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Sample records for agonist d-cycloserine dcs

  1. The NMDA receptor partial agonist d-cycloserine does not enhance motor learning

    PubMed Central

    Günthner, Jan; Scholl, Jacqueline; Favaron, Elisa; Harmer, Catherine J; Johansen-Berg, Heidi; Reinecke, Andrea

    2016-01-01

    Rationale: There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning. Methods: Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task. Results: D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses). Conclusion: The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms. PMID:27436230

  2. Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation.

    PubMed

    Riekkinen, P; Ikonen, S; Riekkinen, M

    1998-05-11

    The present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D-cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions.

  3. Differential neuroprotective effects of the NMDA receptor-associated glycine site partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and D-cycloserine in lithium-pilocarpine status epilepticus.

    PubMed

    Peterson, Steven L; Purvis, Rebecca S; Griffith, James W

    2004-09-01

    The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including a glutamatergic phase that is inhibited by NMDA antagonists. The present study determined whether 1-aminocyclopropanecarboxylic acid (ACPC) or D-cycloserine (DCS), both partial agonists of the strychnine-insensitive glycine site on the NMDA receptor ionophore complex, exerted anticonvulsant or neuroprotectant activity in Li-pilo SE. ACPC or DCS were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to proceed for 3 h before termination with propofol. The rats were sacrificed 24 h following pilocarpine administration. Neither drug had an effect on the latency to seizure onset or the duration of seizure activity. ACPC administered 5 min after SE onset produced significant neuroprotection in cortical regions, amygdala and CA1 of the hippocampus. In contrast, when administered as exposure treatment ACPC enhanced the neural damage in the thalamus and CA3 of the hippocampus suggesting the neuropathology in those regions is mediated by a different subset of NMDA receptors. DCS had no neuroprotectant activity in Li-pilo SE but exacerbated neuronal damage in the thalamus. Neither drug affected the cholinergic convulsions but both had differential effects on neural damage. This suggests that the SE-induced seizure activity and subsequent neuronal damage involve independent mechanisms.

  4. D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

    ERIC Educational Resources Information Center

    Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

    2012-01-01

    The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

  5. D-Cycloserine for Treatment Nonresponders with Obsessive-Compulsive Disorder: A Case Report

    ERIC Educational Resources Information Center

    Norberg, Melissa M.; Gilliam, Christina M.; Villavicencio, Anna; Pearlson, Godfrey D.; Tolin, David F.

    2012-01-01

    Despite being the most effective treatment available, as many as one third of patients who receive exposure and response prevention (ERP) for obsessive-compulsive disorder (OCD) do not initially respond to treatment. Recent research suggests that the n-methyl d-aspartate (NMDA) receptor partial agonist D-Cycloserine (DCS) may speed up the course…

  6. D-Cycloserine Enhances Memory Consolidation of Hippocampus-Dependent Latent Extinction

    ERIC Educational Resources Information Center

    Gabriele, Amanda; Packard, Mark G.

    2007-01-01

    Adult male Long-Evans rats were trained to run in a straight-alley maze for food reward and subsequently received hippocampus-dependent latent extinction training. Immediately following latent extinction, rats received peripheral injections of the NMDA receptor partial agonist D-cycloserine (DCS, 15 mg/kg), or saline. Twenty-four hours later, rats…

  7. Differential Effects of D-Cycloserine and ACBC at NMDA Receptors in the Rat Entorhinal Cortex Are Related to Efficacy at the Co-Agonist Binding Site.

    PubMed

    Lench, Alex M; Robson, Emma; Jones, Roland S G

    2015-01-01

    Partial agonists at the NMDA receptor co-agonist binding site may have potential therapeutic efficacy in a number of cognitive and neurological conditions. The entorhinal cortex is a key brain area in spatial memory and cognitive processing. At synapses in the entorhinal cortex, NMDA receptors not only mediate postsynaptic excitation but are expressed in presynaptic terminals where they tonically facilitate glutamate release. In a previous study we showed that the co-agonist binding site of the presynaptic NMDA receptor is endogenously and tonically activated by D-serine released from astrocytes. In this study we determined the effects of two co-agonist site partial agonists on both presynaptic and postsynaptic NMDA receptors in layer II of the entorhinal cortex. The high efficacy partial agonist, D-cycloserine, decreased the decay time of postsynaptic NMDA receptor mediated currents evoked by electrical stimulation, but had no effect on amplitude or other kinetic parameters. In contrast, a lower efficacy partial agonist, 1-aminocyclobutane-1-carboxylic acid, decreased decay time to a greater extent than D-cycloserine, and also reduced the peak amplitude of the evoked NMDA receptor mediated postsynaptic responses. Presynaptic NMDA receptors, (monitored indirectly by effects on the frequency of AMPA receptor mediated spontaneous excitatory currents) were unaffected by D-cycloserine, but were reduced in effectiveness by 1-aminocyclobutane-1-carboxylic acid. We discuss these results in the context of the effect of endogenous regulation of the NMDA receptor co-agonist site on receptor gating and the potential therapeutic implications for cognitive disorders.

  8. D-cycloserine as an augmentation strategy for cognitive behavioral therapy for anxiety disorders: an update.

    PubMed

    Hofmann, Stefan G; Sawyer, Alice T; Asnaani, Anu

    2012-01-01

    Cognitive behavioral therapy (CBT) has been shown to be an effective intervention for anxiety disorders. However, despite its proven efficacy, some patients fail to respond to an adequate course of treatment. In attempts to improve the efficacy of CBT, researchers have augmented the core learning processes of the intervention with d-cycloserine (DCS), an N-Methyl-D-Aspartate partial agonist. This article reviews the current literature on DCS as an augmentation strategy for CBT for anxiety disorders. We will describe the memory enhancing properties of DCS, review findings from randomized controlled studies of DCS in anxious populations and discuss mechanism, dosing and timing issues.

  9. D-cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement.

    PubMed

    Ledgerwood, Lana; Richardson, Rick; Cranney, Jacquelyn

    2004-06-01

    Several recent studies have reported that D-cycloserine (DCS), a partial N-methyl-D-aspartate agonist, facilitates extinction of learned fear in rats. Other studies have shown that representation of the unconditioned stimulus (US) can reinstate learned fear after extinction. This study examined whether this reinstatement effect occurs in Sprague-Dawley rats given DCS at the time of extinction. Results showed that saline-treated rats exhibited the reinstatement effect but DCS-treated rats did not (Experiments 1 and 2). This lack of reinstatement in DCS-treated rats was not due to residual effects of DCS on either US or context processing (Experiment 3). Overall, these results (a) raise questions about the mechanisms underlying DCS facilitation of extinction and (b) suggest that DCS might have substantial practical benefit.

  10. The Therapeutic Role of d-Cycloserine in Schizophrenia.

    PubMed

    Goff, D

    2016-01-01

    The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl d-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial agonist, d-cycloserine (DCS), aims to enhance plasticity by intermittent treatment. Early trials have demonstrated benefit with intermittent DCS dosing for negative symptoms and memory. When combined with cognitive remediation, intermittent DCS treatment enhanced learning on a practiced auditory discrimination task and when added to cognitive behavioral therapy, DCS improved delusional severity in subjects who received DCS with the first CBT session. These studies require replication, but point toward a promising strategy for the treatment of schizophrenia and other disorders of plasticity. PMID:27288073

  11. D-cycloserine augmentation of cognitive behavioral therapy for anxiety disorders: an update.

    PubMed

    Hofmann, Stefan G; Otto, Michael W; Pollack, Mark H; Smits, Jasper A

    2015-01-01

    Although cognitive behavioral therapy (CBT) is a generally effective treatment for treating anxiety disorders, there is clearly still room for further improvements. Recent advances in neuroscience of extinction learning led to novel clinical strategies to augment exposure-based treatments with d-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate receptor. This review provides an update on the current knowledge of DCS as an augmentation strategy of CBT for anxiety disorders. The adequacy of the CBT to be augmented, the dose of DCS, and the timing and duration of augmentation efforts all appear to be important moderating variables. Moreover, there is evidence that DCS may also augment fear memory reconsolidation if the fear level remains high after the exposure. Future studies need to examine whether DCS can augment CBT when administered after exposure in order to develop a tailored administration strategy to maximize its clinical utility.

  12. D-cycloserine effects on extinction of conditioned responses to drug-related cues.

    PubMed

    Myers, Karyn M; Carlezon, William A

    2012-06-01

    D-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disorders in people. Recent preclinical and clinical studies have examined the effect of DCS on extinction of conditioned responses elicited by cues paired with administration of or withdrawal from drugs of abuse, including physiological responses, craving, withdrawal, and drug-seeking behavior. DCS facilitates extinction and blunts postextinction recovery of these responses in animal models, including place conditioning and drug self-administration, but DCS effects on CET in substance users/abusers are less robust. Some of the null effects in the clinical literature might be attributable to issues related to sample size, data characteristics, DCS administration, and participant characteristics, among others. In this review we describe the preclinical and clinical literatures on DCS modulation of extinction of addiction-related conditioned responses, consider possible limitations of the clinical studies that have been published to date, and propose ways of designing future clinical studies so as to maximize the probability of detecting a DCS effect. We also discuss concerns with regard to potential harmful effects of DCS-coupled CET in addicts and describe how these concerns might be mitigated. We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction.

  13. D-Cycloserine Effects on Extinction of Conditioned Responses to Drug-Related Cues

    PubMed Central

    Myers, Karyn M.; Carlezon, William A.

    2012-01-01

    D-cycloserine (DCS) is an N-methyl-D-aspartate (NMDA) receptor partial agonist that facilitates extinction of conditioned fear in animals and cue exposure therapy (CET) for fear and anxiety disorders in people. Recent preclinical and clinical studies have examined the effect of DCS on extinction of conditioned responses elicited by cues paired with administration of or withdrawal from drugs of abuse, including physiological responses, craving, withdrawal, and drug-seeking behavior. DCS facilitates extinction and blunts postextinction recovery of these responses in animal models, including place conditioning and drug self-administration, but DCS effects on CET in substance users/abusers are less robust. Some of the null effects in the clinical literature might be attributable to issues related to sample size, data characteristics, DCS administration, and participant characteristics, among others. In this review we describe the preclinical and clinical literatures on DCS modulation of extinction of addiction-related conditioned responses, consider possible limitations of the clinical studies that have been published to date, and propose ways of designing future clinical studies so as to maximize the probability of detecting a DCS effect. We also discuss concerns with regard to potential harmful effects of DCS-coupled CET in addicts and describe how these concerns might be mitigated. We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction. PMID:22579305

  14. Facilitation of fear extinction by D-cycloserine: theoretical and clinical implications.

    PubMed

    Richardson, Rick; Ledgerwood, Lana; Cranney, Jacquelyn

    2004-01-01

    Anxiety disorders are among the most common psychological disturbances in the industrialized world. Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may lead to improvements in treatment effectiveness. We review the evidence that D-cycloserine (DCS), a partial NMDA agonist, facilitates extinction of learned fear in rats. Although only a few studies have examined the effects of DCS on extinction of learned fear, this work suggests that this drug may have a number of potential clinical benefits. In addition, attempts at interpreting this research illustrate our limited understanding of the processes involved in extinction.

  15. The Effect of D-Cycloserine on Immediate vs. Delayed Extinction of Learned Fear

    ERIC Educational Resources Information Center

    Langton, Julia M.; Richardson, Rick

    2010-01-01

    We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior…

  16. Effects of D-cycloserine on the extinction of appetitive operant learning.

    PubMed

    Vurbic, Drina; Gold, Benjamin; Bouton, Mark E

    2011-08-01

    Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction.

  17. A Trial of D-Cycloserine to Treat Stereotypies in Older Adolescents and Young Adults With Autism Spectrum Disorder

    PubMed Central

    Urbano, Maria; Okwara, Leonore; Manser, Paul; Hartmann, Kathrin; Herndon, Amy; Deutsch, Stephen I.

    2015-01-01

    Objectives Autism spectrum disorders (ASDs) have core impairments in social communication as well as the presence of repetitive, stereotypic behaviors and restricted interests. Older adolescents and young adults are particularly impacted by these deficits. Preclinical data implicate glutamatergic dysfunction in the pathophysiology of ASDs. D-Cycloserine (DCS), a partial glycineB agonist at the N-methyl-D-aspartic acid receptor site, has been shown to improve sociability in mouse models and a small human study. The sensitivity of the obligatory glycineB co-agonist binding site may change with daily administration of DCS as a result of agonist-induced desensitization. The efficacy of a “pulsed” once-weekly administration versus “daily” administration of DCS was compared. Methods Males and females, ages 14 to 25 years, with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision diagnosis of an ASD were enrolled in a double-blind, randomized 10-week trial consisting of 8 weeks of active drug with either weekly or daily administration of 50 mg of DCS followed by a 2-week follow-up visit. Results For the purposes of this study, no statistical or clinical differences existed between the 2 dosage groups on the Aberrant Behavior Checklist subscale 3, which measures stereotypies/repetitive movements. When combining groups, a statistically significant decrease of 37% was found from baseline to week 8 when study drug was completed using a linear mixed effects model (P = 0.003). Conclusions D-Cycloserine was shown to be effective in improving stereotypic symptoms in older adolescents and young adults with ASDs measured by the Aberrant Behavior Checklist subscale 3. In addition, DCS was safe and well tolerated. PMID:24824660

  18. D-cycloserine deters reacquisition of cocaine self-administration by augmenting extinction learning.

    PubMed

    Nic Dhonnchadha, Bríd A; Szalay, Jonathan J; Achat-Mendes, Cindy; Platt, Donna M; Otto, Michael W; Spealman, Roger D; Kantak, Kathleen M

    2010-01-01

    Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse.

  19. d-Cycloserine Attenuates Reactivity to Smoking Cues in Nicotine Dependent Smokers: A Pilot Investigation

    PubMed Central

    Santa Ana, Elizabeth J.; Rounsaville, Bruce J.; Frankforter, Tami L.; Nich, Charla; Babuscio, Theresa; Poling, James; Gonsai, Kishorchandra; Hill, Kevin P.; Carroll, Kathleen M.

    2009-01-01

    Increasing evidence indicates that smoking cues contribute to nicotine self-administration and attenuating conditioned reactivity to smoking cues may aid abstinence of smoking and prevention of smoking relapse in individuals with nicotine dependence. Based on prior studies showing that the partial N-methyl-d-aspartate (NMDA) agonist d-cycloserine (DCS) facilitates extinction of learned fear during behavioral exposure therapy in humans and facilitates extinction of cocaine-induced conditioned place preference in animals, we evaluated whether DCS would have potential for reducing reactivity to smoking cues when combined with cue exposure treatment in humans with nicotine dependence. In this double-blind placebo controlled pilot laboratory study, twenty-five smokers were recruited from the general community and randomized to DCS or placebo, plus cue exposure therapy. DCS significantly attenuated smoking cue reactivity in response to in-vivo smoking cues based on physiological reactivity and subjective urge-to-smoke ratings and led to a significantly smaller expired carbon monoxide (CO) level at the 1-week follow-up compared to placebo, although exploratory analyses indicated no effect on smoking behavior overall. These findings provide promising support for DCS combined with cue exposure therapy in attenuating conditioned reactivity to smoking cues. PMID:19592176

  20. Enhancement of Psychosocial Treatment With D-Cycloserine: Models, Moderators, and Future Directions.

    PubMed

    Otto, Michael W; Kredlow, M Alexandra; Smits, Jasper A J; Hofmann, Stefan G; Tolin, David F; de Kleine, Rianne A; van Minnen, Agnes; Evins, A Eden; Pollack, Mark H

    2016-08-15

    Advances in the understanding of the neurobiology of fear extinction have resulted in the development of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure treatment. We review a decade of research that has focused on the efficacy of DCS for augmenting the mechanisms (e.g., fear extinction) and outcome of exposure treatment across the anxiety disorders. Following a series of small-scale studies offering strong support for this clinical application, more recent larger-scale studies have yielded mixed results, with some showing weak or no effects. We discuss possible explanations for the mixed findings, pointing to both patient and session (i.e., learning experiences) characteristics as possible moderators of efficacy, and offer directions for future research in this area. We also review recent studies that have aimed to extend the work on DCS augmentation of exposure therapy for the anxiety disorders to DCS enhancement of learning-based interventions for addiction, anorexia nervosa, schizophrenia, and depression. Here, we attend to both DCS effects on facilitating therapeutic outcomes and additional therapeutic mechanisms beyond fear extinction (e.g., appetitive extinction, hippocampal-dependent learning).

  1. D-cycloserine facilitates context-specific fear extinction learning.

    PubMed

    Bouton, Mark E; Vurbic, Drina; Woods, Amanda M

    2008-10-01

    D-cycloserine (DCS) may facilitate fear extinction learning, but the behavioral consequences and mechanisms behind this effect are not well understood at present. In this paper, we re-analyze data from previously reported null result experiments and find that rats showing above-median extinction learning during DCS treatment benefited from the drug, whereas rats showing below-median (and in this case little) extinction learning did not. Two additional experiments found that DCS facilitated extinction learning when specifically combined with a moderate, but not a small, number of extinction trials. DCS thus facilitates extinction learning only if the behavioral procedure first engages the extinction learning process. The benefits of the drug, however, were specific to the context in which extinction was learned--i.e., DCS did not prevent or influence the renewal of fear observed when the extinguished cue was tested in the original conditioning context.

  2. Effects of D-cycloserine on extinction: translation from preclinical to clinical work.

    PubMed

    Davis, Michael; Ressler, Kerry; Rothbaum, Barbara O; Richardson, Rick

    2006-08-15

    Administration of benzodiazepines or serotonin reuptake inhibitors in combination with behavior therapy for the treatment of many anxiety disorders has generally lead to only modest gains. In this article we suggest that pharmacotherapy aimed not at treating the symptoms of anxiety but instead aimed at improving the learning that takes place in exposure therapy might actually improve the effectiveness of exposure therapy. This idea was based on animal work showing that the partial N-methyl-D-aspartate (NMDA) agonist D-cycloserine (DCS) facilitated extinction of fear when given either before or shortly after exposure to fearful cues, reduced return of fear that is normally seen when extinction training is followed by stress, and led to generalized extinction, where DCS given in combination with exposure to one fearful cue led to extinction to another cue previously paired with the same aversive event. These finding suggested that DCS might facilitate exposure-based psychotherapy, which was verified in a small clinical study showing that DCS facilitated exposure therapy for fear of heights in a well-controlled virtual reality environment.

  3. Augmentation Treatment of Psychotherapy for Anxiety Disorders with D-Cycloserine

    PubMed Central

    Hofmann, Stefan G.; Pollack, Mark H.; Otto, Michael W.

    2007-01-01

    Anxiety disorders are among the most common mental disorders. One of the most effective strategies to treat anxiety disorders is exposure therapy with or without cognitive intervention. Fear reduction in exposure therapy is similar to extinction learning. Preclinical studies suggest that extinction learning can be blocked by antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor, and facilitated with D-cycloserine (DCS), a partial agonist at the glycine recognition site of the NMDA receptor in the amygdala. DCS is an established antibiotic drug for the chronic treatment of tuberculosis in humans, but has only recently been investigated as an augmentation therapy for psychological treatment procedures. The review of the literature provides preliminary support for the use of acute dosing of DCS as an adjunctive intervention to exposure therapy for anxiety disorders, including specific phobia and social anxiety disorder. Negative results have recently been reported in the treatment of subclinical fears of animals. These studies suggest that DCS needs to be administered on an acute rather than a chronic dosing schedule, include sufficient time for memory consolidation, and be administered together with psychological treatment that leaves sufficient room for further improvement. It remains to be seen whether these highly promising findings represent reliable pharmacological strategies to enhance exposure therapy of anxiety disorders. PMID:17227287

  4. D-cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms.

    PubMed

    Grillon, Christian

    2009-10-01

    Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes.

  5. D-cycloserine facilitation of fear extinction and exposure-based therapy might rely on lower-level, automatic mechanisms.

