wing strikes and boxing, we predicted that the left foreleg/wing is quicker in exploring/striking than the right one. We characterised wing strike and boxing using high-speed videos, calculating mean velocity of aggressive displays. For both sexes, aggressive displays that led to success were faster than unsuccessful ones. However, left wing/legs were not faster than right ones while performing aggressive acts. Further research is needed on proximate causes allowing enhanced fighting success of lateralised aggressive behaviour. This is the first report supporting the adaptive role of lateralisation of aggressive displays in insects.

EPHRIN-A5 REGULATES INTER-MALE AGGRESSION IN MICE

PubMed Central

Sheleg, Michal; Yochum, Carrie L.; Richardson, Jason R.; Wagner, George C.; Zhou, Renping

2015-01-01

The Eph family of receptor tyrosine kinases play key roles in both the patterning of the developing nervous system and neural plasticity in the mature brain. To determine functions of ephrin-A5, a GPI-linked ligand to the Eph receptors, in animal behavior regulations, we examined effects of its inactivation on male mouse aggression. When tested in the resident-intruder paradigm for offensive aggression, ephrin-A5-mutant animals (ephrin-A5−/−) exhibited severe reduction in conspecific aggression compared to wild-type controls. On the contrary, defensive aggression in the form of target biting was higher in ephrin-A5−/− mice, indicating that the mutant mice are capable of attacking behavior. In addition, given the critical role of olfaction in aggressive behavior, we examined the ability of the ephrin-A5−/− mice to smell and found no differences between the mutant and control animals. Testosterone levels in the mutant mice were also found to be within the normal range. Taken together, our data reveal a new role of ephrin-A5 in the regulation of aggressive behavior in mice. PMID:25746458

Neuroimaging and Neurocognitive Correlates of Aggression and Violence in Schizophrenia

PubMed Central

Weiss, Elisabeth M.

2012-01-01

Individuals diagnosed with major mental disorders such as schizophrenia are more likely to have engaged in violent behavior than mentally healthy members of the same communities. Although aggressive acts can have numerous causes, research about the underlying neurobiology of violence and aggression in schizophrenia can lead to a better understanding of the heterogeneous nature of that behavior and can assist in developing new treatment strategies. The purpose of this paper is to review the recent literature and discuss some of the neurobiological correlates of aggression and violence. The focus will be on schizophrenia, and the results of neuroimaging and neuropsychological studies that have directly investigated brain functioning and/or structure in aggressive and violent samples will be discussed as well as other domains that might predispose to aggression and violence such as deficits in responding to the emotional expressions of others, impulsivity, and psychopathological symptoms. Finally gender differences regarding aggression and violence are discussed. In this context several methodological and conceptional issues that limited the comparison of these studies will be addressed. PMID:24278673

Dose-response study for the highly aggressive and metastatic primary F3II mammary carcinoma under direct current.

PubMed

González, Maraelys M; Morales, Dasha F; Cabrales, Luis E B; Pérez, Daniel J; Montijano, Juan I; Castañeda, Antonio R S; González, Victoriano G S; Posada, Oscar O; Martínez, Janet A; Delgado, Arlem G; Martínez, Karina G; Mon, Mayrel L; Monzón, Kalet L; Ciria, Héctor M C; Beatón, Emilia O; Brooks, Soraida C A; González, Tamara R; Jarque, Manuel V; Mateus, Miguel A Ó; Rodríguez, Jorge L G; Calzado, Enaide M

2018-06-05

Electrochemical treatment has been suggested as an effective alternative to local cancer therapy. Nevertheless, its effectiveness decreases when highly aggressive primary tumors are treated. The aim of this research was to understand the growth kinetics of the highly aggressive and metastatic primary F3II tumor growing in male and female BALB/c/Cenp mice under electrochemical treatment. Different amounts of electric charge (6, 9, and 18 C) were used. Two electrodes were inserted into the base, perpendicular to the tumor's long axis, keeping about 1 cm distance between them. Results have shown that the F3II tumor is highly sensitive to direct current. The overall effectiveness (complete response + partial response) of this physical agent was ≥75.0% and observed in 59.3% (16/27) of treated F3II tumors. Complete remission of treated tumors was observed in 22.2% (6/27). An unexpected result was the death of 11 direct current-treated animals (eight females and three males). It is concluded that direct current may be addressed to significantly affect highly aggressive and metastatic primary tumor growth kinetics, including the tumor complete response. Bioelectromagnetics. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Suppression of Peroxiredoxin 4 in Glioblastoma Cells Increases Apoptosis and Reduces Tumor Growth

PubMed Central

Kim, Tae Hyong; Song, Jieun; Alcantara Llaguno, Sheila R.; Murnan, Eric; Liyanarachchi, Sandya; Palanichamy, Kamalakannan; Yi, Ji-Yeun; Viapiano, Mariano Sebastian; Nakano, Ichiro; Yoon, Sung Ok; Wu, Hong; Parada, Luis F.; Kwon, Chang-Hyuk

2012-01-01

Glioblastoma multiforme (GBM), the most common and aggressive primary brain malignancy, is incurable despite the best combination of current cancer therapies. For the development of more effective therapies, discovery of novel candidate tumor drivers is urgently needed. Here, we report that peroxiredoxin 4 (PRDX4) is a putative tumor driver. PRDX4 levels were highly increased in a majority of human GBMs as well as in a mouse model of GBM. Reducing PRDX4 expression significantly decreased GBM cell growth and radiation resistance in vitro with increased levels of ROS, DNA damage, and apoptosis. In a syngenic orthotopic transplantation model, Prdx4 knockdown limited GBM infiltration and significantly prolonged mouse survival. These data suggest that PRDX4 can be a novel target for GBM therapies in the future. PMID:22916164

The fear of other persons' laughter: Poor neuronal protection against social signals of anger and aggression.

PubMed

Papousek, Ilona; Schulter, Günter; Rominger, Christian; Fink, Andreas; Weiss, Elisabeth M

2016-01-30

The fear of other persons' laughter (gelotophobia) occurs in the context of several psychiatric conditions, particularly in the schizophrenia spectrum and social phobia. It entails severe personal and inter-personal problems including heightened aggression and possibly violence. Individuals with gelotophobia (n=30; 24 with social phobia or Cluster A diagnosis) and matched symptom-free controls (n=30) were drawn from a large screening sample (n=1440). EEG coherences were recorded during the confrontation with other people's affect expressions, to investigate the brain's modulatory control over the emotionally laden perceptual input. Gelotophobia was associated with more loose functional coupling of prefrontal and posterior cortex during the processing of expressions of anger and aggression, thus leaving the individual relatively unprotected from becoming affected by these social signals. The brain's response to social signals of anger/aggression and the accompanied heightened permeability for this kind of information explains the particular sensitivity to actual or supposed malicious aspects of laughter (and possibly of other ambiguous social signals) in individuals with gelotophobia, which represents the core feature of the condition. Heightened perception of stimuli that could be perceived as offensive, which is inherent in several psychiatric conditions, may be particularly evident in the fear of other persons' laughter. Copyright © 2015. Published by Elsevier Ireland Ltd.

Perspective training to treat anger problems after brain injury: Two case studies.

PubMed

Winegardner, Jill; Keohane, Clare; Prince, Leyla; Neumann, Dawn

2016-06-18

People with acquired brain injury (ABI) often show increased anger and aggression. Anger has been linked to attributions of hostile intent. The more intentional and hostile the judgments of other's behaviours are, the angrier the responses tend to be. Some people with ABI tend to make harsher attributions than healthy controls (negative attribution bias). Poor perspective-taking may distort assessment of others' intentions, thereby contributing to this bias and subsequent anger responses. Examine changes in anger and perspective-taking after a Perspectives Group in two participants with ABI. This study is a case report exploring observational changes in anger, hostility, verbal and physical aggression and perspective-taking in two males with ABI and severe emotion dysregulation. Participants and their spouses also provided qualitative feedback through a semi-structured interview following perspectives training. The six-week "Perspectives Group" used hypothetical and real-life situations to teach participants to consider the perspectives of others when determining their intentions. Both participants showed post-treatment declines in aggression. Although only minimal changes occurred on the perspective-taking measure, spouses described important behavioural changes in their partners that indicated both decreased aggression and better perspective taking. These preliminary findings support further investigation of perspectives training for reducing anger after ABI.

Sexual Conspecific Aggressive Response (SCAR): A Model of Sexual Trauma that Disrupts Maternal Learning and Plasticity in the Female Brain.

PubMed

Shors, Tracey J; Tobόn, Krishna; DiFeo, Gina; Durham, Demetrius M; Chang, Han Yan M

2016-01-25

Sexual aggression can disrupt processes related to learning as females emerge from puberty into young adulthood. To model these experiences in laboratory studies, we developed SCAR, which stands for Sexual Conspecific Aggressive Response. During puberty, a rodent female is paired daily for 30-min with a sexually-experienced adult male. During the SCAR experience, the male tracks the anogenital region of the female as she escapes from pins. Concentrations of the stress hormone corticosterone were significantly elevated during and after the experience. Moreover, females that were exposed to the adult male throughout puberty did not perform well during training with an associative learning task nor did they learn well to express maternal behaviors during maternal sensitization. Most females that were exposed to the adult male did not learn to care for offspring over the course of 17 days. Finally, females that did not express maternal behaviors retained fewer newly-generated cells in their hippocampus whereas those that did express maternal behaviors retained more cells, most of which would differentiate into neurons within weeks. Together these data support SCAR as a useful laboratory model for studying the potential consequences of sexual aggression and trauma for the female brain during puberty and young adulthood.

Neuroimaging correlates of aggression in schizophrenia: an update.

PubMed

Hoptman, Matthew J; Antonius, Daniel

2011-03-01

Aggression in schizophrenia is associated with poor treatment outcomes, hospital admissions, and stigmatization of patients. As such it represents an important public health issue. This article reviews recent neuroimaging studies of aggression in schizophrenia, focusing on PET/single photon emission computed tomography and MRI methods. The neuroimaging literature on aggression in schizophrenia is in a period of development. This is attributable in part to the heterogeneous nature and basis of that aggression. Radiological methods have consistently shown reduced activity in frontal and temporal regions. MRI brain volumetric studies have been less consistent, with some studies finding increased volumes of inferior frontal structures, and others finding reduced volumes in aggressive individuals with schizophrenia. Functional MRI studies have also had inconsistent results, with most finding reduced activity in inferior frontal and temporal regions, but some also finding increased activity in other regions. Some studies have made a distinction between types of aggression in schizophrenia in the context of antisocial traits, and this appears to be useful in understanding the neuroimaging literature. Frontal and temporal abnormalities appear to be a consistent feature of aggression in schizophrenia, but their precise nature likely differs because of the heterogeneous nature of that behavior.

Gliomagenesis and neural stem cells: Key role of hypoxia and concept of tumor "neo-niche".

PubMed

Diabira, Sylma; Morandi, Xavier

2008-01-01

Gliomas represent the most common primary brain tumors and the most devastating pathology of the central nervous system. Despite progress in conventional treatments, the prognosis remains dismal. Recent studies have suggested that a glioma brain tumor may arise from a "cancer stem cell". To understand this theory we summarize studies of the concepts of neural stem cell, and its specialized microenvironment, namely the niche which can regulate balanced self-renewal, differentiation and stem cell quiescence. We summarize the molecular mechanism known or postulated to be involved in the disregulation of normal stem cells features allowing them to undergo neoplasic transformation. We seek data pointing out the key role of hypoxia in normal homeostasis of stem cells and in the initiation, development and aggressiveness of gliomas. We develop the concept of tumor special microenvironment and we propose the new concept of neo-niche, surrounding the glioma, in which hypoxia could be a key factor to recruit and deregulate different stem cells for gliogenesis process. Substantial advances in treatment would come from obtaining better knowledge of molecular impairs of this disease.

Chronophin is a glial tumor modifier involved in the regulation of glioblastoma growth and invasiveness.

PubMed

Schulze, M; Fedorchenko, O; Zink, T G; Knobbe-Thomsen, C B; Kraus, S; Schwinn, S; Beilhack, A; Reifenberger, G; Monoranu, C M; Sirén, A-L; Jeanclos, E; Gohla, A

2016-06-16

Glioblastoma is the most aggressive primary brain tumor in adults. Although the rapid recurrence of glioblastomas after treatment is a major clinical challenge, the relationships between tumor growth and intracerebral spread remain poorly understood. We have identified the cofilin phosphatase chronophin (gene name: pyridoxal phosphatase, PDXP) as a glial tumor modifier. Monoallelic PDXP loss was frequent in four independent human astrocytic tumor cohorts and increased with tumor grade. We found that aberrant PDXP promoter methylation can be a mechanism leading to further chronophin downregulation in glioblastomas, which correlated with shorter glioblastoma patient survival. Moreover, we observed an inverse association between chronophin protein expression and cofilin phosphorylation levels in glioma tissue samples. Chronophin-deficient glioblastoma cells showed elevated cofilin phosphorylation, an increase in polymerized actin, a higher directionality of cell migration, and elevated in vitro invasiveness. Tumor growth of chronophin-depleted glioblastoma cells xenografted into the immunodeficient mouse brain was strongly impaired. Our study suggests a mechanism whereby the genetic and epigenetic alterations of PDXP resulting in altered chronophin expression may regulate the interplay between glioma cell proliferation and invasion.

Nonsmall Cell Lung Carcinoma with Giant Cell Features Expressing Programmed Death-Ligand 1: A Report of a Patient Successfully Treated with Pembrolizumab

PubMed Central

Nakayama, Shingo; Sasaki, Mamoru; Morinaga, Shojiroh

2018-01-01

Giant cell carcinoma, a rare variant of nonsmall cell lung carcinoma (NSCLC), is characterized by aggressive progression and poor response to conventional chemotherapy. This report is the first to describe a patient with NSCLC and giant cell features who was successfully treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). A 69-year-old woman was diagnosed with NSCLC with multiple brain metastases. Histological evaluation of lung biopsy specimens revealed proliferation of pleomorphic giant tumor cells with poor cohesiveness, findings consistent with giant cell carcinoma. Immunostaining showed that a high proportion of the tumor cells were positive for expression of programmed death-ligand 1 (PD-L1). The patient received stereotactic radiotherapy for the brain metastases, followed by administration of pembrolizumab. Treatment with pembrolizumab resulted in the rapid regression of the primary lung nodule, with the progression-free period maintained for at least four treatment cycles. Immunotherapy targeting PD-1/PD-L1 may be an option for patients with PD-L1-positive NSCLC with giant cell features. PMID:29736285

Nonsmall Cell Lung Carcinoma with Giant Cell Features Expressing Programmed Death-Ligand 1: A Report of a Patient Successfully Treated with Pembrolizumab.

PubMed

Nakayama, Shingo; Sasaki, Mamoru; Morinaga, Shojiroh; Minematsu, Naoto

2018-01-01

Giant cell carcinoma, a rare variant of nonsmall cell lung carcinoma (NSCLC), is characterized by aggressive progression and poor response to conventional chemotherapy. This report is the first to describe a patient with NSCLC and giant cell features who was successfully treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). A 69-year-old woman was diagnosed with NSCLC with multiple brain metastases. Histological evaluation of lung biopsy specimens revealed proliferation of pleomorphic giant tumor cells with poor cohesiveness, findings consistent with giant cell carcinoma. Immunostaining showed that a high proportion of the tumor cells were positive for expression of programmed death-ligand 1 (PD-L1). The patient received stereotactic radiotherapy for the brain metastases, followed by administration of pembrolizumab. Treatment with pembrolizumab resulted in the rapid regression of the primary lung nodule, with the progression-free period maintained for at least four treatment cycles. Immunotherapy targeting PD-1/PD-L1 may be an option for patients with PD-L1-positive NSCLC with giant cell features.

Assessment of rat optic nerve damage due to microbeam radiation therapy in the treatment of glioblastomas.

PubMed

Mohamed, A; Worobec, S; Schultke, E

2008-01-01

Glioblastomas are the most common and aggressive subtype of human primary brain tumors. Due to their uncontrolled cellular proliferation, intense invasion, and lack of apoptosis, they are extremely difficult to treat. Currently, different approaches such as surgery, chemotherapy and radiation therapy have been employed as possible treatments however thus far; these treatments are not curative. Currently, microbeam radiation therapy (MRT) is being trialed in animal models of malignant brain tumors (rats) to aid in treatment. Some of the protocols tested have been shown to significantly increase survival rates. However, due to the high x-ray doses uses in MRT, the surrounding tissue of the targeted Glioblastomas may be irreversibly damaged. In previous studies, lens damage and clouding of the cornea have been observed in microbeam exposed eyes. However, to date no studies have assessed optic nerve damage. Therefore, this study examines the potential rat optic nerve damage following exposure to microbeam radiation therapy in the treatment of Glioblastomas. Although there appears to be no significant damage to the optic nerve, slight inflammation was observed within the extra ocular muscle.

Behavioral Analysis of Genetically Modified Mice Indicates Essential Roles of Neurosteroidal Estrogen

PubMed Central

Honda, Shin-Ichiro; Wakatsuki, Toru; Harada, Nobuhiro

2011-01-01

Aromatase in the mouse brain is expressed only in the nerve cells of specific brain regions with a transient peak during the neonatal period when sexual behaviors become organized. The aromatase-knockout (ArKO) mouse, generated to shed light on the physiological functions of estrogen in the brain, exhibited various abnormal behaviors, concomitant with undetectable estrogen and increased androgen in the blood. To further elucidate the effects of neurosteroidal estrogens on behavioral phenotypes, we first prepared an brain-specific aromatase transgenic (bsArTG) mouse by introduction of a human aromatase transgene controlled under a −6.5 kb upstream region of the brain-specific promoter of the mouse aromatase gene into fertilized mouse eggs, because the −6.5 kb promoter region was previously shown to contain the minimal essential element responsible for brain-specific spatiotemporal expression. Then, an ArKO mouse expressing the human aromatase only in the brain was generated by crossing the bsArTG mouse with the ArKO mouse. The resulting mice (ArKO/bsArTG mice) nearly recovered from abnormal sexual, aggressive, and locomotive (exploratory) behaviors, in spite of having almost the same serum levels of estrogen and androgen as the adult ArKO mouse. These results suggest that estrogens locally synthesized in the specific neurons of the perinatal mouse brain directly act on the neurons and play crucial roles in the organization of neuronal networks participating in the control of sexual, aggressive, and locomotive (exploratory) behaviors. PMID:22654807

Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders?

PubMed Central

Baler, Ruben D.; Volkow, Nora D.; Fowler, Joanna S.; Benveniste, Helene

2008-01-01

Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development — but not during adult life — is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke–induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke. PMID:18592036

Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest.

PubMed

Long, Patrick M; Tighe, Scott W; Driscoll, Heather E; Fortner, Karen A; Viapiano, Mariano S; Jaworski, Diane M

2015-08-01

Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-l-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth. © 2015 Wiley Periodicals, Inc.

Acetate supplementation as a means of inducing glioblastoma stem-like cell growth arrest

PubMed Central

Long, Patrick M.; Tighe, Scott W.; Driscoll, Heather E.; Fortner, Karen A.; Viapiano, Mariano S.; Jaworski, Diane M.

2015-01-01

Glioblastoma (GBM), the most common primary adult malignant brain tumor, is associated with a poor prognosis due, in part, to tumor recurrence mediated by chemotherapy and radiation resistant glioma stem-like cells (GSCs). The metabolic and epigenetic state of GSCs differs from their non-GSC counterparts, with GSCs exhibiting greater glycolytic metabolism and global hypoacetylation. However, little attention has been focused on the potential use of acetate supplementation as a therapeutic approach. N-acetyl-L-aspartate (NAA), the primary storage form of brain acetate, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis, are significantly reduced in GBM tumors. We recently demonstrated that NAA supplementation is not an appropriate therapeutic approach since it increases GSC proliferation and pursued an alternative acetate source. The FDA approved food additive Triacetin (glyceryl triacetate, GTA) has been safely used for acetate supplementation therapy in Canavan disease, a leukodystrophy due to ASPA mutation. This study characterized the effects of GTA on the proliferation and differentiation of six primary GBM-derived GSCs relative to established U87 and U251 GBM cell lines, normal human cerebral cortical astrocytes, and murine neural stem cells. GTA reduced proliferation of GSCs greater than established GBM lines. Moreover, GTA reduced growth of the more aggressive mesenchymal GSCs greater than proneural GSCs. Although sodium acetate induced a dose-dependent reduction of GSC growth, it also reduced cell viability. GTA-mediated growth inhibition was not associated with differentiation, but increased protein acetylation. These data suggest that GTA-mediated acetate supplementation is a novel therapeutic strategy to inhibit GSC growth. PMID:25573156

The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

PubMed

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-10-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Verbal versus Physical Aggression in Intermittent Explosive Disorder

PubMed Central

Look, Amy E.; McCloskey, Michael S.; Coccaro, Emil F.

2015-01-01

Intermittent Explosive Disorder (IED) is the only adult psychiatric diagnosis for which pathological aggression is primary. DSM-IV criteria focused on physical aggression, but DSM-5 allows for an IED diagnosis in the presence of frequent verbal aggression with or without concurrent physical aggression. It remains unclear how individuals with verbal aggression differ from those with physical aggression with respect to cognitive-affective deficits and psychosocial functioning. The current study compared individuals who met IED criteria with either frequent verbal aggression without physical aggression (IED-V), physical aggression without frequent verbal aggression (IED-P), or both frequent verbal aggression and physical aggression (IED-B) as well as a non-aggressive personality-disordered (PD) comparison group using behavioral and self-report measures of aggression, anger, impulsivity, and affective lability, and psychosocial impairment. Results indicate all IED groups showed increased anger/aggression, psychosocial impairment, and affective lability relative to the PD group. The IED-B group showed greater trait anger, anger dyscontrol, and aggression compared to the IED-V and IED-P groups. Overall, the IED-V and IED-P groups reported comparable deficits and impairment. These results support the inclusion of verbal aggression within the IED criteria and suggest a more severe profile for individuals who engage in both frequent verbal arguments and repeated physical aggression. PMID:25534757

Amygdala reactivity to fearful faces correlates positively with impulsive aggression.

PubMed

da Cunha-Bang, Sofi; Fisher, Patrick M; Hjordt, Liv V; Holst, Klaus; Knudsen, Gitte M

2018-01-07

Facial expressions robustly activate the amygdala, a brain structure playing a critical role in aggression. Whereas previous studies suggest that amygdala reactivity is related to various measures of impulsive aggression, we here estimate a composite measure of impulsive aggression and evaluate whether it is associated with amygdala reactivity to angry and fearful faces. We estimated amygdala reactivity with functional magnetic resonance imaging in 47 men with varying degree of aggressive traits (19 incarcerated violent offenders and 28 healthy controls). We modeled a composite "impulsive aggression" trait construct (LV agg ) using a linear structural equation model, with a single latent variable capturing the shared correlation between five self-report measures of trait aggression, anger and impulsivity. We tested for associations between amygdala reactivity and the LV agg , adjusting for age and group. The LV agg was significantly positively associated with amygdala reactivity to fearful (p = 0.001), but not angry faces (p = 0.9). We found no group difference in amygdala reactivity to fearful or angry faces. The findings suggest that that amygdala reactivity to fearful faces is represented by a composite index of impulsive aggression and provide evidence that impulsive aggression is associated with amygdala reactivity in response to submissive cues, i.e., fearful faces.

Systematic Evaluation of Aggressive Air Sampling for Bacillus ...

EPA Pesticide Factsheets

Report The primary objectives of this project were to evaluate the Aggressive Air Sampling (AAS) method compared to currently used surface sampling methods and to determine if AAS is a viable option for sampling Bacillus anthracis spores.

Corticostriatal Connectivity in Antisocial Personality Disorder by MAO-A Genotype and Its Relationship to Aggressive Behavior.

PubMed

Kolla, Nathan J; Dunlop, Katharine; Meyer, Jeffrey H; Downar, Jonathan

2018-05-09

The influence of genetic variation on resting-state neural networks represents a burgeoning line of inquiry in psychiatric research. Monoamine oxidase A, an X-linked gene, is one example of a molecular target linked to brain activity in psychiatric illness. Monoamine oxidase A genetic variants, including the high and low variable nucleotide tandem repeat polymorphisms, have been shown to differentially affect brain functional connectivity in healthy humans. However, it is currently unknown whether these same polymorphisms influence resting-state brain activity in clinical conditions. Given its high burden on society and strong connection to violent behavior, antisocial personality disorder is a logical condition to study, since in vivo markers of monoamine oxidase A brain enzyme are reduced in key affect-modulating regions, and striatal levels of monoamine oxidase A show a relation with the functional connectivity of this same region. We utilized monoamine oxidase A genotyping and seed-to-voxel-based functional connectivity to investigate the relationship between genotype and corticostriatal connectivity in 21 male participants with severe antisocial personality disorder and 19 male healthy controls. Dorsal striatal connectivity to the frontal pole and anterior cingulate gyrus differentiated antisocial personality disorder subjects and healthy controls by monoamine oxidase A genotype. Furthermore, the linear relationship of proactive aggression to superior ventral striatal-angular gyrus functional connectivity differed by monoamine oxidase A genotype in the antisocial personality disorder groups. These results suggest that monoamine oxidase A genotype may affect corticostriatal connectivity in antisocial personality disorder and that these functional connections may also underlie use of proactive aggression in a genotype-specific manner.

Parametric PET/MR Fusion Imaging to Differentiate Aggressive from Indolent Primary Prostate Cancer with Application for Image-Guided Prostate Cancer Biopsies

DTIC Science & Technology

2013-10-01

AD_________________ Award Number: W81XWH-12-1-0597 TITLE: Parametric PET /MR Fusion Imaging to...Parametric PET /MR Fusion Imaging to Differentiate Aggressive from Indolent Primary Prostate Cancer with Application for Image-Guided Prostate Cancer Biopsies...The study investigates whether fusion PET /MRI imaging with 18F-choline PET /CT and diffusion-weighted MRI can be successfully applied to target prostate

Trends in North American newspaper reporting of brain injury in ice hockey.

PubMed

Cusimano, Michael D; Sharma, Bhanu; Lawrence, David W; Ilie, Gabriela; Silverberg, Sarah; Jones, Rochelle

2013-01-01

The frequency and potential long-term effects of sport-related traumatic brain injuries (TBI) make it a major public health concern. The culture within contact sports, such as ice hockey, encourages aggression that puts youth at risk of TBI such as concussion. Newspaper reports play an important role in conveying and shaping the culture around health-related behaviors. We qualitatively studied reports about sport-related TBI in four major North American newspapers over the last quarter-century. We used the grounded-theory approach to identify major themes and then did a content analysis to compare the frequency of key themes between 1998-2000 and 2009-2011. The major themes were: perceptions of brain injury, aggression, equipment, rules and regulations, and youth hockey. Across the full study period, newspaper articles from Canada and America portrayed violence and aggression that leads to TBI both as integral to hockey and as an unavoidable risk associated with playing the game. They also condemned violence in ice hockey, criticized the administrative response to TBI, and recognized the significance of TBI. In Canada, aggression was reported more often recently and there was a distinctive shift in portraying protective equipment as a solution to TBI in earlier years to a potential contributing factor to TBI later in the study period. American newspapers gave a greater attention to 'perception of risks' and the role of protective equipment, and discussed TBI in a broader context in the recent time period. Newspapers from both countries showed similar recent trends in regards to a need for rule changes to curb youth sport-related TBI. This study provides a rich description of the reporting around TBI in contact sport. Understanding this reporting is important for evaluating whether the dangers of sport-related TBI are being appropriately communicated by the media.

How doth the little busy bee: unexpected metabolism.

PubMed

Barros, L Felipe; Sierralta, Jimena; Weber, Bruno

2015-01-01

Brain energy metabolism powers information processing and behavior, much as electricity powers a computer. However, a recent study in insects suggests that this relationship is more interesting, causally linking aggressive behavior to energetics. These findings may also shed new light on aerobic glycolysis, a long-standing riddle of human brain physiology. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gene Expression Profiling of Nonhuman Primates Exposed to Aerosolized Venezuelan Equine Encephalitis Virus

DTIC Science & Technology

2007-12-01

endogenous pyrogens occur slightly earlier in s.c. infections, but are more pro- longed by aerosol. Lymphopenia also seems to be more aggressive in...brain) Brain P-value (lung) Lung P-value (spleen) Spleen Antigen processing, endogenous antigen via MHC class I (BP) HLA-A 213932_x_at 8.58E-05 2.40

Prevalence of traumatic brain injury in incarcerated groups compared to the general population: a meta-analysis.

PubMed

Farrer, Thomas J; Hedges, Dawson W

2011-03-30

Traumatic brain injury can cause numerous behavioral abnormalities including aggression, violence, impulsivity, and apathy, factors that can be associated with criminal behavior and incarceration. To better characterize the association between traumatic brain injury and incarceration, we pooled reported frequencies of lifetime traumatic brain injury of any severity among incarcerated samples and compared the pooled frequency to estimates of the lifetime prevalence of traumatic brain injury in the general population. We found a significantly higher prevalence of traumatic brain injury in the incarcerated groups compared to the general population. As such, there appears to be an association between traumatic brain injury and incarceration. Copyright © 2011 Elsevier Inc. All rights reserved.

Neuroimaging studies of aggressive and violent behavior: current findings and implications for criminology and criminal justice.

PubMed

Bufkin, Jana L; Luttrell, Vickie R

2005-04-01

With the availability of new functional and structural neuroimaging techniques, researchers have begun to localize brain areas that may be dysfunctional in offenders who are aggressive and violent. Our review of 17 neuroimaging studies reveals that the areas associated with aggressive and/or violent behavioral histories, particularly impulsive acts, are located in the prefrontal cortex and the medial temporal regions. These findings are explained in the context of negative emotion regulation, and suggestions are provided concerning how such findings may affect future theoretical frameworks in criminology, crime prevention efforts, and the functioning of the criminal justice system.

Psychopathy & Aggression: When Paralimbic Dysfunction Leads to Violence

PubMed Central

Anderson, Nathaniel E.; Kiehl, Kent A.

2015-01-01

Psychopaths can be alarmingly violent, both in the frequency with which they engage in violence and the gratuitous extent of their violent acts. Indeed, one principal utility of the clinical construct of psychopathy is in predicting future violent behavior in criminal offenders. Aggression is a complex construct that intersects psychopathy at many levels. This chapter provides a review of psychopathy as a clinical construct including the most prominent cognitive and neurobiological models which serve to account for its pathophysiology. We then describe how the brain abnormalities implicated in psychopathy may lead to diverse behavioral outcomes, which can include aggression in its many forms. PMID:24306955

Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

PubMed Central

Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

2014-01-01

The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

Neural and Behavioral Correlates of Alcohol-Induced Aggression Under Provocation

PubMed Central

Gan, Gabriela; Sterzer, Philipp; Marxen, Michael; Zimmermann, Ulrich S; Smolka, Michael N

2015-01-01

Although alcohol consumption is linked to increased aggression, its neural correlates have not directly been studied in humans so far. Based on a comprehensive neurobiological model of alcohol-induced aggression, we hypothesized that alcohol-induced aggression would go along with increased amygdala and ventral striatum reactivity and impaired functioning of the prefrontal cortex (PFC) under alcohol. We measured neural and behavioral correlates of alcohol-induced aggression in a provoking vs non-provoking condition with a variant of the Taylor aggression paradigm (TAP) allowing to differentiate between reactive (provoked) and proactive (unprovoked) aggression. In a placebo-controlled cross-over design with moderate alcohol intoxication (~0.6 g/kg), 35 young healthy adults performed the TAP during functional magnetic resonance imaging (fMRI). Analyses revealed that provoking vs non-provoking conditions and alcohol vs placebo increased aggression and decreased brain responses in the anterior cingulate cortex/dorso-medial PFC (provoking

Implantation of GL261 neurospheres into C57/BL6 mice: a more reliable syngeneic graft model for research on glioma-initiating cells.

PubMed

Yi, Liang; Zhou, Chun; Wang, Bing; Chen, Tunan; Xu, Minhui; Xu, Lunshan; Feng, Hua

2013-08-01

Recent studies have demonstrated that inflammatory cells and inflammatory mediators are indispensable components of the tumor-initiating cell (TIC) niche and regulate the malignant behavior of TICs. However, conventional animal models for glioma-initiating cell (GIC) studies are based on the implantation of GICs from human glioblastoma (GBM) into immunodeficient mice without the regulation of immune system. Whether animal models can mimic the cellular microenvironment of malignancy and evaluate the biological features of GICs accurately is unclear. Here, we detected the biological features of neurosphere-like tumor cells derived from the murine GBM cell line GL261 (GL261-NS) and from primary human GBM (PGBM-NS) in vitro, injected GL261-NS into syngeneic C57/BL6 mouse brain and injected PGBM-NS into NOD/SCID mouse brain, respectively. The tumorigenic characteristics of the two different orthotopic transplantation models were analyzed and the histological discrepancy between grafts and human primary GBM was compared. We found that GICs enriched in GL261-NS, GL261-NS and PGBM-NS exhibited increased GIC potential and enhanced chemoresistance in vitro. GL261-NS was significantly more aggressive compared to GL261 adhesive cells (GL261-AC) in vivo and the enhanced aggression was more significant in syngeneic mice compared to immunodeficient mice. The discrepancy of tumorigenicity between GL261-NS and GL261-AC in C57/BL6 mice was also larger compared to that between PGBM-NS and PGBM-AC in immunodeficient mice. Syngrafts derived from GL261-NS in C57/BL6 mice corresponded to the human GBM histologically better, compared with xenografts derived from PGBM-NS in NOD/SCID mice, which lack inflammatory cells and inflammatory mediators. We conclude that the inflammatory niche is involved in the tumorigenicity of GICs and implantation of GL261-NS into C57/BL6 mice is a more reliable syngeneic graft model for in vivo study on GICs relative to the immunodeficiency model.

Brain tumor - primary - adults

MedlinePlus

... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

PubMed Central

Gonçalves da Silva, Patrícia Benites; Teixeira dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Leite Pereira, Márcia Cristina; Furukawa, Gabriela; Gimenes da Cruz, Daniel Sanzio; Goldfeder, Mauricio Barbugiani; Reily Rocha, Clarissa Ribeiro; Rosenberg, Carla; Okamoto, Oswaldo Keith

2017-01-01

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. PMID:28186969

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

PubMed

da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

2017-03-21

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

Comparative effects on rat primary astrocytes and C6 rat glioma cells cultures after 24-h exposure to silver nanoparticles (AgNPs)

NASA Astrophysics Data System (ADS)

Salazar-García, Samuel; Silva-Ramírez, Ana Sonia; Ramirez-Lee, Manuel A.; Rosas-Hernandez, Hector; Rangel-López, Edgar; Castillo, Claudia G.; Santamaría, Abel; Martinez-Castañon, Gabriel A.; Gonzalez, Carmen

2015-11-01

The aim of this work was to compare the effects of 24-h exposure of rat primary astrocytes and C6 rat glioma cells to 7.8 nm AgNPs. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and current treatments lead to diverse side-effects; for this reason, it is imperative to investigate new approaches, including those alternatives provided by nanotechnology, like nanomaterials (NMs) such as silver nanoparticles. Herein, we found that C6 rat glioma cells, but no primary astrocytes, decreased cell viability after AgNPs treatment; however, both cell types diminished their proliferation. The decrease of glioma C6 cells proliferation was related with necrosis, while in primary astrocytes, the decreased proliferation was associated with the induction of apoptosis. The ionic control (AgNO3) exerted a different profile than AgNPs; the bulk form did not modify the basal effect in each determination, whereas cisplatin, a well-known antitumoral drug used as a comparative control, promoted cytotoxicity in both cell types at specific concentrations. Our findings prompt the need to determine the fine molecular and cellular mechanisms involved in the differential biological responses to AgNPs in order to develop new tools or alternatives based on nanotechnology that may contribute to the understanding, impact and use of NMs in specific targets, like glioblastoma cells.