    PubMed

    Grillon, Christian

    2009-10-01

    Exposure-based therapy, a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate receptor agonist. This review discusses the potential mechanisms involved in this facilitation and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several laboratory-based investigations found that DCS had no effect on extinction in humans. This report proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. The DCS studies in animals seem to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS might act preferentially on lower- rather than higher-order learning. This report presents evidence suggesting that, in humans, DCS might similarly affect lower-order learning during exposure-based therapy and, consequently, might be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted with fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus intervals and intense unconditioned stimulus to promote lower-order conditioning processes. PMID:19520359

  6. Opposing effects of d-cycloserine on fear despite a common extinction duration: Interactions between brain regions and behavior

    PubMed Central

    Bolkan, Scott S.; Lattal, K. Matthew

    2014-01-01

    A number of studies have reported that D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate glutamate receptor, can facilitate the loss of conditioned fear if it is administered during an extinction trial. Here we examine the effects of DCS injected into the hippocampus or amygdala on extinction of context-evoked freezing after contextual fear conditioning in C57BL/6 mice. We find that DCS administered prior to an extinction session decreased freezing from the outset of the session regardless of which brain region was targeted. Retention tests revealed opposite effects on fear expression despite identical behavioral treatments: intra-hippocampal DCS inhibited fear expression while intra-amygdala DCS potentiated fear expression. Following post-extinction session injections of DCS, we found a similar though less pronounced effect. Closer inspection of the data revealed that the effects of DCS interacted with the behavior of the subjects during extinction. Intra-hippocampal injections of DCS enhanced extinction in those mice that showed the greatest amount of within-session extinction, but had less pronounced effects on mice that showed the least within-session extinction. Intra-amygdala injections of DCS impaired extinction in those mice that showed the least within-session, but there was some evidence that the effect in the amygdala did not depend on behavior during extinction. These findings demonstrate that even with identical extinction preparations and trial durations, the effects of DCS administered into the hippocampus and amygdala can heavily depend on the organism’s behavior during the extinction session. The broader implication of these findings is that the effects of pharmacological treatments designed to enhance extinction by targeting hippocampal or amygdalar processes may depend greatly on the responsivity of the subject to the behavioral treatment. PMID:24374132

  7. D-Cycloserine Augmentation of Cognitive-Behavioral Therapy: Directions for Pilot Research in Pediatric Obsessive-Compulsive Disorder

    ERIC Educational Resources Information Center

    Storch, Eric A.; McKay, Dean; Reid, Jeannette M.; Geller, Daniel A.; Goodman, Wayne K.; Lewin, Adam B.; Murphy, Tanya K.

    2010-01-01

    This paper discusses a recent translational success in combining behavioral psychotherapy with a novel medication, d-cycloserine (DCS), to augment cognitive-behavioral therapy (CBT) for anxiety disorders. The literature on behavioral theory of exposure-based therapies is provided, followed by a discussion of the role of DCS in enhancing extinction…

  8. d-Cycloserine combined with cue exposure therapy fails to attenuate subjective and physiological craving in cocaine dependence

    PubMed Central

    Santa Ana, Elizabeth J.; Prisciandaro, James J.; Saladin, Michael E.; McRae-Clark, Aimee L.; Shaftman, Stephanie R.; Nietert, Paul J.; Brady, Kathleen T.

    2014-01-01

    Background Based on preclinical studies showing that the partial N-methyl-d-aspartate (NMDA) agonist d-cycloserine (DCS) facilitates extinction of cocaine self-administration and cocaine-induced conditioned place preference, we evaluated whether 50 mg of DCS would reduce craving to cocaine cues when combined with cue exposure (CE) in cocaine dependent humans. Methods In this double-blind placebo-controlled pilot study, 47 cocaine dependent participants were randomized to DCS or placebo (PBO), plus CE. Participants received DCS or PBO 30 minutes prior to two CE sessions, conducted one day apart. Craving and heart rate was assessed prior to CE sessions, during CE trials, and after CE trials. These measures were assessed again at a 1-week follow-up (session 3) after the second CE session. Results DCS failed to significantly attenuate cocaine cue reactivity based on subjective craving and physiological reactivity (heart rate) compared to PBO. The CE protocol, consisting of repeated exposure to drug cues combined with skills training, resulted in extinction to cocaine cues as suggested by decreased craving within and between sessions in both treatment conditions. All participants exhibited elevated heart rate with repeated exposures, demonstrating a potentiation in heart rate between sessions. PMID:25808169

  9. d-cycloserine reverses the detrimental effects of stress on learning in females and enhances retention in males.

    PubMed

    Waddell, Jaylyn; Mallimo, Elyse; Shors, Tracey

    2010-01-01

    Exposure to acute, inescapable stress produces a facilitation of subsequent classical eyeblink conditioning in male rats. The same stress exposure produces a profound deficit in classical eyeblink conditioning in females. Activation of N-methyl-d-aspartate receptors (NMDAr) is necessary for the effect of stress on learning in males while the contribution of NMDAr activation to the deficit in learning after stress is unknown. Here, we tested the influence of d-cycloserine (DCS), a positive modulator of the NMDAr, in stressed or unstressed male and female rats. Groups of males and females were exposed to an acute stressful event. One day later, they began training with four sessions of trace eyeblink conditioning. Each day before training, they were injected with DCS (15mg/kg) or saline. Females treated with DCS during training responded similarly to those that were untreated. However, those that were stressed and the next day treated with the drug during training did not express the typical learning deficit, i.e. they learned to time the CR very well. Because the drug was administered well after the stressor, these data indicate that DCS reversed the negative effects of stress on learning in females. In males, the effect of DCS was subtle, resulting in higher asymptotic responding, and enhanced retention in a drug-free retention test. Thus, as shown previously, training in the presence of an NMDA receptor agonist enhances associative learning and memory retention. In addition, it can reverse learning deficits that have already been induced.

  10. D-cycloserine in Prelimbic Cortex Reverses Scopolamine-Induced Deficits in Olfactory Memory in Rats

    PubMed Central

    Portero-Tresserra, Marta; Cristóbal-Narváez, Paula; Martí-Nicolovius, Margarita; Guillazo-Blanch, Gemma; Vale-Martínez, Anna

    2013-01-01

    A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks. PMID:23936452

  11. D-Cycloserine improves functional outcome after traumatic brain injury with wide therapeutic window

    SciTech Connect

    Adeleye, A.; Biegon, A.; Adeleye, A.; Shohami, E.; Nachman, D.; Alexandrovich, A.; Trembovler, V.; Yaka, R.; Shoshan, Y.; Dhawan, J.; Biegon, A.

    2009-12-01

    It has been long thought that hyperactivation of N-methyl-D-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4 h to 2 weeks after brain injury, activation at 24 h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist d-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p.) DCS or vehicle once (8, 16, 24, or 72 h) twice (24 and 48 h) or three times (24, 48 and 72 h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72 h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8 h or 16 h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24 h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h or by cresyl violet at 28 days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24 h.

  12. D-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice.

    PubMed

    Deutsch, Stephen I; Pepe, Gerald J; Burket, Jessica A; Winebarger, Erin E; Herndon, Amy L; Benson, Andrew D

    2012-02-23

    Balb/c mice are a model of impaired sociability and social motivation relevant to autism spectrum disorders (ASDs). Impaired sociability of 8-week old Balb/c mice is attenuated by agonists of the glycine(B) site on the NMDA receptor, such as d-cycloserine. Although ASDs are often recognized in toddlerhood, there is interest in earlier identification (e.g., before 6 months) and disease-modifying interventions to improve functional outcomes. Thus, we wondered if d-cycloserine could improve sociability in 4-week old Balb/c mice, similar to its effects in 8-week old mice. d-Cycloserine improved measures of impaired sociability in 4-week old (i.e., one-week post-weanling) Balb/c mice. Moreover, because stereotypies can compete with the salience of social stimuli, we compared Balb/c and Swiss Webster mice on several spontaneous stereotypic behaviors emerging during social interaction with a social stimulus mouse. Interestingly, similar to 8-week old mice, spontaneous stereotypic behaviors during social interaction were more intense in the 4-week old Swiss Webster mice; furthermore, d-cycloserine reduced their intensity. Thus, d-cycloserine improves both sociability and stereotypic behaviors, but these effects may lack strain-selectivity. A prosocial effect of d-cycloserine was observed at a dose as low as 32.0mg/kg in Balb/c mice. d-cycloserine has the therapeutic properties of a desired medication for ASDs; specifically, a medication should not improve stereotypic behaviors at the expense of worsening sociability and vice versa. The data suggest that targeting the NMDA receptor can have promising therapeutic effects on two prominent domains of psychopathology in ASDs: impaired sociability and spontaneous stereotypic behaviors.

  13. D-Cycloserine as an augmentation strategy for cognitive behavioral therapy of anxiety disorders

    PubMed Central

    2013-01-01

    The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful. PMID:23768232

  14. D-cycloserine prevents relational memory deficits and suppression of long-term potentiation induced by scopolamine in the hippocampus.

    PubMed

    Portero-Tresserra, Marta; Del Olmo, Nuria; Martí-Nicolovius, Margarita; Guillazo-Blanch, Gemma; Vale-Martínez, Anna

    2014-11-01

    Previous research has demonstrated that systemic D-cycloserine (DCS), a partial agonist of the N-methyl-D-aspartate receptor (NMDAR), enhances memory processes in different learning paradigms and attenuates mnemonic deficits produced by diverse pharmacological manipulations. In the present study two experiments were conducted in rats to investigate whether DCS administered in the hippocampus may rescue relational memory deficits and improve deficient synaptic plasticity, both induced by an intracerebral injection of the muscarinic receptor antagonist scopolamine (SCOP). In experiment 1, we assessed whether DCS would prevent SCOP-induced amnesia in an olfactory learning paradigm requiring the integrity of the cholinergic system, the social transmission of food preference (STFP). The results showed that DCS (10 μg/site) injected into the ventral hippocampus (vHPC) before STFP acquisition compensated the 24-h retention deficit elicited by post-training intra-vHPC SCOP (40 μg/site), although it did not affect memory expression in non-SCOP treated rats. In experiment 2, we evaluated whether the perfusion of DCS in hippocampal slices may potentiate synaptic plasticity in CA1 synapses and thus recover SCOP-induced deficits in long-term potentiation (LTP). We found that DCS (50 µM and 100 µM) was able to rescue SCOP (100 µM)-induced LTP maintenance impairment, in agreement with the behavioral findings. Additionally, DCS alone (50 µM and 100 µM) enhanced field excitatory postsynaptic potentials prior to high frequency stimulation, although it did not significantly potentiate LTP. Our results suggest that positive modulation of the NMDAR, by activation of the glycine-binding site, may compensate relational memory impairments due to hippocampal muscarinic neurotransmission dysfunction possibly through enhancements in LTP maintenance.

  15. D-Cycloserine improves the impaired sociability of the Balb/c mouse.

    PubMed

    Deutsch, Stephen I; Burket, Jessica A; Jacome, Luis F; Cannon, William R; Herndon, Amy L

    2011-01-15

    The genetically inbred Balb/c mouse strain shows evidence of impaired sociability in a standard paradigm. For example, relative to 8-week-old male outbred Swiss-Webster mice, 8 week-old male Balb/c mice spend less time sniffing and in the vicinity of an enclosed 4 week-old male ICR stimulus mouse and, when allowed to interact freely with the stimulus mouse for five minutes, make fewer discrete episodes of social approach and show suppression of locomotor activity. We explored the effect of D-cycloserine (320mg/kg, intraperitoneally), a partial glycine agonist that binds to the obligatory co-agonist glycine binding site on the NMDA receptor, on the sociability of the Balb/c and Swiss-Webster mouse strains in a standard paradigm. The results show that treatment with D-cycloserine increased the locomotor activity of the Balb/c mouse strain in the presence of an enclosed social stimulus mouse and when these mice were allowed to interact freely with each other. Also, D-cycloserine increased the number of discrete episodes of social approach when Balb/c mice were allowed to interact freely with social stimulus mice. However, D-cycloserine had similar effects on measures of sociability in the Swiss-Webster mouse, raising the possibility that the positive effects on the sociability of the Balb/c mouse strain may be mediated by indirect effects on locomotion, arousal, and anxiety.

  16. A trial of d-cycloserine to treat the social deficit in older adolescents and young adults with autism spectrum disorders.

    PubMed

    Urbano, Maria; Okwara, Leonore; Manser, Paul; Hartmann, Kathrin; Deutsch, Stephen I

    2015-01-01

    Autism spectrum disorders are difficult for older adolescents and young adults as impaired social communication affects the transition to adult life. d-Cycloserine, a partial glycine agonist at the N-methyl-d-aspartic acid receptor, was tested in a double-blind randomized trial in 20 older adolescents and young adults with autism spectrum disorders using two dosing strategies (50 mg daily versus 50 mg weekly) for 8 weeks with a 2-week follow-up after discontinuation. d-Cycloserine caused statistically and clinically significant improvement with no differentiation between dosing strategies on the Social Responsiveness Scale and the Aberrant Behavior Checklist before and after d-cycloserine administration.

  17. Learning and memory in conditioned fear extinction: effects of D-cycloserine.

    PubMed

    Vervliet, Bram

    2008-03-01

    This review addresses the effects of the cognitive enhancer D-cycloserine (DCS) on the memory processes that occur in conditioned fear extinction, which is the experimental model for exposure techniques to reduce clinical anxiety. All reported rat studies show an enhanced fear extinction effect when DCS is administered acutely before or shortly after extinction training. DCS also promotes the generalization of this fear extinction effect. In addition, DCS reduces some forms of relapse (reduced reinstatement, reduced spontaneous recovery), but not others (contextual renewal, rapid reacquisition). It is argued that this pattern of results is best explained by assuming that DCS promotes extinction learning to the background context, resulting in enhanced contextual inhibition. Four human studies have produced mixed results, but some methodological issues complicate the reported failures. It is concluded that DCS is a promising tool as an adjunct to extinction techniques in exposure treatment, but that more pre-clinical and clinical research is needed to fully characterize its behavioral consequences.

  18. d-Cycloserine Facilitation of Exposure Therapy Improves Weight Regain in Patients With Anorexia Nervosa: A Pilot Randomized Controlled Trial

    PubMed Central

    Levinson, Cheri A.; Rodebaugh, Thomas L.; Fewell, Laura; Kass, Andrea E.; Riley, Elizabeth N.; Stark, Lynn; McCallum, Kimberly; Lenze, Eric J.

    2016-01-01

    Objective Exposure therapy in anorexia nervosa has preliminarily been shown to be effective for increasing food intake. d-Cycloserine is a glutamatergic N-methyl-d-aspartate receptor agonist that has been shown to facilitate the benefits of exposure therapy for anxiety disorders by enhancing the emotional learning in the exposures; therefore, we examined d-cycloserine–facilitation of exposure therapy to increase body mass index (BMI) in patients with anorexia nervosa. Method Participants (N = 36) with anorexia nervosa (diagnosed via DSM-IV) were recruited from a partial hospitalization eating disorder clinic between February 2013 and November 2013. Participants were randomly assigned to receive exposure therapy plus d-cycloserine (n = 20) or placebo (n = 16). Participants completed psychoeducation and 4 sessions of exposure therapy, with medication (d-cycloserine vs placebo) given prior to the first 3 exposure sessions. They also completed a 1-month follow-up. Results As hypothesized, participants in the d-cycloserine group showed a significantly greater increase in BMI than those in the placebo group (Wilk Λ = 0.86, F3,32 = 2.20, P = .043, ηp2 = 0.12). d-Cycloserine participants gained 3 pounds relative to 0.5 pounds in the placebo group. Both groups experienced significantly decreased anxiety over the course of therapy (Wilk Λ = 0.80, F3,32 = 3.32, P = .023, ηp2 = 0.20). Conclusions This study preliminarily demonstrates that d-cycloserine facilitates exposure therapy for anorexia nervosa, leading to increased weight gain. A potential mechanism is that participants who receive d-cycloserine may generalize learning from within-session exposures to food intake during other similar meals, resulting in sustained increases in BMI. Further research is needed to confirm these findings and test the putative mechanism that generalized learning from exposure therapy can increase BMI and stabilize a healthy weight. Trial Registration ClinicalTrials.gov identifier: NCT

  19. D-cycloserine 24 and 48 hours after asphyxial cardiac arrest has no effect on hippocampal CA1 neuropathology

    PubMed Central

    Combs, Vélvá M; Crispell, Heather D; Drew, Kelly L

    2014-01-01

    Stimulation of N-methyl-D-aspartate receptors (NMDAR) contributes to regenerative neuroplasticity following the initial excitotoxic insult during cerebral ischemia. Stimulation of NMDAR with the partial NMDAR agonist D-cycloserine (DCS) improves outcome and restores hippocampal synaptic plasticity in models of closed head injury. We thus hypothesized that DCS would improve outcome following restoration of spontaneous circulation (ROSC) from cardiac arrest (CA). DCS (10 mg/kg, IP) was administered to Sprague-Dawley rats (male, 250–330 g; 63–84 days old) 24 and 48 hours after 6 or 8 minutes of asphyxial CA. Heart rate and blood pressure declined similarly in all groups. Animals showed neurological deficits after 6 and 8 minutes CA (P<0.05, Tukey) and these deficits recovered more quickly after 6 minutes than after 8 minutes of CA. CA decreased the number of healthy neurons within CA1 with no difference between 6 and 8 minutes duration of CA (180.8±27.6 (naïve, n=5) versus 46.3±33.8 (all CA groups, n=27) neurons per mm CA1). DCS had no effect on neurological deficits or CA1 hippocampal cell counts (P>0.05, Tukey). PMID:25099755

  20. A Randomized, Placebo-controlled Laboratory Study of the Effects of D-cycloserine on Craving in Cocaine-dependent Individuals

    PubMed Central

    Price, Kimber L.; Baker, Nathaniel L.; McRae-Clark, Aimee L.; Saladin, Michael E.; DeSantis, Stacia M.; Ana, Elizabeth J. Santa; Brady, Kathleen T.

    2012-01-01

    Rationale D-cycloserine (DCS), a partial glutamate NMDA receptor agonist, enhances extinction of conditioned fear responding; preliminary data suggests that it may facilitate extinction of drug cue reactivity. Objective This study investigates DCS effects on cocaine cue craving and drug use in cocaine-dependent subjects. Methods Thirty-two subjects were randomly assigned to receive 1) DCS only, 2) DCS before sessions 1 and 3, PBO before session 2 or 3) PBO only 15-min before each of 3 1-hour cocaine cue exposure sessions conducted 1 day apart. Craving ratings were obtained before, during and after sessions. Drug use and cue-induced craving were assessed 1 week after the last cue session. Results Repeated presentation of cocaine cues resulted in decreased craving both within and between sessions. DCS did not facilitate extinction learning and may have enhanced craving. The group that received 3 doses of DCS had significantly higher craving than the PBO group at the baseline ratings taken before sessions 2 and 3, as well as significantly higher cue-induced craving at follow-up. The group that received 2 doses of DCS did not differ from the PBO group. There were no group differences in post-extinction cocaine use. Conclusions The reduction of cocaine cue reactivity in the PBO group suggests that the study procedures were sufficient to produce extinction. Under these conditions, DCS did not facilitate extinction and may have enhanced craving. Further studies of glutamatergic agents and extinction in cocaine dependence should include consideration of procedural variables that could have a major impact on study outcomes. PMID:22234379

  1. The Effect of D-cycloserine on Subliminal Cue Exposure in Spider Fearful Individuals

    PubMed Central

    Gutner, Cassidy A.; Weinberger, Joel; Hofmann, Stefan G.

    2012-01-01

    Research on d-cycloserine (DCS) has demonstrated a significant effect on symptom reduction in human studies that utilized conventional exposure-based approaches. Recent studies have offered promising results for targeting fears through subliminal paradigms. In this double-blind, randomized placebo controlled study, 45 spider fearful individuals received DCS or placebo pills prior to completing a subliminal cue exposure task to images of spiders. Participants completed self-report questionnaires and a behavioral approach task to a live caged tarantula. After repeated exposure to subliminal spider cues, participants in the DCS group reported a greater reduction in disgust than individuals in the placebo group. No difference was observed in fear ratings. These findings suggest that DCS augments the reduction in disgust in spider fearful subjects after subliminal exposure to spider cues. PMID:22992160

  2. The effect of D-cycloserine on subliminal cue exposure in spider fearful individuals.

    PubMed

    Gutner, Cassidy A; Weinberger, Joel; Hofmann, Stefan G

    2012-01-01

    Research on D-cycloserine (DCS) has demonstrated a significant effect on symptom reduction in human studies that utilized conventional exposure-based approaches. Recent studies have offered promising results for targeting fears through subliminal paradigms. In this double-blind, randomized placebo-controlled study, 45 spider fearful individuals received DCS or placebo pills prior to completing a subliminal cue exposure task to images of spiders. Participants completed self-report questionnaires and a behavioral approach task to a live caged tarantula. After repeated exposure to subliminal spider cues, participants in the DCS group reported a greater reduction in disgust than individuals in the placebo group. No difference was observed in fear ratings. These findings suggest that DCS augments the reduction in disgust in spider fearful subjects after subliminal exposure to spider cues. PMID:22992160

  3. Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

    PubMed

    Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

    2016-02-01

    D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction. PMID:26400817

  4. Molecular mechanisms of D-cycloserine in facilitating fear extinction: insights from RNAseq.

    PubMed

    Malan-Müller, Stefanie; Fairbairn, Lorren; Daniels, Willie M U; Dashti, Mahjoubeh Jalali Sefid; Oakeley, Edward J; Altorfer, Marc; Kidd, Martin; Seedat, Soraya; Gamieldien, Junaid; Hemmings, Sîan Megan Joanna

    2016-02-01

    D-cycloserine (DCS) has been shown to be effective in facilitating fear extinction in animal and human studies, however the precise mechanisms whereby the co-administration of DCS and behavioural fear extinction reduce fear are still unclear. This study investigated the molecular mechanisms of intrahippocampally administered D-cycloserine in facilitating fear extinction in a contextual fear conditioning animal model. Male Sprague Dawley rats (n = 120) were grouped into four experimental groups (n = 30) based on fear conditioning and intrahippocampal administration of either DCS or saline. The light/dark avoidance test was used to differentiate maladapted (MA) (anxious) from well-adapted (WA) (not anxious) subgroups. RNA extracted from the left dorsal hippocampus was used for RNA sequencing and gene expression data was compared between six fear-conditioned + saline MA (FEAR + SALINE MA) and six fear-conditioned + DCS WA (FEAR + DCS WA) animals. Of the 424 significantly downregulated and 25 significantly upregulated genes identified in the FEAR + DCS WA group compared to the FEAR + SALINE MA group, 121 downregulated and nine upregulated genes were predicted to be relevant to fear conditioning and anxiety and stress-related disorders. The majority of downregulated genes transcribed immune, proinflammatory and oxidative stress systems molecules. These molecules mediate neuroinflammation and cause neuronal damage. DCS also regulated genes involved in learning and memory processes, and genes associated with anxiety, stress-related disorders and co-occurring diseases (e.g., cardiovascular diseases, digestive system diseases and nervous system diseases). Identifying the molecular underpinnings of DCS-mediated fear extinction brings us closer to understanding the process of fear extinction.

  5. Combining d-cycloserine with motor training does not result in improved general motor learning in neurologically intact people or in people with stroke.

    PubMed

    Cherry, Kendra M; Lenze, Eric J; Lang, Catherine E

    2014-06-15

    Neurological rehabilitation involving motor training has resulted in clinically meaningful improvements in function but is unable to eliminate many of the impairments associated with neurological injury. Thus there is a growing need for interventions that facilitate motor learning during rehabilitation therapy, to optimize recovery. d-Cycloserine (DCS), a partial N-methyl-d-aspartate (NMDA) receptor agonist that enhances neurotransmission throughout the central nervous system (Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M. Arch Gen Psychiatry 61: 1136-1144, 2004), has been shown to facilitate declarative and emotional learning. We therefore tested whether combining DCS with motor training facilitates motor learning after stroke in a series of two experiments. Forty-one healthy adults participated in experiment I, and twenty adults with stroke participated in experiment II of this two-session, double-blind study. Session one consisted of baseline assessment, subject randomization, and oral administration of DCS or placebo (250 mg). Subjects then participated in training on a balancing task, a simulated feeding task, and a cognitive task. Subjects returned 1-3 days later for posttest assessment. We found that all subjects had improved performance from pretest to posttest on the balancing task, the simulated feeding task, and the cognitive task. Subjects who were given DCS before motor training, however, did not show enhanced learning on the balancing task, the simulated feeding task, or the associative recognition task compared with subjects given placebo. Moreover, training on the balancing task did not generalize to a similar, untrained balance task. Our findings suggest that DCS does not enhance motor learning or motor skill generalization in neurologically intact adults or in adults with stroke.

  6. Combining d-cycloserine with motor training does not result in improved general motor learning in neurologically intact people or in people with stroke

    PubMed Central

    Cherry, Kendra M.; Lenze, Eric J.

    2014-01-01

    Neurological rehabilitation involving motor training has resulted in clinically meaningful improvements in function but is unable to eliminate many of the impairments associated with neurological injury. Thus there is a growing need for interventions that facilitate motor learning during rehabilitation therapy, to optimize recovery. d-Cycloserine (DCS), a partial N-methyl-d-aspartate (NMDA) receptor agonist that enhances neurotransmission throughout the central nervous system (Ressler KJ, Rothbaum BO, Tannenbaum L, Anderson P, Graap K, Zimand E, Hodges L, Davis M. Arch Gen Psychiatry 61: 1136–1144, 2004), has been shown to facilitate declarative and emotional learning. We therefore tested whether combining DCS with motor training facilitates motor learning after stroke in a series of two experiments. Forty-one healthy adults participated in experiment I, and twenty adults with stroke participated in experiment II of this two-session, double-blind study. Session one consisted of baseline assessment, subject randomization, and oral administration of DCS or placebo (250 mg). Subjects then participated in training on a balancing task, a simulated feeding task, and a cognitive task. Subjects returned 1–3 days later for posttest assessment. We found that all subjects had improved performance from pretest to posttest on the balancing task, the simulated feeding task, and the cognitive task. Subjects who were given DCS before motor training, however, did not show enhanced learning on the balancing task, the simulated feeding task, or the associative recognition task compared with subjects given placebo. Moreover, training on the balancing task did not generalize to a similar, untrained balance task. Our findings suggest that DCS does not enhance motor learning or motor skill generalization in neurologically intact adults or in adults with stroke. PMID:24671538

  7. D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

    PubMed

    MacKillop, J; Few, L R; Stojek, M K; Murphy, C M; Malutinok, S F; Johnson, F T; Hofmann, S G; McGeary, J E; Swift, R M; Monti, P M

    2015-01-01

    Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning. PMID:25849983

  8. D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach.

    PubMed

    MacKillop, J; Few, L R; Stojek, M K; Murphy, C M; Malutinok, S F; Johnson, F T; Hofmann, S G; McGeary, J E; Swift, R M; Monti, P M

    2015-04-07

    Cue-elicited craving for alcohol is well established but extinction-based treatment to extinguish this response has generated only modest positive outcomes in clinical trials. Basic and clinical research suggests that D-cycloserine (DCS) enhances extinction to fear cues under certain conditions. However, it remains unclear whether DCS would also accelerate extinction of cue-elicited craving for alcohol. The goal of the current study was to examine whether, compared with placebo (PBO), DCS enhanced extinction of cue-elicited craving among treatment-seeking individuals with alcohol use disorders (AUDs). Participants were administered DCS (50 mg) or PBO 1 h before an alcohol extinction paradigm in a simulated bar environment on two occasions. The extinction procedures occurred 1 week apart and were fully integrated into outpatient treatment. Subjective craving for alcohol was the primary variable of interest. Follow-up cue reactivity sessions were conducted 1 week and 3 weeks later to ascertain persisting DCS effects. Drinking outcomes and tolerability were also examined. DCS was associated with augmented reductions in alcohol craving to alcohol cues during the first extinction session and these effects persisted through all subsequent sessions, suggesting facilitation of extinction. Participants in the DCS condition reported significant short-term reductions in drinking, although these did not persist to follow-up, and found the medication highly tolerable. These findings provide evidence that DCS enhances extinction of cue-elicited craving for alcohol in individuals with AUDs in the context of outpatient treatment. The potential clinical utility of DCS is discussed, including methodological considerations and context-dependent learning.

  9. Impaired visual memory in rats reared in isolation is reversed by D-cycloserine in the adult rat.

    PubMed

    Strømme Johannesen, Tone; Myhrer, Trond

    2002-02-15

    Previous studies have shown that environmental factors can influence cholinergic and glutamatergic activity in the developing brain, and that the variations in neurochemistry are accompanied by behavioral changes in later life. Rats reared in isolated, social, or enriched environments were tested with a visual discrimination task in adulthood. The results show that saline-treated rats reared in isolation exhibited impaired retention of the discrimination task compared to rats raised in social or enriched environments. However, systemic administration of the NMDA receptor agonist, D-cycloserine (3 mg/kg), restored normal memory function in cognitively impoverished rats. Acquisition of the task was not affected by the rearing conditions. D-Cycloserine is considered to be an efficient cognitive enhancer probably able to compensate for assumed loss of NMDA receptors during isolated rearing. PMID:11864642

  10. Dose timing of D-cycloserine to augment cognitive behavioral therapy for social anxiety: Study design and rationale.

    PubMed

    Hofmann, Stefan G; Carpenter, Joseph K; Otto, Michael W; Rosenfield, David; Smits, Jasper A J; Pollack, Mark H

    2015-07-01

    The use of D-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive-behavioral therapy (CBT) represents a promising new translational research direction with the goal to accelerate and optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and design for a randomized controlled trial examining the relative efficacy of tailoring DCS administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for social anxiety disorder (n = 156). Specifically, tailored post-session DCS administration will be compared against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This study aims to serve as the first step toward developing an algorithm for the personalized use of DCS during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for anxiety disorders.

  11. Dose Timing of D-cycloserine to Augment Cognitive Behavioral Therapy for Social Anxiety: Study Design and Rationale

    PubMed Central

    Carpenter, Joseph K.; Otto, Michael W.; Rosenfield, David; Smits, Jasper A. J.; Pollack, Mark H.

    2015-01-01

    The use of d-cycloserine (DCS) as a cognitive enhancer to augment exposure-based cognitive-behavioral therapy (CBT) represents a promising new translational research direction with the goal to accelerate and optimize treatment response for anxiety disorders. Some studies suggest that DCS may not only augment extinction learning but could also facilitate fear memory reconsolidation. Therefore, the effect of DCS may depend on fear levels reported at the end of exposure sessions. This paper presents the rationale and design for an ongoing randomized controlled trial examining the relative efficacy of tailoring DCS administration based on exposure success (i.e. end fear levels) during a 5-session group CBT protocol for social anxiety disorder (n = 156). Specifically, tailored post-session DCS administration will be compared against untailored post-session DCS, untailored pre-session DCS, and pill placebo in terms of reduction in social anxiety symptoms and responder status. In addition, a subset of participants (n = 96) will undergo a fear extinction retention experiment prior to the clinical trial in which they will be randomly assigned to receive either DCS or placebo prior to extinguishing a conditioned fear. The results from this experimental paradigm will clarify the mechanism of the effects of DCS on exposure procedures. This study aims to serve as the first step toward developing an algorithm for the personalized use of DCS during CBT for social anxiety disorder, with the ultimate goal of optimizing treatment outcome for anxiety disorders. ClinicalTrials.gov identifier: NCT02066792 PMID:26111923

  12. Examining the efficacy of d-cycloserine to augment therapeutic learning in depression.

    PubMed

    Otto, Michael W; Lee, Josephine; Hofmann, Stefan G; Hearon, Bridget A; Smits, Jasper A J; Rosenfield, David; Fava, Maurizio; Wright, Jesse H

    2016-05-01

    Despite advances in individual and combined treatments for major depression, issues with non-response and partial-response remain relatively common, motivating the search for new treatment strategies. This study aims to develop one such novel treatment. In this proof-of-concept study, we are investigating whether the treatment enhancing effects of d-cycloserine (DCS) administration can be extended outside the extinction-learning paradigms where they have been primarily examined. Using uniform delivery of cognitive behavioral therapy (CBT) content via computer-administered interventions for depression, we are assessing the value of pre-session administrations of DCS for retention of therapeutic learning. Recall of this information is evaluated in conjunction with performance on standardized tests of memory recall with both emotional and non-emotional stimuli. Specifically, in a randomized, double-blind trial we will compare the benefits of two pre-session administrations of DCS augmentation to those achieved by similar administrations of modafinil or placebo. Because modafinil is associated with a number of discriminable effects in addition to cognitive enhancement (e.g., feelings of vigor, alertness, positive mood); whereas these effects would not be expected with DCS, we will assess drug context effects in relation to memory augmentation effects. PMID:27094721

  13. Augmentation of exposure therapy with post-session administration of d-cycloserine

    PubMed Central

    Tart, Candyce D.; Handelsman, Pamela R.; DeBoer, Lindsey B.; Rosenfield, David; Pollack, Mark H.; Hofmann, Stefan G.; Powers, Mark B.; Otto, Michael W.; Smits, Jasper A.J.

    2013-01-01

    Background Pre-session administration of d-cycloserine (DCS) has been found to augment exposure therapy outcomes in a variety of anxiety disorders. To be able to enhance learning only for successful exposure sessions, it would be beneficial to have the option of administering DCS after rather than before the session, a strategy encouraged by pre-clinical work. We believe the present study is the first published report on the efficacy of post-session administration of DCS in humans. Method Adults (N = 29) with a DSM-IV diagnosis of acrophobia were randomized to receive two sessions of virtual reality exposure therapy (VRE) in combination with placebo or 50 mg of DCS. Instead of administering the pill prior to each of the sessions, as has been done in extant work, we administered the pill immediately following each session. Measures of acrophobia severity were collected at baseline, at each treatment session, 1-week post-treatment, and at 1-month follow-up. Results Mixed-effects repeated-measures ANOVAs and GLMMs revealed significant improvement in all outcome measures over time, but no between-group differences were observed. At post-treatment, 63.5% of patients in the placebo condition vs. 60.0% of those in the DCS condition were in remission. At 1-month follow up, 63.4% of those in the placebo condition vs. 66.6% of those in the DCS condition were in remission. Conclusions These findings do not support the application of post-session DCS administration for augmenting the efficacy of exposure-based treatments. Possible reasons for these findings are discussed. Trial Registry: The Trial is registered at ClinicalTrials.gov (NCT01102803). PMID:23098672

  14. Does D-Cycloserine Enhance Exposure Therapy for Anxiety Disorders in Humans? A Meta-Analysis

    PubMed Central

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  −0.34; CI: −0.54 to −0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients. PMID:24991926

  15. Does D-cycloserine enhance exposure therapy for anxiety disorders in humans? A meta-analysis.

    PubMed

    Rodrigues, Helga; Figueira, Ivan; Lopes, Alessandra; Gonçalves, Raquel; Mendlowicz, Mauro Vitor; Coutinho, Evandro Silva Freire; Ventura, Paula

    2014-01-01

    The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d =  -0.34; CI: -0.54 to -0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients.

  16. D-cycloserine augmentation in behavioral therapy for obsessive-compulsive disorder: a meta-analysis

    PubMed Central

    Xia, Jing; Du, Yanqiu; Han, Jiyang; Liu, Guo; Wang, Xumei

    2015-01-01

    Objective To evaluate the overall effect of D-cycloserine (DCS) augmentation on exposure and response prevention (ERP) therapy for obsessive-compulsive disorder (OCD). Methods Clinical studies on the effect of DCS augmentation on ERP therapy for OCD compared to placebo were included for meta analysis. The primary outcome was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Meta-analyses were performed with a random-effect model or a fixed-effect model using the Cochrane Review Manager (RevMan, version 5.2) to calculate the odds ratio and the mean difference, with their corresponding 95% confidence intervals. Results A total of six studies was included in the current meta-analyses, and their data were extracted. Among them, four were for analyses of DCS and Y-BOCS at midtreatment, six for analysis at posttreatment, and four at 3-month follow-up. Besides, three of the six eligible studies were included in the meta-analysis of the DCS and Clinical Global Impression–Severity Scale at posttreatment, and three in the meta-analysis of DCS and proportions of treatment responders and of subjects attaining clinical remission status criteria at posttreatment. Our meta-analyses do not reveal a significant effect of DCS augmentation in ERP therapy for OCD patients, except when measured at midtreatment. Compared to the placebo group, DCS augmentation did show a trend toward significantly lower/decreased Y-BOCS; when measured at posttreatment and in the subpopulation of DCS taken before some of the ERP sessions, DCS augmentation showed a trend toward significantly lower/decreased Y-BOCS. Conclusion Our result suggested that with the careful optimization of DCS-augmented ERP therapy by fine-tuning timing and dosing of DCS administration and number and frequency of ERP sessions, DCS may enhance the efficacy of ERP therapy in reducing the symptomatic severity of OCD patients, especially at early stage of the treatment; therefore, DCS augmentation could possibly reduce treatment

  17. Enhancing panic and smoking reduction treatment with d-cycloserine: Study protocol for a randomized controlled trial.

    PubMed

    Smits, Jasper A J; Kauffman, Brooke Y; Lee-Furman, Eunjung; Zvolensky, Michael J; Otto, Michael W; Piper, Megan E; Powers, Mark B; Rosenfield, David

    2016-05-01

    There has been relatively little attention focused on treatment strategies for smokers with panic attacks despite their increased risk of relapse. Panic and Smoking Reduction Treatment (PSRT) integrates standard smoking cessation treatment with an exposure-based intervention targeting the mechanisms underlying panic-smoking relations. Building upon emerging evidence supporting the efficacy of d-cycloserine (DCS) for augmenting exposure-based therapy, we are conducting an initial test of the efficacy of DCS for enhancing PSRT outcomes. Utilizing a randomized, double-blind trial comparing PSRT+DCS to PSRT+placebo, we will obtain initial effect sizes for short-term and long-term smoking cessation outcomes and perform an initial test of putative mechanisms. PMID:27015966

  18. d-cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia

    PubMed Central

    Smits, Jasper A. J.; Rosenfield, David; Otto, Michael W.; Powers, Mark B.; Hofmann, Stefan G.; Telch, Michael J.; Pollack, Mark H.; Tart, Candyce D.

    2013-01-01

    Background Whereas some studies have shown clear evidence for an augmentation effect of d-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of the extinction trials. Therefore, we conducted a re-analysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e. exposure success). Methods In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (N=14) or 50 mg of DCS (N=15) immediately after each session. Results Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just prior to concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when subjective fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared to those receiving placebo. Conclusions DCS appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposures. Trial Registry The Trial is registered at ClinicalTrials.gov (NCT01102803). PMID:23332511

  19. Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder.

    PubMed

    de Kleine, Rianne A; Smits, Jasper A J; Hendriks, Gert-Jan; Becker, Eni S; van Minnen, Agnes

    2015-08-01

    Augmentation of exposure therapy with d-cycloserine (DCS) has proven efficacious across anxiety disorders, although results in PTSD have been mixed. Work in animals and anxiety-disordered patients suggest that the potentiating effects of DCS are dependent on the level of extinction learning during extinction training and exposure treatment, respectively. The aim of the current study was to replicate and extend previous work by examining the association between the degree of extinction learning and DCS efficacy in our randomized clinical trial on DCS (50 mg) versus placebo enhancement of exposure therapy in a chronic mixed-trauma PTSD sample (N=67; de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012). The decline in subjective units of distress ratings collected during and across the exposure sessions were evaluated as indices of extinction learning. First, we examined whether extinction learning during an exposure session moderated DCS effects on self-reported PTSD symptoms at the next session. Second, we examined whether averaged extinction learning over the course of treatment interacted with group assignment to predict change over time and post treatment outcome. We did not find evidence that DCS effects were moderated by the degree of extinction learning, although, extinction learning was related to outcome regardless of group assignment. In PTSD, not one extinction-learning index has been consistently linked to DCS enhanced exposure treatment outcome. More (experimental) work needs to been done to unravel the complex interplay between extinction learning and DCS enhancement, especially in PTSD patients.

  20. A pilot randomized controlled trial of D-cycloserine and distributed practice as adjuvants to constraint-induced movement therapy after stroke.

    PubMed

    Nadeau, Stephen E; Davis, Sandra E; Wu, Samuel S; Dai, Yunfeng; Richards, Lorie G

    2014-01-01

    Background. Phase III trials of rehabilitation of paresis after stroke have proven the effectiveness of intensive and extended task practice, but they have also shown that many patients do not qualify, because of severity of impairment, and that many of those who are treated are left with clinically significant deficits. Objective. To test the value of 2 potential adjuvants to normal learning processes engaged in constraint-induced movement therapy (CIMT): greater distribution of treatment over time and the coadministration of d-cycloserine, a competitive agonist at the glycine site of the N-methyl-D-aspartate glutamate receptor. Methods. A prospective randomized single-blind parallel-group trial of more versus less condensed therapy (2 vs 10 weeks) and d-cycloserine (50 mg) each treatment day versus placebo (in a 2 × 2 design), as potential adjuvants to 60 hours of CIMT. Results. Twenty-four participants entered the study, and 22 completed it and were assessed at the completion of treatment and 3 months later. Neither greater distribution of treatment nor treatment with d-cycloserine significantly augmented retention of gains achieved with CIMT. Conclusions. Greater distribution of practice and treatment with d-cycloserine do not appear to augment retention of gains achieved with CIMT. However, concentration of CIMT over 2 weeks ("massed practice") appears to confer no advantage either.