Primary lymphoma of the brain

MedlinePlus

Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival

PubMed Central

Herzog, Susann; Fink, Matthias Alexander; Weitmann, Kerstin; Friedel, Claudius; Hadlich, Stefan; Langner, Sönke; Kindermann, Katharina; Holm, Tobias; Böhm, Andreas; Eskilsson, Eskil; Miletic, Hrvoje; Hildner, Markus; Fritsch, Michael; Vogelgesang, Silke; Havemann, Christoph; Ritter, Christoph Alexander; Meyer zu Schwabedissen, Henriette Elisabeth; Rauch, Bernhard; Hoffmann, Wolfgang; Kroemer, Heyo Klaus; Schroeder, Henry; Bien-Möller, Sandra

2015-01-01

Background The current therapy for glioblastoma multiforme (GBM), the most aggressive and common primary brain tumor of adults, involves surgery and a combined radiochemotherapy that controls tumor progression only for a limited time window. Therefore, the identification of new molecular targets is highly necessary. Inhibition of kinases has become a standard of clinical oncology, and thus the oncogenic kinase Pim1 might represent a promising target for improvement of GBM therapy. Methods Expression of Pim1 and associated signaling molecules was analyzed in human GBM samples, and the potential role of this kinase in patients' prognosis was evaluated. Furthermore, we analyzed the in vivo role of Pim1 in GBM cell growth in an orthotopic mouse model and examined the consequences of Pim1 inhibition in vitro to clarify underlying pathways. Results In comparison with normal brain, a strong upregulation of Pim1 was demonstrated in human GBM samples. Notably, patients with short overall survival showed a significantly higher Pim1 expression compared with GBM patients who lived longer than the median. In vitro experiments with GBM cells and analysis of patients' GBM samples suggest that Pim1 regulation is dependent on epidermal growth factor receptor. Furthermore, inhibition of Pim1 resulted in reduced cell viability accompanied by decreased cell numbers and increased apoptotic cells, as seen by elevated subG1 cell contents and caspase-3 and -9 activation, as well as modulation of several cell cycle or apoptosis regulatory proteins. Conclusions Altogether, Pim1 could be a novel therapeutic target, which should be further analyzed to improve the outcome of patients with aggressive GBM. PMID:25155357

Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

PubMed

Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

2017-03-01

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Brain Cancer Stem Cells in Adults and Children: Cell Biology and Therapeutic Implications.

PubMed

Abou-Antoun, Tamara J; Hale, James S; Lathia, Justin D; Dombrowski, Stephen M

2017-04-01

Brain tumors represent some of the most malignant cancers in both children and adults. Current treatment options target the majority of tumor cells but do not adequately target self-renewing cancer stem cells (CSCs). CSCs have been reported to resist the most aggressive radiation and chemotherapies, and give rise to recurrent, treatment-resistant secondary malignancies. With advancing technologies, we now have a better understanding of the genetic, epigenetic and molecular signatures and microenvironmental influences which are useful in distinguishing between distinctly different tumor subtypes. As a result, efforts are now underway to identify and target CSCs within various tumor subtypes based on this foundation. This review discusses progress in CSC biology as it relates to targeted therapies which may be uniquely different between pediatric and adult brain tumors. Studies to date suggest that pediatric brain tumors may benefit more from genetic and epigenetic targeted therapies, while combination treatments aimed specifically at multiple molecular pathways may be more effective in treating adult brain tumors which seem to have a greater propensity towards microenvironmental interactions. Ultimately, CSC targeting approaches in combination with current clinical therapies have the potential to be more effective owing to their ability to compromise CSCs maintenance and the mechanisms which underlie their highly aggressive and deadly nature.

The role of stereotactic radiosurgery and whole brain radiation therapy as primary treatment in the treatment of patients with brain oligometastases — A systematic review

PubMed Central

Sheehan, Jason P.

2016-01-01

The management of patients presenting with a limited number of brain metastases (BM) (oligo-metastases, defined as less than 3 BM) has evolved from Whole-Brain Radiotherapy (WBRT) alone to more aggressive strategies adding surgical resection and Stereotactic Radiosurgery (SRS) to the armamentarium. In choosing treatment modalities, the relative importance of the patient’s age and clinical parameters, the number or volume of BM and the potential treatment related adverse-effects has been a matter of much debate. For patients with oligometastatic BM, local therapy using SRS in addition to WBRT was shown to improve time to neurologic deterioration, relapse rate and Overall Survival (OS). In patients who receive local therapy (SRS or surgery), adjuvant WBRT was shown to improve regional (brain) relapse rate. In the contemporary era, the beneficial effect of WBRT on lengthening the time of neurologic independence or OS when compared to no further treatment is unclear. One Meta-analysis pooling of information from several reports concluded that for younger patients (<50 years), SRS alone favored survival and that the initial omission of WBRT did not impact distant brain relapse rates. Other recent reports demonstrated on the contrary an OS benefit, more pronounced in good prognosis patients (diagnosis-specific Graded Prognostic Assessment 2.4–4.0) treated with SRS+WBRT compared to those who received SRS alone. As of today, there remains a role for both SRS and WBRT in the management of patients with oligo-metastatic BM but consensus about when to employ one or both is lacking. The exact patient selection criteria to benefit from either or both are still a matter of active research and heated debate. PMID:29296432

The neurobiology of abnormal manifestations of aggression--a review of hypothalamic mechanisms in cats, rodents, and humans.

PubMed

Haller, Jozsef

2013-04-01

Aggression research was for long dominated by the assumption that aggression-related psychopathologies result from the excessive activation of aggression-promoting brain mechanisms. This assumption was recently challenged by findings with models of aggression that mimic etiological factors of aggression-related psychopathologies. Subjects submitted to such procedures show abnormal attack features (mismatch between provocation and response, disregard of species-specific rules, and insensitivity toward the social signals of opponents). We review here 12 such laboratory models and the available human findings on the neural background of abnormal aggression. We focus on the hypothalamus, a region tightly involved in the execution of attacks. Data show that the hypothalamic mechanisms controlling attacks (general activation levels, local serotonin, vasopressin, substance P, glutamate, GABA, and dopamine neurotransmission) undergo etiological factor-dependent changes. Findings suggest that the emotional component of attacks differentiates two basic types of hypothalamic mechanisms. Aggression associated with increased arousal (emotional/reactive aggression) is paralleled by increased mediobasal hypothalamic activation, increased hypothalamic vasopressinergic, but diminished hypothalamic serotonergic neurotransmission. In aggression models associated with low arousal (unemotional/proactive aggression), the lateral but not the mediobasal hypothalamus is over-activated. In addition, the anti-aggressive effect of serotonergic neurotransmission is lost and paradoxical changes were noticed in vasopressinergic neurotransmission. We conclude that there is no single 'neurobiological road' to abnormal aggression: the neural background shows qualitative, etiological factor-dependent differences. Findings obtained with different models should be viewed as alternative mechanisms rather than conflicting data. The relevance of these findings for understanding and treating of aggression-related psychopathologies is discussed. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'. Copyright © 2012 Elsevier Inc. All rights reserved.

Aggression, social competence, and academic achievement in Chinese children: a 5-year longitudinal study.

PubMed

Chen, Xinyin; Huang, Xiaorui; Chang, Lei; Wang, Li; Li, Dan

2010-08-01

The primary purpose of this longitudinal study was to examine, in a sample of Chinese children (initial M age = 8 years, N = 1,140), contributions of aggression to the development of social competence and academic achievement. Five waves of panel data on aggression and social and school performance were collected from peer evaluations, teacher ratings, and school records in Grades 2 to 5. Structural equation modeling revealed that aggression had unique effects on later social competence and academic achievement after their stabilities were controlled, particularly in the junior grades. Aggression also had significant indirect effects on social and academic outcomes through multiple pathways. Social competence and academic achievement contributed to the development of each other, but not aggression. The results indicate cascade effects of aggression in Chinese children from a developmental perspective.

A patient-specific computational model of hypoxia-modulated radiation resistance in glioblastoma using 18F-FMISO-PET

PubMed Central

Rockne, Russell C.; Trister, Andrew D.; Jacobs, Joshua; Hawkins-Daarud, Andrea J.; Neal, Maxwell L.; Hendrickson, Kristi; Mrugala, Maciej M.; Rockhill, Jason K.; Kinahan, Paul; Krohn, Kenneth A.; Swanson, Kristin R.

2015-01-01

Glioblastoma multiforme (GBM) is a highly invasive primary brain tumour that has poor prognosis despite aggressive treatment. A hallmark of these tumours is diffuse invasion into the surrounding brain, necessitating a multi-modal treatment approach, including surgery, radiation and chemotherapy. We have previously demonstrated the ability of our model to predict radiographic response immediately following radiation therapy in individual GBM patients using a simplified geometry of the brain and theoretical radiation dose. Using only two pre-treatment magnetic resonance imaging scans, we calculate net rates of proliferation and invasion as well as radiation sensitivity for a patient's disease. Here, we present the application of our clinically targeted modelling approach to a single glioblastoma patient as a demonstration of our method. We apply our model in the full three-dimensional architecture of the brain to quantify the effects of regional resistance to radiation owing to hypoxia in vivo determined by [18F]-fluoromisonidazole positron emission tomography (FMISO-PET) and the patient-specific three-dimensional radiation treatment plan. Incorporation of hypoxia into our model with FMISO-PET increases the model–data agreement by an order of magnitude. This improvement was robust to our definition of hypoxia or the degree of radiation resistance quantified with the FMISO-PET image and our computational model, respectively. This work demonstrates a useful application of patient-specific modelling in personalized medicine and how mathematical modelling has the potential to unify multi-modality imaging and radiation treatment planning. PMID:25540239

Some neuroanatomical insights to impulsive aggression in schizophrenia.

PubMed

Leclerc, Marcel P; Regenbogen, Christina; Hamilton, Roy H; Habel, Ute

2018-06-13

Patients with schizophrenia are at increased risk of engaging in violence towards others, compared to both the general population and most other patient groups. We have here explored the role of cortico-limbic impairments in schizophrenia, and have considered these brain regions specifically within the framework of a popular neuroanatomical model of impulsive aggression. In line with this model, evidence in patients with aggressive schizophrenia implicated structural deficits associated with impaired decision-making, emotional control and evaluation, and social information processing, especially in the orbitofrontal and ventrolateral prefrontal cortex. Given the pivotal role of the orbitofrontal and ventrolateral cortex in emotion control and evaluation, structural deficits may result in inappropriate use of socially relevant information and improper recognition of impulses that are in need for regulation. Furthermore, we have extended the original model and incorporated the striatum, important for the generation of aggressive impulses, as well as the hippocampus, a region critical for decision-making, into the model. Lastly, we discuss the question whether structural impairments are specific to aggressive schizophrenia. Our results suggest, that similar findings can be observed in other aggressive patient populations, making the observed impairments non-specific to aggressive schizophrenia. This points towards a shared condition, across pathologies, a potential common denominator being impulsive aggression. Copyright © 2018. Published by Elsevier B.V.

Endogenous testosterone is associated with lower amygdala reactivity to angry faces and reduced aggressive behavior in healthy young women

PubMed Central

Buades-Rotger, Macià; Engelke, Christin; Beyer, Frederike; Keevil, Brian G.; Brabant, Georg; Krämer, Ulrike M.

2016-01-01

Testosterone and cortisol have been proposed to influence aggressive behavior by altering the neural processing of facial threat signals. However, this has not been investigated in direct social interactions. Here, we explored the joint impact of testosterone, cortisol, and brain reactivity to anger expressions on women’s reactive aggression in the Social Threat Aggression Paradigm (STAP). The STAP is a competitive reaction time task in which the purported opponent displays either an angry or a neutral facial expression at the beginning of each trial and delivers increasingly loud sound blasts to the participants, successfully provoking them. Strikingly, salivary testosterone at scan-time was negatively related to both aggression and basolateral amygdala (BLA) reactivity to angry faces, whereas cortisol had no effect. When the opponent looked angry, BLA-orbitofrontal coupling was reduced, and BLA reactivity was positively related to aggression. The latter relationship was fully mediated by bilateral superior temporal gyrus (STG) activation. Our results thus support previous neurobiological models of aggression, and extend them by demonstrating that fast amygdala responses to threat modulate STG activity in order to favor aggressive retaliation. Furthermore, our study agrees with recent evidence underscoring a fear-reducing and strategically prosocial effect of testosterone on human social behavior. PMID:27924836

Brain morphology of childhood aggressive behavior: A multi-informant study in school-age children.

PubMed

Thijssen, Sandra; Ringoot, Ank P; Wildeboer, Andrea; Bakermans-Kranenburg, Marian J; El Marroun, Hanan; Hofman, Albert; Jaddoe, Vincent W V; Verhulst, Frank C; Tiemeier, Henning; van IJzendoorn, Marinus H; White, Tonya

2015-09-01

Few studies have focused on the neuroanatomy of aggressive behavior in children younger than 10 years. Here, we explored the neuroanatomical correlates of aggression in a population-based sample of 6- to 9-year-old children using a multiple-informant approach. Magnetic resonance (MR) scans were acquired from 566 children from the Generation R study who participated in the Berkeley Puppet Interview and whose parents had completed the Child Behavior Checklist. Linear regression analyses were used to examine associations between aggression and amygdala and hippocampal volume. We performed surface-based analyses to study the association between aggression and cortical thickness, surface area, and gyrification. Aggressive behavior was associated with smaller amygdala (p < .05) but not hippocampal volume. Aggression was associated with a thinner cortex in the left precentral cortex (p < .01) and in a cluster including the right inferior parietal, supramarginal, and postcentral cortex (p < .001). Gender moderated the association between aggression and cortical thickness in the right medial posterior cortex (p = .001) and the right prefrontal cortex (p < .001). Aggression was associated with decreased gyrification in a large cluster including the right precentral, postcentral, frontal, and parietal cortex (p = .01). Moreover, aggression was associated with decreased gyrification in the right occipital and parietal cortex (p = .02). We found novel evidence that childhood aggressive behavior is related to decreased amygdala volume, decreased sensorimotor cortical thickness, and decreased global right hemisphere gyrification. Aggression is related to cortical thickness in regions associated with the default mode network, with negative associations in boys and positive associations in girls.

Epilepsy, Antiepileptic Drugs, and Aggression: An Evidence-Based Review

PubMed Central

Besag, Frank; Ettinger, Alan B.; Mula, Marco; Gobbi, Gabriella; Comai, Stefano; Aldenkamp, Albert P.; Steinhoff, Bernhard J.

2016-01-01

Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases. PMID:27255267

Dopamine D2 Receptors Act Upstream of AVP in the Latero-Anterior Hypothalamus to Modulate Adolescent Anabolic/Androgenic Steroid-Induced Aggression in Syrian Hamsters

PubMed Central

Morrison, Thomas R.; Ricci, Lesley A.; Melloni, Richard H.

2015-01-01

In pubertal male Syrian hamsters, exposure to anabolic/androgenic steroids (AAS) during adolescence facilitates a high level of offensive aggression modulated by the enhanced development and activity of the vasopressin (AVP) and dopamine (DA) neural systems within the latero-anterior hypothalamus (LAH), i.e., a brain region implicated in the control of aggression. The present studies provide a detailed report of the pharmacologic interactions between AVP and DA D2 receptor signaling within the LAH in the control of adolescent AAS-induced offensive aggression. Male Syrian hamsters were treated with AAS throughout adolescence and tested for aggression after local infusion of the DA D2 receptor antagonist eticlopride (ETIC) alone, or in combination with AVP in the LAH in an effort to determine the influence of DA D2 receptors relative to AVP-receptor mediated aggression mechanisms. As previously shown, ETIC infusion into the LAH suppressed adolescent AAS-induced aggressive responding; however, the AAS-induced aggressive phenotype was rescued by the co-infusion of AVP into the LAH. These behavioral data indicate that interactions between AVP and DA neural systems within the LAH modulate the control of aggression following adolescent exposure to AAS and that DA D2 receptor signaling functions upstream of AVP in the LAH to control this behavioral response. PMID:25798632

Neural sensitivity to sex steroids predicts individual differences in aggression: implications for behavioural evolution.

PubMed

Rosvall, K A; Bergeon Burns, C M; Barske, J; Goodson, J L; Schlinger, B A; Sengelaub, D R; Ketterson, E D

2012-09-07

Testosterone (T) regulates many traits related to fitness, including aggression. However, individual variation in aggressiveness does not always relate to circulating T, suggesting that behavioural variation may be more closely related to neural sensitivity to steroids, though this issue remains unresolved. To assess the relative importance of circulating T and neural steroid sensitivity in predicting behaviour, we measured aggressiveness during staged intrusions in free-living male and female dark-eyed juncos (Junco hyemalis). We compared aggressiveness to plasma T levels and to the abundance of androgen receptor (AR), aromatase (AROM) and oestrogen receptor alpha (ORα) mRNA in behaviourally relevant brain areas (avian medial amygdala, hypothalamus and song control regions). We also asked whether patterns of covariation among behaviour and endocrine parameters differed in males and females, anticipating that circulating T may be a better predictor of behaviour in males than in females. We found that circulating T related to aggressiveness only in males, but that gene expression for ORα, AR and AROM covaried with individual differences in aggressiveness in both sexes. These findings are among the first to show that individual variation in neural gene expression for three major sex steroid-processing molecules predicts individual variation in aggressiveness in both sexes in nature. The results have broad implications for our understanding of the mechanisms by which aggressive behaviour may evolve.

Brain and Adrenal Metabolic Responses to Stress (The Role of Brain Catecholamines in Regulation of Response to Stress).

DTIC Science & Technology

1982-03-15

gland was studied in stress states with the finding that there were delayed effects of cold stress*1 on key enzymes effecting the ability to form...phosphorylation. A series of studies were conducted of the effects of various drugs on aggressive behavior. Isolation housing was shown to alter cyclic AMP...mechanisms in the brain. Social behavior was studied in relation to drugs and the effects of amphetamine in relation to paranoid behavior demonstrated using a

EGFR Amplification and IDH Mutations in Glioblastoma Patients of the Northeast of Morocco

PubMed Central

Louati, Sara; Chbani, Laila; El Fatemi, Hind; Hammas, Nawal; Mikou, Karima; Maaroufi, Mustapha; Benzagmout, Mohammed; Boujraf, Said; El Bardai, Sanae; Giry, Marine; Marie, Yannick; Chaoui El Faiz, Mohammed; Mokhtari, Karima; Amarti, Afaf; Bennis, Sanae

2017-01-01

Glioblastomas are the most frequent and aggressive primary brain tumors which are expressing various evolutions, aggressiveness, and prognosis. Thus, the 2007 World Health Organization classification based solely on the histological criteria is no longer sufficient. It should be complemented by molecular analysis for a true histomolecular classification. The new 2016 WHO classification of tumors of the central nervous system uses molecular parameters in addition to histology to reclassify these tumors and reduce the interobserver variability. The aim of this study is to determine the prevalence of IDH mutations and EGFR amplifications in the population of the northeast region of Morocco and then to compare the results with other studies. Methods. IDH1 codon 132 and IDH2 codon 172 were directly sequenced and the amplification of exon 20 of EGFR gene was investigated by qPCR in 65 glioblastoma tumors diagnosed at the University Hospital of Fez between 2010 and 2014. Results. The R132H IDH1 mutation was observed in 8 of 65 tumor samples (12.31%). No mutation of IDH2 was detected. EGFR amplification was identified in 17 cases (26.15%). Conclusion. A systematic search of both histological and molecular markers should be requisite for a good diagnosis and a better management of glioblastomas. PMID:28785587

EGFR Amplification and IDH Mutations in Glioblastoma Patients of the Northeast of Morocco.

PubMed

Senhaji, Nadia; Louati, Sara; Chbani, Laila; El Fatemi, Hind; Hammas, Nawal; Mikou, Karima; Maaroufi, Mustapha; Benzagmout, Mohammed; Boujraf, Said; El Bardai, Sanae; Giry, Marine; Marie, Yannick; Chaoui El Faiz, Mohammed; Mokhtari, Karima; Idbaih, Ahmed; Amarti, Afaf; Bennis, Sanae

2017-01-01

Glioblastomas are the most frequent and aggressive primary brain tumors which are expressing various evolutions, aggressiveness, and prognosis. Thus, the 2007 World Health Organization classification based solely on the histological criteria is no longer sufficient. It should be complemented by molecular analysis for a true histomolecular classification. The new 2016 WHO classification of tumors of the central nervous system uses molecular parameters in addition to histology to reclassify these tumors and reduce the interobserver variability. The aim of this study is to determine the prevalence of IDH mutations and EGFR amplifications in the population of the northeast region of Morocco and then to compare the results with other studies. Methods . IDH1 codon 132 and IDH2 codon 172 were directly sequenced and the amplification of exon 20 of EGFR gene was investigated by qPCR in 65 glioblastoma tumors diagnosed at the University Hospital of Fez between 2010 and 2014. Results . The R132H IDH1 mutation was observed in 8 of 65 tumor samples (12.31%). No mutation of IDH2 was detected. EGFR amplification was identified in 17 cases (26.15%). Conclusion . A systematic search of both histological and molecular markers should be requisite for a good diagnosis and a better management of glioblastomas.

Omega-3 (ω-3) and social skills interventions for reactive aggression and childhood externalizing behavior problems: a randomized, stratified, double-blind, placebo-controlled, factorial trial.

PubMed

Raine, Adrian; Ang, Rebecca P; Choy, Olivia; Hibbeln, Joseph R; Ho, Ringo M-H; Lim, Choon Guan; Lim-Ashworth, Nikki S J; Ling, Shichun; Liu, Jean C J; Ooi, Yoon Phaik; Tan, Yi Ren; Fung, Daniel S S

2018-05-10

While studies suggest that nutritional supplementation may reduce aggressive behavior in children, few have examined their effects on specific forms of aggression. This study tests the primary hypothesis that omega-3 (ω-3), both alone and in conjunction with social skills training, will have particular post-treatment efficacy for reducing childhood reactive aggression relative to baseline. In this randomized, double-blind, stratified, placebo-controlled, factorial trial, a clinical sample of 282 children with externalizing behavior aged 7-16 years was randomized into ω-3 only, social skills only, ω-3 + social skills, and placebo control groups. Treatment duration was 6 months. The primary outcome measure was reactive aggression collected at 0, 3, 6, 9, and 12 months, with antisocial behavior as a secondary outcome. Children in the ω-3-only group showed a short-term reduction (at 3 and 6 months) in self-report reactive aggression, and also a short-term reduction in overall antisocial behavior. Sensitivity analyses and a robustness check replicated significant interaction effects. Effect sizes (d) were small, ranging from 0.17 to 0.31. Findings provide some initial support for the efficacy of ω-3 in reducing reactive aggression over and above standard care (medication and parent training), but yield only preliminary and limited support for the efficacy of ω-3 in reducing overall externalizing behavior in children. Future studies could test further whether ω-3 shows promise in reducing more reactive, impulsive forms of aggression.

Clonal Evolution of Glioblastoma under Therapy

PubMed Central

Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik; Frattini, Veronique; Rosenbloom, Daniel I. S.; Zairis, Sakellarios; Abate, Francesco; Liu, Zhaoqi; Elliott, Oliver; Shin, Yong-Jae; Lee, Jin-Ku; Lee, In-Hee; Park, Woong-Yang; Eoli, Marica; Blumberg, Andrew J.; Lasorella, Anna; Nam, Do-Hyun; Finocchiaro, Gaetano; Iavarone, Antonio; Rabadan, Raul

2017-01-01

Glioblastoma (GBM) constitutes the most common and aggressive primary brain tumor. To better understand how GBM evolves we analyzed longitudinal genomic and transcriptomic data of 114 patients. The analysis reveals a highly branched evolutionary pattern in which 63% of patients experience expression-based subtype changes. The branching pattern together with estimates of evolutionary rates suggest that the relapse associated clone typically preexisted years before diagnosis. 15% of tumors present hypermutations at relapse in highly expressed genes with a clear mutational signature. We find that 11% of recurrent tumors harbor mutations in LTBP4, a protein binding to TGF-β. Silencing LTBP4 in GBM cells leads to TGF-β activity suppression and decreased proliferation. In IDH1-wild-type recurrent GBM, high LTBP4 expression is associated with worse prognosis, highlighting the TGF-β pathway as a potential therapeutic target in GBM. PMID:27270107

Gliosarcoma: A rare variant of glioblastoma multiforme in paediatric patient: Case report and review of literature

PubMed Central

Meena, Ugan Singh; Sharma, Sumit; Chopra, Sanjeev; Jain, Shashi Kant

2016-01-01

Gliosarcoma is rare central nervous system tumour and a variant of glioblastoma multiforme with bimorphic histological pattern of glial and sarcomatous differentiation. It occurs in elderly between 5th and 6th decades of life and extremely rare in children. It is highly aggressive tumour and managed like glioblastoma multiforme. A 12-year-old female child presented with complaints of headache and vomiting from 15 d and blurring of vision from 3 d. Magnetic resonance imaging of brain shows heterogeneous mass in right parieto-occipital cortex. A right parieto-occipito-temporal craniotomy with complete excision of mass revealed a primary glioblastoma on histopathological investigation. Treatment consists of maximum surgical excision followed by adjuvant radiotherapy. The etiopathogenesis, treatment modalities and prognosis is discussed. The available literature is also reviewed. PMID:27672648

Transcriptome analysis of genes and gene networks involved in aggressive behavior in mouse and zebrafish.

PubMed

Malki, Karim; Du Rietz, Ebba; Crusio, Wim E; Pain, Oliver; Paya-Cano, Jose; Karadaghi, Rezhaw L; Sluyter, Frans; de Boer, Sietse F; Sandnabba, Kenneth; Schalkwyk, Leonard C; Asherson, Philip; Tosto, Maria Grazia

2016-09-01

Despite moderate heritability estimates, the molecular architecture of aggressive behavior remains poorly characterized. This study compared gene expression profiles from a genetic mouse model of aggression with zebrafish, an animal model traditionally used to study aggression. A meta-analytic, cross-species approach was used to identify genomic variants associated with aggressive behavior. The Rankprod algorithm was used to evaluated mRNA differences from prefrontal cortex tissues of three sets of mouse lines (N = 18) selectively bred for low and high aggressive behavior (SAL/LAL, TA/TNA, and NC900/NC100). The same approach was used to evaluate mRNA differences in zebrafish (N = 12) exposed to aggressive or non-aggressive social encounters. Results were compared to uncover genes consistently implicated in aggression across both studies. Seventy-six genes were differentially expressed (PFP < 0.05) in aggressive compared to non-aggressive mice. Seventy genes were differentially expressed in zebrafish exposed to a fight encounter compared to isolated zebrafish. Seven genes (Fos, Dusp1, Hdac4, Ier2, Bdnf, Btg2, and Nr4a1) were differentially expressed across both species 5 of which belonging to a gene-network centred on the c-Fos gene hub. Network analysis revealed an association with the MAPK signaling cascade. In human studies HDAC4 haploinsufficiency is a key genetic mechanism associated with brachydactyly mental retardation syndrome (BDMR), which is associated with aggressive behaviors. Moreover, the HDAC4 receptor is a drug target for valproic acid, which is being employed as an effective pharmacological treatment for aggressive behavior in geriatric, psychiatric, and brain-injury patients. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Frontal white matter changes and aggression in methamphetamine dependence.

PubMed

Lederer, Katharina; Fouche, Jean-Paul; Wilson, Don; Stein, Dan J; Uhlmann, Anne

2016-02-01

Chronic methamphetamine (MA) use can lead to white matter (WM) changes and increased levels of aggression. While previous studies have examined WM abnormalities relating to cognitive impairment, associations between WM integrity and aggression in MA dependence remain unclear. Diffusion Tensor Imaging (DTI) was used to investigate WM changes in 40 individuals with MA dependence and 40 matched healthy controls. A region of interest (ROI) approach using tract based spatial statistics (TBSS) in FSL was performed. We compared fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity (λ║) and perpendicular diffusivity (λ┴) in WM tracts of the frontal brain. A relationship of WM with aggression scores from the Buss & Perry Questionnaire was investigated. Mean scores for anger (p < 0.001), physical aggression (p = 0.032) and total aggression (p = 0.021) were significantly higher in the MA group relative to controls. ROI analysis showed increased MD (U = 439.5, p = 0.001) and λ┴ (U = 561.5, p = 0.021) values in the genu of the corpus callosum, and increased MD (U = 541.5, p = 0.012) values in the right cingulum in MA dependence. None of the WM changes were significantly associated with aggression scores. This study provides evidence of frontal WM changes and increased levels of aggression in individuals with MA dependence. The lack of significant associations between WM and aggressive behaviour may reflect methodological issues in measuring such behaviour, or may indicate that the neurobiology of aggression is not simply correlated with WM damage but is more complex.

Exogenous Testosterone Rapidly Increases Aggressive Behavior in Dominant and Impulsive Men.

PubMed

Carré, Justin M; Geniole, Shawn N; Ortiz, Triana L; Bird, Brian M; Videto, Amber; Bonin, Pierre L

2017-08-15

Although traditional wisdom suggests that baseline levels of testosterone (T) promote aggressive behavior, decades of research have produced findings that have been largely weak and inconsistent. However, more recent experimental work suggests that exogenous administration of T rapidly potentiates amygdala and hypothalamus responses to angry facial expressions. Notably, these brain regions are rich in androgen receptors and play a key role in modulating aggressive behavior in animal models. The present experiment extends this work by examining whether acutely increasing T potentiates aggressive behavior in men. In a double-blind, placebo-controlled, between-subject design, healthy adult men (n = 121) were administered either T or placebo, and subsequently engaged in a well-validated decision-making game that measures aggressive behavior in response to social provocation. In light of prior correlational research, we also assessed the extent to which T's effects on aggressive behavior would depend on variability in trait dominance and/or trait self-control. Exogenous T on its own did not modulate aggressive behavior. However, T's effects on aggression were strongly influenced by variation in trait dominance and trait self-control. Specifically, T caused an increase in aggressive behavior, but only among men scoring relatively high in trait dominance or low in trait self-control. These findings are the first to demonstrate that T can rapidly (within 60 minutes) potentiate aggressive behavior, but only among men with dominant or impulsive personality styles. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

A comparison of brain gene expression levels in domesticated and wild animals.

PubMed

Albert, Frank W; Somel, Mehmet; Carneiro, Miguel; Aximu-Petri, Ayinuer; Halbwax, Michel; Thalmann, Olaf; Blanco-Aguiar, Jose A; Plyusnina, Irina Z; Trut, Lyudmila; Villafuerte, Rafael; Ferrand, Nuno; Kaiser, Sylvia; Jensen, Per; Pääbo, Svante

2012-09-01

Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits). We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea) as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30-75 genes (less than 1%) of expressed genes were differentially expressed), while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH) were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different.

A Comparison of Brain Gene Expression Levels in Domesticated and Wild Animals

PubMed Central

Albert, Frank W.; Somel, Mehmet; Carneiro, Miguel; Aximu-Petri, Ayinuer; Halbwax, Michel; Thalmann, Olaf; Blanco-Aguiar, Jose A.; Trut, Lyudmila; Villafuerte, Rafael; Ferrand, Nuno; Kaiser, Sylvia; Jensen, Per; Pääbo, Svante

2012-01-01

Domestication has led to similar changes in morphology and behavior in several animal species, raising the question whether similarities between different domestication events also exist at the molecular level. We used mRNA sequencing to analyze genome-wide gene expression patterns in brain frontal cortex in three pairs of domesticated and wild species (dogs and wolves, pigs and wild boars, and domesticated and wild rabbits). We compared the expression differences with those between domesticated guinea pigs and a distant wild relative (Cavia aperea) as well as between two lines of rats selected for tameness or aggression towards humans. There were few gene expression differences between domesticated and wild dogs, pigs, and rabbits (30–75 genes (less than 1%) of expressed genes were differentially expressed), while guinea pigs and C. aperea differed more strongly. Almost no overlap was found between the genes with differential expression in the different domestication events. In addition, joint analyses of all domesticated and wild samples provided only suggestive evidence for the existence of a small group of genes that changed their expression in a similar fashion in different domesticated species. The most extreme of these shared expression changes include up-regulation in domesticates of SOX6 and PROM1, two modulators of brain development. There was almost no overlap between gene expression in domesticated animals and the tame and aggressive rats. However, two of the genes with the strongest expression differences between the rats (DLL3 and DHDH) were located in a genomic region associated with tameness and aggression, suggesting a role in influencing tameness. In summary, the majority of brain gene expression changes in domesticated animals are specific to the given domestication event, suggesting that the causative variants of behavioral domestication traits may likewise be different. PMID:23028369

18F-Fluorocholine PET/CT, Brain MRI, and 5-Aminolevulinic Acid for the Assessment of Tumor Resection in High-Grade Glioma.

PubMed

García Vicente, Ana María; Jiménez Aragón, Fátima; Villena Martín, Maikal; Jiménez Londoño, German Andrés; Borrás Moreno, Jose María

2017-06-01

High-grade glioma is a very aggressive and infiltrative tumor in which complete resection is a chance for a better outcome. We present the case of a 57-year-old man with a brain lesion suggestive of high-grade glioma. Brain MRI and F-fluorocholine PET/CT were performed previously to plan the surgery. Surgery was microscope assisted after the administration of 5-aminolevulinic acid. Postsurgery brain MRI and PET were blind evaluated to the surgery results and reported as probably gross total resection.

Alterations of the levels of primary antioxidant enzymes in different grades of human astrocytoma tissues.

PubMed

Yen, Hsiu-Chuan; Lin, Chih-Lung; Chen, Bing-Shian; Chen, Chih-Wei; Wei, Kuo-Chen; Yang, Mei-Lin; Hsu, Jee-Ching; Hsu, Yung-Hsing

2018-06-03

Malignant astrocytoma is the most commonly occurring brain tumor in humans. Oxidative stress is implicated in the development of cancers. Superoxide dismutase 2 (SOD2) was found to exert tumor suppressive effect in basic research, but increased SOD2 protein level was associated with higher aggressiveness of human astrocytomas. However, studies reporting alterations of antioxidant enzymes in human astrocytomas often employed less accurate methods or included different types of tumors. Here we analyzed the mRNA levels, activities, and protein levels of primary antioxidant enzymes in control brain tissues and various grades of astrocytomas obtained from 40 patients. SOD1 expression, SOD1 activity, and SOD1 protein level were lower in Grade IV astrocytomas. SOD2 expression was lower in low-grade (Grades I and II) and Grade III astrocytomas than in controls, but SOD2 expression and SOD2 protein level were higher in Grade IV astrocytomas than in Grade III astrocytomas. Although there was no change in SOD2 activity and a lower activity of citrate synthase (CS), the MnSOD:CS ratio increased in Grade IV astrocytomas compared with controls and low-grade astrocytomas. Furthermore, SOD1 activity, CS activity, SOD1 expression, GPX4 expression, and GPX4 protein level were inversely correlated with the malignancy, whereas catalase activity, catalase protein, SOD2 protein level, and the SOD2:CS ratio were positively correlated with the degree of malignancy. Lower SOD2:CS ratio was associated with poor outcomes for Grade IV astrocytomas. This is the first study to quantify changes of various primary antioxidant enzymes in different grades of astrocytomas at different levels concurrently in human astrocytomas.

Inhibition of multidrug resistance protein 1 (MRP1) improves chemotherapy drug response in primary and recurrent glioblastoma multiforme.