  1. Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine.

    PubMed

    Prosser, Gareth A; de Carvalho, Luiz Pedro S

    2013-02-01

    D-cycloserine (DCS) is an antibiotic that is currently used in second-line treatment of tuberculosis. DCS is a structural analogue of D-alanine, and targets two enzymes involved in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). The mechanisms of inhibition of DCS have been well-assessed using Alr and Ddl enzymes from various bacterial species, but little is known regarding the interactions of DCS with the mycobacterial orthologues of these enzymes. We have over-expressed and purified recombinant Mycobacterium tuberculosis Ddl (MtDdl; Rv2981c), and report a kinetic examination of the enzyme with both its native substrate and DCS. MtDdl is activated by K(+), follows an ordered ter ter mechanism and displays distinct affinities for D-Ala at each D-Ala binding site (K(m,D-Ala1) = 0.075 mm, K(m,D-Ala2) = 3.6 mm). ATP is the first substrate to bind and is necessary for subsequent binding of D-alanine or DCS. The pH dependence of MtDdl kinetic parameters indicate that general base chemistry is involved in the catalytic step. DCS was found to competitively inhibit D-Ala binding at both MtDdl D-Ala sites with equal affinity (K(i,DCS1) = 14 μm, K(i,DCS2) = 25 μm); however, each enzyme active site can only accommodate a single DCS molecule at a given time. The pH dependence of K(i,DCS2) revealed a loss of DCS binding affinity at high pH (pK(a) = 7.5), suggesting that DCS binds optimally in the zwitterionic form. The results of this study may assist in the design and development of novel Ddl-specific inhibitors for use as anti-mycobacterial agents.

  2. Effects of external phase on D-cycloserine loaded W/O nanocapsules prepared by the interfacial polymerization method.

    PubMed

    Musumeci, Teresa; Ventura, Cinzia A; Carbone, Claudia; Pignatello, Rosario; Puglisi, Giovanni

    2011-07-01

    Water in oil (W/O) polybutylcyanoacrylate nanocapsules containing D-cycloserine (D-CS) for intranasal delivery were prepared by the interfacial polymerization method. Different oils, as external phase, for the preparation of the initial W/O miniemulsions were used and their effect on mean size and other physico-chemical properties were evaluated by photon correlation spectroscopy (PCS) and scanning electron microscopy (SEM) analysis. Two probes at different hydrophilicity were used to verify the internal aqueous nature of the core. Both miniemulsions and nanocapsules mean size and polydispersity index were influenced by the used external phase. Different entrapment efficiency were obtained for D-cycloserine-loaded nanocapsules correlated to the used oil [ranging from 39 to 51% encapsulation efficiency (E.E.)]. In vitro drug release showed an initial burst effect (ranging from 20 to 40%) followed by a slow release of D-CS for all preparations. This study demonstrated that many relevant physico-chemical and technological properties of polybutylcyanoacrylate nanocapsules prepared by interfacial polymerization of miniemulsions are significantly influenced by the external oil phase used.

  3. The Future of D-Cycloserine and Other Cognitive Modifiers in Obsessive-Compulsive and Related Disorders

    PubMed Central

    Sulkowski, Michael L.; Geller, Daniel A.; Lewin, Adam B.; Murphy, Tanya K.; Mittelman, Andrew; Brown, Ashley; Storch, Eric A.

    2014-01-01

    Variants of exposure therapy are effective for treating obsessive-compulsive and related disorders (OCRDs). However, significant numbers of patients do not respond adequately to exposure therapy resulting in continued distress and functional impairment. Therefore, novel approaches to augmenting exposure therapy are needed to adequately treat non- and partial-responders. Emerging research suggests that interventions that augment learning and memory processes associated with exposure therapy (i.e., extinction training) may display promise in enhancing treatment response in OCRDs. As the most studied example, d-cycloserine (DCS) is a relatively safe cognitive enhancer that appears to accelerate treatment gains associated with exposure therapy. This article reviews research on the use of DCS and other putative cognitive modifiers as they relate to the treatment (or prospective treatment) of obsessive-compulsive disorder and other OCRDs. PMID:25383074

  4. Unraveling Comparative Anti-Amyloidogenic Behavior of Pyrazinamide and D-Cycloserine: A Mechanistic Biophysical Insight

    PubMed Central

    Chaturvedi, Sumit Kumar; Zaidi, Nida; Alam, Parvez; Khan, Javed Masood; Qadeer, Atiyatul; Siddique, Ibrar Ahmad; Asmat, Shamoon; Zaidi, Yusra; Khan, Rizwan Hasan

    2015-01-01

    Amyloid fibril formation by proteins leads to variety of degenerative disorders called amyloidosis. While these disorders are topic of extensive research, effective treatments are still unavailable. Thus in present study, two anti-tuberculosis drugs, i.e., pyrazinamide (PYZ) and D-cycloserine (DCS), also known for treatment for Alzheimer’s dementia, were checked for the anti-aggregation and anti-amyloidogenic ability on Aβ-42 peptide and hen egg white lysozyme. Results demonstrated that both drugs inhibit the heat induced aggregation; however, PYZ was more potent and decelerated the nucleation phase as observed from various spectroscopic and microscopic techniques. Furthermore, pre-formed amyloid fibrils incubated with these drugs also increased the PC12/SH-SY5Y cell viability as compare to the amyloid fibrils alone; however, the increase was more pronounced for PYZ as confirmed by MTT assay. Additionally, molecular docking study suggested that the greater inhibitory potential of PYZ as compare to DCS may be due to strong binding affinity and more occupancy of hydrophobic patches of HEWL, which is known to form the core of the protein fibrils. PMID:26312749

  5. Does d-Cycloserine Augmentation of CBT Improve Therapeutic Homework Compliance for Pediatric Obsessive–Compulsive Disorder?

    PubMed Central

    Park, Jennifer M.; Small, Brent J.; Geller, Daniel A.; Murphy, Tanya K.; Lewin, Adam B.; Storch, Eric A.

    2014-01-01

    Clinical studies in adults and children with obsessive–compulsive disorder (OCD) have shown that d-cycloserine (DCS) can improve treatment response by enhancing fear extinction learning during exposure-based psychotherapy. Some have hypothesized that improved treatment response is a function of increased compliance and engagement in therapeutic homework tasks, a core component of behavioral treatment. The present study examined the relationship between DCS augmented cognitive-behavioral therapy (CBT) and homework compliance in a double-blind, placebo controlled trial with 30 youth with OCD. All children received 10 CBT sessions, the last seven of which included exposure and response prevention paired with DCS or placebo dosed 1 h before the session started. Results suggested that DCS augmented CBT did not predict improved homework compliance over the course of treatment, relative to the placebo augmented CBT group. However, when groups were collapsed, homework compliance was directly associated with treatment outcome. These findings suggest that while DCS may not increase homework compliance over time, more generally, homework compliance is an integral part of pediatric OCD treatment outcome. PMID:24999301

  6. Does d-Cycloserine Augmentation of CBT Improve Therapeutic Homework Compliance for Pediatric Obsessive-Compulsive Disorder?

    PubMed

    Park, Jennifer M; Small, Brent J; Geller, Daniel A; Murphy, Tanya K; Lewin, Adam B; Storch, Eric A

    2014-07-01

    Clinical studies in adults and children with obsessive-compulsive disorder (OCD) have shown that d-cycloserine (DCS) can improve treatment response by enhancing fear extinction learning during exposure-based psychotherapy. Some have hypothesized that improved treatment response is a function of increased compliance and engagement in therapeutic homework tasks, a core component of behavioral treatment. The present study examined the relationship between DCS augmented cognitive-behavioral therapy (CBT) and homework compliance in a double-blind, placebo controlled trial with 30 youth with OCD. All children received 10 CBT sessions, the last seven of which included exposure and response prevention paired with DCS or placebo dosed 1 h before the session started. Results suggested that DCS augmented CBT did not predict improved homework compliance over the course of treatment, relative to the placebo augmented CBT group. However, when groups were collapsed, homework compliance was directly associated with treatment outcome. These findings suggest that while DCS may not increase homework compliance over time, more generally, homework compliance is an integral part of pediatric OCD treatment outcome. PMID:24999301

  7. Medial orbitofrontal cortex lesion prevents facilitatory effects of d-cycloserine during fear extinction.

    PubMed

    Sierra, Rodrigo O; Nítola, Laura P; Duran, Johanna M; Prieto, Daysi R; León, Laura A; Cardenas, Fernando P

    2016-01-01

    Animal models of fear extinction have an important clinical relevance to pharmacological and exposure-based therapies for anxiety disorders. Lesions of prefrontal structures impair fear extinction. On the other hand, d-cycloserine is able to enhance this process. We hypothesize that the integrity of cortical structures involved in inhibitory control of emotional responses is crucial for the facilitatory effects of d-cycloserine. Here, we showed that medial orbitofrontal cortex lesion prevents d-cycloserine enhancement of fear extinction. These preliminary results suggest that effects of pharmacological treatments could be dependent on cortical activity state to promote fear memory reduction.

  8. Effect of a positive reinforcing stimulus on fear memory reconsolidation in ethanol withdrawn rats: Influence of d-cycloserine.

    PubMed

    Ortiz, Vanesa; Molina, Víctor Alejandro; Martijena, Irene Delia

    2016-12-15

    The pharmacological blockade of memory reconsolidation has been suggested as a potential treatment to the attenuation of maladaptive memories associated to psychiatric disorders and drug addiction. To interfere with the process of fear memory reconsolidation using a manipulation safer than pharmacological interventions, here we examined whether a positive reinforcing stimulus (non-alcoholic beer, NB) post-memory retrieval can decrease the fear response in ethanol withdrawn (ETOH) animals. We first evaluated the potential interfering effect of NB on memory reconsolidation in non-ethanol dependent (control, CON) rats. Non-alcoholic beer intake shortly after memory retrieval attenuated the fear response in CON rats. A resistance to destabilization/reconsolidation process was previously observed in ETOH rats, which was reversed by the activation of NMDA receptor induced by pre-retrieval d-cycloserine (DCS) administration. Therefore, the influence of DCS (5mg/kg; i.p.) to facilitate the disruptive effect of NB on fear memory was examined in ETOH animals. As expected, NB was ineffective to attenuate the fear response in ETOH rats, with DCS being necessary to promote the disruptive effect of NB on the reconsolidation in these animals. Hence, DCS/reinforcing stimulus in combination with memory reactivation can be considered as an alternative approach for disrupting resistant fear memories.

  9. Effect of a positive reinforcing stimulus on fear memory reconsolidation in ethanol withdrawn rats: Influence of d-cycloserine.

    PubMed

    Ortiz, Vanesa; Molina, Víctor Alejandro; Martijena, Irene Delia

    2016-12-15

    The pharmacological blockade of memory reconsolidation has been suggested as a potential treatment to the attenuation of maladaptive memories associated to psychiatric disorders and drug addiction. To interfere with the process of fear memory reconsolidation using a manipulation safer than pharmacological interventions, here we examined whether a positive reinforcing stimulus (non-alcoholic beer, NB) post-memory retrieval can decrease the fear response in ethanol withdrawn (ETOH) animals. We first evaluated the potential interfering effect of NB on memory reconsolidation in non-ethanol dependent (control, CON) rats. Non-alcoholic beer intake shortly after memory retrieval attenuated the fear response in CON rats. A resistance to destabilization/reconsolidation process was previously observed in ETOH rats, which was reversed by the activation of NMDA receptor induced by pre-retrieval d-cycloserine (DCS) administration. Therefore, the influence of DCS (5mg/kg; i.p.) to facilitate the disruptive effect of NB on fear memory was examined in ETOH animals. As expected, NB was ineffective to attenuate the fear response in ETOH rats, with DCS being necessary to promote the disruptive effect of NB on the reconsolidation in these animals. Hence, DCS/reinforcing stimulus in combination with memory reactivation can be considered as an alternative approach for disrupting resistant fear memories. PMID:27522017

  10. D-Cycloserine Augmentation of Exposure Therapy for Post-Traumatic Stress Disorder: A Pilot Randomized Clinical Trial

    PubMed Central

    Difede, JoAnn; Cukor, Judith; Wyka, Katarzyna; Olden, Megan; Hoffman, Hunter; Lee, Francis S; Altemus, Margaret

    2014-01-01

    Viewing post-traumatic stress disorder (PTSD) as a disorder of emotional learning, this study used a cognitive enhancer synergistically with virtual reality exposure (VRE) therapy for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo-controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at pre-treatment, following sessions 3, 6, 10, post-treatment, and at 6 months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at 6 weeks, with medium to large between-group effect sizes immediately post-treatment and 6 months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at post-treatment; 69% vs 17% at 6 months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared with the VRE-placebo group. These results suggest a promising new treatment for PTSD. PMID:24217129

  11. Structure of the Mycobacterium tuberculosis D-Alanine:D-Alanine Ligase, a Target of the Antituberculosis Drug D-Cycloserine

    SciTech Connect

    Bruning, John B.; Murillo, Ana C.; Chacon, Ofelia; Barletta, Raúl G.; Sacchettini, James C.

    2011-09-28

    D-Alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 {angstrom}. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC{sub 50}) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.

  12. D-Cycloserine enhances social exploration in the Balb/c mouse.

    PubMed

    Jacome, Luis F; Burket, Jessica A; Herndon, Amy L; Deutsch, Stephen I

    2011-05-30

    Inbred Balb/c mice show deficits of sociability. The endogenous tone of NMDA receptor-mediated neurotransmission is altered in Balb/c mice, which may explain the beneficial effect of D-cycloserine on impaired sociability. In the current study, Balb/c mice spent more time than the Swiss Webster comparator strain in the open arms of an elevated plus maze (EPM), suggesting that they are not more anxious or fearful in the absence of a social stimulus mouse. Moreover, Balb/c and Swiss Webster mice did not differ in the amount of time they spent exploring an inanimate object in an open field. Differences in exploratory activity between strains emerged only when a salient social stimulus mouse was enclosed in the open field. D-Cycloserine increased the amount of time Balb/c mice spent exploring the enclosed stimulus mouse to levels observed in vehicle-treated Swiss Webster mice. Finally, irrespective of strain, D-cycloserine increased exploratory activity as measured in open arm entries in the EPM, when no enclosed stimulus mouse was present. The data show that mouse strain influences D-cycloserine's effect on exploration in the presence of a salient social stimulus mouse. In the absence of an enclosed stimulus mouse, D-cycloserine increased open arm entries significantly in both the sociability-impaired Balb/c and comparator Swiss Webster strains. Thus, D-cycloserine positively affects exploratory activity in general, but strain differences emerge when the stimulus eliciting exploration is a salient social stimulus mouse versus an inanimate object. Further, the sociability deficit of the Balb/c mouse is not an epiphenomenon of increased generalized anxiety.

  13. Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke

    PubMed Central

    Butler, Andrew J.; Kallos, Justiss; Housley, Stephen N.; LaPlaca, Michelle C.; Traynelis, Stephen F.; Wolf, Steven L.

    2015-01-01

    Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors. PMID:26587287

  14. Randomized, Placebo-Controlled, Double-Blind Pilot Study of D-Cycloserine in Chronic Stroke.

    PubMed

    Butler, Andrew J; Kallos, Justiss; Housley, Stephen N; LaPlaca, Michelle C; Traynelis, Stephen F; Wolf, Steven L

    2015-01-01

    Stroke is a leading cause of death and disability in the USA. Up to 60% of patients do not fully recover despite intensive physical therapy treatment. N-Methyl-D-aspartate receptors (NMDA-R) have been shown to play a role in synaptic plasticity when activated. D-Cycloserine promotes NMDA receptor function by binding to receptors with unoccupied glycine sites. These receptors are involved in learning and memory. We hypothesized that D-cycloserine, when combined with robotic-assisted physiotherapy (RAP), would result in greater gains compared with placebo + RAP in stroke survivors. Participants (n = 14) were randomized to D-cycloserine plus RAP or placebo plus RAP. Functional, cognitive, and quality-of-life measures were used to assess recovery. There was significant improvement in grip strength of the affected hand within both groups from baseline to 3 weeks (95% confidence interval for mean change, 3.95 ± 2.96 to 4.90 ± 3.56 N for D-cycloserine and 5.72 ± 3.98 to 8.44 ± 4.90 N for control). SIS mood domain showed improvement for both groups (95% confidence interval for mean change, 72.6 ± 16.3 to 82.9 ± 10.9 for D-cycloserine and 82.9 ± 13.5 to 90.3 ± 9.9 for control). This preliminary study does not provide evidence that D-cycloserine can provide greater gains in learning compared with placebo for stroke survivors. PMID:26587287

  15. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.

    PubMed

    Desjardins, Christopher A; Cohen, Keira A; Munsamy, Vanisha; Abeel, Thomas; Maharaj, Kashmeel; Walker, Bruce J; Shea, Terrance P; Almeida, Deepak V; Manson, Abigail L; Salazar, Alex; Padayatchi, Nesri; O'Donnell, Max R; Mlisana, Koleka P; Wortman, Jennifer; Birren, Bruce W; Grosset, Jacques; Earl, Ashlee M; Pym, Alexander S

    2016-05-01

    A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss of function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss of function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted use of this toxic drug among patients with susceptible infections. PMID:27064254

  16. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance

    PubMed Central

    Desjardins, Christopher A.; Cohen, Keira A.; Munsamy, Vanisha; Abeel, Thomas; Maharaj, Kashmeel; Walker, Bruce J.; Shea, Terrance P.; Almeida, Deepak V.; Manson, Abigail L.; Salazar, Alex; Padayatchi, Nesri; O’Donnell, Max R.; Mlisana, Koleka P.; Wortman, Jennifer; Birren, Bruce W.; Grosset, Jacques; Earl, Ashlee M.; Pym, Alexander S.

    2016-01-01

    A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss-of-function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss-of-function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted utilization of this toxic drug among patients with susceptible infections. PMID:27064254

  17. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.

    PubMed

    Desjardins, Christopher A; Cohen, Keira A; Munsamy, Vanisha; Abeel, Thomas; Maharaj, Kashmeel; Walker, Bruce J; Shea, Terrance P; Almeida, Deepak V; Manson, Abigail L; Salazar, Alex; Padayatchi, Nesri; O'Donnell, Max R; Mlisana, Koleka P; Wortman, Jennifer; Birren, Bruce W; Grosset, Jacques; Earl, Ashlee M; Pym, Alexander S

    2016-05-01

    A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss of function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss of function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted use of this toxic drug among patients with susceptible infections.

  18. A role beyond learning for NMDA receptors in reward-based decision-making-a pharmacological study using d-cycloserine.

    PubMed

    Scholl, Jacqueline; Günthner, Jan; Kolling, Nils; Favaron, Elisa; Rushworth, Matthew Fs; Harmer, Catherine J; Reinecke, Andrea

    2014-11-01

    N-methyl-D-aspartate (NMDA) receptors are known to fulfill crucial functions in many forms of learning and plasticity. More recently, biophysical models, however, have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision-making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors in reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.

  19. Once-Weekly D-Cycloserine Effects on Negative Symptoms and Cognition in Schizophrenia: An Exploratory Study

    PubMed Central

    Goff, Donald C.; Cather, Corinne; Gottlieb, Jennifer D.; Evins, A. Eden; Walsh, Jared; Raeke, Lisa; Otto, Michael W.; Schoenfeld, David; Green, Michael F.

    2008-01-01

    Background Daily dosing with D-cycloserine has inconsistently improved negative symptoms in schizophrenia patients, whereas intermittent dosing significantly facilitated exposure-based therapy in two studies of patients with phobic anxiety. In animal models, single dose administration enhances memory consolidation, but tachyphylaxis develops with repeated dosing. The objective of this exploratory study was to assess whether once-weekly dosing with D-cycloserine will produce persistent improvements in negative symptoms and cognition. Methods Fifty stable adult schizophrenia outpatients treated with any antipsychotic except clozapine were enrolled and 38 were randomized, double-blind, in a parallel-group, 8-week add-on trial of D-cycloserine 50 mg or placebo administered once-weekly. Symptom rating scales and a cognitive battery were administered at baseline and week 8 before the dose of study drug. As an exploratory analysis of memory consolidation, the Logical Memory Test, modified to measure recall after 7 days, was administered at baseline and after the first weekly dose of D-cycloserine. The primary outcome measures were change from baseline to week 8 on the SANS total score and on a composite cognitive score. Results Thirty-three subjects (87%) completed the trial. D-cycloserine significantly improved SANS total scores compared to placebo at week 8. Cognitive performance did not improve with D-cycloserine at 8 weeks. Delayed thematic recall on the Logical Memory Test was significantly improved with the first dose of D-cycloserine compared to placebo. Performance on immediate thematic recall and item recall on the Logical Memory Test did not differ between treatments. Conclusions Once-weekly dosing with D-cycloserine for 8 weeks produced persistent improvement of negative symptoms compared to placebo, although statistical significance was, in part, the result of worsening of negative symptoms with placebo. Consistent with animal models, a single dose of D-cycloserine

  20. D-Cycloserine acts via increasing the GluN1 protein expressions in the frontal cortex and decreases the avoidance and risk assessment behaviors in a rat traumatic stress model.

    PubMed

    Sarıdoğan, Gökçe Elif; Aykaç, Aslı; Cabadak, Hülya; Cerit, Cem; Çalışkan, Mecit; Gören, M Zafer

    2015-10-15

    D-cycloserine (DCS), an FDA approved anti-tuberculosis drug has extensively been studied for its cognitive enhancer effects in psychiatric disorders. DCS may enhance the effects of fear extinction trainings in animals during exposure therapy and hence we investigated the effects of DCS on distinct behavioral parameters in a predator odor stress model and tested the optimal duration for repeated daily administrations of the agent. Cat fur odor blocks were used to produce stress and avoidance and risk assessment behavioral parameters were used where DCS or saline were used as treatments in adjunct to extinction trainings. We observed that DCS facilitated extinction training by providing further extinction of avoidance responses, risk assessment behaviors and increased the contact with the cue in a setting where DCS was administered before extinction trainings for 3 days without producing a significant tolerance. In amygdala and hippocampus, GluN1 protein expressions decreased 72h after the fear conditioning in the traumatic stress group suggesting a possible down-regulation of NMDARs. We observed that extinction learning increased GluN1 proteins both in the amygdaloid complex and the dorsal hippocampus of the rats receiving extinction training or extinction training with DCS. Our findings also indicate that DCS with extinction training increased GluN1 protein levels in the frontal cortex. We may suggest that action of DCS relies on enhancement of the consolidation of fear extinction in the frontal cortex. PMID:26225843

  1. Advances in the treatment of pediatric obsessive–compulsive d-cycloserine with exposure and response prevention

    PubMed Central

    McGuire, Joseph F; Lewin, Adam B; Geller, Daniel A; Brown, Ashley; Ramsey, Kesley; Mutch, Jane; Mittelman, Andrew; Micco, Jamie; Jordan, Cary; Wilhelm, Sabine; Murphy, Tanya K; Small, Brent J; Storch, Eric A

    2012-01-01

    SUMMARY Exposure-based cognitive-behavioral therapy and serotonin reuptake inhibitor medications are efficacious treatment options for the management of pediatric obsessive-compulsive disorder. Despite established efficacy, many youths receiving either therapy remain symptomatic after acute treatment. Regardless of the rationale for persistent symptoms, a clear need emerges for treatment options that restore functioning efficiently to symptomatic youths. One innovative approach builds upon the identified role of NMDA receptors in the fear extinction process. Instead of breaking existing connections during fear extinction, new associations develop that eventually predominate over prior associations. Recent investigations have explored augmenting exposure-based cognitive-behavioral therapy with the NMDA partial agonist d-cycloserine, with preliminary results demonstrating expedited treatment gains and moderately larger effects above exposure and response prevention therapy alone. A large randomized clinical trial is underway to evaluate the efficacy and efficiency of this therapeutic combination in pediatric obsessive–compulsive disorder. Results from this trial may translate into improved management practices. PMID:24174993

  2. REVERSAL OF d-CYCLOSERINE INHIBITION OF BACTERIAL GROWTH BY ALANINE

    PubMed Central

    Zygmunt, Walter A.

    1962-01-01

    Zygmunt, Walter A. (Mead Johnson & Co., Evansville, Ind.). Reversal of d-cycloserine inhibition of bacterial growth by alanine. J. Bacteriol. 84:154–156. 1962.—Reversal of the antibacterial activity of d-4-amino-3-isoxazolidone by alanine in bacterial cultures actively growing on chemically defined media was compared in cultures requiring exogenous alanine and those capable of its synthesis. dl-Alanine was the most effective reversal agent in Pediococcus cerevisiae, an alanine-requiring organism, and d-alanine was effective in Escherichia coli and Staphylococcus aureus, organisms synthesizing alanine. With all three cultures, l-alanine was the least effective reversal agent. PMID:16561951

  3. Pre-training blocks the improving effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation performance in aged rats.

    PubMed

    Aura, J; Riekkinen, P

    2000-03-01

    We investigated the effect of pre-training on the improvement of spatial navigation performance provided by a cholinesterase inhibitor, tetrahydroaminoacridine (3 mg/kg, i.p.), and a positive modulator of NMDA receptor, D-cycloserine (10 mg/kg, i.p.), or their combination in aged rats. Pre-training consisted of spatial or non-spatial conditions and took place in either the same or a separate room. We found that any kind of pre-training was able to eliminate the enhancing effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation. However, none of these pre-training conditions was able to block the age-related deficit in spatial navigation. These results indicate that tetrahydroaminoacridine and D-cycloserine, separately or in combination, do not themselves alleviate the age-related spatial memory deficit, but may enhance procedural aspects of water maze learning in aged rats.

  4. D-cycloserine does not improve but might slightly speed up the outcome of in-vivo exposure therapy in patients with severe agoraphobia and panic disorder in a randomized double blind clinical trial.

    PubMed

    Siegmund, Anja; Golfels, Fabian; Finck, Claudia; Halisch, Anna; Räth, Daniela; Plag, Jens; Ströhle, Andreas

    2011-08-01

    D-cycloserine (DCS)-augmented exposure therapy has proven efficacy in the treatment of acrophobia, social phobia, panic disorder and OCD. Here we studied whether DCS can also improve the effect of cognitive behavioral therapy (CBT) in patients with agoraphobia and panic disorder. To this end, 39 patients with the diagnoses of agoraphobia and panic disorder were treated with 11 sessions of CBT including three individual in-vivo exposure sessions (flooding), augmented with either 50mg of DCS (N=20) or placebo (N=19) in a randomized double blind design. Primary outcome was the total score of the panic and agoraphobia scale. Both groups profited considerably from therapy and DCS did not significantly improve this outcome (p=0.475; η(2)p = 0.01). However, there was a statistical trend (p=0.075; η(2)p = 0.17) in the more severely ill patients that DCS accelerated symptom reduction in the primary outcome at post-therapy. No serious adverse effects occurred during the trial. We conclude that in patients with agoraphobia and panic disorder, DCS seems to lack an additional benefit to efficient cbt, probably due to a floor effect. Nonetheless, the acceleration of symptom reduction in severely ill patients might represent a valuable treatment option deserving further investigation.

  5. Sleep-Dependent Declarative Memory Consolidation—Unaffected after Blocking NMDA or AMPA Receptors but Enhanced by NMDA Coagonist D-Cycloserine

    PubMed Central

    Feld, Gordon B; Lange, Tanja; Gais, Steffen; Born, Jan

    2013-01-01

    Sleep has a pivotal role in the consolidation of declarative memory. The coordinated neuronal replay of information encoded before sleep has been identified as a key process. It is assumed that the repeated reactivation of firing patterns in glutamatergic neuron assemblies translates into plastic synaptic changes underlying the formation of longer-term neuronal representations. Here, we tested the effects of blocking and enhancing glutamatergic neurotransmission during sleep on declarative memory consolidation in humans. We conducted three placebo-controlled, crossover, double-blind studies in which participants learned a word-pair association task. Afterwards, they slept in a sleep laboratory and received glutamatergic modulators. Our first two studies aimed at impairing consolidation by administering the NMDA receptor blocker ketamine and the AMPA receptor blocker caroverine during retention sleep, which, paradoxically, remained unsuccessful, inasmuch as declarative memory performance was unaffected by the treatment. However, in the third study, administration of the NMDA receptor coagonist D-cycloserine (DCS) during retention sleep facilitated consolidation of declarative memory (word pairs) but not consolidation of a procedural control task (finger sequence tapping). Administration of DCS during a wake interval remained without effect on retention of word pairs but improved encoding of numbers. From the overall pattern, we conclude that the consolidation of hippocampus-dependent declarative memory during sleep relies on NMDA-related plastic processes that differ from those processes leading to wake encoding. We speculate that glutamatergic activation during sleep is not only involved in consolidation but also in forgetting of hippocampal memory with both processes being differentially sensitive to DCS and unselective blockade of NMDA and AMPA receptors. PMID:23887151

  6. Characterization of Chlamydia MurC-Ddl, a fusion protein exhibiting D-alanyl-D-alanine ligase activity involved in peptidoglycan synthesis and D-cycloserine sensitivity.

    PubMed

    McCoy, Andrea J; Maurelli, Anthony T

    2005-07-01

    Recent characterization of chlamydial genes encoding functional peptidoglycan (PG)-synthesis proteins suggests that the Chlamydiaceae possess the ability to synthesize PG yet biochemical evidence for the synthesis of PG has yet to be demonstrated. The presence of D-amino acids in PG is a hallmark of bacteria. Chlamydiaceae do not appear to encode amino acid racemases however, a D-alanyl-D-alanine (D-Ala-D-Ala) ligase homologue (Ddl) is encoded in the genome. Thus, we undertook a genetics-based approach to demonstrate and characterize the D-Ala-D-Ala ligase activity of chlamydial Ddl, a protein encoded as a fusion with MurC. The full-length murC-ddl fusion gene from Chlamydia trachomatis serovar L2 was cloned and placed under the control of the arabinose-inducible ara promoter and transformed into a D-Ala-D-Ala ligase auxotroph of Escherichia coli possessing deletions of both the ddlA and ddlB genes. Viability of the E. coliDeltaddlADeltaddlB mutant in the absence of exogenous D-Ala-D-Ala dipeptide became dependent on the expression of the chlamydial murC-ddl thus demonstrating functional ligase activity. Domain mapping of the full-length fusion protein and site-directed mutagenesis of the MurC domain revealed that the structure of the full fusion protein but not MurC enzymatic activity was required for ligase activity in vivo. Recombinant MurC-Ddl exhibited substrate specificity for D-Ala. Chlamydia growth is inhibited by D-cycloserine (DCS) and in vitro analysis provided evidence for the chlamydial MurC-Ddl as the target for DCS sensitivity. In vivo sensitivity to DCS could be reversed by addition of exogenous D-Ala and D-Ala-D-Ala. Together, these findings further support our hypothesis that PG is synthesized by members of the Chlamydiaceae family and suggest that D-amino acids, specifically D-Ala, are present in chlamydial PG.

  7. Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

    PubMed Central

    Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D.; Whittle, Nigel

    2016-01-01

    Background: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. Methods: The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Results: Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. Conclusions: By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. PMID:26625894

  8. A Randomized, Double-blind Evaluation of D-cycloserine or Alprazolam Combined with Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder (PTSD) in Iraq and Afghanistan War Veterans

    PubMed Central

    Rothbaum, Barbara Olasov; Price, Matthew; Jovanovic, Tanja; Norrholm, Seth D.; Gerardi, Maryrose; Dunlop, Boadie; Davis, Michael; Bradley, Bekh; Duncan, Erica; Rizzo, Albert “Skip”; Ressler, Kerry J.

    2014-01-01

    Objective To determine the effectiveness of Virtual Reality Exposure (VRE) augmented with D-cycloserine (50mg) or alprazolam (0.25mg), compared to placebo, in reducing PTSD due to military trauma in Iraq and Afghanistan. Method A double-blind, placebo-controlled randomized clinical trial comparing augmentation methods for VRE for subjects (n= 156) with PTSD was conducted. Results PTSD symptoms significantly improved from pre- to post-treatment over the 6-session VRE treatment (p<.001) across all conditions and were maintained at 3, 6, and 12 months follow-up. There were no overall differences between the D-cycloserine group on symptoms at any time-point. The alprazolam and placebo conditions significantly differed on the post-treatment Clinician Administered PTSD scale (p = .006) and the 3-month post-treatment PTSD diagnosis, such that the alprazolam group showed greater rates of PTSD (79.2% alprazolam vs. 47.8% placebo). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only (p<.005). At post-treatment, the D-cycloserine group was the lowest on cortisol reactivity (p<.05) and startle response during VR scenes (p<.05). Conclusions A small number of VRE sessions were associated with reduced PTSD diagnosis and symptoms in Iraq/Afghanistan veterans, although there was no control condition for the VRE. Overall, there was no advantage of D-cycloserine on PTSD symptoms in primary analyses. In secondary analyses, benzodiazepine use during treatment may impair recovery, and D-cycloserine may enhance VRE in patients who demonstrate within-session learning. D-cycloserine augmentation treatment in PTSD patients may reduce cortisol and startle reactivity compared to the alprazolam and placebo treatment, consistent with the animal literature. PMID:24743802

  9. EFFECTS OF D-CYCLOSERINE ON CUE-INDUCED CRAVING AND CIGARETTE SMOKING AMONG CONCURRENT COCAINE- AND NICOTINE-DEPENDENT VOLUNTEERS

    PubMed Central

    Yoon, Jin H.; Newton, Thomas F.; Haile, Colin N.; Bordnick, Patrick S.; Fintzy, Rachel E.; Culbertson, Chris; Mahoney, James J.; Hawkins, Rollin Y.; LaBounty, Kathleen R.; Ross, Elizabeth L.; Aziziyeh, Adel I.; De La Garza, Richard

    2012-01-01

    Rates of cigarette smoking are 3- to 4-fold greater among those with cocaine-dependence, and compared to non-users, cocaine users are at greater risk of incurring smoking-related negative health effects and death. The current study examined D-cycloserine’s (0 or 50 mg once weekly) 2) effects on 1) extinction of cue-induced craving for cigarettes, 2) cigarette smoking in conjunction with cognitive-behavioral therapy, and 3) safety and tolerability in cocaine-dependent smokers. This was a double-blind, placebo-controlled, between groups, outpatient study. Participants (N=29) were concurrent cocaine- and nicotine-dependent volunteers seeking treatment for their cigarette smoking. Study visits were 3 times per week for 4 consecutive weeks. At each visit, participants received cognitive-behavioral therapy for smoking, were exposed to smoking cues. A subset of participants (N=22) returned for 6-month follow-up visits. While craving decreased, no significant effects of D-cycloserine treatment were observed. Likewise, significant decreases in smoking were observed at study days 6 (p <0.002) and 12 (p <0.0001) relative to baseline, although no participants achieved complete abstinence. However, there was no effect of D-cycloserine on cigarette smoking during treatment or at 6-mos follow-up. The treatment was safe and tolerable, with nearly 90% of treatment sessions attended based on an intent-to-treat analysis. While no effects of D-cycloserine on craving or smoking were observed in the current study, the results do suggest smoking treatment is well accepted and may be effective for cocaine-dependent individuals. PMID:22560371

  10. Impact of DCS-facilitated cue exposure therapy on brain activation to cocaine cues in cocaine dependence

    PubMed Central

    Prisciandaro, James J.; Myrick, Hugh; Henderson, Scott; McRae-Clark, Aimee L.; Ana, Elizabeth J. Santa; Saladin, Michael E.; Brady, Kathleen T.

    2013-01-01

    Background The development of addiction is marked by a pathological associative learning process that imbues incentive salience to stimuli associated with drug use. Recent efforts to treat addiction have targeted this learning process using cue exposure therapy augmented with D-cycloserine (DCS), a glutamatergic agent hypothesized to enhance extinction learning. To better understand the impact of DCS-facilitated extinction on neural reactivity to drug cues, the present study reports fMRI findings from a randomized, double-blind, placebo-controlled trial of DCS-facilitated cue exposure for cocaine dependence. Methods Twenty-five participants completed two MRI sessions (before and after intervention), with a cocaine-cue reactivity fMRI task. The intervention consisted of 50mg of DCS or placebo, combined with two sessions of cocaine cue exposure and skills training. Results Participants demonstrated cocaine cue activation in a variety of brain regions at baseline. From the pre- to post-study scan, participants experienced decreased activation to cues in a number of regions (e.g., accumbens, caudate, frontal poles). Unexpectedly, placebo participants experienced decreases in activation to cues in the left angular and middle temporal gyri and the lateral occipital cortex, while DCS participants did not. Conclusions Three trials of DCS-facilitated cue exposure therapy for cocaine dependence have found that DCS either increases or does not significantly impact response to cocaine cues. The present study adds to this literature by demonstrating that DCS may prevent extinction to cocaine cues in temporal and occipital brain regions. Although consistent with past research, results from the present study should be considered preliminary until replicated in larger samples. PMID:23497788

  11. Kaiser Crater DCS

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 29, 2004 This image shows two representations of the same infra-red image covering a portion of Kaiser Crater. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    In this image, the basaltic sand dunes in bottom of Kaiser crater are colored a bright pink/magenta. The spectral features are clean and prominent on these dust-free surfaces and the dark color of the basaltic dunes helps them to absorb sunlight and produces higher surface temperatures, which also contributes to the image colors.

    Image information: IR instrument. Latitude -46.5, Longitude 20.3 East (339.7 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin

  12. DCS in Hesperia Planum

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released July 30, 2004 This image shows two representations of the same infra-red image in Hesperia Planum, west of Herschel Crater. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    The two primary compositions that cover most of Mars - dust and basalt (probably in the form of sand) - are well represented in this image. In this image, the dust is green in color and the basalt is pink/magenta. The strongest basaltic signatures appear in the bottoms of craters, which act as topographic traps for the sand. Green dust streaks appear behind many of the smaller craters. The topographic relief of the crater prevents the wind from cleansing the dust from the surface. These features enable the determination of the prevailing wind direction in the region.

    Image information: IR instrument. Latitude -16.6, Longitude 119.3 East (240.7 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS

  13. Evidence Report: Risk of Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Conkin, Johnny; Norcross, Jason R.; Wessel, James H., III; Klein, Jill S.; Dervay, Joseph P.; Gernhardt, Michael L.

    2016-01-01

    Given that tissue inert gas partial pressure is often greater than ambient pressure during phases of a mission, primarily during extravehicular activity (EVA), there is a possibility of decompression sickness (DCS).

  14. IDO⁺ DCs and signalling pathways.

    PubMed

    Wang, Yue; Yang, Bao-Hong; Li, Hui; Cao, Shui; Ren, Xiu-Bao; Yu, Jin-Pu

    2013-03-01

    Dendritic cells (DCs) have traditionally been viewed as constituting an 'information management' system that functions solely to integrate a diverse array of incoming signals, in order to induce immune reactivity. In recent years, however, there has been a shift towards viewing these cells as key regulators in the orchestration of immunological tolerance, with increasing recognition that they are capable of suppressing T-cell responses depending on signalling processes and localised biochemical conditions. Indoleamine 2,3-dioxygenase (IDO) competent (IDO⁺) DCs are a subset of human DCs which are programmed to a tolerogenic state and play a vital role in establishing and maintaining a tumour-suppressing milieu. The expression of IDO in these DCs represents a key mechanism responsible for inducing the tolerogenic state. However, the mechanisms by which IDO becomes dysregulated in this subset of DCs have not yet been described. In this review, the function of IDO⁺ DCs within the cancer-tolerogenic milieu, as well as the signals responsible for expression of IDO in this subset, will be discussed.

  15. pDCs Take a Deep Breath to Fight Viruses.

    PubMed

    Berod, Luciana; Sparwasser, Tim

    2016-06-21

    Conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) serve non-overlapping functions in immune responses. In this issue of Immunity, Pearce and colleagues (2016) report that pDCs use different metabolic pathways from cDCs to support their specialized function. PMID:27332726

  16. USDI DCS technical support: Mississippi Test Facility

    NASA Technical Reports Server (NTRS)

    Preble, D. M.

    1975-01-01

    The objective of the technical support effort is to provide hardware and data processing support to DCS users so that application of the system may be simply and effectively implemented. Technical support at Mississippi Test Facility (MTF) is concerned primarily with on-site hardware. The first objective of the DCP hardware support was to assure that standard measuring apparatus and techniques used by the USGS could be adapted to the DCS. The second objective was to try to standardize the miscellaneous variety of parameters into a standard instrument set. The third objective was to provide the necessary accessories to simplify the use and complement the capabilities of the DCP. The standard USGS sites have been interfaced and are presently operating. These sites are stream gauge, ground water level and line operated quality of water. Evapotranspiration, meteorological and battery operated quality of water sites are planned for near future DCP operation. Three accessories which are under test or development are the Chu antenna, solar power supply and add-on memory. The DCP has proven to be relatively easy to interface with many monitors. The large antenna is awkward to install and transport. The DCS has met the original requirements well; it has and is proving that an operation, satellite-based data collection system is feasible.