PubMed

Tivnan, Amanda; Zakaria, Zaitun; O'Leary, Caitrín; Kögel, Donat; Pokorny, Jenny L; Sarkaria, Jann N; Prehn, Jochen H M

2015-01-01

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer with extremely poor prognostic outcome despite intensive treatment. All chemotherapeutic agents currently used have no greater than 30-40% response rate, many fall into the range of 10-20%, with delivery across the blood brain barrier (BBB) or chemoresistance contributing to the extremely poor outcomes despite treatment. Increased expression of the multidrug resistance protein 1(MRP1) in high grade glioma, and it's role in BBB active transport, highlights this member of the ABC transporter family as a target for improving drug responses in GBM. In this study we show that small molecule inhibitors and gene silencing of MRP1 had a significant effect on GBM cell response to temozolomide (150 μM), vincristine (100 nM), and etoposide (2 μM). Pre-treatment with Reversan (inhibitor of MRP1 and P-glycoprotein) led to a significantly improved response to cell death in the presence of all three chemotherapeutics, in both primary and recurrent GBM cells. The presence of MK571 (inhibitor of MRP1 and multidrug resistance protein 4 (MRP4) led to an enhanced effect of vincristine and etoposide in reducing cell viability over a 72 h period. Specific MRP1 inhibition led to a significant increase in vincristine and etoposide-induced cell death in all three cell lines assessed. Treatment with MK571, or specific MRP1 knockdown, did not have any effect on temozolomide drug response in these cells. These findings have significant implications in providing researchers an opportunity to improve currently used chemotherapeutics for the initial treatment of primary GBM, and improved treatment for recurrent GBM patients.

HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors.

PubMed

Ahmed, Nabil; Salsman, Vita S; Kew, Yvonne; Shaffer, Donald; Powell, Suzanne; Zhang, Yi J; Grossman, Robert G; Heslop, Helen E; Gottschalk, Stephen

2010-01-15

Glioblastoma multiforme (GBM) is the most aggressive human primary brain tumor and is currently incurable. Immunotherapies have the potential to target GBM stem cells, which are resistant to conventional therapies. Human epidermal growth factor receptor 2 (HER2) is a validated immunotherapy target, and we determined if HER2-specific T cells can be generated from GBM patients that will target autologous HER2-positive GBMs and their CD133-positive stem cell compartment. HER2-specific T cells from 10 consecutive GBM patients were generated by transduction with a retroviral vector encoding a HER2-specific chimeric antigen receptor. The effector function of HER2-specific T cells against autologous GBM cells, including CD133-positive stem cells, was evaluated in vitro and in an orthotopic murine xenograft model. Stimulation of HER2-specific T cells with HER2-positive autologous GBM cells resulted in T-cell proliferation and secretion of IFN-gamma and interleukin-2 in a HER2-dependent manner. Patients' HER2-specific T cells killed CD133-positive and CD133-negative cells derived from primary HER2-positive GBMs, whereas HER2-negative tumor cells were not killed. Injection of HER2-specific T cells induced sustained regression of autologous GBM xenografts established in the brain of severe combined immunodeficient mice. Gene transfer allows the reliable generation of HER2-specific T cells from GBM patients, which have potent antitumor activity against autologous HER2-positive tumors including their putative stem cells. Hence, the adoptive transfer of HER2-redirected T cells may be a promising immunotherapeutic approach for GBM.

Diagnosis and management of primary central nervous system lymphoma.

PubMed

Han, Catherine H; Batchelor, Tracy T

2017-11-15

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole-brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced-dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314-24. © 2017 American Cancer Society. © 2017 American Cancer Society.

Rhabdoid Meningioma of Brain - A Rare Aggressive Tumor

PubMed Central

Mondal, Sajeeb; Pradhan, Rajashree; Pal, Subrata; Chatterjee, Sharmistha; Bandyapadhyay, Arindam; Bhattacharyya, Debosmita

2017-01-01

Rhabdoid meningioma is a rare aggressive variant of meningioma, regarded as WHO Grade III type. Histologically and cytologically, it is distinctive type having abundant eosinophilic cytoplasm, cytoplasmic inclusion with eccentrically placed vesicular nuclei and prominent nucleoli. High recurrence rate and poor outcome are important features. Here, we are presenting a rare case of rhabdoid meningioma found in a recurrent meningioma of the posterior fossa in a middle-aged female. We emphasized the squash cytology and histology finding of the rare neoplasm. PMID:28900335

Redirected aggression as a conflict management tactic in the social cichlid fish Julidochromis regani.

PubMed

Ito, Munehiko H; Yamaguchi, Motoomi; Kutsukake, Nobuyuki

2018-01-31

Conflict management consists of social behaviours that reduce the costs of conflict among group members. Redirected aggression-that is, when a recently attacked individual attacks a third party immediately after the original aggression-is considered a conflict management tactic, as it may reduce the victim's probability of being the object of further aggression. Redirected aggression has been reported in many vertebrates, but few quantitative studies have been conducted on this behaviour in fishes. We examined the function of redirected aggression in Julidochromis regani , a social cichlid fish. Behavioural experiments showed that redirected aggression functioned to divert the original aggressor's attention towards a third party and to pre-empt an attack towards the victim by the third-party individual, specifically among females. We found, however, that redirected aggression did not delay the recurrence of aggression by the original aggressor. These results suggest that a primary function of redirected aggression is to maintain the dominance of its actor against a subordinate occupying an adjacent rank. This study provides, to our knowledge, the first evidence that redirected aggression functions to manage conflict in social fish. © 2018 The Author(s).

Design and Analysis of Blast Induced Traumatic Brain Injury Mechanism Using a Surrogate Headform: Instrumentation and Outcomes

DTIC Science & Technology

2011-05-01

51 4.5.1: FABRY -PÉROT FIBER OPTIC GAUGES...aggressive social behavior, impaired thinking, language, learning, emotions, behavior, sensation, and neuro-degenerative diseases such as epilepsy...Alzheimer’s disease , Parkinson’s disease , and other brain disorders that become more prevalent with age [9, Figure 2.1: Causes of TBI- A diagram of

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli

PubMed Central

Hasen, Nina S.; Gammie, Stephen C.

2010-01-01

The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2-/- knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female. PMID:21070815

DNM3, p65 and p53 from exosomes represent potential clinical diagnosis markers for glioblastoma multiforme

PubMed Central

Yang, Jian-kai; Song, Jian; Huo, Hao-ran; Zhao, Yin-long; Zhang, Guang-yu; Zhao, Zong-mao; Sun, Guo-zhu; Jiao, Bao-hua

2017-01-01

Background: Glioblastoma multiforme (GBM) is the most aggressive and deadly primary brain cancer that arises from astrocytes and classified as grade IV. Recently, exosomes have been reported as an essential mediator in diverse cancer carcinogenesis and metastasis. However, their role in GBM is still unclear. In this study, we aimed to investigate whether blood exosomes can be potential clinical diagnostic markers for GBM. Methods: We used a xenograft orthotopic mouse model to detect the differentially expressed genes in the brain and blood exosomes of original/recurrent GBM. Results: We found that recurrent GBM had stronger growth capacity and lethality than original GBM in the mouse model. A gene microarray of original tumors and blood exosomes from GBM orthotopic xenografts results showed that DNM3, p65 and CD117 expressions increased, whereas PTEN and p53 expressions decreased in both original tumors and blood exosomes. In the recurrent GBM tumor model, DNM3 and p65 showed increased expressions, whereas ST14 and p53 showed decreased expressions in tumor and blood exosomes of the recurrent GBM mouse model. Conclusion: In summary, we found that DNM3, p65 and p53 had a similar trend in brain and blood exosomes both for original and recurrent GBM, and could serve as potential clinical diagnostic markers for GBM. PMID:29449895

Functional identification of an aggression locus in the mouse hypothalamus

PubMed Central

Lin, Dayu; Boyle, Maureen P.; Dollar, Piotr; Lee, Hyosang; Perona, Pietro; Lein, Ed S.; Anderson, David J.

2010-01-01

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behavior, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these behaviors. PMID:21307935

Functional identification of an aggression locus in the mouse hypothalamus.

PubMed

Lin, Dayu; Boyle, Maureen P; Dollar, Piotr; Lee, Hyosang; Lein, E S; Perona, Pietro; Anderson, David J

2011-02-10

Electrical stimulation of certain hypothalamic regions in cats and rodents can elicit attack behaviour, but the exact location of relevant cells within these regions, their requirement for naturally occurring aggression and their relationship to mating circuits have not been clear. Genetic methods for neural circuit manipulation in mice provide a potentially powerful approach to this problem, but brain-stimulation-evoked aggression has never been demonstrated in this species. Here we show that optogenetic, but not electrical, stimulation of neurons in the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) causes male mice to attack both females and inanimate objects, as well as males. Pharmacogenetic silencing of VMHvl reversibly inhibits inter-male aggression. Immediate early gene analysis and single unit recordings from VMHvl during social interactions reveal overlapping but distinct neuronal subpopulations involved in fighting and mating. Neurons activated during attack are inhibited during mating, suggesting a potential neural substrate for competition between these opponent social behaviours.

Genetics of Aggression in Alzheimer’s Disease (AD)

PubMed Central

Lukiw, Walter J.; Rogaev, Evgeny I.

2017-01-01

Alzheimer’s disease (AD) is a terminal, age-related neurological syndrome exhibiting progressive cognitive and memory decline, however AD patients in addition exhibit ancillary neuropsychiatric symptoms (NPSs) and these include aggression. In this communication we provide recent evidence for the mis-regulation of a small family of genes expressed in the human hippocampus that appear to be significantly involved in expression patterns common to both AD and aggression. DNA array- and mRNA transcriptome-based gene expression analysis and candidate gene association and/or genome-wide association studies (CGAS, GWAS) of aggressive attributes in humans have revealed a surprisingly small subset of six brain genes that are also strongly associated with altered gene expression patterns in AD. These genes encoded on five different chromosomes (chr) include the androgen receptor (AR; chrXq12), brain-derived neurotrophic factor (BDNF; chr11p14.1), catechol-O-methyl transferase (COMT; chr22q11.21), neuronal specific nitric oxide synthase (NOS1; chr12q24.22), dopamine beta-hydroxylase (DBH chr9q34.2) and tryptophan hydroxylase (TPH1, chr11p15.1 and TPH2, chr12q21.1). Interestingly, (i) the expression of three of these six genes (COMT, DBH, NOS1) are highly variable; (ii) three of these six genes (COMT, DBH, TPH1) are involved in DA or serotonin metabolism, biosynthesis and/or neurotransmission; and (iii) five of these six genes (AR, BDNF, COMT, DBH, NOS1) have been implicated in the development, onset and/or propagation of schizophrenia. The magnitude of the expression of genes implicated in aggressive behavior appears to be more pronounced in the later stages of AD when compared to MCI. These recent genetic data further indicate that the extent of cognitive impairment may have some bearing on the degree of aggression which accompanies the AD phenotype. PMID:28443016

Studying Sexual Aggression: A Review of the Evolution and Validity of Laboratory Paradigms

PubMed Central

Davis, Kelly Cue; George, William H.; Nagayama Hall, Gordon C.; Parrott, Dominic J.; Tharp, Andra Teten; Stappenbeck, Cynthia A.

2018-01-01

Objective Researchers have endeavored for decades to develop and implement experimental assessments of sexual aggression and its precursors to capitalize on the many scientific advantages offered by laboratory experiments, such as rigorous control of key variables and identification of causal relationships. The purpose of this review is to provide an overview of and commentary on the evolution of these laboratory-based methods. Conclusions To date, two primary types of sexual aggression laboratory studies have been developed: those that involve behavioral analogues of sexual aggression and those that assess postulated precursors to sexually aggressive behavior. Although the study of sexual aggression in the laboratory is fraught with methodological challenges, validity concerns, and ethical considerations, advances in the field have resulted in greater methodological rigor, more precise dependent measures, and improved experimental validity, reliability, and realism. Because highly effective sexual aggression prevention strategies remain elusive, continued laboratory-based investigation of sexual aggression coupled with translation of critical findings to the development and modification of sexual aggression prevention programs remains an important task for the field. PMID:29675289

Sound the Alarm: The Effect of Narcissism on Retaliatory Aggression Is Moderated by dACC Reactivity to Rejection.

PubMed

Chester, David S; DeWall, C Nathan

2016-06-01

Narcissists behave aggressively when their egos are threatened by interpersonal insults. This effect has been explained in terms of narcissists' motivation to reduce the discrepancy between their grandiose self and its threatened version, though no research has directly tested this hypothesis. If this notion is true, the link between narcissism and retaliatory aggression should be moderated by neural structures that subserve discrepancy detection, such as the dorsal anterior cingulate cortex (dACC). This study tested the hypothesis that narcissism would only predict greater retaliatory aggression in response to social rejection when the dACC was recruited by the threat. Thirty participants (15 females; Mage  = 18.86, SD = 1.25; 77% White) completed a trait narcissism inventory, were socially accepted and then rejected while undergoing fMRI, and then could behave aggressively toward one of the rejecters by blasting him or her with unpleasant noise. When narcissists displayed greater dACC activation during rejection, they behaved aggressively. But there was only a weak or nonsignificant relation between narcissism and aggression among participants with a blunted dACC response. Narcissism's role in aggressive retaliation to interpersonal threats is likely determined by the extent to which the brain's discrepancy detector registers the newly created gap between the grandiose and threatened selves. © 2015 Wiley Periodicals, Inc.

Mild expression differences of MECP2 influencing aggressive social behavior

PubMed Central

Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

2014-01-01

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior. PMID:24648499

Mild expression differences of MECP2 influencing aggressive social behavior.

PubMed

Tantra, Martesa; Hammer, Christian; Kästner, Anne; Dahm, Liane; Begemann, Martin; Bodda, Chiranjeevi; Hammerschmidt, Kurt; Giegling, Ina; Stepniak, Beata; Castillo Venzor, Aracely; Konte, Bettina; Erbaba, Begun; Hartmann, Annette; Tarami, Asieh; Schulz-Schaeffer, Walter; Rujescu, Dan; Mannan, Ashraf U; Ehrenreich, Hannelore

2014-05-01

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (~50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3'UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2 mRNA expression differs in peripheral blood mononuclear cells by ~50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3'UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior.

Attentional Bias to Negative Emotion as a Function of Approach and Withdrawal Anger Styles: An ERP Investigation

PubMed Central

Stewart, Jennifer L.; Silton, Rebecca Levin; Sass, Sarah M.; Fisher, Joscelyn E.; Edgar, J. Christopher; Heller, Wendy; Miller, Gregory A.

2010-01-01

Although models of emotion have focused on the relationship between anger and approach motivation associated with aggression, anger is also related to withdrawal motivation. Anger-out and anger-in styles are associated with psychopathology and may disrupt the control of attention within the context of negatively valenced information. The present study used event-related brain potentials (ERPs) to examine whether anger styles uniquely predict attentional bias to negative stimuli during an emotion-word Stroop task. High anger-out predicted larger N200, P300, and N400 to negative words, suggesting that aggressive individuals exert more effort to override attention to negative information. In contrast, high anger-in predicted smaller N400 amplitude to negative words, indicating that negative information may be readily available (primed) for anger suppressors, requiring fewer resources. Individuals with an anger-out style might benefit from being directed away from provocative stimuli that might otherwise consume their attention and foster overt aggression. Findings indicating that anger-out and anger-in were associated with divergent patterns of brain activity provide support for distinguishing approach- and withdrawal-related anger styles. PMID:20109502

Where are we now? And where are we going? A report from the Accelerate Brain Cancer Cure (ABC2) Low-grade Glioma Research Workshop

PubMed Central

Huse, Jason T.; Wallace, Max; Aldape, Kenneth D.; Berger, Mitchel S.; Bettegowda, Chetan; Brat, Daniel J.; Cahill, Daniel P.; Cloughesy, Timothy; Haas-Kogan, Daphne A.; Marra, Marco; Miller, C. Ryan; Nelson, Sarah J.; Salama, Sofie R.; Soffietti, Riccardo; Wen, Patrick Y.; Yip, Stephen; Yen, Katharine; Costello, Joseph F.; Chang, Susan

2014-01-01

Diffuse gliomas consist of both low- and high-grade varieties, each with distinct morphological and biological features. The often extended periods of relative indolence exhibited by low-grade gliomas (LGG; WHO grade II) differ sharply from the aggressive, rapidly fatal clinical course of primary glioblastoma (GBM; WHO grade IV). Nevertheless, until recently, the molecular foundations underlying this stark biological contrast between glioma variants remained largely unknown. The discoveries of distinctive and highly recurrent genomic and epigenomic abnormalities in LGG have both informed a more accurate classification scheme and pointed to viable avenues for therapeutic development. As such, the field of neuro-oncology now seems poised to capitalize on these gains to achieve significant benefit for LGG patients. This report will briefly recount the proceedings of a workshop held in January 2013 and hosted by Accelerate Brain Cancer Cure (ABC2) on the subject of LGG. While much of the meeting covered recent insights into LGG biology, its focus remained on how best to advance the clinical management, whether by improved preclinical modeling, more effective targeted therapeutics and clinical trial design, or innovative imaging technology. PMID:24305708

Applying gene regulatory network logic to the evolution of social behavior.

PubMed

Baran, Nicole M; McGrath, Patrick T; Streelman, J Todd

2017-06-06

Animal behavior is ultimately the product of gene regulatory networks (GRNs) for brain development and neural networks for brain function. The GRN approach has advanced the fields of genomics and development, and we identify organizational similarities between networks of genes that build the brain and networks of neurons that encode brain function. In this perspective, we engage the analogy between developmental networks and neural networks, exploring the advantages of using GRN logic to study behavior. Applying the GRN approach to the brain and behavior provides a quantitative and manipulative framework for discovery. We illustrate features of this framework using the example of social behavior and the neural circuitry of aggression.

Exploring the differential associations between components of executive functioning and reactive and proactive aggression.

PubMed

Hecht, Lisa K; Latzman, Robert D

2018-02-01

A large body of literature confirms the importance of executive functioning (EF) in the explanation of aggressive and antisocial behaviors. However, the common and specific associations between subtypes of aggression, such as reactive (RA), proactive aggression (PA), and EF are unclear. The current study explored the nuanced associations between components of EF and subtypes of aggression, using a latent variable approach. Participants were 384 racially diverse undergraduate students (ages 18-52 years) who completed a self-report measure of RA and PA, and traditional neuropsychological tasks of EF. The appropriateness of using a nested bifactor model of EF was confirmed, and this bifactor model of EF was then used to examine the specific associations between components of EF and RA and PA. Results revealed that components of EF are differentially associated with RA and PA. Specifically, impulsive, provoked aggression (i.e., RA) was associated with lower levels of goal-oriented inhibition and higher levels of flexibility, whereas planned, goal-oriented aggression (i.e., PA) was associated with higher levels of working memory. Findings from the current study underscore the importance of considering the multidimensional nature of EF, as well as the heterogeneity within aggression, rather than considering either construct as a single monolithic construct. The current study suggests that potentially unique brain-based pathways from aspects of EF to subtypes of aggression may exist, and points toward potential avenues through which to intervene.

mTOR-Dependent Cell Proliferation in the Brain.

PubMed

Ryskalin, Larisa; Lazzeri, Gloria; Flaibani, Marina; Biagioni, Francesca; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

2017-01-01

The mammalian Target of Rapamycin (mTOR) is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis. These effects are based on the modulation of different metabolic pathways. Upregulation of mTOR associates with various pathological conditions, such as obesity, neurodegeneration, and brain tumors. This is the case of high-grade gliomas with a high propensity to proliferation and tissue invasion. Glioblastoma Multiforme (GBM) is a WHO grade IV malignant, aggressive, and lethal glioma. To date, a few treatments are available although the outcome of GBM patients remains poor. Experimental and pathological findings suggest that mTOR upregulation plays a major role in determining an aggressive phenotype, thus determining relapse and chemoresistance. Among several activities, mTOR-induced autophagy suppression is key in GBM malignancy. In this article, we discuss recent evidence about mTOR signaling and its role in normal brain development and pathological conditions, with a special emphasis on its role in GBM.

mTOR-Dependent Cell Proliferation in the Brain

PubMed Central

Lazzeri, Gloria; Frati, Alessandro

2017-01-01

The mammalian Target of Rapamycin (mTOR) is a molecular complex equipped with kinase activity which controls cell viability being key in the PI3K/PTEN/Akt pathway. mTOR acts by integrating a number of environmental stimuli to regulate cell growth, proliferation, autophagy, and protein synthesis. These effects are based on the modulation of different metabolic pathways. Upregulation of mTOR associates with various pathological conditions, such as obesity, neurodegeneration, and brain tumors. This is the case of high-grade gliomas with a high propensity to proliferation and tissue invasion. Glioblastoma Multiforme (GBM) is a WHO grade IV malignant, aggressive, and lethal glioma. To date, a few treatments are available although the outcome of GBM patients remains poor. Experimental and pathological findings suggest that mTOR upregulation plays a major role in determining an aggressive phenotype, thus determining relapse and chemoresistance. Among several activities, mTOR-induced autophagy suppression is key in GBM malignancy. In this article, we discuss recent evidence about mTOR signaling and its role in normal brain development and pathological conditions, with a special emphasis on its role in GBM. PMID:29259984

Building the case for a novel teleost model of non-breeding aggression and its neuroendocrine control.

PubMed

Quintana, Laura; Zubizarreta, Lucía; Jalabert, Cecilia; Batista, Gervasio; Perrone, Rossana; Silva, Ana

2016-10-01

In vertebrates, aggression has been traditionally associated with high levels of circulating androgens in breeding males. Nevertheless, the centrality of androgens as primary modulators of aggression is being reconsidered in at least in two particular cases: (1) territorial aggression outside the breeding season, and (2) aggression by females. We are developing the weakly electric fish, Gymnotus omarorum, as a novel, advantageous model system to address these two alternative forms of aggression. This species displays a short, escalated contest, after which a clear hierarchical status emerges. Subordination of individuals involves three sequential decisions: interruptions of their electric discharges, retreats, and chirps. These decisions are influenced by both size asymmetry between contenders and aggression levels of dominants. Both females and males are aggressive, and do not differ in fighting ability nor in the value placed on the resource. Aggression is completely independent of gonadal hormones: dominance status is unrelated to circulating androgen and estrogen levels, and gonadectomy in males does not affect aggression. Nevertheless, estrogenic pathways participate in the modulation of this non-breeding aggression. Our results parallel those put forth in other taxa, heightening the value of G. omarorum as a model to identify commonalities in neuroendrocrine strategies of vertebrate aggression control. Copyright © 2016 Elsevier Ltd. All rights reserved.

Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

PubMed

Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E; Wilk, Anna; Vashistha, Himanshu; Zapata, Adriana; Walker, Chelsey; Velasco-Gonzalez, Cruz; Parsons, Christopher; Wieland, Scott; Levitt, Daniel; Reiss, Krzysztof; Prakash, Om

2014-10-01

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

Correlations of inflammatory gene pathways, corticolimbic functional activities, and aggression in pediatric bipolar disorder: a preliminary study.

PubMed

Barzman, Drew; Eliassen, Jim; McNamara, Robert; Abonia, Pablo; Mossman, Douglas; Durling, Michele; Adler, Caleb; DelBello, Melissa; Lin, Ping-I

2014-11-30

The mechanisms underlying aggression in adolescents with bipolar disorder have been poorly understood. The present study has investigated the associations among TNF gene expressions, functional brain activations under the frustrative non-reward task, and aggression in adolescents with bipolar disorder. Baseline gene expressions and aggressive tendencies were measured with the RNA-sequencing and Brief Rating of Aggression by Children and Adolescents (BRACHA), respectively. Our results show that activity levels of left subgenual anterior cingulate gyrus (ACG), right amygdala, left Brodmann area 10 (orbitofrontal cortex), and right thalamus were inversely correlated with BRACHA scores and were activated with frustrative non-reward during the affective Posner Task. In addition, 11 TNF related gene expressions were significantly correlated with activation of amygdala or ACG during the affective Posner Task. Three TNF gene expressions were inversely correlated with BRACHA score while one TNF gene (TNFAIP3) expression was positively correlated with BRACHA score. Therefore, TNF-related inflammatory cytokine genes may play a role in neural activity associated with frustrative non-reward and aggressive behaviors in pediatric bipolar disorder. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Alcohol and aggressive behavior in men--moderating effects of oxytocin receptor gene (OXTR) polymorphisms.

PubMed

Johansson, A; Bergman, H; Corander, J; Waldman, I D; Karrani, N; Salo, B; Jern, P; Algars, M; Sandnabba, K; Santtila, P; Westberg, L

2012-03-01

We explored if the disposition to react with aggression while alcohol intoxicated was moderated by polymorphic variants of the oxytocin receptor gene (OXTR). Twelve OXTR polymorphisms were genotyped in 116 Finnish men [aged 18-30, M = 22.7, standard deviation (SD) = 2.4] who were randomly assigned to an alcohol condition in which they received an alcohol dose of 0.7 g pure ethanol/kg body weight or a placebo condition. Aggressive behavior was measured using a laboratory paradigm in which it was operationalized as the level of aversive noise administered to a fictive opponent. No main effects of the polymorphisms on aggressive behavior were found after controlling for multiple testing. The interactive effects between alcohol and two of the OXTR polymorphisms (rs4564970 and rs1488467) on aggressive behavior were nominally significant and remained significant for the rs4564970 when controlled for multiple tests. To the best of our knowledge, this is the first experimental study suggesting interactive effects of specific genetic variants and alcohol on aggressive behavior in humans. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Callous-Unemotional Traits, Proactive Aggression, and Treatment Outcomes of Aggressive Children with Attention-Deficit/Hyperactivity Disorder

PubMed Central

Blader, Joseph C.; Pliszka, Steven R.; Kafantaris, Vivian; Foley, Carmel A.; Crowell, Judith A.; Carlson, Gabrielle A.; Sauder, Colin; Margulies, David M.; Sinha, Christa; Sverd, Jeffrey; Matthews, Thomas L.; Bailey, Brigitte Y.; Daviss, W. Burleson

2013-01-01

Objective Stimulant treatment improves impulse control among children with attention-deficit/hyperactivity disorder (ADHD). Decreased aggression often accompanies stimulant pharmacotherapy, suggesting that impulsiveness is integral to their aggressive behavior. However, children with high callous-unemotional (CU) traits and proactive aggression may benefit less from ADHD pharmacotherapy because their aggressive behavior seems more purposeful and deliberate. This study’s objective was to determine if pretreatment CU traits and proactive aggression affect treatment outcomes among aggressive children with ADHD receiving stimulant monotherapy. Method We implemented a stimulant optimization protocol with 160 6- to 13-year-olds (mean [SD] age of 9.31 [2.02] years; 78.75% males) with ADHD, oppositional defiant or conduct disorder, and significant aggressive behavior. Family-focused behavioral intervention was provided concurrently. Primary outcome was the Retrospective Modified Overt Aggression Scale. The Antisocial Process Screening Device and the Aggression Scale, also completed by parents, measured CU traits and proactive aggression, respectively. Analyses examined moderating effects of CU traits and proactive aggression on outcomes. Results 82 children (51%) experienced remission of aggressive behavior. Neither CU traits nor proactive aggression predicted remission (CU traits: odds ratio=0.94, 95% CI=0.80–1.11; proactive aggression, odds ratio=1.05, 95% CI=0.86–1.29). Children whose overall aggression remitted showed decreases in CU traits (effect size=−0.379, 95% CI=−0.60 to −0.16) and proactive aggression (effect size=−0.463, 95% CI=−0.69 to −0.23). Conclusions Findings suggest that pretreatment CU traits and proactive aggression do not forecast worse outcomes for aggressive children with ADHD receiving optimized stimulant pharmacotherapy. With such treatment, CU traits and proactive aggression may decline alongside other behavioral improvements. PMID:24290461

Aggression Profiles in the Spanish Child Population: Differences in Perfectionism, School Refusal and Affect

PubMed Central

Vicent, María; Inglés, Cándido J.; Sanmartín, Ricardo; Gonzálvez, Carolina; García-Fernández, José Manuel

2018-01-01

The aim of this study was to identify the existence of combinations of aggression components (Anger, Hostility, Physical Aggression and Verbal Aggression) that result in different profiles of aggressive behavior in children, as well as to test the differences between these profiles in scores of perfectionism, school refusal and affect. It is interesting to analyze these variables given: (a) their clinical relevance due to their close relationship with the overall psychopathology; and (b) the need for further evidence regarding how they are associated with aggressive behavior. The sample consisted of 1202 Spanish primary education students between the ages of 8 and 12. Three aggressive behavior profiles for children were identified using Latent Class Analysis (LCA): High Aggression (Z scores between 0.69 and 0.7), Moderate Aggression (Z scores between −0.39 and −0.47) and Low Aggression (Z scores between −1.36 and −1.58). These profiles were found for 49.08%, 38.46% and 12.48% of the sample, respectively. High Aggression scored significantly higher than Moderate Aggression and Low Aggression on Socially Prescribed Perfectionism (SPP), Self-Oriented Perfectionism (SOP), the first three factors of school refusal (i.e., FI. Negative Affective, FII. Social Aversion and/or Evaluation, FIII. To Pursue Attention), and Negative Affect (NA). In addition, Moderate Aggression also reported significantly higher scores than Low Aggression for the three first factors of school refusal and NA. Conversely, Low Aggression had significantly higher mean scores than High Aggression and Moderate Aggression on Positive Affect (PA). Results demonstrate that High Aggression was the most maladaptive profile having a high risk of psychological vulnerability. Aggression prevention programs should be sure to include strategies to overcome psychological problems that characterize children manifesting high levels of aggressive behavior. PMID:29441002

An ERP study on hostile attribution bias in aggressive and nonaggressive individuals.

PubMed

Gagnon, Jean; Aubin, Mercédès; Emond, Fannie Carrier; Derguy, Sophie; Brochu, Alex Fernet; Bessette, Monique; Jolicoeur, Pierre

2017-05-01

Hostile attribution bias (e.g., tendency to interpret the intention of others as hostile in ambiguous social contexts) has been associated with impulsive aggression in adults, but the results are mixed and the complete sequence of hostile inferential processes leading to aggression has not been investigated yet. The goal of this event-related brain potentials (ERPs) study was to track the neural activity associated with the violation of expectations about hostile versus nonhostile intentions in aggressive and nonaggressive individuals and examine how this neural activity relates to self-reported hostile attributional bias and impulsive aggression in real life. To this end, scenarios with a hostile versus nonhostile social context followed by a character's ambiguous aversive behavior were presented to readers, and ERPs to critical words that specified the hostile versus nonhostile intent behind the behavior were analysed. Thirty-seven aggressive and fifty nonaggressive individuals participated in the study. The presentation of a critical word that violated hostile expectation caused an N400 response that was significantly larger in aggressive than nonaggressive individuals. Results also showed an enhanced late positive potential-like component in aggressive individuals when hostile intention scenarios took place in a nonhostile context, which is associated with impulsive aggression in real life even after having controlled for the effect of self-reported hostile attributional bias. The Hostile Expectancy Violation paradigm evaluated in this study represents a promising tool to investigate the relationship between the online processing of hostile intent in others and impulsive aggression. Aggr. Behav. 43:217-229, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Basal forebrain projections to the lateral habenula modulate aggression reward.

PubMed

Golden, Sam A; Heshmati, Mitra; Flanigan, Meghan; Christoffel, Daniel J; Guise, Kevin; Pfau, Madeline L; Aleyasin, Hossein; Menard, Caroline; Zhang, Hongxing; Hodes, Georgia E; Bregman, Dana; Khibnik, Lena; Tai, Jonathan; Rebusi, Nicole; Krawitz, Brian; Chaudhury, Dipesh; Walsh, Jessica J; Han, Ming-Hu; Shapiro, Matt L; Russo, Scott J

2016-06-30

Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

Characterisation of aggression in Huntington's disease: rates, types and antecedents in an inpatient rehabilitation setting.

PubMed

Brown, Anahita; Sewell, Katherine; Fisher, Caroline A

2017-10-01

To systematically review aggression in an inpatient Huntington's cohort examining rates, types and antecedents. Although the prevalence of aggression in Huntington's disease is high, research into this problematic behaviour has been limited. Few studies have investigated the nature of aggressive behaviour in Huntington's disease or antecedents that contribute to its occurrence. A systematic, double-coded, electronic medical file audit. The electronic hospital medical records of 10 people with Huntington's disease admitted to a brain disorders unit were audited for a 90-day period using the Overt Aggression Scale-Modified for Neurorehabilitation framework, yielding 900 days of clinical data. Nine of 10 clients exhibited aggression during the audit period. Both verbal (37·1%) aggression and physical aggression were common (33·8%), along with episodes of mixed verbal and physical aggression (15·2%), while aggression to objects/furniture was less prevalent (5·5%). The most common antecedent was physical guidance with personal care, far exceeding any other documented antecedents, and acting as the most common trigger for four of the nine clients who exhibited aggression. For the remaining five clients, there was intraindividual heterogeneity in susceptibility to specific antecedents. In Huntington's sufferers at mid- to late stages following disease onset, particular care should be made with personal care assistance due to the propensity for these procedures to elicit an episode of aggression. However, given the degree of intraindividual heterogeneity in susceptibility to specific antecedents observed in the present study, individualised behaviour support plans and sensory modulation interventions may be the most useful in identifying triggers and managing aggressive episodes. Rates of aggression in Huntington's disease inpatients can be high. Knowledge of potential triggers, such as personal care, is important for nursing and care staff, so that attempts can be made to minimise distress for patients and maximise the personal safety of care staff. © 2016 John Wiley & Sons Ltd.

Trends in North American Newspaper Reporting of Brain Injury in Ice Hockey

PubMed Central

Cusimano, Michael D.; Sharma, Bhanu; Lawrence, David W.; Ilie, Gabriela; Silverberg, Sarah; Jones, Rochelle

2013-01-01

The frequency and potential long-term effects of sport-related traumatic brain injuries (TBI) make it a major public health concern. The culture within contact sports, such as ice hockey, encourages aggression that puts youth at risk of TBI such as concussion. Newspaper reports play an important role in conveying and shaping the culture around health-related behaviors. We qualitatively studied reports about sport-related TBI in four major North American newspapers over the last quarter-century. We used the grounded-theory approach to identify major themes and then did a content analysis to compare the frequency of key themes between 1998–2000 and 2009–2011. The major themes were: perceptions of brain injury, aggression, equipment, rules and regulations, and youth hockey. Across the full study period, newspaper articles from Canada and America portrayed violence and aggression that leads to TBI both as integral to hockey and as an unavoidable risk associated with playing the game. They also condemned violence in ice hockey, criticized the administrative response to TBI, and recognized the significance of TBI. In Canada, aggression was reported more often recently and there was a distinctive shift in portraying protective equipment as a solution to TBI in earlier years to a potential contributing factor to TBI later in the study period. American newspapers gave a greater attention to ‘perception of risks’ and the role of protective equipment, and discussed TBI in a broader context in the recent time period. Newspapers from both countries showed similar recent trends in regards to a need for rule changes to curb youth sport-related TBI. This study provides a rich description of the reporting around TBI in contact sport. Understanding this reporting is important for evaluating whether the dangers of sport-related TBI are being appropriately communicated by the media. PMID:23613957

Genetic determinants of aggression and impulsivity in humans.

PubMed

Pavlov, Konstantin A; Chistiakov, Dimitry A; Chekhonin, Vladimir P

2012-02-01

Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.

Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

DTIC Science & Technology

2015-12-01

production in two human glioblastoma xenograft models where the blood–brain barrier (BBB) was disrupted relative to normal brain, suggesting that HP...rodent mammary adenocarcinoma and murine lymphoma xenografts ) has shown ample conversion to leucine.98 In this preclinical study, SNR and contrast were...4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner, Oncogene 33 (2013) 4433–4441. Real

Clinical characteristics of aggression in children and adolescents admitted to a tertiary care centre.

PubMed

Jacob, Preeti; Seshadri, Shekhar; Girimaji, Satish C; Srinath, Shoba; Sagar, John Vijay

2013-12-01

Identification and management of aggression is a major mental health priority in hospitalised patients. However, no such studies have been done in child and adolescent in-patients in India. To study the clinical and demographic features; characteristics of the aggression and methods employed to manage aggression in child and adolescent in-patients. Child and adolescent in-patients between the ages of 4 and 16 years who were aggressive were included. The tools used were the MINI-International Neuropsychiatric Interview (M.I.N.I) KID, Overt Aggression Scale (OAS), Children's Global Assessment Scale (CGAS), and a Semi-structured interview regarding each aggressive episode. 31 patients displayed aggressive behaviour out of the 131 patients who were admitted during the study period. Aggressive acts were more common in males, those with academic difficulties, who had a past history of aggression, with suicidal ideation or suicidal attempts. Aggression occurred across diagnostic categories but a significant proportion was diagnosed to have Disruptive Behaviour Disorders either as a primary diagnosis or as comorbidity. 90.6% were on psychotropic medication prior to admission. Around 2/3rd of aggressive episodes occurred in the evening and family members (85.7%) were the most common targets of aggression. There are a few factors that can possibly help identify and predict aggression in children and adolescents in a hospital setting. More research is required to understand aggression in clinical settings. Copyright © 2013 Elsevier B.V. All rights reserved.

Optimal Treatment Decision for Brain Metastases of Unknown Primary Origin: The Role and Timing of Radiosurgery

PubMed Central

Han, Hyun Jin; Chang, Won Seok; Jung, Hyun Ho; Park, Yong Gou

2016-01-01

Background Up to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors. Methods We retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group. Results Of the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups. Conclusion Identification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor. PMID:27867920

Early metabolic/cellular-level resuscitation following terminal brain stem herniation: implications for organ transplantation.

PubMed

Arbour, Richard B

2013-01-01

Patients with terminal brain stem herniation experience global physiological consequences and represent a challenging population in critical care practice as a result of multiple factors. The first factor is severe depression of consciousness, with resulting compromise in airway stability and lung ventilation. Second, with increasing severity of brain trauma, progressive brain edema, mass effect, herniation syndromes, and subsequent distortion/displacement of the brain stem follow. Third, with progression of intracranial pathophysiology to terminal brain stem herniation, multisystem consequences occur, including dysfunction of the hypothalamic-pituitary axis, depletion of stress hormones, and decreased thyroid hormone bioavailability as well as biphasic cardiovascular state. Cardiovascular dysfunction in phase 1 is a hyperdynamic and hypertensive state characterized by elevated systemic vascular resistance and cardiac contractility. Cardiovascular dysfunction in phase 2 is a hypotensive state characterized by decreased systemic vascular resistance and tissue perfusion. Rapid changes along the continuum of hyperperfusion versus hypoperfusion increase risk of end-organ damage, specifically pulmonary dysfunction from hemodynamic stress and high-flow states as well as ischemic changes consequent to low-flow states. A pronounced inflammatory state occurs, affecting pulmonary function and gas exchange and contributing to hemodynamic instability as a result of additional vasodilatation. Coagulopathy also occurs as a result of consumption of clotting factors as well as dilution of clotting factors and platelets consequent to aggressive crystalloid administration. Each consequence of terminal brain stem injury complicates clinical management within this patient demographic. In general, these multisystem consequences are managed with mechanism-based interventions within the context of caring for the donor's organs (liver, kidneys, heart, etc.) after death by neurological criteria. These processes begin far earlier in the continuum of injury, at the moment of terminal brain stem herniation. As such, aggressive, mechanism-based care, including hormonal replacement therapy, becomes clinically appropriate before formal brain death declaration to support cardiopulmonary stability following terminal brain stem herniation.

Serotonin has opposite effects on the aggressiveness of crayfish, facing either a smaller or a larger rival: alteration of size perception.

PubMed

Bacqué-Cazenave, Julien; Cattaert, Daniel; Delbecque, Jean Paul; Fossat, Pascal

2018-04-26

We injected serotonin (5-HT) in adult male crayfish before pairing them with size-matched non-injected competitors, and we observed dyadic agonistic interactions. Paradoxically, 5-HT elicited opposite behavioral responses if the injected animal was opposed by a smaller or larger rival: the level of aggressiveness of the injected crayfish was higher in front of a larger rival but lower in front of a smaller rival. Our results indicate that the effects of 5-HT on aggressiveness are dependent on the perception of the relative size difference of the opponent. In both cases, however, 5-HT significantly delayed the decision to retreat. We conclude that 5-HT does not primarily act on aggressiveness but rather on the brain centers that integrate risk assessment and/or decision-making, which then modulate the aggressive response. Our study supports a reinterpretation of the role of 5-HT in crustacean agonistic behavior that may be of interest for other animals. © 2018. Published by The Company of Biologists Ltd.

Novel vaccines for glioblastoma: clinical update and perspective

PubMed Central

Winograd, Evan K; Ciesielski, Michael J; Fenstermaker, Robert A

2016-01-01

Glioblastoma is the most common primary brain cancer. Aggressive treatment with surgery, radiation therapy and chemotherapy provides limited overall survival benefit. Glioblastomas have a formidable tumor microenvironment that is hostile to immunological effector cells and these cancers produce profound systemic immunosuppression. However, surgical resection of these tumors creates conditions that favor the use of immunotherapeutic strategies. Therefore, extensive surgical resection, when feasible, will remain part of the equation to provide an environment in which active specific immunotherapy has the greatest chance of working. Toward that end, a number of vaccination protocols are under investigation. Vaccines studied to date have produced cellular and humoral antitumor responses, but unequivocal clinical efficacy has yet to be demonstrated. In addition, focus is shifting toward the prospect of therapies involving vaccines in combination with immune checkpoint inhibitors and other immunomodulatory agents so that effector cells remain active against their targets systemically and within the tumor microenvironment. PMID:27993092

New molecules and old drugs as emerging approaches to selectively target human glioblastoma cancer stem cells.

PubMed

Würth, Roberto; Barbieri, Federica; Florio, Tullio

2014-01-01

Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM), the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs), since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.

A mathematical model describes the malignant transformation of low grade gliomas: Prognostic implications.

PubMed

Bogdańska, Magdalena U; Bodnar, Marek; Piotrowska, Monika J; Murek, Michael; Schucht, Philippe; Beck, Jürgen; Martínez-González, Alicia; Pérez-García, Víctor M

2017-01-01

Gliomas are the most frequent type of primary brain tumours. Low grade gliomas (LGGs, WHO grade II gliomas) may grow very slowly for the long periods of time, however they inevitably cause death due to the phenomenon known as the malignant transformation. This refers to the transition of LGGs to more aggressive forms of high grade gliomas (HGGs, WHO grade III and IV gliomas). In this paper we propose a mathematical model describing the spatio-temporal transition of LGGs into HGGs. Our modelling approach is based on two cellular populations with transitions between them being driven by the tumour microenvironment transformation occurring when the tumour cell density grows beyond a critical level. We show that the proposed model describes real patient data well. We discuss the relationship between patient prognosis and model parameters. We approximate tumour radius and velocity before malignant transformation as well as estimate the onset of this process.

[Sexual aggression against girls and adult women--causes and consequences].

PubMed

Bitzer, J

2005-04-01

The causes of sexual aggression are multiple. Bioevolutionary rooted behavioral dispositions (sexual aggressiveness of men as a reproductive strategy) are enforced by specific male dominated structures of society and socially determined stereotypes of female roles which deter women from self determination of their sexuality; these macrosocial factors combine with individual conditions of socialization, in which violence plays an important role. With respect to the consequences of sexual aggression primary victimization (the trauma itself with physical and psychological harm) can be distinguished from secondary victimization (devaluation and mistrust in the social environment). The degree of negative health outcomes depends on risk factors like previous abuse, severity of the violent act, and lack of social support. Prevention must aim at changes of societal conditions that enhance sexual aggression and the establishment of programs for men and women at risk in which techniques of control of sexual aggression, attenuation and inhibition can be learnt.

Power of being present: the role of mindfulness on the relation between men's alcohol use and sexual aggression toward intimate partners.

PubMed

Gallagher, Kathryn E; Hudepohl, Adam D; Parrott, Dominic J

2010-01-01

The primary aim of this investigation was to examine the association between men's level of mindfulness and histories of alcohol consumption and sexual aggression toward intimate partners. Participants were 167 heterosexual drinking males who completed self-report measures of mindfulness, frequency and quantity of alcohol consumption during the past 12 months and sexual aggression against intimate partners during the past 12 months. Results indicated that a history of consuming larger amounts when drinking was associated with more frequent sexual coercion/aggression among men who reported low, but not high, levels of mindfulness. However, drinking more frequently by itself was not associated with more frequent sexual coercion/aggression. These results support the attention-allocation model and suggest implications for future intervention research aimed at reducing alcohol-related aggression. © 2010 Wiley-Liss, Inc.

Personal and Social Characteristics of Schoolchildren Involved in Bullying in Primary Education

ERIC Educational Resources Information Center

Sanchez, Consuelo; Cerezo, Fuensanta

2010-01-01

Introduction: According to the latest Ombudsman's report, aggressive behavior happens frequently in our country's schools (Spain), appearing in all its manifestations: insults, threats, physical aggression, social isolation, etc. Now, however, we are witnessing a growing interest in this phenomenon and the possible risk factors that may help us…

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses

PubMed Central

Stefansson, Ingunn M.; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M.; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B.; Wik, Elisabeth; Akslen, Lars A.

2015-01-01

Aims Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. Methods and Results By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Conclusions Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis. PMID:26485755

Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses.

PubMed

Bredholt, Geir; Mannelqvist, Monica; Stefansson, Ingunn M; Birkeland, Even; Bø, Trond Hellem; Øyan, Anne M; Trovik, Jone; Kalland, Karl-Henning; Jonassen, Inge; Salvesen, Helga B; Wik, Elisabeth; Akslen, Lars A

2015-11-24

Tumor necrosis is associated with aggressive features of endometrial cancer and poor prognosis. Here, we investigated gene expression patterns and potential treatment targets related to presence of tumor necrosis in primary endometrial cancer lesions. By DNA microarray analysis, expression of genes related to tumor necrosis reflected multiple tumor-microenvironment interactions like tissue hypoxia, angiogenesis and inflammation pathways. A tumor necrosis signature of 38 genes and a related patient cluster (Cluster I, 67% of the cases) were associated with features of aggressive tumors such as type II cancers, estrogen receptor negative tumors and vascular invasion. Further, the tumor necrosis signature was increased in tumor cells grown in hypoxic conditions in vitro. Multiple genes with increased expression are known to be activated by HIF1A and NF-kB. Our findings indicate that the presence of tumor necrosis within primary tumors is associated with hypoxia, angiogenesis and inflammation responses. HIF1A, NF-kB and PI3K/mTOR might be potential treatment targets in aggressive endometrial cancers with presence of tumor necrosis.

Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.

PubMed

Suki, Dima; Khoury Abdulla, Rami; Ding, Minming; Khatua, Soumen; Sawaya, Raymond

2014-10-01

Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis. Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990-2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes. Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2-77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24-34 months) and 9 months (95% CI 6-11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3-1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6-11 months). The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

Psychological Aggression, Physical Aggression, and Injury in Nonpartner Relationships Among Men and Women in Treatment for Substance-Use Disorders*

PubMed Central

Murray, Regan L.; Chermack, Stephen T.; Walton, Maureen A.; Winters, Jamie; Booth, Brenda M.; Blow, Frederic C.

2008-01-01

Objective: This study focused on the prevalence and predictors of psychological aggression, physical aggression, and injury rates in nonintimate partner relationships in a substance-use disorder treatment sample. Method: The sample included 489 (76% men, 24% women) participants who completed screening measures for inclusion in a randomized control trial for an aggression-prevention treatment. Primary outcome measures included rates of past-year psychological aggression, physical aggression, and injury (both from the participant to nonpartners and from nonpartners to the participant). Potential predictors included individual factors (e.g., age, gender), developmental factors (e.g., family history of drug use, childhood physical abuse), and recent factors (e.g., depression, cocaine use). Results: Rates of participant-tononpartner psychological aggression (83%), physical aggression (61%), and injury (47%) were high, as were rates of nonpartner-to-participant aggression. Bivariate analyses revealed significant relationships between the aggression outcomes and most of the individual, developmental, and recent factors. However, multivariate analyses (zero-inflated Poisson regression) revealed that age, treatment status, current symptoms of depression, heavy periods of drinking, and cocaine use were related most frequently to the occurrence of aggression to and from nonpartners. Conclusions: Nonpartner aggression may be as common within a substance-use disorder sample as partner aggression, and it is associated with heavy drinking episodes, cocaine use, and depressive symptoms. The findings highlight the need for the development of effective violence interventions addressing violence in nonpartner relationship types. PMID:18925348

Trpc2-deficient lactating mice exhibit altered brain and behavioral responses to bedding stimuli.

PubMed

Hasen, Nina S; Gammie, Stephen C

2011-03-01

The trpc2 gene encodes an ion channel involved in pheromonal detection and is found in the vomeronasal organ. In tprc2(-/-) knockout (KO) mice, maternal aggression (offspring protection) is impaired and brain Fos expression in females in response to a male are reduced. Here we examine in lactating wild-type (WT) and KO mice behavioral and brain responses to different olfactory/pheromonal cues. Consistent with previous studies, KO dams exhibited decreased maternal aggression and nest building, but we also identified deficits in nighttime nursing and increases in pup weight. When exposed to the bedding tests, WT dams typically ignored clean bedding, but buried male-soiled bedding from unfamiliar males. In contrast, KO dams buried both clean and soiled bedding. Differences in brain Fos expression were found between WT and KO mice in response to either no bedding, clean bedding, or soiled bedding. In the accessory olfactory bulb, a site of pheromonal signal processing, KO mice showed suppressed Fos activation in the anterior mitral layer relative to WT mice in response to clean and soiled bedding. However, in the medial and basolateral amygdala, KO mice showed a robust Fos response to bedding, suggesting that regions of the amygdala canonically associated with pheromonal sensing can be active in the brains of KO mice, despite compromised signaling from the vomeronasal organ. Together, these results provide further insights into the complex ways by which pheromonal signaling regulates the brain and behavior of the maternal female. Copyright © 2010 Elsevier B.V. All rights reserved.

Hypopituitarism in primary haemochromatosis; recovery after iron depletion.

PubMed Central

Gama, R.; Smith, M. J.; Wright, J.; Marks, V.

1995-01-01

We report a case of primary haemochromatosis complicated by anterior hypopituitarism which recovered after aggressive venesection therapy. Reversal of anterior hypopituitarism in haemochromatosis following iron depletion has not been previously described. PMID:7596937

Bilateral tuberculous otomastoiditis in an immmunocompetent 5-year-old child: CT and MRI findings (2009: 3b).

PubMed

Munoz, Alberto; Ruiz-Contreras, Jesus; Jimenez, Ana; Maté, Irene; Calvo, Marta; Villafruela, Miguel; del-Pozo, Gloria

2009-06-01

Bilateral tuberculous mastoiditis (TOM) in an immunocompetent child is a very uncommon form of tuberculous infection presentation. This report shows the CT and MR imaging of bilateral tuberculous otomastoiditis consisting of aggressive signs of middle ear and mastoid involvement with bony destruction and periauricular collections with no signs of brain involvement. Differential diagnosis at pediatric age of destructive lesions such as mainly aggressive forms of histiocytosis is underscored. This form of bilateral TOM at this early age has not been described from a radiological perspective.

Appetitive and reactive aggression are differentially associated with the STin2 genetic variant in the serotonin transporter gene.

PubMed

Hemmings, Sian Megan Joanna; Xulu, Khethelo; Sommer, Jessica; Hinsberger, Martina; Malan-Muller, Stefanie; Tromp, Gerard; Elbert, Thomas; Weierstall, Roland; Seedat, Soraya

2018-04-30

Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 × 10 -5 ). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression.

Tuberculous ventriculitis: A rare complication of central nervous system tuberculosis.

PubMed

Vaziri, Siavash; Soleiman-Meigooni, Saeed; Rajabi, Jalil; Asgari, Ali

2016-06-01

Tuberculous ventriculitis is an inflammatory infection of the ventricular system of the brain, and is caused by Mycobacterium tuberculosis. We herein present the case of an immunocompromised patient with brain tuberculomas who developed ventriculitis during treatment. The patient was successfully treated with a high dose of steroid, long-term antituberculosis drugs, and aggressive supportive care. Copyright © 2016 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

The Sociobiological Foundations of Stability and Support Operations

DTIC Science & Technology

1999-01-01

of fatherhood. Parental responsibility is not a factor for the warrior rapist as future proof of paternity is unlikely. In raping the wives and...allows a single parent to replicate his genetic code for as long as the reproductive resources last. If there is a change in the environment or the...aggression. The mammalian brain controls, among other emotions, social behavior and the nurturing of children . The surrounding primate brain gives man

Comparative mRNA analysis of behavioral and genetic mouse models of aggression.

PubMed

Malki, Karim; Tosto, Maria G; Pain, Oliver; Sluyter, Frans; Mineur, Yann S; Crusio, Wim E; de Boer, Sietse; Sandnabba, Kenneth N; Kesserwani, Jad; Robinson, Edward; Schalkwyk, Leonard C; Asherson, Philip

2016-04-01

Mouse models of aggression have traditionally compared strains, most notably BALB/cJ and C57BL/6. However, these strains were not designed to study aggression despite differences in aggression-related traits and distinct reactivity to stress. This study evaluated expression of genes differentially regulated in a stress (behavioral) mouse model of aggression with those from a recent genetic mouse model aggression. The study used a discovery-replication design using two independent mRNA studies from mouse brain tissue. The discovery study identified strain (BALB/cJ and C57BL/6J) × stress (chronic mild stress or control) interactions. Probe sets differentially regulated in the discovery set were intersected with those uncovered in the replication study, which evaluated differences between high and low aggressive animals from three strains specifically bred to study aggression. Network analysis was conducted on overlapping genes uncovered across both studies. A significant overlap was found with the genetic mouse study sharing 1,916 probe sets with the stress model. Fifty-one probe sets were found to be strongly dysregulated across both studies mapping to 50 known genes. Network analysis revealed two plausible pathways including one centered on the UBC gene hub which encodes ubiquitin, a protein well-known for protein degradation, and another on P38 MAPK. Findings from this study support the stress model of aggression, which showed remarkable molecular overlap with a genetic model. The study uncovered a set of candidate genes including the Erg2 gene, which has previously been implicated in different psychopathologies. The gene networks uncovered points at a Redox pathway as potentially being implicated in aggressive related behaviors. © 2016 Wiley Periodicals, Inc.

Alterations in anterior cingulate cortex myoinositol and aggression in veterans with suicidal behavior: A proton magnetic resonance spectroscopy study.

PubMed

Sheth, Chandni; Prescot, Andrew; Bueler, Elliott; DiMuzio, Jennifer; Legarreta, Margaret; Renshaw, Perry F; Yurgelun-Todd, Deborah; McGlade, Erin

2018-06-30

Studies investigating the neurochemical changes that correspond with suicidal behavior (SB) have not yielded conclusive results. Suicide correlates such as aggression have been used to explore risk factors for SB. Yet the neurobiological basis for the association between aggression and SB is unclear. Aggression and SB are both prevalent in veterans relative to civilian populations. The current study evaluated the relationship between brain chemistry in the anterior (ACC) and the posterior cingulate cortex (POC), as well as the relationship between aggression and SB in a veteran population using proton magnetic resonance spectroscopy ( 1 H-MRS). Single-voxel MRS data at 3 Tesla (T) were acquired from the ACC and POC voxels using a 2-dimensional J-resolved point spectroscopy sequence and quantified using the ProFit algorithm. Participants also completed a structured diagnostic interview and a clinical battery. Our results showed that the myoinositol (mI)/H2O ratio in the ACC and POC was significantly higher in veterans who reported SB when compared to veterans who did not. The two groups did not differ significantly with regard to other metabolites. Second, verbal aggression and SB measures positively correlated with mI/H2O in the ACC. Finally, verbal aggression mediated the relationship between mI/H2O in the ACC and SB. Copyright © 2018 Elsevier B.V. All rights reserved.

An evaluation of antisocial behaviour in children after traumatic brain injury: the prospect of improving the quality of life in rehabilitation.

PubMed

Tomaszewski, Wiesław; Buliński, Leszek; Mirski, Andrzej; Rasmus, Anna; Kowalczyk, Jakub; Bazan, Maria; Pąchalska, Maria

2014-01-01

The aim of the article is to present the consequences of traumatic brain injury in children, associated with general cognition and behavioural disorders, mainly of the antisocial type. A total of 20 school-age children took part in the study, including six girls and 14 boys. The average age of the children was 13.35 years (standard deviation SD = 1.95). The research instruments included an analysis of documentation, a structured clinical interview, MMSE and Frontal Behavioral Inventory (FBInv) with additional set of five supplementary questions directed for detection of antisocial behavior. The research was conducted from the beginning of January 2009 until the end of May 2009. As hypothesized, the functioning of the children with traumatic brain injury is severely disrupted, because of the presence of cognitive impairment, however, dementia is not manifested. In a significant number of the children with traumatic brain injury we found not only the frontal syndrome, but also the occurrence of antisocial behaviour. The most commonly reported behavioural problems were: disorganization commonly referred to as laziness, hypersensitivity, and anxiety. The most common types of anti-social behaviour were: impulsivity, physical and verbal aggression, and also an outburst of anger. The children with traumatic brain injury suffer from a cognitive disorders and behavioural problems, especially impulsivity, physical and verbal aggression, increased anxiety, and disorganization. The occurrence of frontal syndrome is related to the development of antisocial behaviour.

Brain tumor - children

MedlinePlus

... children; Neuroglioma - children; Oligodendroglioma - children; Meningioma - children; Cancer - brain tumor (children) ... The cause of primary brain tumors is unknown. Primary brain tumors may ... (spread to nearby areas) Cancerous (malignant) Brain tumors ...

Annexin 2A sustains glioblastoma cell dissemination and proliferation

PubMed Central

Maule, Francesca; Bresolin, Silvia; Rampazzo, Elena; Boso, Daniele; Puppa, Alessandro Della; Esposito, Giovanni; Porcù, Elena; Mitola, Stefania; Lombardi, Giuseppe; Accordi, Benedetta; Tumino, Manuela; Basso, Giuseppe; Persano, Luca

2016-01-01

Glioblastoma (GBM) is the most devastating tumor of the brain, characterized by an almost inevitable tendency to recur after intensive treatments and a fatal prognosis. Indeed, despite recent technical improvements in GBM surgery, the complete eradication of cancer cell disseminated outside the tumor mass still remains a crucial issue for glioma patients management. In this context, Annexin 2A (ANXA2) is a phospholipid-binding protein expressed in a variety of cell types, whose expression has been recently associated with cell dissemination and metastasis in many cancer types, thus making ANXA2 an attractive putative regulator of cell invasion also in GBM. Here we show that ANXA2 is over-expressed in GBM and positively correlates with tumor aggressiveness and patient survival. In particular, we associate the expression of ANXA2 to a mesenchymal and metastatic phenotype of GBM tumors. Moreover, we functionally characterized the effects exerted by ANXA2 inhibition in primary GBM cultures, demonstrating its ability to sustain cell migration, matrix invasion, cytoskeletal remodeling and proliferation. Finally, we were able to generate an ANXA2-dependent gene signature with a significant prognostic potential in different cohorts of solid tumor patients, including GBM. In conclusion, we demonstrate that ANXA2 acts at multiple levels in determining the disseminating and aggressive behaviour of GBM cells, thus proving its potential as a possible target and strong prognostic factor in the future management of GBM patients. PMID:27429043

A Scary Onset of a Rare and Aggressive Type of Primary Breast Sarcoma: A Case Report.

PubMed

Ramalho, Inês; Campos, Sara; Rebelo, Teresa; Figueiredo Dias, Margarida

2016-01-01

Primary breast sarcoma, arising from connective tissue within the breast, is extremely rare, accounting for less than 1% of all primary breast malignancies and no more than 5% of all sarcomas. The rarity of this pathology limits most studies to case reports and small retrospective studies, which has led to a lack of consensus on the clinical management. We report a clinical case of a 52-year-old woman, perimenopausal, previously healthy, with regular breast surveillance, who presented with a large (>20 cm) and rapidly expanding hypervascularized tumor of the left breast developed over 10 days, with a very thin preulcerative skin over the last 4 days. There was no systemic dissemination. The patient was submitted to total mastectomy and excision of axillary adenopathy. The tumor was diagnosed histologically as malignant phyllodes tumor associated with areas of high-grade sarcoma. Due to rapid growth and aggressive histological characteristics, adjuvant chemotherapy and radiotherapy were performed. There is a lot of evidence that tumors larger than 5 cm are associated with a poor prognosis. Despite the poor prognosis associated with this aggressive entity, the patient had no recurrence during 5 years of follow-up. We review the relevant literature about primary breast sarcomas.

A Scary Onset of a Rare and Aggressive Type of Primary Breast Sarcoma: A Case Report

PubMed Central

Ramalho, Inês; Campos, Sara; Rebelo, Teresa; Figueiredo Dias, Margarida

2016-01-01

Primary breast sarcoma, arising from connective tissue within the breast, is extremely rare, accounting for less than 1% of all primary breast malignancies and no more than 5% of all sarcomas. The rarity of this pathology limits most studies to case reports and small retrospective studies, which has led to a lack of consensus on the clinical management. We report a clinical case of a 52-year-old woman, perimenopausal, previously healthy, with regular breast surveillance, who presented with a large (>20 cm) and rapidly expanding hypervascularized tumor of the left breast developed over 10 days, with a very thin preulcerative skin over the last 4 days. There was no systemic dissemination. The patient was submitted to total mastectomy and excision of axillary adenopathy. The tumor was diagnosed histologically as malignant phyllodes tumor associated with areas of high-grade sarcoma. Due to rapid growth and aggressive histological characteristics, adjuvant chemotherapy and radiotherapy were performed. There is a lot of evidence that tumors larger than 5 cm are associated with a poor prognosis. Despite the poor prognosis associated with this aggressive entity, the patient had no recurrence during 5 years of follow-up. We review the relevant literature about primary breast sarcomas. PMID:28101028

Bidirectional Regulation of Aggression in Mice by Hippocampal Alpha-7 Nicotinic Acetylcholine Receptors.

PubMed

Lewis, Alan S; Pittenger, Steven T; Mineur, Yann S; Stout, Dawson; Smith, Philip H; Picciotto, Marina R

2018-05-01

Humans with 15q13.3 microdeletion syndrome (15q13.3DS) are typically hemizygous for CHRNA7, the gene coding for the α7 nicotinic acetylcholine receptor (nAChR), and manifest a variable neuropsychiatric phenotype that frequently includes persistent aggression. In mice, nAChR activation by nicotine is anti-aggressive, or 'serenic,' an effect which requires α7 nAChRs and is recapitulated by GTS-21, an α7 nAChR partial agonist. Pharmacotherapies potentiating α7 nAChR signaling have also been shown to reduce aggression in human 15q13.3DS. These findings identify the α7 nAChR as an important regulator of aggressive behavior, but the underlying neurobiological substrates remain to be determined. We therefore investigated the brain regions and potential neural circuits in which α7 nAChRs regulate aggressive behavior in male mice. As in 15q13.3DS, mice heterozygous for Chrna7 were significantly more aggressive compared to wild-type controls in the resident-intruder test. We subsequently examined the hippocampus, where α7 nAChRs are highly expressed, particularly in GABAergic interneurons. Resident-intruder interactions strongly activated granule cells in the dentate gyrus (DG). In contrast, GTS-21, which reduces aggression in mice, reduced DG granule cell activity during resident-intruder interactions. Short hairpin RNA knockdown of Chrna7 in the DG enhanced baseline aggression and eliminated the serenic effects of both nicotine and GTS-21 on attack latency. These data further implicate α7 nAChRs in regulation of aggression, and demonstrate that hippocampal α7 nAChR signaling is necessary and sufficient to limit aggression. These findings suggest that nAChR-mediated regulation of hippocampal excitatory-inhibitory balance could be a promising therapeutic intervention for aggression arising in certain forms of neuropsychiatric disease.

The Role of Emotion Regulation in the Predictive Association between Social Information Processing and Aggressive Behavior in Adolescents

ERIC Educational Resources Information Center

Calvete, Esther; Orue, Izaskun

2012-01-01

The primary aim of this study was to assess the moderating role of emotion regulation in the relationship between some components of social information processing (hostile interpretation and anger) and aggressive behavior. The secondary aim was to assess whether emotion regulation, hostile interpretation, and anger account for gender differences…

The Use of Aggression in Primary School Boys' Decisions about Inclusion in and Exclusion from Playground Football Games

ERIC Educational Resources Information Center

Woods, Ruth

2009-01-01

Background: Sociometric studies have shown that some aggressive boys are popular, perceived as popular or cool, dominant, and central in the peer group (Estell, Cairns, Farmer, & Cairns, 2002; Milich & Landau, 1984; Prinstein & Cillessen, 2003; Rodkin, Farmer, Pearl, & Van Acker, 2006). This is not predicted by social information…

Biomarkers of aggression in dementia.

PubMed

Gotovac, Kristina; Nikolac Perković, Matea; Pivac, Nela; Borovečki, Fran

2016-08-01

Dementia is a clinical syndrome defined by progressive global impairment of acquired cognitive abilities. It can be caused by a number of underlying conditions. The most common types of dementia are Alzheimer's disease (AD), frontotemporal dementia (FTD), vascular cognitive impairment (VCI) and dementia with Lewy bodies (DLB). Despite the fact that cognitive impairment is central to the dementia, noncognitive symptoms, most commonly described nowadays as neuropsychiatric symptoms (NPS) exist almost always at certain point of the illness. Aggression as one of the NPS represents danger both for patients and caregivers and the rate of aggression correlates with the loss of independence, cognitive decline and poor outcome. Therefore, biomarkers of aggression in dementia patients would be of a great importance. Studies have shown that different genetic factors, including monoamine signaling and processing, can be associated with various NPS including aggression. There have been significant and multiple neurotransmitter changes identified in the brains of patients with dementia and some of these changes have been involved in the etiology of NPS. Aggression specific changes have also been observed in neuropathological studies. The current consensus is that the best approach for development of such biomarkers may be incorporation of genetics (polymorphisms), neurobiology (neurotransmitters and neuropathology) and neuroimaging techniques. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced intensity dependence and aggression history indicate previous regular ecstasy use in abstinent polydrug users.

PubMed

Wan, Li; Baldridge, Robyn M; Colby, Amanda M; Stanford, Matthew S

2009-11-13

Intensity dependence is an electrophysiological measure of intra-individual stability of the augmenting/reducing characteristic of N1/ P2 event-related potential amplitudes in response to stimuli of varying intensities. Abstinent ecstasy users typically show enhanced intensity dependence and higher levels of impulsivity and aggression. Enhanced intensity dependence and high impulsivity and aggression levels may be due to damage in the brain's serotonergic neurons as a result of ecstasy use. The present study investigated whether intensity dependence, impulsivity and aggression history can be used as indicators of previous chronic ecstasy usage. Forty-four abstinent polydrug users (8 women; age 19 to 61 years old) were recruited. All participants were currently residents at a local substance abuse facility receiving treatment and had been free of all drugs for a minimum of 21 days. The study found significantly enhanced intensity dependence of tangential dipole source activity and a history of more aggressive behavior in those who had previously been involved in chronic ecstasy use. Intensity dependence of the tangential dipole source and aggressive behavior history correctly identified 73.3% of those who had been regular ecstasy users and 78.3% of those who had not. Overall, 76.3% of the participants were correctly classified.

Oxytocin in the medial prefrontal cortex regulates maternal care, maternal aggression and anxiety during the postpartum period

PubMed Central

Sabihi, Sara; Dong, Shirley M.; Durosko, Nicole E.; Leuner, Benedetta

2014-01-01

The neuropeptide oxytocin (OT) acts on a widespread network of brain regions to regulate numerous behavioral adaptations during the postpartum period including maternal care, maternal aggression, and anxiety. In the present study, we examined whether this network also includes the medial prefrontal cortex (mPFC). We found that bilateral infusion of a highly specific oxytocin receptor antagonist (OTR-A) into the prelimbic (PL) region of the mPFC increased anxiety-like behavior in postpartum, but not virgin, females. In addition, OTR blockade in the postpartum mPFC impaired maternal care behaviors and enhanced maternal aggression. Overall, these results suggest that OT in the mPFC modulates maternal care and aggression, as well as anxiety-like behavior, during the postpartum period. Although the relationship among these behaviors is complicated and further investigation is required to refine our understanding of OT actions in the maternal mPFC, these data nonetheless provide new insights into neural circuitry of OT-mediated postpartum behaviors. PMID:25147513

Female impulsive aggression: a sleep research perspective.

PubMed

Lindberg, Nina; Tani, Pekka; Putkonen, Hanna; Sailas, Eila; Takala, Pirjo; Eronen, Markku; Virkkunen, Matti

2009-01-01

The rate of violent crimes among girls and women appears to be increasing. One in every five female prisoners has been reported to have antisocial personality disorder. However, it has been quite unclear whether the impulsive, aggressive behaviour among women is affected by the same biological mechanisms as among men. Psychiatric sleep research has attempted to identify diagnostically sensitive and specific sleep patterns associated with particular disorders. Most psychiatric disorders are typically characterized by a severe sleep disturbance associated with decreased amounts of slow wave sleep (SWS), the physiologically significant, refreshing part of sleep. Among men with antisocial behaviour with severe aggression, on the contrary, increased SWS has been reported, reflecting either specific brain pathology or a delay in the normal development of human sleep patterns. In our preliminary study among medication-free, detoxified female homicidal offenders with antisocial personality disorder, the same profound abnormality in sleep architecture was found. From the perspective of sleep research, the biological correlates of severe impulsive aggression seem to share similar features in both sexes.

AgRP Neural Circuits Mediate Adaptive Behaviors in the Starved State

PubMed Central

Padilla, Stephanie L.; Qiu, Jian; Soden, Marta E.; Sanz, Elisenda; Nestor, Casey C; Barker, Forrest D.; Quintana, Albert; Zweifel, Larry S.; Rønnekleiv, Oline K.; Kelly, Martin J.; Palmiter, Richard D.

2016-01-01

In the face of starvation animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents for example will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression, and fear. Hypothalamic AgRP neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principle bed nucleus of the stria terminalis, which plays a role in suppressing territorial aggression and reducing contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues. PMID:27019015

Transgressive ethics: Professional work ethics as a perspective on ‘aggressive organ harvesting’

PubMed Central

Jensen, Anja MB

2013-01-01

Occasionally brain-dead organ donors go into cardiac arrest before reaching the operating theater. In such cases, the needed resuscitation of the potential donor stimulates a range of concerns among the responsible staff. If the intensive care unit staff are going to carry out the organ retrieval, they must rush in with demanding treatment measures such as defibrillation shock and cardiac massage that may break breast bones and make the donor vomit. Such treatment measures conflict with widespread ideals of tranquility in donor care and yet they are currently under consideration in Danish intensive care units. Why is this type of ‘aggressive organ harvesting’, as it is sometimes called, considered a likely development, even to the extent that the interviewed health professionals request a policy prescribing procurement measures they morally deplore? We suggest that to understand this change of treatment norms, we must move close to everyday work practices and appreciate the importance of material–technical treatment options as well as the interplay of professional ethics and identity. The cardiac treatment of brain-dead donors may thereby illuminate how treatment norms develop on the ground and thus can theoretically develop our understanding of the mechanisms associated with increasingly ‘aggressive organ harvesting’.