  17. The closely related CD103+ dendritic cells (DCs) and lymphoid-resident CD8+ DCs differ in their inflammatory functions.

    PubMed

    Jiao, Zhijun; Bedoui, Sammy; Brady, Jamie L; Walter, Anne; Chopin, Michael; Carrington, Emma M; Sutherland, Robyn M; Nutt, Stephen L; Zhang, Yuxia; Ko, Hyun-Ja; Wu, Li; Lew, Andrew M; Zhan, Yifan

    2014-01-01

    Migratory CD103+ and lymphoid-resident CD8+ dendritic cells (DCs) share many attributes, such as dependence on the same transcription factors, cross-presenting ability and expression of certain surface molecules, such that it has been proposed they belong to a common sub-lineage. The functional diversity of the two DC types is nevertheless incompletely understood. Here we reveal that upon skin infection with herpes simplex virus, migratory CD103+ DCs from draining lymph nodes were more potent at inducing Th17 cytokine production by CD4+ T cells than CD8+ DCs. This superior capacity to drive Th17 responses was also evident in CD103+ DCs from uninfected mice. Their differential potency to induce Th17 differentiation was reflected by higher production of IL-1β and IL-6 by CD103+ DCs compared with CD8+ DCs upon stimulation. The two types of DCs from isolated lymph nodes also differ in expression of certain pattern recognition receptors. Furthermore, elevated levels of GM-CSF, typical of those found in inflammation, substantially increased the pool size of CD103+ DCs in lymph nodes and skin. We argue that varied levels of GM-CSF may explain the contrasting reports regarding the positive role of GM-CSF in regulating development of CD103+ DCs. Together, we find that these two developmentally closely-related DC subsets display functional differences and that GM-CSF has differential effect on the two types of DCs.

  18. DCS/FTS Commercial Satellite Communications System

    NASA Astrophysics Data System (ADS)

    Shimabukuro, T.; Rosner, R.; Pearsall, C.

    In order to control the rising costs of telephonic services and meeting the increasing demand for wideband video and data services within U.S. Federal Government agencies, the Defense Communications Agency and the General Services Administration have begun the implementation of a leased Commercial Satellite Communications System. Service volume demand, commonality of service requirements, and common geographic communities of interest facilitate economies of scale in the course of meeting DOD and other Federal agencies' objectives. The service, which incorporates the Federal Telecommunications Service and is therefore designated DCS/FTS, is presently studied with respect to military and national objectives.

  19. Evidence Report: Risk of Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Conkin, Johnny; Norcross, Jason R.; Wessel, James H. III; Abercromby, Andrew F. J.; Klein, Jill S.; Dervay, Joseph P.; Gernhardt, Michael L.

    2013-01-01

    The Risk of Decompression Sickness (DCS) is identified by the NASA Human Research Program (HRP) as a recognized risk to human health and performance in space, as defined in the HRP Program Requirements Document (PRD). This Evidence Report provides a summary of the evidence that has been used to identify and characterize this risk. Given that tissue inert gas partial pressure is often greater than ambient pressure during phases of a mission, primarily during extravehicular activity (EVA), there is a possibility that decompression sickness may occur.

  20. Opposing roles of Dectin-1 expressed on human pDCs and mDCs in Th2 polarization

    PubMed Central

    Joo, HyeMee; Upchurch, Katherine; Zhang, Wei; Ni, Ling; Li, Dapeng; Xue, Yaming; Li, Xiao-Hua; Hori, Toshiyuki; Zurawski, Sandra; Liu, Yong-Jun; Zurawski, Gerard; Oh, SangKon

    2015-01-01

    Dendritic cells (DCs) can induce and control host immune responses. DC subset-dependent functional specialties and their ability to display functional plasticity, which is mainly driven by signals via pattern-recognition receptors (PRRs), identify DCs as immune orchestrators. A PRR Dectin-1 is expressed on myeloid DCs (mDCs) and is known to play important roles in Th17 induction and activation during fungal and certain bacterial infections. Here, we first demonstrate that human plasmacytoid DCs (pDCs) express Dectin-1 in both mRNA and protein levels. More interestingly, Dectin-1-activated pDCs promote Th2-type T cell responses; whereas Dectin-1-activated mDCs decrease both. Such contrasting outcome of Th2-type T cell responses by the two DC subsets are mainly due to their distinct abilities to control surface OX40L expression in response to β-glucan. This study provides new insights for the regulation of host immune responses by Dectin-1 expressed on DCs. PMID:26123355

  1. Agonistic induction of PPARγ reverses cigarette smoke–induced emphysema

    PubMed Central

    Shan, Ming; You, Ran; Yuan, Xiaoyi; Frazier, Michael V.; Porter, Paul; Seryshev, Alexander; Hong, Jeong-Soo; Song, Li-zhen; Zhang, Yiqun; Hilsenbeck, Susan; Whitehead, Lawrence; Zarinkamar, Nazanin; Perusich, Sarah; Corry, David B.; Kheradmand, Farrah

    2014-01-01

    The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema. PMID:24569375

  2. Transcranial direct current stimulation (tDCS) and language

    PubMed Central

    Monti, Alessia; Ferrucci, Roberta; Fumagalli, Manuela; Mameli, Francesca; Cogiamanian, Filippo; Ardolino, Gianluca; Priori, Alberto

    2013-01-01

    Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation technique inducing prolonged brain excitability changes and promoting cerebral plasticity, is a promising option for neurorehabilitation. Here, we review progress in research on tDCS and language functions and on the potential role of tDCS in the treatment of post-stroke aphasia. Currently available data suggest that tDCS over language-related brain areas can modulate linguistic abilities in healthy individuals and can improve language performance in patients with aphasia. Whether the results obtained in experimental conditions are functionally important for the quality of life of patients and their caregivers remains unclear. Despite the fact that important variables are yet to be determined, tDCS combined with rehabilitation techniques seems a promising therapeutic option for aphasia. PMID:23138766

  3. Augmentation of cognitive behavioral therapy with pharmacotherapy.

    PubMed

    Ganasen, K A; Ipser, J C; Stein, D J

    2010-09-01

    There has long been interest in combining pharmacotherapy with psychotherapy, including cognitive behavioral therapy (CBT). More recently, basic research on fear extinction has led to interest in augmentation of CBT with the N-methyl Daspartate (NMDA) glutamate receptor partial agonist D-cycloserine (DCS) for anxiety disorders. In this article, the literature on clinical trials that have combined pharmacotherapy and CBT is briefly reviewed, focusing particularly on the anxiety disorders. The literature on CBT and DCS is then systematically reviewed. A series of randomized placebo-controlled trials on panic disorder, obsessive-compulsive disorder, social anxiety disorder, and specific phobia suggest that low dose DCS before therapy sessions may be more effective compared with CBT alone in certain anxiety disorders. The strong translational foundation of this work is compelling, and the positive preliminary data gathered so far encourage further work. Issues for future research include delineating optimal dosing, and demonstrating effectiveness in real-world settings.

  4. Enhancing exposure-based therapy from a translational research perspective

    PubMed Central

    Hofmann, Stefan G.

    2007-01-01

    Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that d-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl- d-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified. PMID:17659253

  5. Enhancing exposure-based therapy from a translational research perspective.

    PubMed

    Hofmann, Stefan G

    2007-09-01

    Combining an effective psychological treatment with conventional anxiolytic medication is typically not more effective than unimodal therapy for treating anxiety disorders. However, recent advances in the neuroscience of fear reduction have led to novel approaches for combining psychological therapy and pharmacological agents. Exposure-based treatments in humans partly rely on extinction to reduce the fear response in anxiety disorders. Animal studies have shown that D-cycloserine (DCS), a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate receptor facilitates extinction learning. Similarly, recent human trials have shown that DCS enhances fear reduction during exposure therapy of some anxiety disorders. This article discusses the biological and psychological mechanisms of extinction learning and the therapeutic value of DCS as an augmentation strategy for exposure therapy. Areas of future research will be identified.

  6. Improved multitasking following prefrontal tDCS.

    PubMed

    Filmer, Hannah L; Mattingley, Jason B; Dux, Paul E

    2013-01-01

    We have a limited capacity for mapping sensory information onto motor responses. This processing bottleneck is thought to be a key factor in determining our ability to make two decisions simultaneously - i.e., to multitask (Pashler, 1984, 1994; Welford, 1952). Previous functional imaging research (Dux, Ivanoff, Asplund, & Marois, 2006; Dux et al., 2009) has localised this bottleneck to the posterior lateral prefrontal cortex (pLPFC) of the left hemisphere. Currently, however, it is unknown whether this region is causally involved in multitasking performance. We investigated the role of the left pLPFC in multitasking using transcranial direct current stimulation (tDCS). The behavioural paradigm included single- and dual-task trials, each requiring a speeded discrimination of visual stimuli alone, auditory stimuli alone, or both visual and auditory stimuli. Reaction times for single- and dual-task trials were compared before, immediately after, and 20 min after anodal stimulation (excitatory), cathodal stimulation (inhibitory), or sham stimulation. The cost of responding to the two tasks (i.e., the reduction in performance for dual- vs single-task trials) was significantly reduced by cathodal stimulation, but not by anodal or sham stimulation. Overall, the results provide direct evidence that the left pLPFC is a key neural locus of the central bottleneck that limits an individual's ability to make two simple decisions simultaneously.

  7. Cisplatin induces tolerogenic dendritic cells in response to TLR agonists via the abundant production of IL-10, thereby promoting Th2- and Tr1-biased T-cell immunity

    PubMed Central

    Kim, Hongmin; Kwon, Kee Woong; Im, Sin-Hyeog; Lee, Bo Ryeong; Ha, Sang-Jun; Shin, Sung Jae

    2016-01-01

    Although many advantageous roles of cisplatin (cis-diamminedichloroplatinum (II), CDDP) have been reported in cancer therapy, the immunomodulatory roles of cisplatin in the phenotypic and functional alterations of dendritic cells (DCs) are poorly understood. Here, we investigated the effect of cisplatin on the functionality of DCs and the changes in signaling pathways activated upon toll-like receptor (TLR) stimulation. Cisplatin-treated DCs down-regulated the expression of cell surface molecules (CD80, CD86, MHC class I and II) and up-regulated endocytic capacity in a dose-dependent manner. Upon stimulation with various TLR agonists, cisplatin-treated DCs showed markedly increased IL-10 production through activation of the p38 MAPK and NF-κB signaling pathways without altering the levels of TNF-α and IL-12p70, indicating the cisplatin-mediated induction of tolerogenic DCs. This effect was dependent on the production of IL-10 from DCs, as neither DCs isolated from IL-10−/− mice nor IL-10-neutralized DCs generated tolerogenic DCs. Interestingly, DCs that were co-treated with cisplatin and lipopolysaccharide (LPS) exhibited a decreased immunostimulatory capacity for inducing the proliferation of Th1- and Th17-type T cells; instead, these DCs contributed to Th2-type T cell immunity. Furthermore, in vitro and in vivo investigations revealed a unique T cell population, IL-10-producing CD3+CD4+LAG-3+CD49b+CD25−Foxp3− Tr1 cells, that was significantly increased without altering the Foxp3+ regulatory T cell population. Taken together, our results suggest that cisplatin induces immune-suppressive tolerogenic DCs in TLR agonist-induced inflammatory conditions via abundant IL-10 production, thereby skewing Th cell differentiation towards Th2 and Tr1 cells. This relationship may provide cancer cells with an opportunity to evade the immune system. PMID:27172902

  8. Dcs Data Viewer, an Application that Accesses ATLAS DCS Historical Data

    NASA Astrophysics Data System (ADS)

    Tsarouchas, C.; Schlenker, S.; Dimitrov, G.; Jahn, G.

    2014-06-01

    The ATLAS experiment at CERN is one of the four Large Hadron Collider experiments. The Detector Control System (DCS) of ATLAS is responsible for the supervision of the detector equipment, the reading of operational parameters, the propagation of the alarms and the archiving of important operational data in a relational database (DB). DCS Data Viewer (DDV) is an application that provides access to the ATLAS DCS historical data through a web interface. Its design is structured using a client-server architecture. The pythonic server connects to the DB and fetches the data by using optimized SQL requests. It communicates with the outside world, by accepting HTTP requests and it can be used stand alone. The client is an AJAX (Asynchronous JavaScript and XML) interactive web application developed under the Google Web Toolkit (GWT) framework. Its web interface is user friendly, platform and browser independent. The selection of metadata is done via a column-tree view or with a powerful search engine. The final visualization of the data is done using java applets or java script applications as plugins. The default output is a value-over-time chart, but other types of outputs like tables, ascii or ROOT files are supported too. Excessive access or malicious use of the database is prevented by a dedicated protection mechanism, allowing the exposure of the tool to hundreds of inexperienced users. The current configuration of the client and of the outputs can be saved in an XML file. Protection against web security attacks is foreseen and authentication constrains have been taken into account, allowing the exposure of the tool to hundreds of users world wide. Due to its flexible interface and its generic and modular approach, DDV could be easily used for other experiment control systems.

  9. Tolerogenic pDCs: spotlight on Foxo3.

    PubMed

    Bronte, Vincenzo

    2011-04-01

    Cancer creates a peculiar inflammatory environment enriched for transcription factors with a negative influence on adaptive immunity. In this issue of the JCI, Watkins and colleagues identify Foxo3 as a master regulator of the tolerogenic program in tumor-associated, plasmacytoid DCs (pDCs). Foxo3 enables pDCs to induce tolerance in tumor antigen-specific CD8+ T cells, turning them into regulatory lymphocytes capable of inhibiting nearby CD8+ T lymphocytes. Provision of tumor-specific CD4+ T helper cells interrupts this circuit by inhibiting Foxo3 expression and fully licensing the antigen-presenting ability of pDCs. These data identify a new target for therapeutic intervention and provide insight into the transcription factor interplay in myeloid cells recruited to the cancer microenvironment.

  10. The uncertain outcome of prefrontal tDCS

    PubMed Central

    Tremblay, Sara; Lepage, Jean-François; Latulipe-Loiselle, Alex; Fregni, Felipe; Pascual-Leone, Alvaro; Théoret, Hugo

    2015-01-01

    Background Transcranial direct current stimulation (tDCS) is increasingly used in research and clinical settings, and the dorsolateral prefrontal cortex (DLPFC) is often chosen as a target for stimulation. While numerous studies report modulation of cognitive abilities following DLPFC stimulation, the wide array of cognitive functions that can be modulated makes it difficult to predict its precise outcome. Objective The present review aims at identifying and characterizing the various cognitive domains affected by tDCS over DLPFC. Methods Articles using tDCS over DLPFC indexed in PubMed and published between 2000 and January 2014 were included in the present review. Results tDCS over DLPFC affects a wide array of cognitive functions, with sometimes apparent conflicting results. Conclusion Prefrontal tDCS has the potential to modulate numerous cognitive functions simultaneously, but to properly interpret the results, a clear a priori hypothesis is necessary, careful technical consideration are mandatory, further insights into the neurobiological impact of tDCS are needed, and consideration should be given to the possibility that some behavioral effects may be partly explained by parallel modulation of related functions. PMID:25456566

  11. Adjuvant for vaccine immunotherapy of cancer--focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.

    PubMed

    Seya, Tsukasa; Shime, Hiroaki; Takeda, Yohei; Tatematsu, Megumi; Takashima, Ken; Matsumoto, Misako

    2015-12-01

    Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer-mediated cell damage. Toll-like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α(+) DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141(+) DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag-presenting DCs. Bacillus Calmette-Guerin peptidoglycan and polyinosinic-polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine-adjuvant immunotherapy for cancer.

  12. DCS of Syrtis Major Sand Migration

    NASA Technical Reports Server (NTRS)

    2004-01-01

    [figure removed for brevity, see original site]

    Released August 2, 2004 This image shows two representations of the same infra-red image of craters and lava flow features in Syrtis Major. On the left is a grayscale image showing surface temperature, and on the right is a false-color composite made from 3 individual THEMIS bands. The false-color image is colorized using a technique called decorrelation stretch (DCS), which emphasizes the spectral differences between the bands to highlight compositional variations.

    The prominent rim of the large crater at the top of the image is blocking migrating sand from entering the crater. This produces a very distinct compositional boundary between the pink/magenta basaltic sand and the green dust covering the crater rim and floor. Many of the smaller craters in this region have dust trails behind them, indicating the prevailing wind direction. At the top of the image, the prevailing wind direction is to the northwest, while at the bottom of the image, the prevailing winds have shifted towards the southwest.

    Image information: IR instrument. Latitude 9.2, Longitude 68.4 East (291.6 West). 100 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip

  13. Cerebellar Transcranial Direct Current Stimulation (ctDCS)

    PubMed Central

    Grimaldi, Giuliana; Argyropoulos, Georgios P.; Bastian, Amy; Cortes, Mar; Davis, Nicholas J.; Edwards, Dylan J.; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M.; Hamada, Masahi; Manto, Mario; Miall, R. Chris; Morales-Quezada, Leon; Pope, Paul A.; Priori, Alberto; Rothwell, John; Tomlinson, S. Paul; Celnik, Pablo

    2016-01-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar–motor cortex connectivity, likely via cerebellar–thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  14. Dendritic cells and NK cells stimulate bystander T cell activation in response to TLR agonists through secretion of IFN-alpha beta and IFN-gamma.

    PubMed

    Kamath, Arun T; Sheasby, Christopher E; Tough, David F

    2005-01-15

    Recognition of conserved features of infectious agents by innate pathogen receptors plays an important role in initiating the adaptive immune response. We have investigated early changes occurring among T cells after injection of TLR agonists into mice. Widespread, transient phenotypic activation of both naive and memory T cells was observed rapidly after injection of molecules acting through TLR3, -4, -7, and -9, but not TLR2. T cell activation was shown to be mediated by a combination of IFN-alphabeta, secreted by dendritic cells (DCs), and IFN-gamma, secreted by NK cells; notably, IFN-gamma-secreting NK cells expressed CD11c and copurified with DCs. Production of IFN-gamma by NK cells could be stimulated by DCs from TLR agonist-injected mice, and although soluble factors secreted by LPS-stimulated DCs were sufficient to induce IFN-gamma, maximal IFN-gamma production required both direct contact of NK cells with DCs and DC-secreted cytokines. In vitro, IFN-alphabeta, IL-18, and IL-12 all contributed to DC stimulation of NK cell IFN-gamma, whereas IFN-alphabeta was shown to be important for induction of T cell bystander activation and NK cell IFN-gamma production in vivo. The results delineate a pathway involving innate immune mediators through which TLR agonists trigger bystander activation of T cells. PMID:15634897

  15. Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells.

    PubMed

    Lee, Young-Hee; Im, Sun-A; Kim, Ji-Wan; Lee, Chong-Kil

    2016-08-01

    DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that the VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), enhance antiviral CTL responses by increasing MHC class I-restricted viral antigen presentation in dendritic cells (DCs). Bone marrow-derived DCs (BM-DCs) were infected with a recombinant vaccinia virus (VV) expressing OVA (VV-OVA), and then treated with CP or RTX. Both CP and RTX increased MHC class I-restricted presentation of virus-encoded endogenous OVA in BM-DCs. Oral administration of CP or RTX significantly increased MHC class I-restricted OVA presentation by splenic and lymph node DCs in VV-OVA-infected mice, as assessed by directly measuring OVA peptide SIINFEKL-K(b) complexes on the cell surface and by performing functional assays using OVA-specific CD8 T cells. Accordingly, oral administration of CP or RTX elicited potent OVA-specific CTL activity in VV-OVA-infected mice. The results from this study demonstrate that VR1 agonists enhance anti-viral CTL responses, as well as a neuro-immune connection in anti-viral immune responses. PMID:27574502

  16. Vanilloid Receptor 1 Agonists, Capsaicin and Resiniferatoxin, Enhance MHC Class I-restricted Viral Antigen Presentation in Virus-infected Dendritic Cells

    PubMed Central

    Lee, Young-Hee; Im, Sun-A; Kim, Ji-Wan

    2016-01-01

    DCs, like the sensory neurons, express vanilloid receptor 1 (VR1). Here we demonstrate that the VR1 agonists, capsaicin (CP) and resiniferatoxin (RTX), enhance antiviral CTL responses by increasing MHC class I-restricted viral antigen presentation in dendritic cells (DCs). Bone marrow-derived DCs (BM-DCs) were infected with a recombinant vaccinia virus (VV) expressing OVA (VV-OVA), and then treated with CP or RTX. Both CP and RTX increased MHC class I-restricted presentation of virus-encoded endogenous OVA in BM-DCs. Oral administration of CP or RTX significantly increased MHC class I-restricted OVA presentation by splenic and lymph node DCs in VV-OVA-infected mice, as assessed by directly measuring OVA peptide SIINFEKL-Kb complexes on the cell surface and by performing functional assays using OVA-specific CD8 T cells. Accordingly, oral administration of CP or RTX elicited potent OVA-specific CTL activity in VV-OVA-infected mice. The results from this study demonstrate that VR1 agonists enhance anti-viral CTL responses, as well as a neuro-immune connection in anti-viral immune responses. PMID:27574502

  17. DCS-Neural-Network Program for Aircraft Control and Testing

    NASA Technical Reports Server (NTRS)

    Jorgensen, Charles C.

    2006-01-01

    A computer program implements a dynamic-cell-structure (DCS) artificial neural network that can perform such tasks as learning selected aerodynamic characteristics of an airplane from wind-tunnel test data and computing real-time stability and control derivatives of the airplane for use in feedback linearized control. A DCS neural network is one of several types of neural networks that can incorporate additional nodes in order to rapidly learn increasingly complex relationships between inputs and outputs. In the DCS neural network implemented by the present program, the insertion of nodes is based on accumulated error. A competitive Hebbian learning rule (a supervised-learning rule in which connection weights are adjusted to minimize differences between actual and desired outputs for training examples) is used. A Kohonen-style learning rule (derived from a relatively simple training algorithm, implements a Delaunay triangulation layout of neurons) is used to adjust node positions during training. Neighborhood topology determines which nodes are used to estimate new values. The network learns, starting with two nodes, and adds new nodes sequentially in locations chosen to maximize reductions in global error. At any given time during learning, the error becomes homogeneously distributed over all nodes.

  18. Expansion of FOXP3high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients

    PubMed Central

    Banerjee, Devi K.; Dhodapkar, Madhav V.; Matayeva, Elyana; Steinman, Ralph M.; Dhodapkar, Kavita M.

    2006-01-01

    CD4+CD25+FOXP3+ regulatory T cells (Treg's) play an important role in the maintenance of immune tolerance. The mechanisms controlling the induction and maintenance of Treg's in humans need to be defined. We find that human myeloid dendritic cells (DCs) are superior to other antigen presenting cells for the maintenance of FOXP3+ Treg's in culture. Coculture of DCs with autologous T cells leads to an increase in both the number of Treg's, as well as the expression of FOXP3 protein per cell both in healthy donors and myeloma patients. DC-mediated expansion of FOXP3high Treg's is enhanced by endogenous but not exogenous interleukin-2 (IL-2), and DC-T-cell contact, including the CD80/CD86 membrane costimulatory molecules. DCs also stimulate the formation of Treg's from CD25- T cells. The efficacy of induction of Treg's by DCs depends on the nature of the DC maturation stimulus, with inflammatory cytokine-treated DCs (Cyt-DCs) being the most effective Treg inducers. DC-induced Treg's from both healthy donors and patients with myeloma are functional and effectively suppress T-cell responses. A single injection of cytokine-matured DCs led to rapid enhancement of FOXP3+ Treg's in vivo in 3 of 3 myeloma patients. These data reveal a role for DCs in increasing the number of functional FOXP3high Treg's in humans. PMID:16763205

  19. A natural history of "agonist".

    PubMed

    Russo, Ruth

    2002-01-01

    This paper constructs a brief history of the biochemical term agonist by exploring the multiple meanings of the root agôn in ancient Greek literature and describing how agonist first appeared in the scientific literature of the 20th century in the context of neurophysiologists' debates about the existence and properties of cellular receptors. While the narrow scientific definition of agonist may appear colorless and dead when compared with the web of allusions spun by the ancient Greek agôn, the scientific power and creativity of agonist actually resides precisely in its exact, restricted meaning for biomedical researchers.

  20. Simultaneous transcranial direct current stimulation (tDCS) and whole-head magnetoencephalography (MEG): assessing the impact of tDCS on slow cortical magnetic fields.

    PubMed

    Garcia-Cossio, Eliana; Witkowski, Matthias; Robinson, Stephen E; Cohen, Leonardo G; Birbaumer, Niels; Soekadar, Surjo R

    2016-10-15

    Transcranial direct current stimulation (tDCS) can influence cognitive, affective or motor brain functions. Whereas previous imaging studies demonstrated widespread tDCS effects on brain metabolism, direct impact of tDCS on electric or magnetic source activity in task-related brain areas could not be confirmed due to the difficulty to record such activity simultaneously during tDCS. The aim of this proof-of-principal study was to demonstrate the feasibility of whole-head source localization and reconstruction of neuromagnetic brain activity during tDCS and to confirm the direct effect of tDCS on ongoing neuromagnetic activity in task-related brain areas. Here we show for the first time that tDCS has an immediate impact on slow cortical magnetic fields (SCF, 0-4Hz) of task-related areas that are identical with brain regions previously described in metabolic neuroimaging studies. 14 healthy volunteers performed a choice reaction time (RT) task while whole-head magnetoencephalography (MEG) was recorded. Task-related source-activity of SCFs was calculated using synthetic aperture magnetometry (SAM) in absence of stimulation and while anodal, cathodal or sham tDCS was delivered over the right primary motor cortex (M1). Source reconstruction revealed task-related SCF modulations in brain regions that precisely matched prior metabolic neuroimaging studies. Anodal and cathodal tDCS had a polarity-dependent impact on RT and SCF in primary sensorimotor and medial centro-parietal cortices. Combining tDCS and whole-head MEG is a powerful approach to investigate the direct effects of transcranial electric currents on ongoing neuromagnetic source activity, brain function and behavior.

  1. Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation

    PubMed Central

    Loschko, Jakob; Schreiber, Heidi A.; Rieke, Gereon J.; Esterházy, Daria; Meredith, Matthew M.; Pedicord, Virginia A.; Yao, Kai-Hui; Caballero, Silvia; Pamer, Eric G.; Mucida, Daniel

    2016-01-01

    Conventional dendritic cells (cDCs) play an essential role in host immunity by initiating adaptive T cell responses and by serving as innate immune sensors. Although both innate and adaptive functions of cDCs are well documented, their relative importance in maintaining immune homeostasis is poorly understood. To examine the significance of cDC-initiated adaptive immunity in maintaining homeostasis, independent of their innate activities, we generated a cDC-specific Cre mouse and crossed it to a floxed MHC class II (MHCII) mouse. Absence of MHCII on cDCs resulted in chronic intestinal inflammation that was alleviated by antibiotic treatment and entirely averted under germ-free conditions. Uncoupling innate and adaptive functions of cDCs revealed that innate immune functions of cDCs are insufficient to maintain homeostasis and antigen presentation by cDCs is essential for a mutualistic relationship between the host and intestinal bacteria. PMID:27001748

  2. Data on PRRSV infection promoted the subtype of porcine dendritic cells from mDCs to pDCs in vivo.

    PubMed

    Liu, Jinling; Wei, Shu; Liu, Lixia; Yu, Lihui; Wang, Chunyan; Zhao, Yujun; Shan, Fengping; Shen, Guoshun

    2016-12-01

    The related study has confirmed that porcine reproductive and respiratory syndrome virus (PRRSV) infection may impair mature states of DCs can lead to suboptimal adaptive immune response ("The role of porcine reproductive and respiratory syndrome virus infection in immunephenotype and Th1/Th2 balance of dendritic cells" (Jinling Liu, We Shu, Liaxia Liu et al., 2016) [1]). In this data article,the porcine dendritic cells (DCs) isolated from porcine peripheral blood and spleen were collected after infection with PRRSV, then the characteristics of the subset differentiation of DCs were analyzed with FACS Calibur Cytometer and fluorescence microscope respectively. This data is an important foundation for further investigation into immune suppression by PRRSV infection, and that, it also provides new data for the development of potential antiviral therapies based on DCs and PRRS vaccines. PMID:27642622

  3. Modulation of Female Genital Tract-Derived Dendritic Cell Migration and Activation in Response to Inflammatory Cytokines and Toll-Like Receptor Agonists

    PubMed Central

    Shey, Muki S.; Maharaj, Niren; Archary, Derseree; Ngcapu, Sinaye; Garrett, Nigel; Abdool Karim, Salim; Passmore, Jo-Ann S.

    2016-01-01

    HIV transmission across the genital mucosa is a major mode of new HIV infections in women. The probability of infection may be influenced by several factors including recruitment and activation of HIV target cells, such as dendritic cells (DCs) and cytokine production, associated with genital inflammation. We evaluated the role of inflammatory cytokines and TLR signaling in migration and activation of genital tract DCs in the human cervical explant model. Hysterectomy tissues from 10 HIV-negative and 7 HIV-positive donor women were separated into ecto- and endocervical explants, and incubated with inflammatory cytokines (TNF-α, IL-1β, IL-8, MIP-1β) or agonists for TLR4 (LPS), TLR2/1 (PAM3) and TLR7/8 (R848). Migration (frequency) and activation (HLA-DR expression) of myeloid and plasmacytoid DCs and Langerhans cells were measured by flow cytometry. We observed that cytokines, LPS and PAM3 induced activation of migrating myeloid and plasmacytoid DCs. LPS induced a 3.6 fold lower levels of migration of plasmacytoid DCs from HIV-infected women compared with HIV-uninfected women (median activation indices of 2.932 vs 0.833). There was however a 4.5 fold increase in migration of Langerhans cells in HIV-infected compared with HIV-uninfected women in response to cytokines (median activation indices of 3.539 vs 0.77). Only TLR agonists induced migration and activation of DCs from endocervical explants. Hormonal contraception use was associated with an increase in activation of DC subsets in the endo and ectocervical explants. We conclude that inflammatory signals in the female genital tract induced DC migration and activation, with possible important implications for HIV susceptibility of cervical tissues. PMID:27171482

  4. Electrifying the motor engram: effects of tDCS on motor learning and control

    PubMed Central

    de Xivry, Jean-Jacques Orban; Shadmehr, Reza

    2014-01-01

    Learning to control our movements accompanies neuroplasticity of motor areas of the brain. The mechanisms of neuroplasticity are diverse and produce what is referred to as the motor engram, i.e. the neural trace of the motor memory. Transcranial direct current stimulation (tDCS) alters the neural and behavioral correlates of motor learning, but its precise influence on the motor engram is unknown. In this review, we summarize the effects of tDCS on neural activity and suggest a few key principles: 1) firing rates are increased by anodal polarization and decreased by cathodal polarization, 2) anodal polarization strengthens newly formed associations, and 3) polarization modulates the memory of new/preferred firing patterns. With these principles in mind, we review the effects of tDCS on motor control, motor learning, and clinical applications. The increased spontaneous and evoked firing rates may account for the modulation of dexterity in non-learning tasks by tDCS. The facilitation of new association may account for the effect of tDCS on learning in sequence tasks while the ability of tDCS to strengthen memories of new firing patterns may underlie the effect of tDCS on consolidation of skills. We then describe the mechanisms of neuroplasticity of motor cortical areas and how they might be influenced by tDCS. We end with current challenges for the fields of brain stimulation and motor learning. PMID:25200178

  5. The rising tide of tDCS in the media and academic literature.

    PubMed

    Dubljević, Veljko; Saigle, Victoria; Racine, Eric

    2014-05-21

    Academic and public interest in tDCS has been fueled by strong claims of therapeutic and enhancement effects. We report a rising tide of tDCS coverage in the media, while regulatory action is lacking and ethical issues need to be addressed.

  6. Effects of transcranial direct current stimulation (tDCS) on behaviour and electrophysiology of language production.

    PubMed

    Wirth, Miranka; Rahman, Rasha Abdel; Kuenecke, Janina; Koenig, Thomas; Horn, Helge; Sommer, Werner; Dierks, Thomas

    2011-12-01

    Excitatory anodal transcranial direct current stimulation (A-tDCS) over the left dorsal prefrontal cortex (DPFC) has been shown to improve language production. The present study examined neurophysiological underpinnings of this effect. In a single-blinded within-subject design, we traced effects of A-tDCS compared to sham stimulation over the left DPFC using electrophysiological and behavioural correlates during overt picture naming. Online effects were examined during A-tDCS by employing the semantic interference (SI-)Effect - a marker that denotes the functional integrity of the language system. The behavioural SI-Effect was found to be reduced, whereas the electrophysiological SI-Effect was enhanced over left compared to right temporal scalp-electrode sites. This modulation is suggested to reflect a superior tuning of neural responses within language-related generators. After -(offline) effects of A-tDCS were detected in the delta frequency band, a marker of neural inhibition. After A-tDCS there was a reduction in delta activity during picture naming and the resting state, interpreted to indicate neural disinhibition. Together, these findings demonstrate electrophysiological modulations induced by A-tDCS of the left DPFC. They suggest that A-tDCS is capable of enhancing neural processes during and after application. The present functional and oscillatory neural markers could detect positive effects of prefrontal A-tDCS, which could be of use in the neuro-rehabilitation of frontal language functions.

  7. Effects of Transcranial Direct Current Stimulation (tDCS) on Behaviour and Electrophysiology of Language Production

    ERIC Educational Resources Information Center

    Wirth, Miranka; Rahman, Rasha Abdel; Kuenecke, Janina; Koenig, Thomas; Horn, Helge; Sommer, Werner; Dierks, Thomas

    2011-01-01

    Excitatory anodal transcranial direct current stimulation (A-tDCS) over the left dorsal prefrontal cortex (DPFC) has been shown to improve language production. The present study examined neurophysiological underpinnings of this effect. In a single-blinded within-subject design, we traced effects of A-tDCS compared to sham stimulation over the left…

  8. Enhanced locomotor adaptation aftereffect in the “broken escalator” phenomenon using anodal tDCS

    PubMed Central

    Kaski, D.; Quadir, S.; Patel, M.; Yousif, N.

    2012-01-01

    The everyday experience of stepping onto a stationary escalator causes a stumble, despite our full awareness that the escalator is broken. In the laboratory, this “broken escalator” phenomenon is reproduced when subjects step onto an obviously stationary platform (AFTER trials) that was previously experienced as moving (MOVING trials) and attests to a process of motor adaptation. Given the critical role of M1 in upper limb motor adaptation and the potential for transcranial direct current stimulation (tDCS) to increase cortical excitability, we hypothesized that anodal tDCS over leg M1 and premotor cortices would increase the size and duration of the locomotor aftereffect. Thirty healthy volunteers received either sham or real tDCS (anodal bihemispheric tDCS; 2 mA for 15 min at rest) to induce excitatory effects over the primary motor and premotor cortex before walking onto the moving platform. The real tDCS group, compared with sham, displayed larger trunk sway and increased gait velocity in the first AFTER trial and a persistence of the trunk sway aftereffect into the second AFTER trial. We also used transcranial magnetic stimulation to probe changes in cortical leg excitability using different electrode montages and eyeblink conditioning, before and after tDCS, as well as simulating the current flow of tDCS on the human brain using a computational model of these different tDCS montages. Our data show that anodal tDCS induces excitability changes in lower limb motor cortex with resultant enhancement of locomotor adaptation aftereffects. These findings might encourage the use of tDCS over leg motor and premotor regions to improve locomotor control in patients with neurological gait disorders. PMID:22323638

  9. The application of tDCS in psychiatric disorders: a brain imaging view

    PubMed Central

    Baeken, Chris; Brunelin, Jerome; Duprat, Romain; Vanderhasselt, Marie-Anne

    2016-01-01

    Background Transcranial direct current stimulation (tDCS) is a non-invasive, non-convulsive technique for modulating brain function. In contrast to other non-invasive brain stimulation techniques, where costs, clinical applicability, and availability limit their large-scale use in clinical practices, the low-cost, portable, and easy-to-use tDCS devices may overcome these restrictions. Objective Despite numerous clinical applications in large numbers of patients suffering from psychiatric disorders, it is not quite clear how tDCS influences the mentally affected human brain. In order to decipher potential neural mechanisms of action of tDCS in patients with psychiatric conditions, we focused on the combination of tDCS with neuroimaging techniques. Design We propose a contemporary overview on the currently available neurophysiological and neuroimaging data where tDCS has been used as a research or treatment tool in patients with psychiatric disorders. Results Over a reasonably short period of time, tDCS has been broadly used as a research tool to examine neuronal processes in the healthy brain. tDCS has also commonly been applied as a treatment application in a variety of mental disorders, with to date no straightforward clinical outcome and not always accompanied by brain imaging techniques. Conclusion tDCS, as do other neuromodulation devices, clearly affects the underlying neuronal processes. However, research on these mechanisms in psychiatric patients is rather limited. A better comprehension of how tDCS modulates brain function will help us to define optimal parameters of stimulation in each indication and may result in the detection of biomarkers in favor of clinical response. PMID:26993785

  10. State dependent effect of transcranial direct current stimulation (tDCS) on methamphetamine craving.

    PubMed

    Shahbabaie, Alireza; Golesorkhi, Mehrshad; Zamanian, Behnam; Ebrahimpoor, Mitra; Keshvari, Fatemeh; Nejati, Vahid; Fregni, Felipe; Ekhtiari, Hamed

    2014-10-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate subjective craving ratings in drug dependents by modification of cortical excitability in dorsolateral prefrontal cortex (DLPFC). Given the mechanism of craving in methamphetamine (meth) users, we aimed to test whether tDCS of DLPFC could also alter self-reported craving in abstinent meth users while being exposed to meth cues. In this double-blinded, crossover, sham-controlled study, thirty two right-handed abstinent male meth users were recruited. We applied 20 min 'anodal' tDCS (2 mA) or 'sham' tDCS over right DLPFC in a random sequence while subjects performed a computerized cue-induced craving task (CICT) starting after 10 min of stimulation. Immediate craving was assessed before the stimulation, after 10 min of tDCS, and after tDCS termination by visual analog scale (VAS) of 0 to 100. Anodal tDCS of rDLPFC altered craving ratings significantly. We found a significant reduction of craving at rest in real tDCS relative to the sham condition (p = 0.016) after 10 min of stimulation. On the other hand, cue-induced VAS craving was rated significantly higher in the real condition in comparison with sham stimulation (p = 0.012). Our findings showed a state dependent effect of tDCS: while active prefrontal tDCS acutely reduced craving at rest in the abstinent meth users, it increased craving during meth-related cue exposure. These findings reflect the important role of the prefrontal cortex in both cue saliency evaluation and urge to meth consumption.

  11. Reliability and Variability of tDCS Induced Changes in the Lower Limb Motor Cortex

    PubMed Central

    Madhavan, Sangeetha; Sriraman, Aishwarya; Freels, Sally

    2016-01-01

    Background: Transcranial direct current stimulation (tDCS) is emerging as a promising adjuvant to enhance motor function. However, there has been increasing reservations about the reliability and variability of the neuromodulatory effects evoked by tDCS. Objective/Hypothesis: The main purpose of this study was to explore the test-retest reliability and inter-individual variability of tDCS of the lower limb M1 and the relationship between transcranial magnetic stimulation (TMS)-related measures and tDCS-induced changes. Methods: Fifteen healthy participants received anodal tDCS of the lower limb M1 either when performing a lower limb motor task or when the limb was at rest. Each condition was tested twice. tDCS induced changes in corticomotor excitability of the tibialis anterior muscle were measured using TMS. A repeated measures ANOVA was performed to examine efficacy of tDCS between the two task conditions. Intraclass correlation coefficients (ICC) and variance component analyses were performed to examine reliability and variability respectively. Results: A significant increase in in corticomotor excitability was noted for the tDCS-task condition at 140% active motor threshold (AMT) and when comparing recruitment curve slopes, but not at 120% and 130% AMT. Overall, ICC values between testing days for each stimulation condition ranged from 0.6–0.9. Higher ICCs were seen for higher TMS intensities (140% AMT) and recruitment curve slopes. Inter-individual variability contributed to 34% of the exhibited variance. Conclusions: Our data suggest that the TMS-related measure used to assess neuromodulation after tDCS has an effect on its perceived test-retest reliability and inter-individual variability. Importantly, we noticed that a high reliability and low variability does not necessarily indicate clinical efficacy of tDCS as some participants showed little to no modulation of corticomotor excitability consistently. PMID:27472368

  12. Facilitation of Fear Extinction by D-Cycloserine: Theoretical and Clinical Implications

    ERIC Educational Resources Information Center

    Cranney, Jacquelyn; Richardson, Rick; Ledgerwood, Lana

    2004-01-01

    Anxiety disorders are among the most common psychological disturbances in the industrialized world. Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may…

  13. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  14. Anodal tDCS targeting the left temporo-parietal junction disrupts verbal reality-monitoring.