[The relationship between reactive/proactive aggression, callous/unemotional traits and behavioural problems in Hungarian adolescents].

PubMed

Bozsik, Csilla; Körmendi, Attila; Inántsy-Pap, Judit; Pataky, Nóra; Gádoros, Júlia; Halász, József

2013-01-01

The relationship between the type of physical aggressive behavior, callous/unemotional traits and behavioral problems was extensively studied in the literature, but no similar data exist in Hungarian adolescents. In the present study, the type of aggressive behavior was assessed in adolescents on a normative sample to study its relationship with callous/unemotional traits and behavioral problems. 223 students were participated in the study after informed consent (girls, n=106, age: 14.2±1.5 years; boys, n=117, age: 13.9±1.6 years) from primary and secondary schools in Miskolc and adjacent areas. The Reactive/Proactive Aggression Questionnaire was used to assess the level of aggressive behavior, the Inventory of Callous Unemotional Traits was used to measure callous/unemotional traits, while behavioral problems were established by the means of the Strengths and Difficulties Questionnaire. In the present non-clinical sample, the level of reactive aggression was higher than the level of proactive aggressive behavior. In boys, proactive and total aggression measures were significantly higher compared to girls. In both genders, reactive aggression was specifically associated with emotional and peer-related problems. Proactive aggression was correlated positively with callous traits in both genders, while self-reported prosocial behavior had an inverse correlation with proactive aggressive behavior in boys. Self reported conduct- and hyperactivity problems were positively correlated with both types of aggressive behavior in both genders. The strongest positive correlation was observed between self-reported conduct symptoms and both types of aggressive behavior. Callous/unemotional traits were related with proactive forms of aggression, similar to literature data. Reactive aggressive behavior was related to peer-related and emotional problems, thus our data outlined the importance of the distinction between the two main types of aggression.

Long-term programing of psychopathology-like behaviors in male rats by peripubertal stress depends on individual's glucocorticoid responsiveness to stress.

PubMed

Walker, Sophie E; Sandi, Carmen

2018-02-07

Experience of adversity early in life and dysregulation of hypothalamus-pituitary-adrenocortical (HPA) axis activity are risk factors often independently associated with the development of psychopathological disorders, including depression, PTSD and pathological aggression. Additional evidence suggests that in combination these factors may interact to shape the development and expression of psychopathology differentially, though little is known about underlying mechanisms. Here, we studied the long-term consequences of early life stress exposure on individuals with differential constitutive glucocorticoid responsiveness to repeated stressor exposure, assessing both socio-affective behaviors and brain activity in regions sensitive to pathological alterations following stress. Two rat lines, genetically selected for either low or high glucocorticoid responsiveness to repeated stress were exposed to a series of unpredictable, fear-inducing stressors on intermittent days during the peripuberty period. Results obtained at adulthood indicated that having high glucocorticoid responses to repeated stress and having experience of peripuberty stress independently enhanced levels of psychopathology-like behaviors, as well as increasing basal activity in several prefrontal and limbic brain regions in a manner associated with enhanced behavioral inhibition. Interestingly, peripuberty stress had a differential impact on aggression in the two rat lines, enhancing aggression in the low-responsive line but not in the already high-aggressive, high-responsive rats. Taken together, these findings indicate that aberrant HPA axis activity around puberty, a key period in the development of social repertoire in both rats and humans, may alter behavior such that it becomes anti-social in nature.

A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors.

PubMed

Staal, Jerome A; Pei, Yanxin; Rood, Brian R

2016-10-19

Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC -amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities.

Physical interventions to manage patients with brain injury: an audit on its use and staff and patient injuries from the techniques.

PubMed

Stubbs, Brendon; Alderman, Nick

2008-08-01

To report the use of physical interventions (PI) used to manage aggressive behaviour in a neurobehavioural unit and any injuries that were sustained to patients and staff during its implementation. A retrospective audit was adopted utilizing a standard accident and incident recording database. Records of PI utilized to manage the aggressive behaviour of 75 adults with acquired brain injury were analysed over the course of one calendar year. In addition duration PI, frequency of use and injuries sustained to staff and patients from its application were investigated. During the 12 month period records were audited, PI was used on 1427 occasions. The majority (90.1%) lasted less than 10 minutes. Injury rates to patients (0.98%) and staff (6.5%) were both considerably lower than those rates reported for other clinical populations. Use of PI with people who have an acquired brain injury is particularly challenging due to complex patterns of physical impairment that can be an outcome of this condition. This study describes how a multidisciplinary approach to the application of PI and the contribution of the physiotherapist in particular can result in comparatively low injury rates.

Core Canonical Pathways Involved in Developing Human Glioblastoma Multiforme (GBM).

PubMed

Ghosh, Somiranjan; Dutta, Sisir; Thorne, Gabriel; Boston, Ava; Barfield, Alexis; Banerjee, Narendra; Walker, Rayshawn; Banerjee, Hirendra Nath

2017-02-01

Glioblastoma multiforme (GBM) is the most common and aggressive type of the primary brain tumors with pathologic hallmarks of necrosis and vascular proliferation. The diagnosis of GBM is currently mostly based on histological examination of brain tumor tissues, after radiological characterization and surgical biopsy. The ability to characterize tumors comprehensively at the molecular level raises the possibility that diagnosis can be made based on molecular profiling with or without histological examination, rather than solely on histological phenotype. The development of novel genomic and proteomic techniques will foster in the identification of such diagnostic and prognostic molecular markers. We analyzed the global differential gene expression of a GBM cell line HTB15 in comparison to normal human Astrocytes, and established a few canonical pathways that are important in determining the molecular mechanisms of cancer using global gene expression microarray, coupled with the Ingenuity Pathway Analysis ( IPA ®). Overall, we revealed a discrete gene expression profile in the experimental model that resembled progression of GBM cancer. The canonical pathway analysis showed the involvement of genes that differentially expressed in such a disease condition that included Inositol pathway, Polo like kinases, nNOS signaling , and Tetrapyrrole biosynthesis . Our findings established that the gene expression pattern of this dreaded brain cancer will probably help the cancer research community by finding out newer therapeutic strategies to combat this dreaded cancer type that leads to the identification of high-risk population in this category, with almost hundred percent mortality rate.

'Roid rage in rats? Testosterone effects on aggressive motivation, impulsivity and tyrosine hydroxylase.

PubMed

Wood, Ruth I; Armstrong, Abigail; Fridkin, Vlad; Shah, Vivek; Najafi, Allison; Jakowec, Michael

2013-02-17

In humans and animals, anabolic-androgenic steroids (AAS) increase aggression, but the underlying behavioral mechanisms are unclear. AAS may increase the motivation to fight. Alternatively, AAS may increase impulsive behavior, consistent with the popular image of 'roid rage. To test this, adolescent male rats were treated chronically with testosterone (7.5mg/kg) or vehicle and tested for aggressive motivation and impulsivity. Rats were trained to respond on a nose-poke on a 10 min fixed-interval schedule for the opportunity to fight in their home cage with an unfamiliar rat. Although testosterone increased aggression (6.3±1.3 fights/5 min vs 2.4±0.8 for controls, p<0.05), there was no difference in operant responding (28.4±1.6 nose-pokes/10 min for testosterone, 32.4±7.0 for vehicle). This suggests that testosterone does not enhance motivation for aggression. To test for impulsivity, rats were trained to respond for food in a delay-discounting procedure. In an operant chamber, one lever delivered one food pellet immediately, the other lever gave 4 pellets after a delay (0, 15, 30 or 45 s). In testosterone- and vehicle-treated rats, body weights and food intake did not differ. However, testosterone-treated rats chose the larger, delayed reward more often (4.5±0.7 times in 10 trials with 45 s delay) than vehicle controls (2.5±0.5 times, p<0.05), consistent with a reduction in impulsive choice. Thus, although chronic high-dose testosterone enhances aggression, this does not include an increase in impulsive behavior or motivation to fight. This is further supported by measurement of tyrosine hydroxylase (TH) by Western immunoblot analysis in brain regions important for motivation (nucleus accumbens, Acb) and executive function (medial prefrontal cortex, PFC). There were no differences in TH between testosterone- and vehicle-treated rats in Acb or PFC. However, testosterone significantly reduced TH (to 76.9±3.1% of controls, p<0.05) in the caudate-putamen, a brain area important for behavioral inhibition, motor control and habit learning. Copyright © 2013 Elsevier Inc. All rights reserved.

‘Roid rage in rats? Testosterone effects on aggressive motivation, impulsivity and tyrosine hydroxylase

PubMed Central

Wood, Ruth I.; Armstrong, Abigail; Fridkin, Vlad; Shah, Vivek; Najafi, Allison; Jakowec, Michael

2013-01-01

In humans and animals, anabolic-androgenic steroids (AAS) increase aggression, but the underlying behavioral mechanisms are unclear. AAS may increase the motivation to fight. Alternatively, AAS may increase impulsive behavior, consistent with the popular image of ‘roid rage. To test this, adolescent male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle and tested for aggressive motivation and impulsivity. Rats were trained to respond on a nose-poke on a 10 min fixed-interval schedule for the opportunity to fight in their home cage with an unfamiliar rat. Although testosterone increased aggression (6.3±1.3 fights/5 min vs 2.4±0.8 for controls, p<0.05), there was no difference in operant responding (28.4±1.6 nose-pokes/ 10 min for testosterone, 32.4±7.0 for vehicle). This suggests that testosterone does not enhance motivation for aggression. To test for impulsivity, rats were trained to respond for food in a delay-discounting procedure. In an operant chamber, one lever delivered one food pellet immediately, the other lever gave 4 pellets after a delay (0, 15, 30 or 45 s). In testosterone- and vehicle-treated rats, body weights and food intake did not differ. However, testosterone-treated rats chose the larger, delayed reward more often (4.5±0.7 times in 10 trials with 45 s delay) than vehicle controls (2.5±0.5 times, p<0.05), consistent with a reduction in impulsive choice. Thus, although chronic high-dose testosterone enhances aggression, this does not include an increase in impulsive behavior or motivation to fight. This is further supported by measurement of tyrosine hydroxylase (TH) by Western immunoblot analysis in brain regions important for motivation (nucleus accumbens, Acb) and executive function (medial prefrontal cortex, PFC). There were no differences in TH between testosterone- and vehicle-treated rats in Acb or PFC. However, testosterone significantly reduced TH (to 76.9±3.1% of controls, p<0.05) in the caudate-putamen, a brain area important for behavioral inhibition, motor control and habit learning. PMID:23266798

Inhibiting 4EBP1 in Glioblastoma. | Office of Cancer Genomics

Cancer.gov

Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the PI3K-mTOR pathway. Although a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma.

Combination radiotherapy in an orthotopic mouse brain tumor model.

PubMed

Kramp, Tamalee R; Camphausen, Kevin

2012-03-06

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 μl every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

A multicenter study of primary brain tumor incidence in Australia (2000–2008)

PubMed Central

Dobes, Martin; Shadbolt, Bruce; Khurana, Vini G.; Jain, Sanjiv; Smith, Sarah F.; Smee, Robert; Dexter, Mark; Cook, Raymond

2011-01-01

There are conflicting reports from Europe and North America regarding trends in the incidence of primary brain tumor, whereas the incidence of primary brain tumors in Australia is currently unknown. We aimed to determine the incidence in Australia with age-, sex-, and benign-versus-malignant histology-specific analyses. A multicenter study was performed in the state of New South Wales (NSW) and the Australian Capital Territory (ACT), which has a combined population of >7 million with >97% rate of population retention for medical care. We retrospectively mined pathology databases servicing neurosurgical centers in NSW and ACT for histologically confirmed primary brain tumors diagnosed from January 2000 through December 2008. Data were weighted for patient outflow and data completeness. Incidence rates were age standardized and trends analyzed using joinpoint analysis. A weighted total of 7651 primary brain tumors were analyzed. The overall US-standardized incidence of primary brain tumors was 11.3 cases 100 000 person-years (±0.13; 95% confidence interval, 9.8–12.3) during the study period with no significant linear increase. A significant increase in primary malignant brain tumors from 2000 to 2008 was observed; this appears to be largely due to an increase in malignant tumor incidence in the ≥65-year age group. This collection represents the most contemporary data on primary brain tumor incidence in Australia. Whether the observed increase in malignant primary brain tumors, particularly in persons aged ≥65 years, is due to improved detection, diagnosis, and care delivery or a true change in incidence remains undetermined. We recommend a direct, uniform, and centralized approach to monitoring primary brain tumor incidence that can be independent of multiple interstate cancer registries. PMID:21727214

Third International Congress on Epilepsy, Brain, and Mind: Part 2.

PubMed

Rektor, Ivan; Schachter, Steven C; Arya, Ravindra; Arzy, Shahar; Braakman, Hilde; Brodie, Martin J; Brugger, Peter; Chang, Bernard S; Guekht, Alla; Hermann, Bruce; Hesdorffer, Dale C; Jones-Gotman, Marilyn; Kanner, Andres M; Garcia-Larrea, Luis; Mareš, Pavel; Mula, Marco; Neufeld, Miri; Risse, Gail L; Ryvlin, Philippe; Seeck, Margitta; Tomson, Torbjörn; Korczyn, Amos D

2015-09-01

Epilepsy is both a disease of the brain and the mind. Here, we present the second of two papers with extended summaries of selected presentations of the Third International Congress on Epilepsy, Brain and Mind (April 3-5, 2014; Brno, Czech Republic). Humanistic, biologic, and therapeutic aspects of epilepsy, particularly those related to the mind, were discussed. The extended summaries provide current overviews of epilepsy, cognitive impairment, and treatment, including brain functional connectivity and functional organization; juvenile myoclonic epilepsy; cognitive problems in newly diagnosed epilepsy; SUDEP including studies on prevention and involvement of the serotoninergic system; aggression and antiepileptic drugs; body, mind, and brain, including pain, orientation, the "self-location", Gourmand syndrome, and obesity; euphoria, obsessions, and compulsions; and circumstantiality and psychiatric comorbidities. Copyright © 2015 Elsevier Inc. All rights reserved.

Too Little? Too Much? Primary care physicians' views on US health care: a brief report.

PubMed

Sirovich, Brenda E; Woloshin, Steven; Schwartz, Lisa M

2011-09-26

Some believe that a substantial amount of US health care is unnecessary, suggesting that it would be possible to control costs without rationing effective services. The views of primary care physicians-the frontline of health care delivery-are not known. Between June and December 2009, we conducted a nationally representative mail survey of US primary care physicians (general internal medicine and family practice) randomly selected from the American Medical Association Physician Masterfile (response rate, 70%; n=627). Forty-two percent of US primary care physicians believe that patients in their own practice are receiving too much care; only 6% said they were receiving too little. The most important factors physicians identified as leading them to practice more aggressively were malpractice concerns (76%), clinical performance measures (52%), and inadequate time to spend with patients (40%). Physicians also believe that financial incentives encourage aggressive practice: 62% said diagnostic testing would be reduced if it did not generate revenue for medical subspecialists (39% for primary care physicians). Almost all physicians (95%) believe that physicians vary in what they would do for identical patients; 76% are interested in learning how aggressive or conservative their own practice style is compared with that of other physicians in their community. Many US primary care physicians believe that their own patients are receiving too much medical care. Malpractice reform, realignment of financial incentives, and more time with patients could remove pressure on physicians to do more than they feel is needed. Physicians are interested in feedback on their practice style, suggesting they may be receptive to change. clinicaltrials.gov Identifier: NCT00853918.

Too Little? Too Much? Primary Care Physicians’ Views on US Health Care

PubMed Central

Sirovich, Brenda E.; Woloshin, Steven; Schwartz, Lisa M.

2011-01-01

Background Some believe that a substantial amount of US health care is unnecessary, suggesting that it would be possible to control costs without rationing effective services. The views of primary care physicians—the frontline of health care delivery—are not known. Methods Between June and December 2009, we conducted a nationally representative mail survey of US primary care physicians (general internal medicine and family practice) randomly selected from the American Medical Association Physician Masterfile (response rate, 70%; n=627). Results Forty-two percent of US primary care physicians believe that patients in their own practice are receiving too much care; only 6% said they were receiving too little. The most important factors physicians identified as leading them to practice more aggressively were malpractice concerns (76%), clinical performance measures (52%), and inadequate time to spend with patients (40%). Physicians also believe that financial incentives encourage aggressive practice: 62% said diagnostic testing would be reduced if it did not generate revenue for medical subspecialists (39% for primary care physicians). Almost all physicians (95%) believe that physicians vary in what they would do for identical patients; 76% are interested in learning how aggressive or conservative their own practice style is compared with that of other physicians in their community. Conclusions Many US primary care physicians believe that their own patients are receiving too much medical care. Malpractice reform, realignment of financial incentives, and more time with patients could remove pressure on physicians to do more than they feel is needed. Physicians are interested in feedback on their practice style, suggesting they may be receptive to change. PMID:21949169

Association between oxytocin and receptor genetic polymorphisms and aggression in a northern Chinese Han population with alcohol dependence.

PubMed

Yang, Ling; Wang, Fan; Wang, Meiling; Han, Mei; Hu, Lufeng; Zheng, Minghua; Ma, Ji; Kang, Yimin; Wang, Pengxiang; Sun, Hongqiang; Zuo, Wei; Xie, Longteng; Wang, Aiju; Yu, Dongsheng; Liu, Yanlong

2017-01-01

Alcohol dependence (AD) is a common chronic brain disorder precipitated by complex interactions between biological, genetic, and environmental risk factors. Aggression often occurs in the context of AD. Previous studies have shown that Oxytocin (OXT) and OXT receptor (OXTR) are involved in the regulation of aggression. The present study investigated whether variations and interactions of OXT and OXTR genes were associated with AD-related aggression in a genetically homogeneous northern Chinese Han population. Three hundred and twenty-four male AD patients and 510 male healthy controls (HCs) were recruited. A Chinese version of the Buss-Perry Aggression Questionnaire was used as a subjective measurement of aggressive behavior. Three variations, rs2254298, rs53576, and rs6133010 were genotyped using TaqMan and ligase detection reaction for all subjects. Generalized Multifactor Dimensionality Reduction was used to detect interactions between genetic attributes and environmental attributes. The frequencies of alleles and genotypes of rs6133010 were significantly different between AD patients and HCs (p<0.001). In HCs, the effect of genotype GG of rs53576 on hostility aggression was significantly stronger than that of genotype AA and AG (p=0.001 and p=0.004, respectively), and the subjects with the interaction combination of rs6133010AA×rs2254298GG×rs53576AG exhibited significant effect on physical aggression (p=0.0107). The present study found that rs6133010 in the OXT gene is associated with AD in the northern Chinese Han population. The polymorphisms of OXT/R may play a key role in the susceptibility of AD-related aggression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

MAOA genotype, social exclusion and aggression: an experimental test of a gene-environment interaction.

PubMed

Gallardo-Pujol, D; Andrés-Pueyo, A; Maydeu-Olivares, A

2013-02-01

In 2002, Caspi and colleagues provided the first epidemiological evidence that genotype may moderate individuals' responses to environmental determinants. However, in a correlational study great care must be taken to ensure the proper estimation of the causal relationship. Here, a randomized experiment was performed to test the hypothesis that the MAOA gene promoter polymorphism (MAOA-LPR) interacts with environmental adversity in determining aggressive behavior using laboratory analogs of real-life conditions. A sample of 57 Caucasian male students of Catalan and Spanish origin was recruited at the University of Barcelona. Ostracism, or social exclusion, was induced as environmental adversity using the Cyberball software. Laboratory aggression was assessed with the Point Subtraction Aggression Paradigm (PSAP), which was used as an analog of antisocial behavior. We also measured aggressiveness by means of the reduced version of the Aggression Questionnaire. The MAOA-LPR polymorphism showed a significant effect on the number of aggressive responses in the PSAP (F(1,53) = 4.63, P = 0.03, partial η(2) = 0.08), as well as social exclusion (F(1,53) = 8.03, P = 0.01, partial η(2) = 0.13). Most notably, however, we found that the MAOA-LPR polymorphism interacts significantly with social exclusion in order to provoke aggressive behavior (F(1,53) = 4.42, P = 0.04, partial η(2) = 0.08), remarkably, the low-activity allele of the MAOA-LPR polymorphism carriers in the ostracized group show significantly higher aggression scores than the rest. Our results support the notion that gene-environment interactions can be successfully reproduced within a laboratory using analogs and an appropriate design. We provide guidelines to test gene-environment interactions hypotheses under controlled, experimental settings. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Effects of paternal and peripubertal stress on aggression, anxiety, and metabolic alterations in the lateral septum.

PubMed

Cordero, M I; Just, N; Poirier, G L; Sandi, C

2016-02-01

Early-life stress and biological predispositions are linked to mood and personality disorders related to aggressive behavior. We previously showed that exposure to peripubertal stress leads to increased anxiety-like behaviors and aggression against males and females, as well as increased aggression against females in their male offspring. Here, we investigated whether paternal (pS) and individual (iS) exposure to peripubertal stress may exert additive effects on the long-term programming of anxiety-like and aggressive behaviors in rats. Given the key role of the lateral septum (LS) in the regulation of anxiety and aggressive behaviors and the hypothesized alterations in balance between neural excitation and inhibition in aggression-related disorders, markers for these processes were examined in the LS. Peripubertal stress was applied both in naïve male rats and in the offspring of peripubertally stressed males, and anxiety-like and aggressive behaviors were assessed at adulthood. Proton magnetic resonance spectroscopy at 6-months, and post-mortem analysis of glutamic acid decarboxylase 67 (GAD67) at 12-months were conducted in LS. We confirmed that aggressive behavior was increased by pS and iS, while only iS increased anxiety-like behavior. Individual stress led to reduced GABA, confirmed by reduced GAD67 immunolabelling, and increased glutamate, N-acetyl-aspartate, phosphocholine and creatine; while pS specifically led to reduced phosphocreatine. pS and iS do not interact and exert a differential impact on the analyzed aspects of brain function and anxiety-like behaviors. These data support the view that early-life stress can affect the behavioral and neurodevelopmental trajectories of individuals and their offspring, which may involve different neurobiological mechanisms. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Candidate genes for cooperation and aggression in the social wasp Polistes dominula.

PubMed

Manfredini, Fabio; Brown, Mark J F; Toth, Amy L

2018-05-01

Cooperation and aggression are ubiquitous in social groups, and the genetic mechanisms underlying these behaviours are of great interest for understanding how social group formation is regulated and how it evolves. In this study, we used a candidate gene approach to investigate the patterns of expression of key genes for cooperation and aggression in the brain of a primitively eusocial wasp, Polistes dominula, during colony founding, when multiple foundresses can join the same nest and establish subtle hierarchies of dominance. We used a comparative approach to select candidate genes for cooperation and aggression looking at two previously published studies on global gene expression in wasps and ants. We tested the expression of these genes in P. dominula wasps that were either displaying aggressive behaviour (dominant and single foundresses) or cooperation (subordinate foundresses and workers) towards nestmates. One gene in particular, the egg yolk protein vitellogenin, known for its reproductive role in insects, displayed patterns of expression that strongly matched wasp social rank. We characterize the genomic context of vitellogenin by building a head co-expression gene network for P. dominula, and we discuss a potential role for vitellogenin as a mediator of social interactions in wasps.

Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

PubMed Central

Santagata, Sandro; Cahill, Daniel P.; Taylor-Weiner, Amaro; Jones, Robert T.; Van Allen, Eliezer M.; Lawrence, Michael S.; Horowitz, Peleg M.; Cibulskis, Kristian; Ligon, Keith L.; Tabernero, Josep; Seoane, Joan; Martinez-Saez, Elena; Curry, William T.; Dunn, Ian F.; Paek, Sun Ha; Park, Sung-Hye; McKenna, Aaron; Chevalier, Aaron; Rosenberg, Mara; Barker, Frederick G.; Gill, Corey M.; Van Hummelen, Paul; Thorner, Aaron R.; Johnson, Bruce E.; Hoang, Mai P.; Choueiri, Toni K.; Signoretti, Sabina; Sougnez, Carrie; Rabin, Michael S.; Lin, Nancy U.; Winer, Eric P.; Stemmer-Rachamimov, Anat; Meyerson, Matthew; Garraway, Levi; Gabriel, Stacey; Lander, Eric S.; Beroukhim, Rameen; Batchelor, Tracy T.; Baselga, Jose; Louis, David N.

2016-01-01

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. PMID:26410082

Profiles of Brain Metastases: Prioritization of Therapeutic Targets.

PubMed

Ferguson, Sherise D; Zheng, Siyuan; Xiu, Joanne; Zhou, Shouhao; Khasraw, Mustafa; Brastianos, Priscilla K; Kesari, Santosh; Hu, Jethro; Rudnick, Jeremy; Salacz, Michael E; Piccioni, David; Huang, Suyun; Davies, Michael A; Glitza, Isabella C; Heymach, John V; Zhang, Jianjun; Ibrahim, Nuhad K; DeGroot, John F; McCarty, Joseph; O'Brien, Barbara J; Sawaya, Raymond; Verhaak, Roeland G W; Reddy, Sandeep K; Priebe, Waldemar; Gatalica, Zoran; Spetzler, David; Heimberger, Amy B

2018-06-19

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of non-small cell lung cancer, breast cancer, and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry), and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification, and mutations among brain metastases, extracranial metastases, and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8178 non-small cell lung cancers (5098 primaries; 2787 systemic metastases; 293 brain metastases), 7064 breast cancers (3496 primaries; 3469 systemic metastases; 99 brain metastases), and 1757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1, and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication, and/or repair. This article is protected by copyright. All rights reserved. © 2018 UICC.

High CD49f expression is associated with osteosarcoma tumor progression: a study using patient-derived primary cell cultures.

PubMed

Penfornis, Patrice; Cai, David Z; Harris, Michael R; Walker, Ryan; Licini, David; Fernandes, Joseph D A; Orr, Griffin; Koganti, Tejaswi; Hicks, Chindo; Induru, Spandana; Meyer, Mark S; Khokha, Rama; Barr, Jennifer; Pochampally, Radhika R

2014-08-01

Overall prognosis for osteosarcoma (OS) is poor despite aggressive treatment options. Limited access to primary tumors, technical challenges in processing OS tissues, and the lack of well-characterized primary cell cultures has hindered our ability to fully understand the properties of OS tumor initiation and progression. In this study, we have isolated and characterized cell cultures derived from four central high-grade human OS samples. Furthermore, we used the cell cultures to study the role of CD49f in OS progression. Recent studies have implicated CD49f in stemness and multipotency of both cancer stem cells and mesenchymal stem cells. Therefore, we investigated the role of CD49f in osteosarcomagenesis. First, single cell suspensions of tumor biopsies were subcultured and characterized for cell surface marker expression. Next, we characterized the growth and differentiation properties, sensitivity to chemotherapy drugs, and anchorage-independent growth. Xenograft assays showed that cell populations expressing CD49f(hi) /CD90(lo) cell phenotype produced an aggressive tumor. Multiple lines of evidence demonstrated that inhibiting CD49f decreased the tumor-forming ability. Furthermore, the CD49f(hi) /CD90(lo) cell population is generating more aggressive OS tumor growth and indicating this cell surface marker could be a potential candidate for the isolation of an aggressive cell type in OSs. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Primary intra-abdominal malignant fibrous histiocytoma: a highly aggressive tumor.

PubMed

Salemis, Nikolaos S; Gourgiotis, Stavros; Tsiambas, Evangelos; Panagiotopoulos, Nikolaos; Karameris, Andreas; Tsohataridis, Efstathios

2010-12-01

Malignant fibrous histiocytoma (MFH) is the most common soft-tissue sarcoma of late adult life occurring predominantly in the extremities. Primary intra-abdominal MFH is a very rare occurrence. The aim of this study is to describe a very rare case of an intra-abdominal MFH with a highly aggressive clinical course. A 67-year-old male was referred to our department with a 2-week history of dull lower abdominal pain and a gradually enlarging right lower abdominal mass, which he first noticed 2 months prior to admission. Computed tomography (CT) scan demonstrated a mass in the right iliac fossa. On exploratory laparotomy, a tumor was found in the right iliac fossa attached to the parietal lateral peritoneum without any evidence of invasion into the adjacent structures. Complete excision of the tumor with clear margins was performed. Histological and immunohistochemical examinations showed a MFH. One month after surgery, while on adjuvant chemotherapy, the patient was readmitted with dyspnea and a slightly palpable mass in the area of the previous radical resection. CT scan revealed local tumor recurrence along with multiple pulmonary metastatic deposits. Unfortunately, despite treatment, the patient died of progressive disease 5 weeks later. Primary intra-abdominal MFH is a very rare but aggressive malignancy with a high tendency of local recurrence and metastatic spread. Early detection and complete surgical excision with clear margins is the treatment of choice. In some cases, however, the tumor can exhibit a highly aggressive clinical course despite radical surgery and adjuvant therapy.

A brief program improves counseling of mothers with children who have persistent aggression.

PubMed

Scholer, Seth J; Reich, Stephanie M; Boshers, Robyn B; Bickman, Len

2012-04-01

To assess whether a multimedia program can affect counseling behavior related to one of the strongest risk factors for violence later in life, persistent early childhood aggression. The design was a controlled trial with unobtrusive measurement in a clinic setting. A researcher, pretending to be the mother of a 2 ½ year old boy, called 19 pediatric residents during clinic hours and requested advice on how to manage her child's persistently hurtful behavior. The intervention was a 40-min lecture focusing on a multimedia program, Play Nicely, which teaches accepted strategies for managing aggression in young children ages 1-7 years. Residents' responses were blindly assessed to determine the treatment effect of the intervention. Compared with the control group (C), residents in the intervention (I) group were more likely to recommend setting the rule (I: 100% vs. C: 31%, p = .01), redirecting (I: 83% vs. C: 8%, p = .003), promoting empathy (I: 50% vs. C: 0%, p = .02), and more likely to discourage the use of physical punishment (I: 83% vs. C: 31%). These are the primary strategies encouraged by the intervention. The magnitude of the effect size was very large for each of these three strategies, ranging from d = 1.1 to 2.3. A brief intervention can improve the counseling behavior of primary care physicians regarding persistent childhood aggression. The findings have implications for child abuse prevention, violence prevention, medical education, and how to improve anticipatory guidance within primary care.

Aggression in Primary Schools: The Predictive Power of the School and Home Environment

ERIC Educational Resources Information Center

Kozina, Ana

2015-01-01

In this study, we analyse the predictive power of home and school environment-related factors for determining pupils' aggression. The multiple regression analyses are performed for fourth- and eighth-grade pupils based on the Trends in Mathematics and Science Study (TIMSS) 2007 (N = 8394) and TIMSS 2011 (N = 9415) databases for Slovenia. At the…

The role of monoamine oxidase A in aggression: current translational developments and future challenges

PubMed Central

Godar, Sean C; Fite, Paula J; McFarlin, Kenneth M; Bortolato, Marco

2016-01-01

Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner’s discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment. PMID:26776902

Corticotropin releasing factor influences aggression and monoamines: Modulation of attacks and retreats

PubMed Central

Carpenter, Russ E.; Korzan, Wayne J.; Bockholt, Craig; Watt, Michael J.; Forster, Gina L.; Renner, Kenneth J.; Summers, Cliff H.

2009-01-01

Salmonids establish social hierarchies as a result of aggressive social interactions. The establishment of dominant or subordinate status is strongly linked to neuroendocrine responses mediated through the stress axis. In this study, we tested the effects of icv CRF on the behavioral outcome, plasma cortisol and monoamine function in trout subjected to a socially aggressive encounter. Rainbow trout were treated with an icv injection of artificial cerebrospinal fluid (aCSF), 500 or 2000 ng ovine CRF, or not injected. Fish were allowed to interact with a similarly sized conspecific for 15 minutes. Following the behavioral interaction, plasma cortisol and central monoamine concentrations were analyzed. Trout treated with CRF were victorious in approximately 60% of the aggressive encounters against aCSF treated opponents. Trout injected with CRF exhibited a reduction in the total number of attacks and decreased latency to attack. When trout were divided winners and losers, only victorious CRF-treated fish exhibited a reduced latency to attack and fewer retreats. Social stress increased cortisol levels in both winners and losers of aggressive interaction. This effect was enhanced with the additional stress incurred from icv injection of aCSF. However, icv CRF in addition to social stress decreased plasma cortisol in both winners and losers. While aggression stimulated significant changes in serotonergic and dopaminergic activity, the magnitude and direction were dependent on limbic brain region, CRF dose, and outcome of social aggression. With broad effects on aggressive behavior, anxiety, stress responsiveness, and central monoaminergic activity, CRF plays an important role modulating the behavioral components of social interaction. PMID:18992791

The role of monoamine oxidase A in aggression: Current translational developments and future challenges.

PubMed

Godar, Sean C; Fite, Paula J; McFarlin, Kenneth M; Bortolato, Marco

2016-08-01

Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner's discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantitative MRI study of the permeability of peritumoral brain edema in lung cancer patients with brain metastases.

PubMed

Wang, Dan; Wang, Ming-Liang; Li, Yue-Hua

2017-08-15

To use Ktrans to evaluate the aggressiveness and vascular permeability of peritumoral edema in cases of lung cancer brain metastases. A total of 68 lung cancer patients with 92 metastatic brain lesions were enrolled (20 metastatic lesions only in the gray matter - group 1; and 72 metastatic lesions located in the gray and white matter junction - group 2). All patients underwent MRI examination, which involved a dual angle (2° and 15°) enhanced T1W-VIBE (volume interpolated breath-hold examination) sequence to calculate the T1 parameter map. We used the enhanced T1-3D sequence to measure the tumor volume. The vascular permeability coefficient (Ktrans) was calculated using the single-compartment Tofts model, motion registration, and quick input mode. We examined the correlations of Ktrans with the edema index (EI), Ktrans with the tumor volume, and Ktrans with the histological expression of MMP-9 or VEGF in the original lung tumor using Pearson's' correlation analysis. Ktrans and EI were highly correlated in group 2 (r=0.66687; P<0.001) and not correlated in group 1 (r=0.33096; P=0.15405). Ktrans was also moderately related to the positive expression of MMP-9 (r=0.50912; P<0.001) and VEGF (r=0.36995; P=0.00138) There is statistical correlation between Ktrans and EI for group 2, and no statistical correlation between Ktrans and EI for group 1. The Ktrans of the peritumoral brain edema may be used to indicate the aggressiveness and vascular permeability of brain metastases in patients with lung cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Apomorphine and piribedil in rats: biochemical and pharmacologic studies.

PubMed

Butterworth, R F; Poignant, J C; Barbeau, A

1975-01-01

We studied the biochemical and pharmacologic modes of action of piribedil and apomorphine in the rat. Although both drugs have many points in common, they are also different in many of their manifestations. Apomorphine causes high-intensity, short-duration stereotyped behavior; it is distributed within the brain in uneven fashion, the striatum being the area of lowest concentration as measured by fluorometry. Direct stereotactic injection within the dopaminergic mesolimbic system, and particularly the tuberculum olfactorium, produced constant intense responses. All effects of apomorphine can be blocked by pimozide, but propanolol, a beta blocker, only reduces aggression and ferocity, leaving stereotyped behaviors intact. Finally, L-5-HTP tends to reduce aggression, ferocity, and to a lesser extent stereotypy; MIF or piribedil, as well as reserpine, potentiates the stereotyped behaviors induced by apomorphine, whereas L-DOPA usually decreases them. Piribedil, on the other hand, causes low-intensity, long-duration stereotyped behavior. It is distributed within the brain almost uniformly. Most effects of piribedil can be blocked by pimozide, but propanolol blocks only aggression and ferocity, leaving stereotyped behaviors intact. On the other hand, clonidine, an alpha-receptor agonist, blocks stereotyped behaviors induced by piribedil but markedly increases aggression, ferocity, and motor activity. L-5-HTP and L-DOPA have little effect on piribedil-induced manifestations. Reserpine decreases piribedil stereotypy. The main metabolite of piribedil, S 584, had no clear-cut pharmacologic action in our hands at the dosage used. It is concluded that both apomorphine and piribedil produce stereotyped behavior by modifying the physiologic balance between mesolimbic and nigrostriatal dopaminergic systems. The other actions of apomorphine and piribedil upon aggression, ferocity, and motor activity are not always in parallel and depend probably on the fact that piribedil is less specific, affecting also noradrenergic, serotonergic, histaminergic, and/or cholinergic circuits. The usefulness of piribedil against some forms of human tremor and its low-intensity antiakinetic action probably result from this pattern of pharmacologic activity.

No Effects of Bilateral tDCS over Inferior Frontal Gyrus on Response Inhibition and Aggression

PubMed Central

Lobbestael, Jill; Arntz, Arnoud; Brugman, Suzanne; Sack, Alexander T.

2015-01-01

Response inhibition is defined as the capacity to adequately withdraw pre-planned responses. It has been shown that individuals with deficits in inhibiting pre-planned responses tend to display more aggressive behaviour. The prefrontal cortex is involved in both, response inhibition and aggression. While response inhibition is mostly associated with predominantly right prefrontal activity, the neural components underlying aggression seem to be left-lateralized. These differences in hemispheric dominance are conceptualized in cortical asymmetry theories on motivational direction, which assign avoidance motivation (relevant to inhibit responses) to the right and approach motivation (relevant for aggressive actions) to the left prefrontal cortex. The current study aimed to directly address the inverse relationship between response inhibition and aggression by assessing them within one experiment. Sixty-nine healthy participants underwent bilateral transcranial Direct Current Stimulation (tDCS) to the inferior frontal cortex. In one group we induced right-hemispheric fronto-cortical dominance by means of a combined right prefrontal anodal and left prefrontal cathodal tDCS montage. In a second group we induced left-hemispheric fronto-cortical dominance by means of a combined left prefrontal anodal and right prefrontal cathodal tDCS montage. A control group received sham stimulation. Response inhibition was assessed with a go/no-go task (GNGT) and aggression with the Taylor Aggression Paradigm (TAP). We revealed that participants with poorer performance in the GNGT displayed more aggression during the TAP. No effects of bilateral prefrontal tDCS on either response inhibition or aggression were observed. This is at odds with previous brain stimulation studies applying unilateral protocols. Our results failed to provide evidence in support of the prefrontal cortical asymmetry model in the domain of response inhibition and aggression. The absence of tDCS effects might also indicate that the methodological approach of shifting cortical asymmetry by means of bilateral tDCS protocols has failed. PMID:26161664

Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive children with attention-deficit/hyperactivity disorder.

PubMed

Blader, Joseph C; Pliszka, Steven R; Kafantaris, Vivian; Foley, Carmel A; Crowell, Judith A; Carlson, Gabrielle A; Sauder, Colin L; Margulies, David M; Sinha, Christa; Sverd, Jeffrey; Matthews, Thomas L; Bailey, Brigitte Y; Daviss, W Burleson

2013-12-01

Stimulant treatment improves impulse control among children with attention-deficit/hyperactivity disorder (ADHD). Decreased aggression often accompanies stimulant pharmacotherapy, suggesting that impulsiveness is integral to aggressive behavior in these children. However, children with high callous-unemotional (CU) traits and proactive aggression may benefit less from ADHD pharmacotherapy, because their aggressive behavior seems more purposeful and deliberate. This study's objective was to determine whether pretreatment CU traits and proactive aggression affect treatment outcomes among aggressive children with ADHD receiving stimulant monotherapy. We implemented a stimulant optimization protocol with 160 children 6 to 13 years of age (mean [SD] age of 9.31 [2.02] years; 78.75% male) with ADHD, oppositional defiant or conduct disorder, and significant aggressive behavior. Family-focused behavioral intervention was provided concurrently. The primary outcome was the Retrospective Modified Overt Aggression Scale. The Antisocial Process Screening Device and the Aggression Scale, also completed by parents, measured CU traits and proactive aggression, respectively. Analyses examined moderating effects of CU traits and proactive aggression on outcomes. In all, 82 children (51%) experienced remission of aggressive behavior. Neither CU traits nor proactive aggression predicted remission (CU traits: odds ratio [OR] = 0.94, 95% CI = 0.80-1.11; proactive aggression, OR = 1.05, 95% CI = 0.86-1.29). Children whose overall aggression remitted showed decreases in CU traits (effect size = -0.379, 95% CI = -0.60 to -0.16) and proactive aggression (effect size = -0.463, 95% CI = -0.69 to -0.23). Findings suggest that pretreatment CU traits and proactive aggression do not forecast worse outcomes for aggressive children with ADHD receiving optimized stimulant pharmacotherapy. With such treatment, CU traits and proactive aggression may decline alongside other behavioral improvements. Clinical trial registration information--Medication Strategies for Treating Aggressive Behavior in Youth With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00228046; and Effectiveness of Combined Medication Treatment for Aggression in Children With Attention Deficit With Hyperactivity Disorder (The SPICY Study); http://clinicaltrials.gov/; NCT00794625. Copyright © 2013 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Curvularia brain abscess.

PubMed

Gadgil, Nisha; Kupferman, Michael; Smitherman, Sheila; Fuller, Gregory N; Rao, Ganesh

2013-01-01

Curvularia is a ubiquitous dematiaceous fungus that is a very rare but often fatal cause of infection in the central nervous system (CNS). In this report, we describe a patient with chronic sinusitis who presented with a Curvularia abscess of the skull base extending into the left frontal lobe. She was successfully treated with aggressive surgical resection and antibiotic therapy. In the published literature, this patient to our knowledge represents the longest period of disease-free follow-up in those afflicted with CNS Curvularia infection, indicating the importance of proper diagnosis and aggressive surgical debridement for a successful outcome. Copyright © 2012 Elsevier Ltd. All rights reserved.

Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells.

PubMed

Chou, Yu-Cheng; Chang, Meng-Ya; Wang, Mei-Jen; Liu, Hsin-Chung; Chang, Shu-Jen; Harnod, Tomor; Hung, Chih-Huang; Lee, Hsu-Tung; Shen, Chiung-Chyi; Chung, Jing-Gung

2017-01-01

Glioblastoma is the most common and aggressive primary brain malignancy. Phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, can induce apoptosis in many human cancer cells. Our previous study disclosed that PEITC induces apoptosis through the extrinsic pathway, dysfunction of mitochondria, reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress, and intrinsic (mitochondrial) pathway in human brain glioblastoma multiforme (GBM) 8401 cells. To the best of our knowledge, we first investigated the effects of PEITC on the genetic levels of GBM 8401 cells in vitro. PEITC may induce G0/G1 cell-cycle arrest through affecting the proteins such as cdk2, cyclin E, and p21 in GBM 8401 cells. Many genes associated with cell-cycle regulation of GBM 8401 cells were changed after PEITC treatment: 48 genes were upregulated and 118 were downregulated. The cell-division cycle protein 20 (CDC20), Budding uninhibited by benzimidazole 1 homolog beta (BUB1B), and cyclin B1 were downregulated, and clusterin was upregulated in GBM 8401 cells treated with PEITC. These changes of gene expression can provide the effects of PEITC on the genetic levels and potential biomarkers for glioblastoma. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 176-187, 2017. © 2015 Wiley Periodicals, Inc.

Arterial spin labeling MR imaging aids to identify cortical venous drainage of dural arteriovenous fistulas.

PubMed

Kang, Ji Hee; Yun, Tae Jin; Rhim, Jong Kook; Cho, Young Dae; Yoo, Dong Hyun; Yoo, Roh-Eul; Kang, Koung Mi; Choi, Seung Hong; Kim, Ji-Hoon; Sohn, Chul-Ho; Han, Moon Hee

2018-05-01

Cortical venous drainage (CVD) increases the probability of intracranial hemorrhage and mortality rate of dural arteriovenous fistulas (DAVF). Although digital subtraction angiography (DSA) is the most accurate method to determine CVD in DAVFs, this modality has limitations due to its invasive nature and radiation issues. The purpose of this study was to evaluate the diagnostic utility of arterial spin-labeling perfusion-weighted images (ASL-PWI) to identify CVD in patients with DAVF.The Institutional Review Board of our hospital approved this retrospective study. ASL-PWI features of 22 patients with DAVF were retrospectively reviewed for the presence of bright signal intensity in cortical veins and brain parenchyma. DAVF with bright signal intensity in cortical veins and/or brain parenchyma was regarded as having CVD. Using DSA as a reference standard, sensitivity, specificity, positive predictive value, and negative predictive value of ASL-PWI for detecting CVD were calculated.Based on DSA features, 11 (11/22, 50%) patients were classified as having "aggressive" pattern with CVD. Eleven (11/22, 50%) patients also showed bright signal intensity in cortical veins (9/22, 41%) and/or brain parenchyma (4/22, 18%) on ASL-PWI. The 11 patients who had "Aggressive" pattern on DSA were the same 11 patients who were classified as having "aggressive" pattern on ASL-PWI. ASL-PWI showed perfect diagnostic performance for identifying CVD with sensitivity, specificity, positive predictive value, and negative predictive value of 100% for all.Thus, ASL-PWI could be used as a noninvasive mean to predict the presence of CVD in patients with DAVFs. It has the potential as a screening tool to evaluate DAVF prior to invasive DSA.

Violence against doctors, a serious concern for healthcare organizations to ponder about.

PubMed

Ahmed, Farah; Khizar Memon, Muhammad; Memon, Sidra

2018-01-01

Aggression and Violence against primary care physicians is reportedly common in Pakistan but there is no any documented study to-date on this burning issue. A formed written questionnaire was distributed among 769 primary care physicians aged 31 ± 7.68 years. Apart from the demographic data, the questionnaire included questions regarding the level of safety that primary care physicians felt during their work setups and on-call duties, along with the experience of aggression against them by the perpetrators & the support provided by the hospital management in such cases. Response rate was 68% i.e. 524 physicians agreed to participate in the study. It was found that majority (85%) of the physicians has faced mild events, 62% have faced moderate events and roughly 38% were subjected to severe violence. Some physicians revealed more than one form of aggression being faced by them in 12 months preceding months which makes the collective percentage greater than 100%. Verbal abuse is the most frequent type of mistreatment faced by the doctors from the patients or their attendants. A considerable number of physicians participated have faced mild violence in which verbal abuse was commonest; followed by moderate and severe events.

Effects of reducing children's television and video game use on aggressive behavior: a randomized controlled trial.

PubMed

Robinson, T N; Wilde, M L; Navracruz, L C; Haydel, K F; Varady, A

2001-01-01

The relationship between exposure to aggression in the media and children's aggressive behavior is well documented. However, few potential solutions have been evaluated. To assess the effects of reducing television, videotape, and video game use on aggressive behavior and perceptions of a mean and scary world. Randomized, controlled, school-based trial. Two sociodemographically and scholastically matched public elementary schools in San Jose, Calif. Third- and fourth-grade students (mean age, 8.9 years) and their parents or guardians. Children in one elementary school received an 18-lesson, 6-month classroom curriculum to reduce television, videotape, and video game use. In September (preintervention) and April (postintervention) of a single school year, children rated their peers' aggressive behavior and reported their perceptions of the world as a mean and scary place. A 60% random sample of children were observed for physical and verbal aggression on the playground. Parents were interviewed by telephone and reported aggressive and delinquent behaviors on the child behavior checklist. The primary outcome measure was peer ratings of aggressive behavior. Compared with controls, children in the intervention group had statistically significant decreases in peer ratings of aggression (adjusted mean difference, -2.4%; 95% confidence interval [CI], -4.6 to -0.2; P =.03) and observed verbal aggression (adjusted mean difference, -0.10 act per minute per child; 95% CI, -0.18 to -0.03; P =.01). Differences in observed physical aggression, parent reports of aggressive behavior, and perceptions of a mean and scary world were not statistically significant but favored the intervention group. An intervention to reduce television, videotape, and video game use decreases aggressive behavior in elementary schoolchildren. These findings support the causal influences of these media on aggression and the potential benefits of reducing children's media use.

Biological aspects of social bonding and the roots of human violence.

PubMed

Pedersen, Cort A

2004-12-01

The brain systems that motivate humans to form emotional bonds with others probably first evolved to mobilize the high-quality maternal care necessary for reproductive success in placental mammals. In these species, the helplessness of infants at birth and their dependence upon nutrition secreted from their mothers' bodies (milk) and parental body heat to stay warm required the evolution of a new motivational system in the brain to stimulate avid and sustained mothering behavior. Other types of social bonds that emerged subsequently in placental mammals, in particular monogamous bonds between breeding pairs, appear to have evolved from motivational brain systems that stimulate maternal behavior. This chapter focuses on aspects of the evolution and neurobiology of maternal and pair bonding and associated behavioral changes that may provide insights into the origins of human violence. The roles of the neuropeptides oxytocin and vasopressin as well as the neurotransmitter dopamine will be emphasized. Maternal and pair bonding are accompanied by increased aggressiveness toward perceived threats to the object of attachment as well as diminished fear and anxiety in stressful situations. The sustained closeness with mother required for the survival of infant mammals opened a new evolutionary niche in which aspects of the mother's care became increasingly important in regulating development in offspring. The quantity and quality of maternal care received during infancy determines adult social competence, ability to cope with stress, aggressiveness, and even preference for addictive substances. Indeed, the development of neurochemical systems within the brain that regulate mothering, aggression, and other types of social behavior, such as the oxytocin and vasopressin systems, are strongly affected by parental nurturing received during infancy. Evidence will be reviewed that the neural circuitry and neurochemistry implicated in studies of lower mammals also facilitate primate/human interpersonal bonding. It is hypothesized that neural bonding systems may also be important for the development in individuals of loyalty to the social group and its culture. Neglect and abuse during early life may cause bonding systems to develop abnormally and compromise capacity for rewarding interpersonal relationships and commitment to societal and cultural values later in life. Other means of stimulating reward pathways in the brain, such as drugs, sex, aggression, and intimidating others, could become relatively more attractive and less constrained by concern about violating trusting relationships. The ability to modify behavior based on negative experiences may be impaired. Unmet needs for social bonding and acceptance early in life might increase the emotional allure of groups (gangs, sects) with violent and authoritarian values and leadership. Social neurobiology has the potential to provide new strategies for treating and preventing violence and associated social dysfunction.

Apathy following traumatic brain injury.

PubMed

Starkstein, Sergio E; Pahissa, Jaime

2014-03-01

Traumatic brain injury (TBI) may result in significant emotional and behavioral changes, such as depression, impulsivity, anxiety, aggressive behavior, and posttraumatic stress disorder. Apathy has been increasingly recognized as a relevant sequela of TBI, with a negative impact on the patients' quality of life as well as their participation in rehabilitation activities. This article reviews the nosologic and phenomenological aspects of apathy in TBI, diagnostic issues, frequency and prevalence, relevant comorbid conditions, potential mechanisms, and treatment. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

An Animal Model for Collective Behavior in Humans: The Impact of Manipulated Trust and Aggression

DTIC Science & Technology

2014-04-30

grouped with males compared with females grouped with females. This raises the issue of the reciprocal impact of gender on the response to owl attack...337–342 Ecksteina MP, Dasa K, Phama BT, Petersona MF, Abbeya CK, Sya JL, Giesbrechta B (2012) Neural decoding of collective wisdom with multi- brain ...spiny mice flee in alternating patterns. Behav Brain Res 155:207–216 Eilam D (2003) Open-field behavior withstands drastic changes in arena size. Behav

Traumatic brain injury: preferred methods and targets for resuscitation.

PubMed

Scaife, Eric R; Statler, Kimberly D

2010-06-01

Severe traumatic brain injury (TBI) is the most common cause of death and disability in pediatric trauma. This review looks at the strategies to treat TBI in a temporal fashion. We examine the targets for resuscitation from field triage to definitive care in the pediatric ICU. Guidelines for the management of pediatric TBI exist. The themes of contemporary clinical research have been compliance with these guidelines and refinement of treatment recommendations developing a more sophisticated understanding of the pathophysiology of the injured brain. In the field, the aim has been to achieve routine compliance with the resuscitation goals. In the hospital, efforts have been directed at improving our ability to monitor the injured brain, developing techniques that limit brain swelling, and customizing brain perfusion. As our understanding of pediatric TBI evolves, the ambition is that age-specific and perhaps individual brain injury strategies based upon feedback from continuous monitors will be defined. In addition, vogue methods such as hypothermia, hypertonic saline, and aggressive surgical decompression may prove to impact brain swelling and outcomes.

Two Dimensional Finite Element Analysis for the Effect of a Pressure Wave in the Human Brain

NASA Astrophysics Data System (ADS)

Ponce L., Ernesto; Ponce S., Daniel

2008-11-01

Brain injuries in people of all ages is a serious, world-wide health problem, with consequences as varied as attention or memory deficits, difficulties in problem-solving, aggressive social behavior, and neuro degenerative diseases such as Alzheimer's and Parkinson's. Brain injuries can be the result of a direct impact, but also pressure waves and direct impulses. The aim of this work is to develop a predictive method to calculate the stress generated in the human brain by pressure waves such as high power sounds. The finite element method is used, combined with elastic wave theory. The predictions of the generated stress levels are compared with the resistance of the arterioles that pervade the brain. The problem was focused to the Chilean mining where there are some accidents happen by detonations and high sound level. There are not formal medical investigation, however these pressure waves could produce human brain damage.

Biology of Bilirubin Photoisomers.

PubMed

Hansen, Thor Willy Ruud

2016-06-01

Phototherapy is the main treatment for neonatal hyperbilirubinemia. In acute treatment of extreme hyperbilirubinemia, intensive phototherapy may have a role in 'detoxifying' the bilirubin molecule to more polar photoisomers, which should be less prone to crossing the blood-brain barrier, providing a 'brain-sparing' effect. This article reviews the biology of bilirubin isomers. Although there is evidence supporting the lower toxicity of bilirubin photoisomers, there are studies showing the opposite. There are methodologic weaknesses in most studies and better-designed experiments are needed. In an infant acutely threatened by bilirubin-induced brain damage, intensified phototherapy should be used expediently and aggressively. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain serotonin synthesis in adult males characterized by physical aggression during childhood: a 21-year longitudinal study.

PubMed

Booij, Linda; Tremblay, Richard E; Leyton, Marco; Séguin, Jean R; Vitaro, Frank; Gravel, Paul; Perreau-Linck, Elisabeth; Lévesque, Mélissa L; Durand, France; Diksic, Mirko; Turecki, Gustavo; Benkelfat, Chawki

2010-06-22

Adults exhibiting severe impulsive and aggressive behaviors have multiple indices of low serotonin (5-HT) neurotransmission. It remains unclear though whether low 5-HT mediates the behavior or instead reflects a pre-existing vulnerability trait. In the present study, positron emission tomography with the tracer alpha-[(11)C]methyl-L-tryptophan ((11)C-AMT) was used to compare 5-HT synthesis capacity in two groups of adult males from a 21-year longitudinal study (mean age +/- SD: 27.1+/-0.7): individuals with a history of childhood-limited high physical aggression (C-LHPA; N = 8) and individuals with normal (low) patterns of physical aggression (LPA; N = 18). The C-LHPA males had significantly lower trapping of (11)C-AMT bilaterally in the orbitofrontal cortex and self-reported more impulsiveness. Despite this, in adulthood there were no group differences in plasma tryptophan levels, genotyping, aggression, emotional intelligence, working memory, computerized measures of impulsivity, psychosocial functioning/adjustment, and personal and family history of mood and substance abuse disorders. These results force a re-examination of the low 5-HT hypothesis as central in the biology of violence. They suggest that low 5-HT does not mediate current behavior and should be considered a vulnerability factor for impulsive-aggressive behavior that may or may not be expressed depending on other biological factors, experience, and environmental support during development.

RESPECT-Mil: Early Intervention & Outcomes Of PTSD & Depression In Primary Care

DTIC Science & Technology

2011-03-21

Brief PTSD & depression screening (all visits)  Pre-clinician diagnostic aid  Patient education materials  Psychosocial options  Care Facilitator...visits)  Pre-clinician diagnostic aid  Patient education materials  Psychosocial options  Care Facilitator assisted follow-up option  Aggressive... Patient education materials  Psychosocial options  Care Facilitator assisted follow-up option  Aggressive facilitator outreach & monitoring  Web-based

Trajectories of Maternal Verbal Aggression across the Middle School Years: Associations with Negative View of Self and Social Problems

ERIC Educational Resources Information Center

Donovan, Kera L.; Brassard, Marla R.

2011-01-01

Objective: The primary research objective was to explore the relationship between trajectories of maternal verbal aggression (VA) experienced by low-income, community middle school students across a three-year period and outcomes that have been found to be related to VA in previous work, including a negative view of self and social problems.…

The effects of dopamine receptor 1 and 2 agonists and antagonists on sexual and aggressive behaviors in male green anoles.

PubMed

Smith, Alexandra N; Kabelik, David

2017-01-01

The propensity to exhibit social behaviors during interactions with same-sex and opposite-sex conspecifics is modulated by various neurotransmitters, including dopamine. Dopamine is a conserved neurotransmitter among vertebrates and dopaminergic receptors are also highly conserved among taxa. Activation of D1 and D2 dopamine receptor subtypes has been shown to modulate social behaviors, especially in mammalian and avian studies. However, the specific behavioral functions of these receptors vary across taxa. In reptiles there have been few studies examining the relationship between dopaminergic receptors and social behaviors. We therefore examined the effects of D1 and D2 agonists and antagonists on sexual and aggressive behaviors in the male green anole lizard (Anolis carolinensis). Treatment with high doses of both D1 and D2 agonists was found to impair both sexual and aggressive behaviors. However, the D1 agonist treatment was also found to impair motor function, suggesting that those effects were likely nonspecific. Lower doses of both agonists and antagonists failed to affect social behaviors. These findings provide some evidence for D2 receptor regulation of social behaviors, but in contrast with previous research, these effects are all inhibitory and no effects were found for manipulations of D1 receptors. A potential reason for the lack of more widespread effects on social behaviors using moderate or low drug doses is that systemic injection of drugs resulted in effects throughout the whole brain, thus affecting counteracting circuits which negated one another, making measurable changes in behavioral output difficult to detect. Future studies should administer drugs directly into brain regions known to regulate sexual and aggressive behaviors.

Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma

NASA Astrophysics Data System (ADS)

Setua, Sonali; Ouberai, Myriam; Piccirillo, Sara G.; Watts, Colin; Welland, Mark

2014-08-01

Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies.Glioblastoma multiforme (GBM) remains the most aggressive and challenging brain tumour to treat. We report the first successful chemo-radiotherapy on patient derived treatment resistant GBM cells using a cisplatin-tethered gold nanosphere. After intracellular uptake, the nanosphere effects DNA damage which initiates caspase-mediated apoptosis in those cells. In the presence of radiation, both gold and platinum of cisplatin, serve as high atomic number radiosensitizers leading to the emission of ionizing photoelectrons and Auger electrons. This resulted in enhanced synergy between cisplatin and radiotherapy mediated cytotoxicity, and photo/Auger electron mediated radiosensitisation leading to complete ablation of the tumour cells in an in vitro model system. This study demonstrates the potential of designed nanoparticles to target aggressive cancers in the patient derived cell lines providing a platform to move towards treatment strategies. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c4nr03693j

Behavioral and Pharmacogenetics of Aggressive Behavior

PubMed Central

Takahashi, Aki; Quadros, Isabel M.; de Almeida, Rosa M. M.; Miczek, Klaus A.

2013-01-01

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to “phasic” effects of pharmacological agents vs “trait”-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene × environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters (e.g., MAO A) or rate-limiting synthetic and metabolic enzymes of 5-HT determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate, and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g. BDNF, nNOS, αCaMKII, Neuropeptide Y). The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior. PMID:22297576

Influence of prenatal iron deficiency and MAOA genotype on response to social challenge in rhesus monkey infants.

PubMed

Golub, M S; Hogrefe, C E; Unger, E L

2012-04-01

Social and emotional behaviors are known to be sensitive to both developmental iron deficiency (ID) and monoamine oxidase A (MAOA) gene polymorphisms. In this study, male rhesus monkey infants deprived of dietary iron in utero were compared with iron sufficient (IS) controls (n = 10/group). Half of each group had low MAOA activity genotypes and half had high MAOA activity genotypes. A series of social response tests were conducted at 3-14 months of age. MAOA genotype influenced attention to a video of aggressive behavior, emotional expression (fear, grimace and sniff) in the social intruder test, social actions (displacement, grooming) in the social dyad test, and aggressive responses to a threatening picture. Interactions between MAOA and prenatal ID were seen in response to the aggressive video, in temperament ratings, in affiliative behavior in the social dyad test, in cortisol response in the social buffering test and in response to a social intruder and to pictures with social and nonsocial themes. In general, the effects of ID were dependent on MAOA genotype in terms of both direction and size of the effect. Nutrition/genotype interactions may shed new light on behavioral consequences of nutritional deprivation during brain development. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Impact of gasoline inhalation on some neurobehavioural characteristics of male rats.

PubMed

Kinawy, Amal A

2009-11-24

This paper examines closely and compares the potential hazards of inhalation of two types of gasoline (car fuel). The first type is the commonly use leaded gasoline and the second is the unleaded type enriched with oxygenate additives as lead substituent in order to raise the octane number. The impacts of gasoline exposure on Na+, K+-ATPase, superoxide dismutase (SOD), acetylcholinesterase (AChE), total protein, reduced glutathione (GSH), and lipid peroxidation (TBARS) in the cerebral cortex, and monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the cerebral cortex, hippocampus, cerebellum and hypothalamus were evaluated. The effect of gasoline exposure on the aggressive behaviour tests was also studied. The present results revealed that gasoline inhalation induced significant fluctuations in the levels of the monoamine neurotransmitters in the studied brain regions. This was concomitant with a decrease in Na+, K+-ATPase activity and total protein content. Moreover, the group exposed to the unleaded gasoline exhibited an increase in lipid peroxidation and a decrease in AChE and superoxide dismutase activities. These physiological impairments were accompanied with a higher tendency towards aggressive behaviour as a consequence to gasoline inhalation. It is concluded from the present work that chronic exposure to either the leaded or the unleaded gasoline vapours impaired the levels of monoamine neurotransmitters and other biochemical parameters in different brain areas and modulated several behavioural aspects related to aggression in rats.

Relations between aggression and adjustment in chinese children: moderating effects of academic achievement.

PubMed

Yang, Fan; Chen, Xinyin; Wang, Li

2014-01-01

The primary purpose of the study was to examine the moderating effects of academic achievement on relations between aggressive behavior and social and psychological adjustment in Chinese children. A sample of children (N = 1,171; 591 boys, 580 girls; initial M age = 9 years) in China participated in the study. Two waves of longitudinal data were collected in Grades 3 and 4 from multiple sources including peer nominations, teacher ratings, self-reports, and school records. The results indicated that the main effects of aggression on adjustment were more evident than those of adjustment on aggression. Moreover, aggression was negatively associated with later leadership status and positively associated with later peer victimization, mainly for high-achieving children. The results suggested that consistent with the resource-potentiating model, academic achievement served to enhance the positive development of children with low aggression. On the other hand, although the findings indicated fewer main effects of adjustment on aggression, loneliness, depression, and perceived social incompetence positively predicted later aggression for low-achieving, but not high-achieving, children, which suggested that consistent with the stress-buffering model, academic achievement protected children with psychological difficulties from developing aggressive behavior. The results indicate that academic achievement is involved in behavioral and socioemotional development in different manners in Chinese children. Researchers should consider an integrative approach based on children's behavioral, psychological, and academic functions in designing prevention and intervention programs.

Developmental effects of androgens in the human brain.

PubMed

Nguyen, T-V

2018-02-01

Neuroendocrine theories of brain development posit that androgens play a crucial role in sex-specific cortical growth, although little is known about the differential effects of testosterone and dehydroepiandrosterone (DHEA) on cortico-limbic development and cognition during adolescence. In this context, the National Institutes of Health Study of Normal Brain Development, a longitudinal study of typically developing children and adolescents aged 4-24 years (n=433), offers a unique opportunity to examine the developmental effects of androgens on cortico-limbic maturation and cognition. Using data from this sample, our group found that higher testosterone levels were associated with left-sided decreases in cortical thickness (CTh) in post-pubertal boys, particularly in the prefrontal cortex, compared to right-sided increases in CTh in somatosensory areas in pre-pubertal girls. Prefrontal-amygdala and prefrontal-hippocampal structural covariance (considered to reflect structural connectivity) also varied according to testosterone levels, with the testosterone-related brain phenotype predicting higher aggression levels and lower executive function, particularly in boys. By contrast, DHEA was associated with a pre-pubertal increase in CTh of several regions involved in cognitive control in both boys and girls. Covariance within several cortico-amygdalar structural networks also varied as a function of DHEA levels, with the DHEA-related brain phenotype predicting improvements in visual attention in both boys and girls. DHEA-related cortico-hippocampal structural covariance, on the other hand, predicted higher scores on a test of working memory. Interestingly, there were significant interactions between testosterone and DHEA, such that DHEA tended to mitigate the anti-proliferative effects of testosterone on brain structure. In sum, testosterone-related effects on the developing brain may lead to detrimental effects on cortical functions (ie, higher aggression and lower executive function), whereas DHEA-related effects may optimise cortical functions (ie, better attention and working memory), perhaps by decreasing the influence of amygdalar and hippocampal afferents on cortical functions. © 2017 British Society for Neuroendocrinology.

Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals.

PubMed

Chistiakov, Dimitry A; Chekhonin, Vladimir P

2017-06-05

To examine whether chronic physical aggression (CPA) in adulthood can be epigenetically programmed early in life due to exposure to early-life adversity. Literature search of public databases such as PubMed/MEDLINE and Scopus. Children/adolescents susceptible for CPA and exposed to early-life abuse fail to efficiently cope with stress that in turn results in the development of CPA later in life. This phenomenon was observed in humans and animal models of aggression. The susceptibility to aggression is a complex trait that is regulated by the interaction between environmental and genetic factors. Epigenetic mechanisms mediate this interaction. Subjects exposed to stress early in life exhibited long-term epigenetic programming that can influence their behaviour in adulthood. This programming affects expression of many genes not only in the brain but also in other systems such as neuroendocrine and immune. The propensity to adult CPA behaviour in subjects experienced to early-life adversity is mediated by epigenetic programming that involves long-term systemic epigenetic alterations in a whole genome.

Tissue mechanics promote IDH1-dependent HIF1α–tenascin C feedback to regulate glioblastoma aggression

PubMed Central

Miroshnikova, Yekaterina A.; Mouw, Janna K.; Barnes, J. Matthew; Pickup, Michael W.; Lakins, Johnathan N.; Kim, Youngmi; Lobo, Khadjia; Persson, Anders I.; Reis, Gerald F.; McKnight, Tracy R.; Holland, Eric C.; Phillips, Joanna J.; Weaver, Valerie M.

2017-01-01

Increased overall survival for patients with glioma brain tumours is associated with mutations in the metabolic regulator isocitrate dehydrogenase 1 (IDH1). Gliomas develop within a mechanically challenged microenvironment that is characterized by a dense extracellular matrix (ECM) that compromises vascular integrity to induce hypoxia and activate HIF1α. We found that glioma aggression and patient prognosis correlate with HIF1α levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant IDH1 restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that our studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. Thus, our work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status. PMID:27820599

Violence among peoples in the light of human frustration and aggression.

PubMed

de Gaay Fortman, Bas

2005-12-05

This article sets out to provide a general background to the study of aggression in the social sciences, with a particular focus on its link to collective violence. While the study of what happens in the human brain appears to be already highly complex, analysis of violent behavior appears to be even more intricate. A deductive system in the sense of a general and clear system of propositions logically connected to one another is not feasible, principally because contrary to the natural sciences there are no verities but merely "stylized facts." One of these concerns the setting of human aggression in the light of frustration, as argued in the frustration-aggression hypothesis developed by Dollard et al. in 1939. Apart from conceiving of aggression as a pure human instinct, it may also be seen as externally driven, while a third possibility concerns culturally "learned" aggression. Proof of the latter is that the strongest correlation appears to be that between current violence and previous manifestations thereof. Attention is paid to the way in which Gurr has rooted his relative deprivation theory on causes of collective violence among peoples in mechanisms of frustration and aggression. That theory is taken a bit further in terms of "perceived acquirement failure," which appears to be highly connected to the role of the state. Based on certain observations by Hannah Arendt, the argument then proceeds to violence as a manifestation of powerlessness. Finally, this leads to a discussion of justice as a crucial factor in what Durkheim used to call a "right to conflict." In this way, human aggression is placed in a broad socio-economic context.

Effects of methamphetamine abuse and serotonin transporter gene variants on aggression and emotion-processing neurocircuitry

PubMed Central

Payer, D E; Nurmi, E L; Wilson, S A; McCracken, J T; London, E D

2012-01-01

Individuals who abuse methamphetamine (MA) exhibit heightened aggression, but the neurobiological underpinnings are poorly understood. As variability in the serotonin transporter (SERT) gene can influence aggression, this study assessed possible contributions of this gene to MA-related aggression. In all, 53 MA-dependent and 47 control participants provided self-reports of aggression, and underwent functional magnetic resonance imaging while viewing pictures of faces. Participants were genotyped at two functional polymorphic loci in the SERT gene: the SERT-linked polymorphic region (SERT-LPR) and the intron 2 variable number tandem repeat polymorphism (STin2 VNTR); participants were then classified as having high or low risk for aggression according to individual SERT risk allele combinations. Comparison of SERT risk allele loads between groups showed no difference between MA-dependent and control participants. Comparison of self-report scores showed greater aggression in MA-dependent than control participants, and in high genetic risk than low-risk participants. Signal change in the amygdala was lower in high genetic risk than low-risk participants, but showed no main effect of MA abuse; however, signal change correlated negatively with MA use measures. Whole-brain differences in activation were observed between MA-dependent and control groups in the occipital and prefrontal cortex, and between genetic high- and low-risk groups in the occipital, fusiform, supramarginal and prefrontal cortex, with effects overlapping in a small region in the right ventrolateral prefrontal cortex. The findings suggest that the investigated SERT risk allele loads are comparable between MA-dependent and healthy individuals, and that MA and genetic risk influence aggression independently, with minimal overlap in associated neural substrates. PMID:22832817

Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment

PubMed Central

Arias-Ramos, Nuria; Ferrer-Font, Laura; Lope-Piedrafita, Silvia; Mocioiu, Victor; Julià-Sapé, Margarida; Pumarola, Martí; Arús, Carles; Candiota, Ana Paula

2017-01-01

Glioblastoma (GBM) is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI). Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the Tumor Responding Index (TRI), was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, n = 2), TRI = 68.2 ± 2.8%, intermediate response (IR, n = 6), TRI = 41.1 ± 4.2% and low response (LR, n = 2), TRI = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between TRI and Ki67 immunostaining. Additionally, ca. 7-day oscillations of TRI were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected. PMID:28524099

Successful Use of Dose Dense Neoadjuvant Chemotherapy and Sodium Valproate with Minimal Toxicity in an Infant with Medulloblastoma in Extremely Poor General Condition.

PubMed

Gupta, Ajay; Kumar, Amit; Abrari, Andaleeb; Patir, Rana; Vaishya, Sandeep

2016-09-01

Medulloblastoma is the most common malignant brain tumor in children. Infants are in the high-risk category. Complete surgical resection is the single most important determinant of prognosis and survival in nonmetastatic disease. Infants with large primaries after incomplete resection/biopsy and poor general condition have bad prognosis. They are considered poor candidates for intensive chemotherapy involving high dose methotrexate/autologous stem cell transplantation as they are often unable to tolerate these aggressive regimens. The patient, withinfantile medulloblastoma, was supposed to have complete resection but only a biopsy could be attempted because of increased tumor vascularity. He was in very poor general condition after surgery and his parents declined aggressive chemotherapy and shunt surgery. He was given dose dense neo-adjuvant chemotherapy along with the histone deactylase inhibitor valproate for 5 cycles, with minimal toxicity, after which the tumor was resected. The examination of the resected specimen revealed a complete pathologic response. He then received a total of 18 cycles of chemotherapy and valproate to complete 1 year of systemic treatment. The child is now 6.5 years of age, disease-free, without evidence of any neurocognitive or developmental abnormalities. We suggest that the role of neoadjuvant chemotherapy should be explored in patients with infantile medulloblastoma in whom upfront complete resection is not possible, considering the gratifying results obtained in our case. Copyright © 2016 Elsevier Inc. All rights reserved.

Correlation of Tumor and Peritumoral Edema Volumes with Survival in Patients with Cerebral Metastases.

PubMed

Kerschbaumer, Johannes; Bauer, Marlies; Popovscaia, Marina; Grams, Astrid E; Thomé, Claudius; Freyschlag, Christian F

2017-02-01

Surgical resection in combination with radiotherapy in selected cases remains the best option for patients with cerebral metastases. Postoperative relapse of brain metastases occurs frequently and can be reduced by postoperative whole-brain radiotherapy (WBRT). Continuous spread of tumor cells from the primary lesions is debated as a cause of recurrence. It is well known that in gliomas, infiltration takes place within the surrounding edema. Obviously, most brain metastases are usually associated with peritumoral edema, which may act as an indicator of infiltration and more aggressive tumor biology. Therefore, we aimed to investigate the correlation of tumor and edema volumes with overall survival in patients with cerebral metastases. A total of 143 patients diagnosed with brain metastasis (male:female=1.1:1) who underwent surgical resection were included retrospectively in this analysis. Clinical data were retrieved from electronic patient files. The volumes of tumor and edema calculated by manual delineation. The ratio of edema to tumor volume was calculated, leading to dichotomization of the patients. The median tumor volume was 20.1 cc (range=0.8-90.8 cc) and the median volume of edema 49.5 cc (range=0-179.9 cc). The volume of metastases did not significantly correlate with overall survival. The ratio of edema to tumor volume was also not a prognostic factor in terms of overall survival. Only surgical resection, preoperative recursive partitioning analysis class, and postoperative addition of WBRT, as well as female sex, demonstrated beneficial effects. The extent of edema surrounding cerebral metastases does not appear to influence overall survival in patients suffering from brain metastases, although it seems to be responsible for most of the patients' symptoms. The hypothesis that the extent of edema was disadvantageous concerning survival was supported by our data. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

The Association Between Familial Homelessness, Aggression, and Victimization Among Children.

PubMed

Jetelina, Katelyn K; Reingle Gonzalez, Jennifer M; Cuccaro, Paula M; Peskin, Melissa F; Elliott, Marc N; Coker, Tumaini R; Mrug, Sylvie; Davies, Susan L; Schuster, Mark A

2016-12-01

The purpose of this study was to evaluate the relationship between the number of periods children were exposed to familial homelessness and childhood aggression and victimization. Survey data were obtained from 4,297 fifth-grade children and their caregivers in three U.S. cities. Children and primary caregivers were surveyed longitudinally in 7th and 10th grades. Family homelessness, measured at each wave as unstable housing, was self-reported by the caregiver. Children were categorized into four mutually exclusive groups: victim only, aggressor only, victim-aggressor, and neither victim nor aggressor at each time point using validated measures. Multinomial, multilevel mixed models were used to evaluate the relationship among periods of homelessness and longitudinal victimization, aggression, and victim aggression compared to children who were nonvictims and nonaggressors. Results suggest that children who experienced family homelessness were more likely than domiciled children to report aggression and victim aggression but not victimization only. Multivariate analyses suggested that even brief periods of homelessness were positively associated with aggression and victim aggression (relative to neither) compared to children who were never homeless. Furthermore, childhood victimization and victim aggression significantly decreased from 5th grade to 10th grade while aggression significantly increased in 10th grade. Children who experienced family homelessness for brief periods of time were significantly more likely to be a victim-aggressor or aggressor compared to those who were never homeless. Prevention efforts should target housing security and other important factors that may reduce children's likelihood of aggression and associated victimization. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Evaluation of inciting causes, alternative targets, and risk factors associated with redirected aggression in cats.

PubMed

Amat, Marta; Manteca, Xavier; Brech, Susana Le; Ruiz de la Torre, José Luís; Mariotti, Valentina M; Fatjó, Jaume

2008-08-15

To identify inciting causes, alternative targets, and risk factors associated with redirected aggression in cats. Case-control study. 19 cats with a history of redirected aggression and 64 cats with no such history. Medical records were reviewed to identify cats evaluated for problems with redirected aggression (case cats), in which the primary inciting stimulus and alternative target of aggression were clearly identifiable. Data obtained from the records and from follow-up interviews included details about the cats and incidents of redirected aggression. Owners of control cats were interviewed via telephone to obtain similar information on their cats. 22 incidents of redirected aggression were reported for the 19 case cats. In 95% of those incidents, loud noises or interactions with other cats were identified as the inciting stimuli. Case cats most commonly redirected their aggression toward the owner, followed by another cat living in the same household. Compared with control cats, case cats were more likely to have a sound phobia but were less likely to be outdoor cats. In addition, case cats were more likely to be from small households (

Childhood EEG frontal alpha power as a predictor of adolescent antisocial behavior: A twin heritability study

PubMed Central

Niv, Sharon; Ashrafulla, Syed; Tuvblad, Catherine; Joshi, Anand; Raine, Adrian; Leahy, Richard; Baker, Laura A.

2015-01-01

High EEG frontal alpha power (FAP) is thought to represent a state of low arousal in the brain, which has been related in past research to antisocial behavior (ASB). We investigated a longitudinal sample of 900 twins in two assessments in late childhood and mid-adolescence to verify whether relationships exist between FAP and both aggressive and nonaggressive ASB. ASB was measured by the Child Behavioral Checklist, and FAP was calculated using connectivity analysis methods that used principal components analysis to derive power of the most dominant frontal activation. Significant positive predictive relationships emerged in males between childhood FAP and adolescent aggressive ASB using multilevel mixed modeling. No concurrent relationships were found. Using bivariate biometric twin modeling analysis, the relationship between childhood FAP and adolescent aggressive ASB in males was found to be entirely due to genetic factors, which were correlated r = 0.22. PMID:25456277

Endophenotypes in the personality disorders

PubMed Central

Siever, Larry J.

2005-01-01

The identification of endophenotypes in the personality disorders may provide a basis for the identification of underlying genotypes that influence the traits and dimensions of the personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability impulsiwity aggression, emotional information processing, cognitive disorganization, social deficits, and psychosis. For example, the propensity to aggression can be evaluated by psychometric measures, interview, laboratory paradigms, neurochemical imaging, and pharmacological studies. These suggest that aggression is a measurable trait that may be related to reduced serotonergic activity. Hyperresponsiveness of amygdala and other limbic structures may be related to affective instability, while structural and functional brain alterations underlie the cognitive disorganization in psychoticlike symptoms of schizotypal personality disorder. Thus, an endophenotypic approach not only provides clues to underlying candidate genes contributing to these behavioral dimensions, but may also point the way to a better understanding of pathophysiological mechanisms. PMID:16262209

Intratumor heterogeneity and clonal evolution in an aggressive papillary thyroid cancer and matched metastases.

PubMed

Le Pennec, Soazig; Konopka, Tomasz; Gacquer, David; Fimereli, Danai; Tarabichi, Maxime; Tomás, Gil; Savagner, Frédérique; Decaussin-Petrucci, Myriam; Trésallet, Christophe; Andry, Guy; Larsimont, Denis; Detours, Vincent; Maenhaut, Carine

2015-04-01

The contribution of intratumor heterogeneity to thyroid metastatic cancers is still unknown. The clonal relationships between the primary thyroid tumors and lymph nodes (LN) or distant metastases are also poorly understood. The objective of this study was to determine the phylogenetic relationships between matched primary thyroid tumors and metastases. We searched for non-synonymous single-nucleotide variants (nsSNVs), gene fusions, alternative transcripts, and loss of heterozygosity (LOH) by paired-end massively parallel sequencing of cDNA (RNA-Seq) in a patient diagnosed with an aggressive papillary thyroid cancer (PTC). Seven tumor samples from a stage IVc PTC patient were analyzed by RNA-Seq: two areas from the primary tumor, four areas from two LN metastases, and one area from a pleural metastasis (PLM). A large panel of other thyroid tumors was used for Sanger sequencing screening. We identified seven new nsSNVs. Some of these were early events clonally present in both the primary PTC and the three matched metastases. Other nsSNVs were private to the primary tumor, the LN metastases and/or the PLM. Three new gene fusions were identified. A novel cancer-specific KAZN alternative transcript was detected in this aggressive PTC and in dozens of additional thyroid tumors. The PLM harbored an exclusive whole-chromosome 19 LOH. We have presented the first, to our knowledge, deep sequencing study comparing the mutational spectra in a PTC and both LN and distant metastases. This study has yielded novel findings concerning intra-tumor heterogeneity, clonal evolution and metastases dissemination in thyroid cancer. © 2015 Society for Endocrinology.

[Personality pathological traits and brain metabolites as predictors of non-abstinence in addicts with personality disorders].

PubMed

Serrani Azcurra, Daniel

2013-01-01

Differences in pathological personality traits and disturbances in brain metabolites between non consumers, abstinent and non abstinent consumers were assessed. Participants (n=113) aged between 18-45 years with personality disorder (PD) were diagnosed with clinical interview and scales for depression, anxiety, impulsivity and dimensions of personality pathology. Brain metabolites were analyzed with magnetic resonance spectroscopy. Data were analyzed with ANOVA and multiple comparisons. Abstinent and non-abstinent differentiated from non-consumers in emotional deregulation, inhibition, and restricted expression; abstinent and non-abstinent differentiated from each other in self-aggression, dissocial behaviour, conduct disorder, stimulus seeking and intimacy problems. N-Acetyl Aspartate and creatine values were lower between non-abstinent in prefrontal, anterior cingulate cortex, cerebellar vermis and superior corona radiata. For abstinent, choline levels were greater in cerebellar vermis and n-acetyl aspartate were lower in dorso-lateral prefrontal and anterior cingulated cortex and insula. Regarding personality traits, insecure attachment, narcissism, lability, self-aggression and anxiety characterize consumers and abstinent, while suspiciousness, rejection and character hardness are found in consumers (non-abstinent and abstinent). Compulsive traits, unplanned body impulsiveness and lack of control in emotional regulation predominated in non-abstinent and participants with co-morbidities. Detachment and inhibition predominate in alcohol abuse disorder and narcissistic traits in substance abuse.

Stenting versus aggressive medical therapy for intracranial arterial stenosis.

PubMed

Chimowitz, Marc I; Lynn, Michael J; Derdeyn, Colin P; Turan, Tanya N; Fiorella, David; Lane, Bethany F; Janis, L Scott; Lutsep, Helmi L; Barnwell, Stanley L; Waters, Michael F; Hoh, Brian L; Hourihane, J Maurice; Levy, Elad I; Alexandrov, Andrei V; Harrigan, Mark R; Chiu, David; Klucznik, Richard P; Clark, Joni M; McDougall, Cameron G; Johnson, Mark D; Pride, G Lee; Torbey, Michel T; Zaidat, Osama O; Rumboldt, Zoran; Cloft, Harry J

2011-09-15

Atherosclerotic intracranial arterial stenosis is an important cause of stroke that is increasingly being treated with percutaneous transluminal angioplasty and stenting (PTAS) to prevent recurrent stroke. However, PTAS has not been compared with medical management in a randomized trial. We randomly assigned patients who had a recent transient ischemic attack or stroke attributed to stenosis of 70 to 99% of the diameter of a major intracranial artery to aggressive medical management alone or aggressive medical management plus PTAS with the use of the Wingspan stent system. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non-stroke-related death, 0.4%) (P=0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P=0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group. In patients with intracranial arterial stenosis, aggressive medical management was superior to PTAS with the use of the Wingspan stent system, both because the risk of early stroke after PTAS was high and because the risk of stroke with aggressive medical therapy alone was lower than expected. (Funded by the National Institute of Neurological Disorders and Stroke and others; SAMMPRIS ClinicalTrials.gov number, NCT00576693.).

A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.

PubMed

Martín, Rubén; Cordova, Claudia; Gutiérrez, Beatriz; Hernández, Marita; Nieto, María L

2017-01-01

Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

Predicting the use of corporal punishment: Child aggression, parent religiosity, and the BDNF gene.

PubMed

Avinun, Reut; Davidov, Maayan; Mankuta, David; Knafo-Noam, Ariel

2018-03-01

Corporal punishment (CP) has been associated with deleterious child outcomes, highlighting the importance of understanding its underpinnings. Although several factors have been linked with parents' CP use, genetic influences on CP have rarely been studied, and an integrative view examining the interplay between different predictors of CP is missing. We focused on the separate and joint effects of religiosity, child aggression, parent's gender, and a valine (Val) to methionine (Met) substitution in the brain-derived neurotrophic factor (BDNF) gene. Data came from a twin sample (51% male, aged 6.5 years). We used mothers' and fathers' self-reports of CP and religiosity, and the other parent's report on child aggression. Complete data were available for 244 mothers and their 466 children, and for 217 fathers and their 409 children. The random split method was employed to examine replicability. For mothers, only the effect of religiosity appeared to replicate. For fathers, several effects predicting CP use replicated in both samples: child aggression, child sex, religiosity, and a three-way (GxExE) interaction implicating fathers' BDNF genotype, child aggression and religiosity. Religious fathers who carried the Met allele and had an aggressive child used CP more frequently; in contrast, secular fathers' CP use was not affected by their BDNF genotype or child aggression. Results were also repeated longitudinally in a subsample with age 8-9 data. Findings highlight the utility of a bio-ecological approach for studying CP use by shedding light on pertinent gene-environment interaction processes. Possible implications for intervention and public policy are discussed. © 2017 Wiley Periodicals, Inc.

Acute and chronic glue sniffing effects and consequences of withdrawal on aggressive behavior.

PubMed

Bouchatta, Otmane; Ouhaz, Zakaria; Ba-Mhamed, Saadia; Kerekes, Nóra; Bennis, Mohamed

2016-05-01

Drug abuse act on brain mechanisms that cause a high-risk individual to engage in aggressive and violent behavior. While a drug-violence relationship exists, the nature of this relationship is often complex, with intoxication, neurotoxic, and withdrawal effects often being confused and/or confounded. Glue sniffing is often a springboard to the abuse of more addictive drugs. Despite its high prevalence and serious consequences, we know relatively little about the aggressive behavioral effects of volatile inhalants abuse, especially glue. The aim of the present study was to investigate the link between the duration of glue exposure, a common substance abuse problem in Morocco, and the level of aggressive behavior during withdrawal. For this we used the isolation-induced aggression model "residents" in three groups of mice. The first group served as control resident animals (n=10, without exposure); the second group as experimental resident mice (n=10) tested before and after acute (first day) and chronic exposure to the glue, and at 1 and 2weeks of withdrawal; and the third group of 10 intruder animals. The results showed that the number of attacks decreased (halved) and the latency of the first attack increased (doubled) following acute glue sniffing. However, the effects of chronic exposure and of 1week of withdrawal led to an increase in the intensity of agonistic encounters. After 2weeks of withdrawal, the intensity of aggressive behavior decreased again. These results indicated that chronic glue exposure and the first week of withdrawal are associated with increased aggression in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapid eye movement sleep behavior disorder: a window on the emotional world of Parkinson disease.

PubMed

Mariotti, Paolo; Quaranta, Davide; Di Giacopo, Raffaella; Bentivoglio, Anna Rita; Mazza, Marianna; Martini, Annalisa; Canestri, Jorge; Della Marca, Giacomo

2015-02-01

REM sleep behavior disorder (RBD) is a parasomnia characterized by motor activity during sleep with dream mentation. Aggressiveness has been considered a peculiar feature of dreams associated with RBD, despite normal score in aggressiveness scales during wakefulness. We aimed to measure daytime aggressiveness and analyze dream contents in a population of patients with Parkinson disease (PD) with and without RBD. This is a single-center prospective observational study; it concerns the description of the clinical features of a medical disorder in a case series. The study was performed in the Department of Neurosciences of the Catholic University in Rome, Italy. Three groups of subjects were enrolled: patients with PD plus RBD, patients with PD without RBD, and healthy controls. The diagnosis of RBD was determined clinically and confirmed by means of overnight, laboratory-based video-polysomnography. For the evaluation of diurnal aggressiveness, the Buss-Perry Aggression Questionnaire (BPAQ) was used. The content of dreams was evaluated by means of the methods of Hall and Van De Castle. Patients with PD without RBD displayed higher levels of anger, and verbal and physical aggressiveness than patients with PD and RBD and controls. Patients with PD and RBD and controls did not differ in hostility. It can be hypothesized that a noradrenergic impairment at the level of the locus coeruleus could, at the same time, explain the presence of RBD, as well as the reduction of diurnal aggressiveness. This finding also suggests a role for REM sleep in regulating homeostasis of emotional brain function. © 2015 Associated Professional Sleep Societies, LLC.

Aggressiveness, violence, homicidality, homicide, and Lyme disease

PubMed Central

Bransfield, Robert C

2018-01-01

Background No study has previously analyzed aggressiveness, homicide, and Lyme disease (LD). Materials and methods Retrospective LD chart reviews analyzed aggressiveness, compared 50 homicidal with 50 non-homicidal patients, and analyzed homicides. Results Most aggression with LD was impulsive, sometimes provoked by intrusive symptoms, sensory stimulation or frustration and was invariably bizarre and senseless. About 9.6% of LD patients were homicidal with the average diagnosis delay of 9 years. Postinfection findings associated with homicidality that separated from the non-homicidal group within the 95% confidence interval included suicidality, sudden abrupt mood swings, explosive anger, paranoia, anhedonia, hypervigilance, exaggerated startle, disinhibition, nightmares, depersonalization, intrusive aggressive images, dissociative episodes, derealization, intrusive sexual images, marital/family problems, legal problems, substance abuse, depression, panic disorder, memory impairments, neuropathy, cranial nerve symptoms, and decreased libido. Seven LD homicides included predatory aggression, poor impulse control, and psychosis. Some patients have selective hyperacusis to mouth sounds, which I propose may be the result of brain dysfunction causing a disinhibition of a primitive fear of oral predation. Conclusion LD and the immune, biochemical, neurotransmitter, and the neural circuit reactions to it can cause impairments associated with violence. Many LD patients have no aggressiveness tendencies or only mild degrees of low frustration tolerance and irritability and pose no danger; however, a lesser number experience explosive anger, a lesser number experience homicidal thoughts and impulses, and much lesser number commit homicides. Since such large numbers are affected by LD, this small percent can be highly significant. Much of the violence associated with LD can be avoided with better prevention, diagnosis, and treatment of LD. PMID:29576731

Hippocampal volume and sensitivity to maternal aggressive behavior: a prospective study of adolescent depressive symptoms.

PubMed

Whittle, Sarah; Yap, Marie B H; Sheeber, Lisa; Dudgeon, Paul; Yücel, Murat; Pantelis, Christos; Simmons, Julian G; Allen, Nicholas B

2011-02-01

It has been suggested that biological factors confer increased sensitivity to environmental influences on depressive symptoms during adolescence, a crucial time for the onset of depressive disorders. Given the critical role of the hippocampus in sensitivity to stress and processing of contextual aspects of the environment, investigation of its role in determining sensitivity to environmental context seems warranted. This study prospectively examined hippocampal volume as a measure of sensitivity to the influence of aggressive maternal behavior on change in depressive symptoms from early to midadolescence. The interaction between aggressive maternal behavior and hippocampal volume was found to predict change in depressive symptoms. Significant sex differences also emerged, whereby only for girls were larger bilateral hippocampal volumes more sensitive to the effects of maternal aggressive behavior, particularly with respect to experiencing the protective effects of low levels of maternal aggressiveness. These findings help elucidate the complex relationships between brain structure, environmental factors such as maternal parenting style, and sensitivity to (i.e., risk for, and protection from) the emergence of depression during this life stage. Given that family context risk factors are modifiable, our findings suggest the potential utility of targeted parenting interventions for the prevention and treatment of adolescent depressive disorder.

The role of serotonergic system at the interface of aggression and suicide

PubMed Central

Bortolato, Marco; Pivac, Nela; Seler, Dorotea Muck; Perkovic, Matea Nikolac; Pessia, Mauro; Di Giovanni, Giuseppe

2013-01-01

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions. PMID:23333677

Neurobiology of aggressive behavior.

PubMed

Delgado, J M

1976-10-30

Causality, neurological mechanisms, and behavioral manifestations may be heterogeneous in different forms of aggressive behavior, but some elements are shared by all forms of violence, including the necessity of sensory inputs, the coding and decoding of information according to acquired frames of reference, and the activation of pre-established patterns of response. Understanding and prevention of violence requires a simultaneous study of its social, cultural, and economic aspects, at parity with an investigation of its neurological mechanisms. Part of the latter information may be obtained through animal experimentation, preferably in non-human primates. Feline predatory behavior has no equivalent in man, and therefore its hypothalamic representation probably does not exist in the human brain. Codes of information, frames of reference for sensory perception, axis to evaluate threats, and formulas for aggressive performance are not established genetically but must be learned individually. We are born with the capacity to learn aggressive behavior, but not with established patterns of violence. Mechanisms for fighting which are acquired by individual experience may be triggered in a similar way by sensory cues, volition, and by electrical stimulation of specific cerebral areas. In monkeys, aggressive responses may be modified by changing the hierarchical position of the stimulated animal, indicating the physiological quality of the neurological mechanisms electrically activated.

Genetic Alterations in Glioma

PubMed Central

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. PMID:24212656

ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells.

PubMed

Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis

2017-06-01

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. © 2017 The Authors.

Subcutaneous tissue metastasis from glioblastoma multiforme: A case report and review of the literature.

PubMed

Frade Porto, Natalia; Delgado Fernández, Juan; García Pallero, María de Los Ángeles; Penanes Cuesta, Juan Ramón; Pulido Rivas, Paloma; Gil Simoes, Ricardo

2018-05-16

Glioblastoma multiforme is the most common primary brain tumor, despite an aggressive clinical course, less than 2% of patients develop extraneural metastasis. We present a 72-year-old male diagnosed with a right temporal glioblastoma due to headache. He underwent total gross resection surgery and after that the patient was treated with adyuvant therapy. Five months after the patient returned with trigeminal neuralgia, and MRI showed an infratemporal cranial mass which infiltrates masticator space, the surrounding bone, the temporal muscle and superior cervical and parotid lymph nodes. The patient underwent a new surgery reaching partial resection of the temporal lesion. After that the patient continued suffering from disabling trigeminal neuralgia, that's why because of the bad clinical situation and the treatment failure we decided to restrict therapeutic efforts. The patient died 3 weeks after the diagnosis of extracranial metastasis. Copyright © 2018 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Crystals in brain and meninges in primary hyperoxaluria and oxalosis.

PubMed Central

Haqqani, M T

1977-01-01

A case of primary hyperoxaluria and oxalosis with chronic renal failure, crystalline myocarditis, and disseminated calcium oxalate crystal deposition in various tissues including the brain and meninges is described. Deposition of crystals in brain and meninges is exceptionally rare in primary oxalosis. Images PMID:838867

Violent offending predicts P300 amplitude.

PubMed

Bernat, Edward M; Hall, Jason R; Steffen, Benjamin V; Patrick, Christopher J

2007-11-01

Prior work has consistently revealed a relationship between antisocial behavior and reduced P300 amplitude. Fewer studies have directly evaluated behavioral indices of aggression and P300, and those that have generally do not account for potential mediating variables such as age, intelligence, and behavioral task performance. The current study assessed the relationship between the total number of convicted violent and non-violent offenses and P300 in a sample of inmates from a medium security state prison. Violent offenses evidenced a robust negative relationship with P300 amplitude, whereas non-violent offenses did not. Additional analyses evaluated age, intelligence, and behavioral task performance as potential mediating variables. Only reaction time significantly predicted P300 amplitude, and mediational analyses showed that this relationship did not account for the violent-offense/P300 relationship. Findings are discussed in terms of personality correlates and neurobiological process related to aggression. There is long-standing interest in the notion that antisocial behavior, and aggression in particular, involves neurobiologically-based deficits in information processing. Neuropsychological research has revealed that antisocial behavior is associated with impaired executive function (c.f. Morgan and Lilienfeld, 2000), and neuroimaging studies have consistently identified frontal lobe abnormalities among violent offenders (Goyer et al., 1994; Raine et al., 1997; Raine et al., 2000; Volkow et al., 1995). Furthermore, research using event-related brain potentials has indicated that antisocial behavior is associated with reduced P300 responses to task-relevant stimuli in target detection tasks (e.g., Bauer et al., 1994; Iacono et al., 2003). These deficits may reflect inefficient neural processing of salient environmental stimuli (Donchin and Coles, 1988), which could potentially contribute to risk for antisocial deviance. Notably, antisocial behavior encompasses both violent and nonviolent transgressions. One unresolved issue is whether P300 amplitude is associated with both violent and non-violent forms of antisocial behavior, or more predominantly with aggressive forms of acting out. Some research has examined P300 response in aggressive individuals specifically (e.g., Barratt et al., 1997); this work has revealed that reduced P300 amplitude is selectively related to impulsive, but not instrumental, aggression. However, this work has not compared associations for aggressive versus non-aggressive offending behavior. Thus, the aim of the present study was to replicate and extend prior research on antisocial behavior and brain response by examining relations between violent and non-violent offenses and P300 amplitude in a sample of adult male inmates. Our prediction was that reduced P300 response would be associated more predominantly with a history of violent offending, and that this effect would be independent of age, intelligence, and task performance effects.

Effects of Postnatal Serotonin Agonism on Fear Response and Memory

USDA-ARS?s Scientific Manuscript database

The neurotransmitter serotonin (5-HT) also acts as a neurogenic compound in the developing brain. Early administration of a 5-HT agonist could alter the development of the serotonergic circuitry, altering behaviors mediated by 5-HT signaling, such as memory, fear and aggression. White leghorn chicks...

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.

PubMed

Gump, Jacob M; Donson, Andrew M; Birks, Diane K; Amani, Vladimir M; Rao, Karun K; Griesinger, Andrea M; Kleinschmidt-DeMasters, B K; Johnston, James M; Anderson, Richard C E; Rosenfeld, Amy; Handler, Michael; Gore, Lia; Foreman, Nicholas; Hankinson, Todd C

2015-05-21

Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP. Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples. We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

Aggressive Rare T-cell Lymphomas with Manifestation in the Skin: A Monocentric Cross-sectional Case Study.

PubMed

Brüggen, Marie-Charlotte; Kerl, Katrin; Haralambieva, Eugenia; Schanz, Urs; Chang, Yun-Tsan; Ignatova, Desislava; Dummer, Reinhard; Cozzio, Antonio; Hoetzenecker, Wolfram; French, Lars E; Guenova, Emmanuella

2018-04-24

Rare T- or NK-cell lymphomas with cutaneous manifestation may display a highly aggressive clinical course and major diagnostic/therapeutic challenges. This report describes our experiences with different lymphomas of this rare category and the therapeutic options used. This retrospective, descriptive, monocentric, cross-sectional case study, identified 4 rare aggressive T-/NK-cell lymphomas with manifestation in the skin, which were diagnosed in a tertiary care centre over a period of 4 years. Two patients had an Epstein-Barr virus-associated extranodal NK/T-cell lymphoma and 2 patients had a primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Concomitant extracutaneous involvement was observed in 2 of all 4 patients. Two patients had fulminant disease progression and resistance to chemotherapy. Two patients underwent allogeneic haematopoietic stem cell transplantation, which resulted in one complete remission and one partial remission. This report emphasizes the importance of an early diagnostic work-up and a prompt aggressive therapeutic approach.

NOS2 expression in glioma cell lines and glioma primary cell cultures: correlation with neurosphere generation and SOX-2 expression.

PubMed

Palumbo, Paola; Miconi, Gianfranca; Cinque, Benedetta; Lombardi, Francesca; La Torre, Cristina; Dehcordi, Soheila Raysi; Galzio, Renato; Cimini, Annamaria; Giordano, Antonio; Cifone, Maria Grazia

2017-04-11

Nitric oxide has been implicated in biology and progression of glioblastoma (GBM) being able to influence the cellular signal depending on the concentration and duration of cell exposure. NOS2 (inducible nitric oxide synthase) have been proposed as a component of molecular profile of several tumors, including glioma, one of the most aggressive primary brain tumor featuring local cancer stem cells responsible for enhanced resistance to therapies and for tumor recurrence. Here, we investigated the NOS2 mRNA expression by reverse transcription-PCR in human glioma primary cultures at several grade of malignancy and glioma stem cell (GSC) derived neurospheres. Glioma cell lines were used as positive controls both in terms of stemness marker expression that of capacity of generating neurospheres. NOS2 expression was detected at basal levels in cell lines and primary cultures and appeared significantly up-regulated in cultures kept in the specific medium for neurospheres. The immunofluorescence analysis of all cell cultures to evaluate the levels of SOX-2, a stemness marker aberrantly up-regulated in GBM, was also performed. The potential correlation between NOS2 expression and ability to generate neurospheres and between NOS2 and SOX-2 levels was also verified. The results show that the higher NOS2 expression is detected in all primary cultures able to arise neurosphere. A high and significant correlation between NOS2 expression and SOX-2 positive cells (%) in all cell cultures maintained in standard conditions has been observed. The results shed light on the potential relevance of NOS2 as a prognostic factor for glioma malignancy and recurrence.

[Serotonergic genes in the development of anxiety/depression-like state and pathology of aggressive behavior in male mice: RNA-seq data].

PubMed

Kudryavtseva, N N; Smagin, D A; Kovalenko, I L; Galyamina, A G; Vishnivetskaya, G B; Babenko, V N; Orlov, Yu L

2017-01-01

In course of daily agonistic interactions, mice tend to stratify into those with chronic social defeats and those that repeatedly display aggression, which lead to the development of mixed anxiety/depression-like state and the pathology of aggressive behavior, respectively. Using the data of whole transcriptome analysis (RNA-seq), the changes in the expression of serotonergic genes involved in the synthesis, inactivation, and reception of serotonin, as well as of the Creb1 (transcription factor) gene and the Bdnf (brain-derived neurotrophic factor) gene were detected in the striatum (STR), ventral tegmental area (VTA), midbrain raphe nuclei (MRN), hypothalamus (HYP), and hippocampus (HIP) of defeated and aggressive male mice. In mice of both groups, the Tph2, Ddc, Slc6a4, Htr2a, Htr3a, Htr5b, Slc18a2, and Bdnf genes were downregulated in the MRN and the Tph2, Ddc, and Slc6a4 genes were upregulated in the VTA. These changes were more significant in defeated mice. The Htr5b gene has first been shown to be involved in mechanisms of depression and pathology of aggressive behavior. In the defeated mice, the expression levels of the Htr4 and Aldh1b1 genes were increased in the MRN, and expression levels of the Maob, Htr4, Htr1a, and Slc18a2 genes were increased in the VTA, while the expression level of the Htr3a gene was decreased. In the HYP of aggressive mice the Maoa, Htr2a, Htr2c, and Creb1 genes were downregulated and the Htr6 gene was upregulated. In the defeated mice, the Maoa and Creb1 genes were downregulated and the Htr6 and Aldh1b1 genes were upregulated in the HYP. In the STR, the Htr1a gene was downregulated and the Htr7 and Bdnf genes were upregulated. The Htr1b gene was upregulated in the HIP. The coexpression of dopaminergic and serotonergic genes in the MRN and VTA in the control of pathological behaviors is discussed. Thus, the complex pattern of differential expression of serotonergic genes in brain regions developing under repeated agonistic interactions in mice in dependence on behavioral pathology have been observed.

Comparative analyses identify molecular signature of MRI-classified SVZ-associated glioblastoma

PubMed Central

Lin, Chin-Hsing Annie; Rhodes, Christopher T.; Lin, ChenWei; Phillips, Joanna J.; Berger, Mitchel S.

2017-01-01

ABSTRACT Glioblastoma (GBM) is a highly aggressive brain cancer with limited therapeutic options. While efforts to identify genes responsible for GBM have revealed mutations and aberrant gene expression associated with distinct types of GBM, patients with GBM are often diagnosed and classified based on MRI features. Therefore, we seek to identify molecular representatives in parallel with MRI classification for group I and group II primary GBM associated with the subventricular zone (SVZ). As group I and II GBM contain stem-like signature, we compared gene expression profiles between these 2 groups of primary GBM and endogenous neural stem progenitor cells to reveal dysregulation of cell cycle, chromatin status, cellular morphogenesis, and signaling pathways in these 2 types of MRI-classified GBM. In the absence of IDH mutation, several genes associated with metabolism are differentially expressed in these subtypes of primary GBM, implicating metabolic reprogramming occurs in tumor microenvironment. Furthermore, histone lysine methyltransferase EZH2 was upregulated while histone lysine demethylases KDM2 and KDM4 were downregulated in both group I and II primary GBM. Lastly, we identified 9 common genes across large data sets of gene expression profiles among MRI-classified group I/II GBM, a large cohort of GBM subtypes from TCGA, and glioma stem cells by unsupervised clustering comparison. These commonly upregulated genes have known functions in cell cycle, centromere assembly, chromosome segregation, and mitotic progression. Our findings highlight altered expression of genes important in chromosome integrity across all GBM, suggesting a common mechanism of disrupted fidelity of chromosome structure in GBM. PMID:28278055

Changes in Signal Intensity of the Dentate Nucleus and Globus Pallidus in Pediatric Patients: Impact of Brain Irradiation and Presence of Primary Brain Tumors Independent of Linear Gadolinium-based Contrast Agent Administration.

PubMed

Tamrazi, Benita; Nguyen, Binh; Liu, Chia-Shang J; Azen, Colleen G; Nelson, Mary B; Dhall, Girish; Nelson, Marvin D

2018-05-01

Purpose To determine whether whole-brain irradiation, chemotherapy, and primary brain pathologic conditions affect magnetic resonance (MR) imaging signal changes in pediatric patients independent of the administration of gadolinium-based contrast agents (GBCAs). Materials and Methods This institutional review board-approved, HIPAA-compliant study included 144 pediatric patients who underwent intravenous GBCA-enhanced MR imaging examinations (55 patients with primary brain tumors and whole-brain irradiation, 19 with primary brain tumors and chemotherapy only, 52 with primary brain tumors without any treatment, and 18 with neuroblastoma without brain metastatic disease). The signal intensities (SIs) in the globus pallidus (GP), thalamus (T), dentate nucleus (DN), and pons (P) were measured on unenhanced T1-weighted images. GP:T and DN:P SI ratios were compared between groups by using the analysis of variance and were analyzed relative to group, total cumulative number of doses of GBCA, age, and sex by using multivariable linear models. Results DN:P ratio for the radiation therapy group was greater than that for the other groups except for the group of brain tumors treated with chemotherapy (P < .05). The number of GBCA doses was correlated with the DN:P ratio for the nontreated brain tumor group (P < .0001). The radiation therapy-treated brain tumor group demonstrated higher DN:P ratios than the nontreated brain tumor group for number of doses less than or equal to 10 (P < .0001), whereas ratios in the nontreated brain tumor group were higher than those in the radiation therapy-treated brain tumor group for doses greater than 20 (P = .05). The GP:T ratios for the brain tumor groups were greater than that for the neuroblastoma group (P = .01). Conclusion Changes in SI of the DN and GP that are independent of the administration of GBCA occur in patients with brain tumors undergoing brain irradiation, as well as in patients with untreated primary brain tumors. © RSNA, 2017.

An Exploratory Trial of Transdermal Nicotine for Aggression and Irritability in Adults with Autism Spectrum Disorder.

PubMed

Lewis, Alan S; van Schalkwyk, Gerrit Ian; Lopez, Mayra Ortiz; Volkmar, Fred R; Picciotto, Marina R; Sukhodolsky, Denis G

2018-03-13

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of 7 mg transdermal nicotine or placebo, each for 1 week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.

Primary Vaginal Melanoma, A Rare and Aggressive Entity. A Case Report and Review of the Literature

PubMed Central

KALAMPOKAS, EMMANOUIL; KALAMPOKAS, THEODOROS; DAMASKOS, CHRISTOS

2017-01-01

Malignant melanoma of the vagina is a rare, aggressive malignancy of poor prognosis. It principally affects post-menopausal women, with a mean age of 57 years, and the factors that contribute to its appearance are not well known. The first case of primary malignant vaginal melanoma was reported in 1887 and modern literature has noted about 500 cases, globally. Vaginal melanomas constitute 0.3% of all malignant melanomas and fewer than 3% of all vaginal carcinomas. To date there is no clear consensus regarding treatment. An early, accurate diagnosis and prompt investigation is essential in reaching appropriate treatment decisions. We present a clinical case of primary vaginal melanoma and review the literature briefly, presenting the current treatment plans and updates of this rare gynecological malignancy. Considerations, epidemiology, associated risk factors, response to therapy and expected outcome are also discussed. Conclusion: Primary malignant vaginal melanoma is a rare but aggressive melanoma that affects women in their 6th and 7th decade of life. The tumor appears as a dark node or spindle but can also be amelanotic. The size of the tumor is indicative of the prognostic factors. Surgery seems to be the only efficient treatment. Postoperative adjuvant therapy might help in preventing recurrence of the tumor. The survival rate is largely dependent on nodal and distant metastasis of the disease after initial tumor resection. There is a dire need to form a proper therapeutic regime to control this disease. PMID:28064232

The significance of BRAF V600E mutation status discordance between primary cutaneous melanoma and brain metastases: The implications for BRAF inhibitor therapy.

PubMed

Hannan, Enda J; O'Leary, Donal P; MacNally, Stephen P; Kay, Elaine W; Farrell, Michael A; Morris, Patrick G; Power, Colm P; Hill, Arnold D K

2017-12-01

To compare BRAF V600E status of primary melanoma and brain metastases to assess for discordance by cross-sectional study, and to evaluate clinical implications on BRAF inhibitor therapy.Brain metastases are common in patients with advanced melanoma. Between 40% and 60% of melanomas demonstrate BRAF mutations, BRAF V600E being most common. Selective BRAF inhibitor therapy has shown improvement in outcome in patients with melanoma. It has been demonstrated that not all metastatic lesions carry the same BRAF mutation status as the primary, but the frequency in which discordance occurs remains unclear. Establishing this may have implications in the use of BRAF inhibitors in patients with melanoma brain metastases.Patients who underwent metastectomy for melanoma brain metastases were identified using our local histopathology database. A review of histology of the primary lesion and the metastasis was performed for each patient, assessing for BRAF mutation status discordance.Fourty-two patients who underwent a brain metastectomy following excision of a melanoma primary were identified over a 7-year period. Median survival was 9 months. The median Breslow thickness for the primary lesion was 3.4 mm. Six patients (14%) had discrepancy between the BRAF status of a melanoma primary and metastatic lesion. Of these 6 patients, 3 had a BRAF mutation positive primary with a BRAF mutation negative metastatic lesion, while the other 3 had a BRAF mutation negative primary with BRAF mutation positive metastasis.There is an important discordance rate in the BRAF mutation status of melanoma primaries versus brain metastases.

TOP2A and EZH2 Provide Early Detection of an Aggressive Prostate Cancer Subgroup.

PubMed

Labbé, David P; Sweeney, Christopher J; Brown, Myles; Galbo, Phillip; Rosario, Spencer; Wadosky, Kristine M; Ku, Sheng-Yu; Sjöström, Martin; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Karnes, R Jeffrey; Schaeffer, Edward M; Jenkins, Robert B; Den, Robert B; Ross, Ashley E; Bowden, Michaela; Huang, Ying; Gray, Kathryn P; Feng, Felix Y; Spratt, Daniel E; Goodrich, David W; Eng, Kevin H; Ellis, Leigh

2017-11-15

Purpose: Current clinical parameters do not stratify indolent from aggressive prostate cancer. Aggressive prostate cancer, defined by the progression from localized disease to metastasis, is responsible for the majority of prostate cancer-associated mortality. Recent gene expression profiling has proven successful in predicting the outcome of prostate cancer patients; however, they have yet to provide targeted therapy approaches that could inhibit a patient's progression to metastatic disease. Experimental Design: We have interrogated a total of seven primary prostate cancer cohorts ( n = 1,900), two metastatic castration-resistant prostate cancer datasets ( n = 293), and one prospective cohort ( n = 1,385) to assess the impact of TOP2A and EZH2 expression on prostate cancer cellular program and patient outcomes. We also performed IHC staining for TOP2A and EZH2 in a cohort of primary prostate cancer patients ( n = 89) with known outcome. Finally, we explored the therapeutic potential of a combination therapy targeting both TOP2A and EZH2 using novel prostate cancer-derived murine cell lines. Results: We demonstrate by genome-wide analysis of independent primary and metastatic prostate cancer datasets that concurrent TOP2A and EZH2 mRNA and protein upregulation selected for a subgroup of primary and metastatic patients with more aggressive disease and notable overlap of genes involved in mitotic regulation. Importantly, TOP2A and EZH2 in prostate cancer cells act as key driving oncogenes, a fact highlighted by sensitivity to combination-targeted therapy. Conclusions: Overall, our data support further assessment of TOP2A and EZH2 as biomarkers for early identification of patients with increased metastatic potential that may benefit from adjuvant or neoadjuvant targeted therapy approaches. Clin Cancer Res; 23(22); 7072-83. ©2017 AACR . ©2017 American Association for Cancer Research.

Oxytocin And Vasopressin Modulation Of The Neural Correlates Of Motivation And Emotion: Results From Functional MRI Studies In Awake Rats

PubMed Central

Febo, Marcelo; Ferris, Craig F.

2014-01-01

Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. PMID:24486356

Brain abnormalities in antisocial individuals: implications for the law.

PubMed

Yang, Yaling; Glenn, Andrea L; Raine, Adrian

2008-01-01

With the increasing popularity in the use of brain imaging on antisocial individuals, an increasing number of brain imaging studies have revealed structural and functional impairments in antisocial, psychopathic, and violent individuals. This review summarizes key findings from brain imaging studies on antisocial/aggressive behavior. Key regions commonly found to be impaired in antisocial populations include the prefrontal cortex (particularly orbitofrontal and dorsolateral prefrontal cortex), superior temporal gyrus, amygdala-hippocampal complex, and anterior cingulate cortex. Key functions of these regions are reviewed to provide a better understanding on how deficits in these regions may predispose to antisocial behavior. Objections to the use of imaging findings in a legal context are outlined, and alternative perspectives raised. It is argued that brain dysfunction is a risk factor for antisocial behavior and that it is likely that imaging will play an increasing (albeit limited) role in legal decision-making. (c) 2008 John Wiley & Sons, Ltd.

Experiences of violence and deficits in academic achievement among urban primary school children in Jamaica.

PubMed

Baker-Henningham, Helen; Meeks-Gardner, Julie; Chang, Susan; Walker, Susan

2009-05-01

The aim of this study was to examine the relationship between children's experiences of three different types of violence and academic achievement among primary school children in Kingston, Jamaica. A cross-sectional study of 1300 children in grade 5 [mean (S.D.) age: 11 (0.5) years] from 29 government primary schools in urban areas of Kingston and St. Andrew, Jamaica, was conducted. Academic achievement (mathematics, reading, and spelling) was assessed using the Wide Range Achievement Test. Children's experiences of three types of violence - exposure to aggression among peers at school, physical punishment at school, and exposure to community violence - were assessed by self-report using an interviewer administered questionnaire. Fifty-eight percent of the children experienced moderate or high levels of all three types of violence. Boys had poorer academic achievement and experienced higher levels of aggression among peers and physical punishment at school than girls. Children's experiences of the three types of violence were independently associated with all three indices of academic achievement. There was a dose-response relationship between children's experiences of violence and academic achievement with children experiencing higher levels of violence having the poorest academic achievement and children experiencing moderate levels having poorer achievement than those experiencing little or none. Exposure to three different types of violence was independently associated with poor school achievement among children attending government, urban schools in Jamaica. Programs are needed in schools to reduce the levels of aggression among students and the use of physical punishment by teachers and to provide support for children exposed to community violence. Children in Jamaica and the wider Caribbean experience significant amounts of violence in their homes, communities, and schools. In this study, we demonstrate a dose-response relationship between primary school children's experiences of three different types of violence and their academic achievement. The study points to the need for validated violence prevention programs to be introduced in Jamaican primary schools. Such programs need to train teachers in appropriate classroom management and discipline strategies and to promote children's social and emotional competence and prevent aggression.

Neural Mechanisms of Cognitive-Behavioral Therapy for Aggression in Children and Adolescents: Design of a Randomized Controlled Trial Within the National Institute for Mental Health Research Domain Criteria Construct of Frustrative Non-Reward

PubMed Central

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

Lethal obesity associated with sodium valproate in a brain-injured patient.

PubMed

Black, Deborah N; Althoff, Robert R; Daye, Kathleen; Pelletier, Corinne A

2005-06-01

A 34-year-old man developed posttraumatic epilepsy and a disinhibited orbitofrontal syndrome following severe head trauma at age 22. After an 11-year prison term marked by repeated impulsive aggression, he was transferred to a state psychiatric hospital. Replacement of phenytoin by valproic acid resulted in a 100-lb weight gain, exacerbation of sleep apnea, and right heart failure. Despite replacement of valproate with topiramate, he died of a cardiorespiratory arrest during a seizure. This case illustrates the potential risks associated with valproate therapy in the obese brain-damaged population.

[Global brain metastases management strategy: a multidisciplinary-based approach].

PubMed

Métellus, P; Tallet, A; Dhermain, F; Reyns, N; Carpentier, A; Spano, J-P; Azria, D; Noël, G; Barlési, F; Taillibert, S; Le Rhun, É

2015-02-01

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources. Copyright © 2015. Published by Elsevier SAS.

Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma

PubMed Central

Walther, Madlin; Schneider, Björn; Linnebacher, Michael; Classen, Carl Friedrich

2018-01-01

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumor with a dismal prognosis. Development of resistance towards cytostatic drugs like the GBM standard drug temozolomide is a severe problem in GBM treatment. One potential source of GBM relapse could be so called cancer stem like cells (CSCs). These represent an undifferentiated subpopulation of cells with high potential for tumor initiation. Furthermore, it has been shown that differentiated GBM cells can regain CSC properties when exposed to continuous temozolomide treatment in vitro. In this study, treatment of several primary GBM cell lines with clinically relevant doses of temozolomide increased their tumorigenicity as determined by colony formation assays in soft agar. Increased tumorigenicity is a known property of CSCs. Hence, therapy options that specifically target CSCs are under investigation. CSCs appear to be particularly dependent on mitochondria biogenesis which may represent a useful target for CSC elimination. Toxicity towards mitochondria is a known side effect of several antibiotics. Thus, addition of antibiotics like doxycycline may represent a useful tool to inhibit CSCs in GBM. Here, we show that combining temozolomide treatment of primary GBM cells with doxycycline could counteract the increase of tumorigenicity induced by temozolomide treatment. PMID:29352318

Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation.

PubMed

Shi, Jinlong; Sun, Baolan; Shi, Wei; Zuo, Hao; Cui, Daming; Ni, Lanchun; Chen, Jian

2015-02-01

Gliomas are the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve therapies, their prognosis remains very poor. Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered frequently in glioma patients and are strongly correlated with improved survival. However, the effect of IDH1 mutations on the chemosensitivity of gliomas remains unclear. In this study, we generated clonal U87 and U251 glioma cell lines overexpressing the R132H mutant protein (IDH1-R132H). Compared with control cells and cells overexpressing IDH wild type (IDH1-WT), both types of IDH1-R132H cells were more sensitive to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP) in a time- and dose-dependent manner. The IDH1-R132H-induced higher chemosensitivity was associated with nicotine adenine disphosphonucleotide (NADPH), glutathione (GSH) depletion, and reactive oxygen species (ROS) generation. Accordingly, this IDH1-R132H-induced growth inhibition was effectively abrogated by GSH in vitro and in vivo. Our study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH1-R132H protein on chemosensitivity. The primary cellular events associated with improved survival are the GSH depletion and increased ROS generation.

Quality of Life in Patients With Primary and Metastatic Brain Tumors in the Literature as Assessed by the FACT-Br.

PubMed

Chiu, Nicholas; Chiu, Leonard; Zeng, Liang; Zhang, Liying; Cella, David; Popovic, Marko; Chow, Ronald; Lam, Henry; Poon, Michael; Chow, Edward

2012-12-01

The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a quality of life (QOL) assessment tool that was originally developed for use in patients with primary brain tumors. However, the tool has also been used to assess QOL in patients with metastatic brain tumors. The purpose of this study is to compare the differences in QOL responses as assessed by the FACT-Br in patients with primary and metastatic brain neoplasms. A systematic literature search was conducted using the OvidSP platform in MEDLINE (1946 to July Week 2 2012) and EMBASE (1980 to 2012 Week 28). Articles in which the FACT-Br was used as a QOL assessment for patients with malignant brain tumors (both primary and metastatic) were included in the study. The weighted means of FACT-Br subscale and overall scores were calculated for the studies. To compare these scores, weighted analysis of variance was conducted and PROC GLM was performed for the data. A P-value of < 0.05 was considered statistically significant. A total of 23 studies (four in brain metastases, 18 in primary brain tumors and 1 in a mixed sample) using the FACT-Br for assessment of QOL were identified. Social and functional well-being were significantly better in patients with primary brain tumors (weighted mean score of 22.2 vs. 10.7, P = 0.0026, 16.9 vs. 6.2, P = 0.0025, respectively). No other scale of the FACT-Br was significantly different between the two groups and the performance status of patients included in both groups was similar. Patients with primary brain cancer seemed to have better social and functional well-being scores than those with metastatic brain tumors. Other QOL domains were similar between these two groups. However, the heterogeneity in the included studies and the low sample size of included samples in patients with metastatic brain tumors could have confounded our findings.

Dual Pathways from Reactive Aggression to Depressive Symptoms in Children: Further Examination of the Failure Model.

PubMed

Evans, Spencer C; Fite, Paula J

2018-04-13

The failure model posits that peer rejection and poor academic performance are dual pathways in the association between early aggressive behavior and subsequent depressive symptoms. We examined this model using an accelerated longitudinal design while also incorporating proactive and reactive aggression and gender moderation. Children in 1st, 3rd, and 5th grades (n = 912; ages 6-12; 48% female) were rated three times annually by their primary teachers on measures of proactive and reactive aggression, peer rejection, academic performance, and depressive symptoms. Using Bayesian cross-classified estimation to account for nested and planned-missing data, path models were estimated to examine whether early reactive aggression predicted subsequent peer rejection and academic performance, and whether these, in turn, predicted subsequent depressive symptoms. From 1st to 3rd grade, reactive aggression predicted peer rejection (not academic performance), proactive aggression predicted academic performance (not peer rejection), and academic performance and peer rejection both predicted depressive symptoms. From 3rd to 5th grade, however, neither peer rejection nor academic performance predicted subsequent depressive symptoms. Results were not moderated by gender. Overall, these findings provide mixed and limited support for the failure model among school-age children. Early reactive aggression may be a key risk factor for social problems, whereas proactive aggression may be linked to improved academic functioning. The "dual pathways" of peer rejection and academic performance may operate during early but not later elementary school. Limitations and implications are discussed.

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial.

PubMed

Derdeyn, Colin P; Chimowitz, Marc I; Lynn, Michael J; Fiorella, David; Turan, Tanya N; Janis, L Scott; Montgomery, Jean; Nizam, Azhar; Lane, Bethany F; Lutsep, Helmi L; Barnwell, Stanley L; Waters, Michael F; Hoh, Brian L; Hourihane, J Maurice; Levy, Elad I; Alexandrov, Andrei V; Harrigan, Mark R; Chiu, David; Klucznik, Richard P; Clark, Joni M; McDougall, Cameron G; Johnson, Mark D; Pride, G Lee; Lynch, John R; Zaidat, Osama O; Rumboldt, Zoran; Cloft, Harry J

2014-01-25

Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70-99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (-0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%]of 224 patients vs 10 [4%] of 227 patients; p=0·0009). The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. National Institute of Neurological Disorders and Stroke (NINDS) and others. Copyright © 2014 Elsevier Ltd. All rights reserved.

Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial

PubMed Central

Derdeyn, Colin P; Chimowitz, Marc I; Lynn, Michael J; Fiorella, David; Turan, Tanya N; Janis, L Scott; Montgomery, Jean; Nizam, Azhar; Lane, Bethany F; Lutsep, Helmi L; Barnwell, Stanley L; Waters, Michael F; Hoh, Brian L; Hourihane, J Maurice; Levy, Elad I; Alexandrov, Andrei V; Harrigan, Mark R; Chiu, David; Klucznik, Richard P; Clark, Joni M; McDougall, Cameron G; Johnson, Mark D; Pride, G Lee; Lynch, John R; Zaidat, Osama O; Rumboldt, Zoran; Cloft, Harry J

2014-01-01

Summary Background Early results of the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial showed that, by 30 days, 33 (14·7%) of 224 patients in the stenting group and 13 (5·8%) of 227 patients in the medical group had died or had a stroke (percentages are product limit estimates), but provided insufficient data to establish whether stenting offered any longer-term benefit. Here we report the long-term outcome of patients in this trial. Methods We randomly assigned (1:1, stratified by centre with randomly permuted block sizes) 451 patients with recent transient ischaemic attack or stroke related to 70–99% stenosis of a major intracranial artery to aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle-modification programme) or aggressive medical management plus stenting with the Wingspan stent. The primary endpoint was any of the following: stroke or death within 30 days after enrolment, ischaemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or stroke or death within 30 days after a revascularisation procedure of the qualifying lesion during follow-up. Primary endpoint analysis of between-group differences with log-rank test was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00576693. Findings During a median follow-up of 32·4 months, 34 (15%) of 227 patients in the medical group and 52 (23%) of 224 patients in the stenting group had a primary endpoint event. The cumulative probability of the primary endpoints was smaller in the medical group versus the percutaneous transluminal angioplasty and stenting (PTAS) group (p=0·0252). Beyond 30 days, 21 (10%) of 210 patients in the medical group and 19 (10%) of 191 patients in the stenting group had a primary endpoint. The absolute differences in the primary endpoint rates between the two groups were 7·1% at year 1 (95% CI 0·2 to 13·8%; p=0·0428), 6·5% at year 2 (−0·5 to 13·5%; p=0·07) and 9·0% at year 3 (1·5 to 16·5%; p=0·0193). The occurrence of the following adverse events was higher in the PTAS group than in the medical group: any stroke (59 [26%] of 224 patients vs 42 [19%] of 227 patients; p=0·0468) and major haemorrhage (29 [13%] of 224 patients vs 10 [4%] of 227 patients; p=0·0009). Interpretation The early benefit of aggressive medical management over stenting with the Wingspan stent for high-risk patients with intracranial stenosis persists over extended follow-up. Our findings lend support to the use of aggressive medical management rather than PTAS with the Wingspan system in high-risk patients with atherosclerotic intracranial arterial stenosis. PMID:24168957

A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.

PubMed

Coccaro, Emil F; Lee, Royce J; Kavoussi, Richard J

2009-04-21

Intermittent explosive disorder (IED) is a disorder of impulsive aggression that affects as many as 7.3% of the U.S. population during some period of life. Since central serotonergic (5-HT) system dysfunction is related to impulsive aggressive behavior, pharmacologic enhancement of 5-HT activity should reduce impulsive aggressive behavior in individuals with IED. A double-blind, randomized, placebo-controlled trial of the selective 5-HT uptake inhibitor fluoxetine was conducted in 100 individuals with IED (research diagnostic criteria) and current histories of impulsive aggressive behavior. The primary efficacy measure was the aggression score from the Overt Aggression Scale-Modified (OAS-M) for Outpatient Use. Secondary efficacy measures included the irritability score from the OAS-M and the Clinical Global Impressions-Improvement scale (CGI-I) score. The study took place between July 1990 and July 1999. Fluoxetine treatment resulted in a sustained reduction in OAS-M aggression, and OAS-M irritability scores, apparent as early as week 2 (p < .01 for aggression and p < .001 for irritability at endpoint). Fluoxetine was also superior to placebo in the proportion of responders on the CGI-I (p < .001). Closer examination of the data revealed that full or partial remission of impulsive aggressive behaviors, as reflected by the A criteria for IED, occurred in 46% of fluoxetine-treated subjects. Fluoxetine did not exert an antidepressant or antianxiety effect, and its effects on impulsive aggression were not influenced by presence of current symptoms of depression or anxiety. Fluoxetine treatment has a clear antiaggressive effect in impulsive aggressive individuals with IED. However, while fluoxetine's antiaggressive effects appear robust, they lead to full or partial remission of IED in less than 50% of subjects treated with fluoxetine. Copyright 2009 Physicians Postgraduate Press, Inc.

Mediators and moderators of long-term effects of violent video games on aggressive behavior: practice, thinking, and action.

PubMed

Gentile, Douglas A; Li, Dongdong; Khoo, Angeline; Prot, Sara; Anderson, Craig A

2014-05-01

Although several longitudinal studies have demonstrated an effect of violent video game play on later aggressive behavior, little is known about the psychological mediators and moderators of the effect. To determine whether cognitive and/or emotional variables mediate the effect of violent video game play on aggression and whether the effect is moderated by age, sex, prior aggressiveness, or parental monitoring. Three-year longitudinal panel study. A total of 3034 children and adolescents from 6 primary and 6 secondary schools in Singapore (73% male) were surveyed annually. Children were eligible for inclusion if they attended one of the 12 selected schools, 3 of which were boys' schools. At the beginning of the study, participants were in third, fourth, seventh, and eighth grades, with a mean (SD) age of 11.2 (2.1) years (range, 8-17 years). Study participation was 99% in year 1. The final outcome measure was aggressive behavior, with aggressive cognitions (normative beliefs about aggression, hostile attribution bias, aggressive fantasizing) and empathy as potential mediators. Longitudinal latent growth curve modeling demonstrated that the effects of violent video game play are mediated primarily by aggressive cognitions. This effect is not moderated by sex, prior aggressiveness, or parental monitoring and is only slightly moderated by age, as younger children had a larger increase in initial aggressive cognition related to initial violent game play at the beginning of the study than older children. Model fit was excellent for all models. Given that more than 90% of youths play video games, understanding the psychological mechanisms by which they can influence behaviors is important for parents and pediatricians and for designing interventions to enhance or mitigate the effects.

Trends in incidence of primary brain cancer in New Zealand, 1995 to 2010.

PubMed

Kim, Stella J-H; Ioannides, Sally J; Elwood, J Mark

2015-04-01

Case-control studies have linked mobile phone use to an increased risk of glioma in the most exposed brain areas, the temporal and parietal lobes, although inconsistently. We examined time trends in the incidence rates of brain malignancies in New Zealand from 1995 to 2010. Data from the New Zealand Cancer Registry was used to calculate incidence rates of primary brain cancer, by age, gender, morphology and anatomical site. Log-linear regression analysis was used to assess trends in the annual incidence of primary brain cancer; annual percentage changes and their 95% confidence intervals were estimated. No consistent increases in all primary brain cancer, glioma, or temporal or parietal lobe glioma were seen. At ages 10-69, the incidence of all brain cancers declined significantly. Incidence of glioma increased at ages over 70. In New Zealand, there has been no consistent increase in incidence rates of primary brain cancers. An increase in glioma at ages over 70 is likely to be due to improvements in diagnosis. As with any such studies, a small effect, or one with a latent period of more than 10 to 15 years, cannot be excluded. © 2015 Public Health Association of Australia.

Psychopharmacology of aggression in children and adolescents with primary neuropsychiatric disorders: a review of current and potentially promising treatment options.

PubMed

Nevels, Robert M; Dehon, Erin E; Alexander, Katrina; Gontkovsky, Samuel T

2010-04-01

Research examining the role of pharmacological therapy in the treatment of children and adolescents with clinical disorders is growing. Clinical disorders that present with comorbid aggression can add a challenge to treatment. Child and adolescent neuropsychiatric disorders associated with aggression include attention-deficit hyperactivity disorder, various mood disorders and in particular bipolar disorders/pediatric mania, schizophrenia, mental retardation, oppositional defiant disorder, conduct disorder, and autism spectrum disorders. This review describes the psychopharmacy to treat these disorders and the aggression that often appears comorbidly. Existing literature regarding the efficacy and safety of psychotropics for youth with neuropsychiatric disorders also is discussed. In addition, general guidelines for psychopharmacy of aggression in children and adolescents are presented. Studies reviewed in this article provide evidence for the use of psychostimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood-stabilizers, atypical antipsychotics, traditional antipsychotics, and selective serotonin reuptake inhibitors in treating pediatric aggression with the choice of medication dependent on symptomology. Despite increased support for pediatric psychotropic use, there is a need for more long-term safety and efficacy studies of existing medications and newer, safer, and more effective agents with fewer side effects for the pharmacological treatment of all childhood disorders in which aggression is prominent. 2010 APA, all rights reserved

The Staff Observation Aggression Scale - Revised (SOAS-R) - adjustment and validation for emergency primary health care.

PubMed

Morken, Tone; Baste, Valborg; Johnsen, Grethe E; Rypdal, Knut; Palmstierna, Tom; Johansen, Ingrid Hjulstad

2018-05-08

Many emergency primary health care workers experience aggressive behaviour from patients or visitors. Simple incident-reporting procedures exist for inpatient, psychiatric care, but a similar and simple incident-report for other health care settings is lacking. The aim was to adjust a pre-existing form for reporting aggressive incidents in a psychiatric inpatient setting to the emergency primary health care settings. We also wanted to assess the validity of the severity scores in emergency primary health care. The Staff Observation Scale - Revised (SOAS-R) was adjusted to create a pilot version of the Staff Observation Scale - Revised Emergency (SOAS-RE). A Visual Analogue Scale (VAS) was added to the form to judge the severity of the incident. Data for validation of the pilot version of SOAS-RE were collected from ten casualty clinics in Norway during 12 months. Variance analysis was used to test gender and age differences. Linear regression analysis was performed to evaluate the relative impact that each of the five SOAS-RE columns had on the VAS score. The association between SOAS-RE severity score and VAS severity score was calculated by the Pearson correlation coefficient. The SOAS-R was adjusted to emergency primary health care, refined and called The Staff Observation Aggression Scale - Revised Emergency (SOAS-RE). A total of 350 SOAS-RE forms were collected from the casualty clinics, but due to missing data, 291 forms were included in the analysis. SOAS-RE scores ranged from 1 to 22. The mean total severity score of SOAS-RE was 10.0 (standard deviation (SD) =4.1) and the mean VAS score was 45.4 (SD = 26.7). We found a significant correlation of 0.45 between the SOAS-RE total severity scores and the VAS severity ratings. The linear regression analysis showed that individually each of the categories, which described the incident, had a low impact on the VAS score. The SOAS-RE seems to be a useful instrument for research, incident-recording and management of incidents in emergency primary care. The moderate correlation between SOAS-RE severity score and the VAS severity score shows that application of both the severity ratings is valuable to follow-up of workers affected by workplace violence.

Bilateral primary malignant lymphoma of the breast.

PubMed

Shpitz, B; Witz, M; Kaufman, Z; Griffel, B; Manor, Y; Dinbar, A

1985-08-01

A rare case of bilateral primary malignant lymphoma of breast in a 76 year old woman is presented. The lesion was examined by electron microscopy and immunochemistry. The diagnosis of primary malignant lymphoma remains a diagnosis by exclusion and requires extensive work-up to exclude widespread malignant process. The behaviour of this malignancy tends to be an aggressive one and the prognosis is generally poor.

Long-term survival in a patient with brain metastases of papillary thyroid carcinoma

PubMed Central

Guelho, Daniela; Ribeiro, Cristina; Melo, Miguel; Carrilho, Francisco

2016-01-01

We present the case of a 43-year-old woman who underwent total thyroidectomy with bilateral lymphadenectomy for a papillary thyroid carcinoma (PTC), solid variant (T4bN1bMx), with V600E BRAF mutation. After ablative therapy, she presented undetectable thyroglobulin (Tg) but progressively increasing anti-Tg antibodies (TgAbs). During follow-up, nodal, lung and brain metastases were identified. She was submitted to surgical excision of lung lesions, radiosurgery of brain metastases and five radioiodine treatments. The latest brain MRI showed no lesions, pulmonary CT showed stable micronodules and there was progressive reduction in TgAbs. This is a peculiar case of a PTC with lung and brain metastatic lesions detected through TgAbs. Initial histological and molecular study suggested a more aggressive clinical behaviour, which was eventually confirmed. Although PTC brain metastases are extremely rare and present poor prognosis, our patient presented a good response to treatment and longer survival than usually reported for similar cases. PMID:26961557

Similar Progression of Morphological and Metabolic Phenotype in R6/2 Mice with Different CAG Repeats Revealed by In Vivo Magnetic Resonance Imaging and Spectroscopy.

PubMed

Sawiak, Stephen J; Wood, Nigel I; Morton, A Jennifer

2016-10-01

Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.

School-based secondary prevention programmes for preventing violence.

PubMed

Mytton, J; DiGuiseppi, C; Gough, D; Taylor, R; Logan, S

2006-07-19

Early aggressive behaviour is a risk factor for later violence and criminal behaviour. Despite over 20 years of violence prevention interventions being delivered in the school setting, questions remain regarding the effectiveness of different interventions for children exhibiting aggressive behaviour. To examine the effect of school based violence prevention programmes for children identified as aggressive or at risk of being aggressive. We searched CENTRAL, Cochrane Injuries Group specialised register, MEDLINE, EMBASE, other specialised databases and reference lists of articles. We also contacted authors and organisations to identify any further studies. We included trials meeting the following criteria; 1) participants were randomly assigned to intervention and control groups; 2) outcome data were collected concurrently; 3) participants comprised children in mandatory education identified as exhibiting, or at risk of, aggressive behaviour; 4) interventions designed to reduce aggression, violence, bullying, conflict or anger; 5) school based interventions; 6) outcomes included aggressive behaviour, school and agency responses to acts of aggression, or violent injuries. Data were collected on design, participants, interventions, outcomes and indicators of study quality. Results of any intervention to no intervention were compared immediately post-intervention and at 12 months using meta-analysis where appropriate. Of 56 trials identified, none reported data on violent injuries. Aggressive behaviour was significantly reduced in intervention groups compared to no intervention groups immediately post intervention in 34 trials with data, (Standardised Mean Difference (SMD) = -0.41; 95% confidence interval (CI) -0.56 to -0.26). This effect was maintained in the seven studies reporting 12 month follow-up (SMD = -0.40, (95% CI -0.73 to -0.06)). School or agency disciplinary actions in response to aggressive behaviour were reduced in intervention groups for nine trials with data, SMD = -0.48; 95% CI -1.16 to 0.19, although this difference may have been due to chance and was not maintained, based on two studies reporting follow-up to two to four months (SMD = 0.03; 95% CI -0.42 to 0.47). Subgroup analyses suggested that interventions designed to improve relationship or social skills may be more effective than interventions designed to teach skills of non-response to provocative situations, but that benefits were similar when delivered to children in primary versus secondary school, and to groups of mixed sex versus boys alone. School-based secondary prevention programmes to reduce aggressive behaviour appear to produce improvements in behaviour greater than would have been expected by chance. Benefits can be achieved in both primary and secondary school age groups and in both mixed sex groups and boys-only groups. Further research is required to establish whether such programmes reduce the incidence of violent injuries or if the benefits identified can be maintained beyond 12 months.

The Developing Brain: A Largely Overlooked Health Endpoint in Risk Assessments for Synthetic Chemical Substances

ERIC Educational Resources Information Center

McElgunn, Barbara

2010-01-01

A large body of experimental animal research on the neurotoxic effects of certain environmental chemicals provides evidence of a cascade of neurobehavioural effects including learning deficits, hyperactivity, anxiety, depression, lack of motivation, increased aggressiveness, altered maternal care and bonding, and an over-reaction to small…

Teaching the At-Risk Teenage Brain

ERIC Educational Resources Information Center

Feinstein, Sheryl

2007-01-01

While all teenage behavior and character traits can be challenging, the issues facing the at-risk teenager are particularly thorny. Anger, aggression, and a lack of good decision-making may happen on a minute-to-minute basis, as teachers try to guide these young adults. Unlocking the key to keeping them in school and facilitating proficiency in…

Suicidal behavior and mild traumatic brain injury in major depression.

PubMed

Oquendo, Maria A; Friedman, Jill Harkavy; Grunebaum, Michael F; Burke, Ainsley; Silver, Jonathan M; Mann, J John

2004-06-01

Traumatic brain injury (TBI) is associated with psychiatric illness, suicidal ideation, suicide attempts, and completed suicide. We investigated the relationship between mild TBI and other risk factors for suicidal behavior in major depressive episode. We hypothesized that mild TBI would be associated with suicidal behavior at least partly because of shared risk factors that contribute to the diathesis for suicidal acts. Depressed patients (N = 325) presenting for treatment were evaluated for psychopathology, traumatic history, and suicidal behavior. Data were analyzed using Student t -test, chi-square statistic, or Fisher exact test. A backward stepwise logistic regression model (N = 255) examined the relationship between attempter status and variables that differed in the TBI and non-TBI patients. Forty-four percent of all subjects reported mild TBI. Subjects with TBI were more likely to be male, have a history of substance abuse, have cluster B personality disorder, and be more aggressive and hostile compared with subjects without TBI. They were also more likely to be suicide attempters, although their suicidal behavior was not different from that of suicide attempters without TBI. Attempt status was mostly predicted by aggression and hostility, but not the presence of TBI. Of note, for males, a history of TBI increased the likelihood of being a suicide attempter, whereas the risk was elevated for females regardless of TBI history. Our data suggest that suicidal behavior and TBI share antecedent risk factors: hostility and aggression. Future studies may yield confirmation using a prospective design.