    PubMed

    Mondino, Marine; Poulet, Emmanuel; Suaud-Chagny, Marie-Françoise; Brunelin, Jerome

    2016-08-01

    Using transcranial direct current stimulation (tDCS) we aimed to investigate the causal role of the left temporo-parietal and prefrontal regions in source-monitoring. Forty-two healthy participants received tDCS while performing a verbal reality-monitoring task (requiring discrimination between imagined and heard words) and a verbal internal source-monitoring task (requiring discrimination between imagined and said words). In 2 randomized crossover studies, 21 participants received active and sham anodal tDCS applied over the left temporo-parietal junction (TPJ) and 21 participants received active and sham cathodal tDCS applied over the left prefrontal cortex (PFC). The reference electrode was placed over the right occipital region in both experiments. Active tDCS over the left TPJ decreased reality-monitoring performance but did not modulate internal source-monitoring performance. Participants were more likely to misattribute self-generated events to externally perceived events (externalization bias). Active tDCS over the left PFC did not modulate performance of participants in both tasks. In summary, anodal tDCS applied over the left TPJ, assumed to enhance cortical excitability, can alter reality-monitoring processes in healthy subjects. Such abnormal reality-monitoring performances have been reported in hallucinating patients with schizophrenia known to display hyperactivity of the left TPJ. Our results highlighted the role of the left TPJ in self/other recognition.

  15. Impact of antipsychotic medication on transcranial direct current stimulation (tDCS) effects in schizophrenia patients.

    PubMed

    Agarwal, Sri Mahavir; Bose, Anushree; Shivakumar, Venkataram; Narayanaswamy, Janardhanan C; Chhabra, Harleen; Kalmady, Sunil V; Varambally, Shivarama; Nitsche, Michael A; Venkatasubramanian, Ganesan; Gangadhar, Bangalore N

    2016-01-30

    Transcranial direct current stimulation (tDCS) has generated interest as a treatment modality for schizophrenia. Dopamine, a critical pathogenetic link in schizophrenia, is also known to influence tDCS effects. We evaluated the influence of antipsychotic drug type (as defined by dopamine D2 receptor affinity) on the impact of tDCS in schizophrenia. DSM-IV-TR-diagnosed schizophrenia patients [N=36] with persistent auditory hallucinations despite adequate antipsychotic treatment were administered add-on tDCS. Patients were divided into three groups based on the antipsychotic's affinity to D2 receptors. An auditory hallucinations score (AHS) was measured using the auditory hallucinations subscale of the Psychotic Symptom Rating Scales (PSYRATS). Add-on tDCS resulted in a significant reduction inAHS. Antipsychotic drug type had a significant effect on AHS reduction. Patients treated with high affinity antipsychotics showed significantly lesser improvement compared to patients on low affinity antipsychotics or a mixture of the two. Furthermore, a significant sex-by-group interaction occurred; type of medication had an impact on tDCS effects only in women. Improvement differences could be due to the larger availability of the dopamine receptor system in patients taking antipsychotics with low D2 affinity. Sex-specific differences suggest potential estrogen-mediated effects. This study reports a first-time observation on the clinical utility of antipsychotic drug type in predicting tDCS effects in schizophrenia.

  16. Development and Validation of a Miniature Programmable tDCS Device.

    PubMed

    Kouzani, Abbas Z; Jaberzadeh, Shapour; Zoghi, Maryam; Usma, Clara; Parastarfeizabadi, Mahboubeh

    2016-01-01

    Research is being conducted on the use of transcranial direct current stimulation (tDCS) for therapeutic effects, and also on the mechanisms through which such therapeutic effects are mediated. A bottleneck in the progress of the research has been the large size of the existing tDCS systems which prevents subjects from performing their daily activities. To help research into the principles, mechanisms, and benefits of tDCS, reduction of size and weight, improvement in simplicity and user friendliness, portability, and programmability of tDCS systems are vital. This paper presents a design for a low-cost, light-weight, programmable, and portable tDCS device. The device is head-mountable and can be concealed in a hat and worn on the head by the subject while receiving the stimulation. The strength of the direct current stimulation can be selected through a simple user interface. The device is constructed and its performance evaluated through bench and in vivo tests. The tests validated the operation of the device in inducing neuromodulatory changes in primary motor cortex, M1, through measuring excitability of dominant M1 of resting right first dorsal interosseus muscle by transcranial magnetic stimulation induced motor evoked potentials. It was observed that the tDCS device induced comparable neuromodulatory effects in M1 as the existing bulky tDCS systems.

  17. Dorsal column stimulation (DCS) in chronic pain: report of 31 cases.

    PubMed Central

    Mittal, B.; Thomas, D. G.; Walton, P.; Calder, I.

    1987-01-01

    Thirty-one patients of chronic pain treated with dorsal column stimulation (DCS) are reported. All of them had been treated previously with drugs and multiple procedures including injections and frequently several operations. After a trial of percutaneous DCS, permanent implantations were carried out. The patients have been followed for up to eight years. Overall, sixty per cent of patients had good to fair relief of pain with DCS. Some of them had a good response for five years and more. Images Fig. 1 Fig. 2 PMID:2955738

  18. Cyber security risk assessment for SCADA and DCS networks.

    PubMed

    Ralston, P A S; Graham, J H; Hieb, J L

    2007-10-01

    The growing dependence of critical infrastructures and industrial automation on interconnected physical and cyber-based control systems has resulted in a growing and previously unforeseen cyber security threat to supervisory control and data acquisition (SCADA) and distributed control systems (DCSs). It is critical that engineers and managers understand these issues and know how to locate the information they need. This paper provides a broad overview of cyber security and risk assessment for SCADA and DCS, introduces the main industry organizations and government groups working in this area, and gives a comprehensive review of the literature to date. Major concepts related to the risk assessment methods are introduced with references cited for more detail. Included are risk assessment methods such as HHM, IIM, and RFRM which have been applied successfully to SCADA systems with many interdependencies and have highlighted the need for quantifiable metrics. Presented in broad terms is probability risk analysis (PRA) which includes methods such as FTA, ETA, and FEMA. The paper concludes with a general discussion of two recent methods (one based on compromise graphs and one on augmented vulnerability trees) that quantitatively determine the probability of an attack, the impact of the attack, and the reduction in risk associated with a particular countermeasure. PMID:17624350

  19. Zero discharge and large-scale DCS are plant highlights

    SciTech Connect

    Solar, R.

    1995-04-01

    This article reports that the Mulberry cogeneration facility has several features that make it notable in the power field. A zero-discharge wastewater system, an inlet-air chilling system, a secondary boiler, and an extensive distributed-control system (DCS) for overall plant operation are examples. Ability to meet the two-stage NO{sub x}-emission limits -- 25 ppm during the first three years and 15 ppm thereafter -- is a unique challenge. The plant design allows the lower limit to be met now, and retrofit with different burners is possible if NO{sub x}-emission limits are tightened later. The facility, near Bartow in Polk County, Fla, is owned by Polk Power Partners LP, whose members include Central and South West Energy Inc (CSW) of Dallas and ARK Energy of Laguna Hills, Calif. The operating company, CSW Operations, is a subsidiary of CSW. Heart of the plant is a single gas-turbine (GT)/HRSG/steam-turbine combined cycle, providing electric power to Tampa Electric Co and Florida Power Corp, with up to 25,000 lb/hr of process steam for an adjacent ethanol plant which was developed by the facility`s partnership. Commercial operation of Mulberry began on Sept 2, 1994.

  20. Cyber security risk assessment for SCADA and DCS networks.

    PubMed

    Ralston, P A S; Graham, J H; Hieb, J L

    2007-10-01

    The growing dependence of critical infrastructures and industrial automation on interconnected physical and cyber-based control systems has resulted in a growing and previously unforeseen cyber security threat to supervisory control and data acquisition (SCADA) and distributed control systems (DCSs). It is critical that engineers and managers understand these issues and know how to locate the information they need. This paper provides a broad overview of cyber security and risk assessment for SCADA and DCS, introduces the main industry organizations and government groups working in this area, and gives a comprehensive review of the literature to date. Major concepts related to the risk assessment methods are introduced with references cited for more detail. Included are risk assessment methods such as HHM, IIM, and RFRM which have been applied successfully to SCADA systems with many interdependencies and have highlighted the need for quantifiable metrics. Presented in broad terms is probability risk analysis (PRA) which includes methods such as FTA, ETA, and FEMA. The paper concludes with a general discussion of two recent methods (one based on compromise graphs and one on augmented vulnerability trees) that quantitatively determine the probability of an attack, the impact of the attack, and the reduction in risk associated with a particular countermeasure.

  1. Restoration of synaptic plasticity and learning in young and aged NCAM-deficient mice by enhancing neurotransmission mediated by GluN2A-containing NMDA receptors.

    PubMed

    Kochlamazashvili, Gaga; Bukalo, Olena; Senkov, Oleg; Salmen, Benedikt; Gerardy-Schahn, Rita; Engel, Andreas K; Schachner, Melitta; Dityatev, Alexander

    2012-02-15

    Neural cell adhesion molecule (NCAM) is the predominant carrier of the unusual glycan polysialic acid (PSA). Deficits in PSA and/or NCAM expression cause impairments in hippocampal long-term potentiation and depression (LTP and LTD) and are associated with schizophrenia and aging. In this study, we show that impaired LTP in adult NCAM-deficient (NCAM(-/-)) mice is restored by increasing the activity of the NMDA subtype of glutamate receptor (GluN) through either reducing the extracellular Mg2+ concentration or applying d-cycloserine (DCS), a partial agonist of the GluN glycine binding site. Pharmacological inhibition of the GluN2A subtype reduced LTP to the same level in NCAM(-/-) and wild-type (NCAM(+/+)) littermate mice and abolished the rescue by DCS in NCAM(-/-) mice, suggesting that the effects of DCS are mainly mediated by GluN2A. The insufficient contribution of GluN to LTD in NCAM(-/-) mice was also compensated for by DCS. Furthermore, impaired contextual and cued fear conditioning levels were restored in NCAM(-/-) mice by administration of DCS before conditioning. In 12-month-old NCAM(-/-), but not NCAM(+/+) mice, there was a decline in LTP compared with 3-month-old mice that could be rescued by DCS. In 24-month-old mice of both genotypes, there was a reduction in LTP that could be fully restored by DCS in NCAM(+/+) mice but only partially restored in NCAM(-/-) mice. Thus, several deficiencies of NCAM(-/-) mice can be ameliorated by enhancing GluN2A-mediated neurotransmission with DCS.

  2. Poly (γ-glutamic acid) based combination of water-insoluble paclitaxel and TLR7 agonist for chemo-immunotherapy.

    PubMed

    Seth, Anushree; Heo, Min Beom; Lim, Yong Taik

    2014-09-01

    Advanced anti-cancer regimens are being introduced for more effective cancer treatment with improved life expectancy. In this research, immuno-stimulating agent toll-like receptor-7 (TLR-7) agonist-imiquimod and low dose chemotherapeutic agent-paclitaxel were synergized to demonstrate tumor therapy along with anti-tumor memory effect. Both therapeutic agents being water insoluble were dispersed in water with the help of water soluble polymer: poly (γ-glutamic acid) (γ-PGA) using a co-solvent systems leading to formation of micro-dispersions of drugs. Paclitaxel and imiquimod formed crystalline microstructures in the size range of 2-3 μm and were stably dispersed in γ-PGA matrix for more than 6 months. Paclitaxel and combination of paclitaxel and imiquimod had significant tumor killing effect in-vitro on various tumor cell lines, while antigen presenting cells (dendritic cells-DCs) treated with the same concentration of imiquimod along with the combination led to enhanced proliferation (250%). In DCs, enhanced secretion of pro-inflammatory and Th1 cytokines was observed in cells co-treated with paclitaxel and imiquimod dispersed in γ-PGA. When administered by intra-tumoral injection in mouse melanoma tumor model, the treatment with combination exemplified drastic inhibition of tumor growth leading to 70% survival as compared to individual components with 0% survival at day 41. The anti-tumor response generated was also found to have systemic memory response since the vaccinated mice significantly deferred secondary tumor development at distant site 6 weeks after treatment. The relative number and activation status of DCs in-vivo was found to be dramatically increased in case of mice treated with combination. The dramatic inhibition of tumor treated with combination is expected to be mediated by both chemotherapeutic killing of tumor cells followed by uptake of released antigen by the DCs and due to enhanced proliferation and activation of the DCs.

  3. Modulation of selective attention by polarity-specific tDCS effects.

    PubMed

    Pecchinenda, Anna; Ferlazzo, Fabio; Lavidor, Michal

    2015-02-01

    Selective attention relies on working memory to maintain an attention set of task priorities. Consequently, selective attention is more efficient when working memory resources are not depleted. However, there is some evidence that distractors are processed even when working memory load is low. We used tDCS to assess whether boosting the activity of the Dorsolateral Prefrontal Cortex (DLPFC), involved in selective attention and working memory, would reduce interference from emotional distractors. Findings showed that anodal tDCS over the DLPFC was not sufficient to reduce interference from angry distractors. In contrast, cathodal tDCS over the DLPFC reduced interference from happy distractors. These findings show that altering the DLPFC activity is not sufficient to establish top-down control and increase selective attention efficiency. Although, when the neural signal in the DLPFC is altered by cathodal tDCS, interference from emotional distractors is reduced, leading to an improved performance.

  4. 75 FR 59686 - Proposed Information Collection; Comment Request; NOAA Space-Based Data Collection System (DCS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-28

    ... National Oceanic and Atmospheric Administration Proposed Information Collection; Comment Request; NOAA Space- Based Data Collection System (DCS) Agreements AGENCY: National Oceanic and Atmospheric... this opportunity to comment on proposed and/or continuing information collections, as required by...

  5. 78 FR 68816 - Proposed Information Collection; Comment Request; NOAA Space-Based Data Collection System (DCS...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-15

    ... National Oceanic and Atmospheric Administration Proposed Information Collection; Comment Request; NOAA Space- Based Data Collection System (DCS) Agreements AGENCY: National Oceanic and Atmospheric... this opportunity to comment on proposed and/or continuing information collections, as required by...

  6. Transcranial Direct Current Stimulation (tDCS) and Aphasia: The Case of Mr. C

    PubMed Central

    Cherney, Leora R.; Babbitt, Edna M.; Hurwitz, Rosalind; Rogers, Lynn M.; Stinear, James; Wang, Xue; Harvey, Richard L.; Parrish, Todd

    2014-01-01

    Purpose To illustrate the ethical challenges that arose from investigating a novel treatment procedure, transcranial direct current stimulation (tDCS), in a research participant with aphasia. Method First, we reviewed the current evidence supporting the use of tDCS in aphasia research, highlighting methodological gaps in our knowledge of tDCS. Second, we examined the case of Mr. C, a person with chronic aphasia who participated in a research protocol investigating the impact of tDCS on aphasia treatment. Results We describe the procedures that he underwent and the resulting behavioral and neurophysiological outcomes bed. Finally, we share the steps that were taken to balance beneficence and nonmaleficence, and to ensure Mr. C’s autonomy. Conclusion: Researchers must consider not only the scientific integrity of their studies, but also potential ethical issues and consequences to the research participants. PMID:23340067

  7. The effects of tDCS upon sustained visual attention are dependent on cognitive load.

    PubMed

    Roe, James M; Nesheim, Mathias; Mathiesen, Nina C; Moberget, Torgeir; Alnæs, Dag; Sneve, Markus H

    2016-01-01

    Transcranial Direct Current Stimulation (tDCS) modulates the excitability of neuronal responses and consequently can affect performance on a variety of cognitive tasks. However, the interaction between cognitive load and the effects of tDCS is currently not well-understood. We recorded the performance accuracy of participants on a bilateral multiple object tracking task while undergoing bilateral stimulation assumed to enhance (anodal) and decrease (cathodal) neuronal excitability. Stimulation was applied to the posterior parietal cortex (PPC), a region inferred to be at the centre of an attentional tracking network that shows load-dependent activation. 34 participants underwent three separate stimulation conditions across three days. Each subject received (1) left cathodal / right anodal PPC tDCS, (2) left anodal / right cathodal PPC tDCS, and (3) sham tDCS. The number of targets-to-be-tracked was also manipulated, giving a low (one target per visual field), medium (two targets per visual field) or high (three targets per visual field) tracking load condition. It was found that tracking performance at high attentional loads was significantly reduced in both stimulation conditions relative to sham, and this was apparent in both visual fields, regardless of the direction of polarity upon the brain's hemispheres. We interpret this as an interaction between cognitive load and tDCS, and suggest that tDCS may degrade attentional performance when cognitive networks become overtaxed and unable to compensate as a result. Systematically varying cognitive load may therefore be a fruitful direction to elucidate the effects of tDCS upon cognitive functions.

  8. tDCS over the left inferior frontal cortex improves speech production in aphasia.

    PubMed

    Marangolo, Paola; Fiori, Valentina; Calpagnano, Maria A; Campana, Serena; Razzano, Carmelina; Caltagirone, Carlo; Marini, Andrea

    2013-01-01

    In this study, we investigated the combined effect of transcranial direct current stimulation (tDCS) and an intensive Conversational therapy treatment on discourse skills in 12 persons with chronic aphasia. Six short video clips depicting everyday life contexts were prepared. Three videoclips were used to elicit spontaneous conversation during treatment. The remaining three were presented only before and after the therapy. Participants were prompted to talk about the contents of each videoclip while stimulated with tDCS (20 min 1 mA) over the left hemisphere in three conditions: anodic tDCS over the Broca's area, anodic tDCS over the Wernicke's area, and a sham condition. Each experimental condition was performed for 10 consecutive daily sessions with 14 days of intersession interval. After stimulation over Broca's area, the participants produced more Content Units, verbs and sentences than in the remaining two conditions. Importantly, this improvement was still detectable 1 month after the end of treatment and its effects were generalized also to the three videoclips that had been administered at the beginning and at the end of the therapy sessions. In conclusion, anodic tDCS applied over the left Broca's area together with an intensive "Conversational Therapy" treatment improves informative speech in persons with chronic aphasia. We believe that positive tDCS effects may be further extended to other language domains, such as the recovery of speech production. PMID:24046740

  9. tDCS modulates cortical nociceptive processing but has little to no impact on pain perception.

    PubMed

    Ihle, Kristin; Rodriguez-Raecke, Rea; Luedtke, Kerstin; May, Arne

    2014-10-01

    Transcranial direct current stimulation (tDCS) effectively modulates cortical excitability. Several studies suggest clinical efficacy in chronic pain syndromes. However, little is known regarding its effects on cortical pain processing. In this double-blind, randomized, cross-over, sham controlled study, we examined the effects of anodal, cathodal, and sham stimulation of the left motor cortex in 16 healthy volunteers using functional imaging during an acute heat pain paradigm as well as pain thresholds, pain intensity ratings, and quantitative sensory testing. tDCS was applied at 1 mA for 15 minutes. Neither cathodal nor anodal tDCS significantly changed brain activation in response to nociceptive stimulation when compared with sham stimulation. However, contrasting the interaction of stimulation modes (anodal/cathodal) resulted in a significant decrease of activation in the hypothalamus, inferior parietal cortex, inferior parietal lobule, anterior insula, and precentral gyrus, contralateral to the stimulation site after anodal stimulation, which showed the opposite behavior after cathodal stimulation. Pain ratings and heat hyperalgesia showed only a subclinical pain reduction after anodal tDCS. Larger-scale clinical trials using higher tDCS intensities or longer durations are necessary to assess the neurophysiological effect and subsequently the therapeutic potential of tDCS.

  10. Differentiation of immature DCs into endothelial-like cells in human esophageal carcinoma tissue homogenates.

    PubMed

    Lu, Jing; Bai, Ruihua; Qin, Zhenzhu; Zhang, Yanyan; Zhang, Xiaoyan; Jiang, Yanan; Yang, Hongyan; Huang, Youtian; Li, Gang; Zhao, Mingyao; Dong, Ziming

    2013-08-01

    We previously reported endothelial-like differentiation (ELD) of immature dendritic cells (iDCs) in the microenvironment derived from EC9706 human esophageal squamous cell carcinoma conditioned medium (CM). However, the CM is far different from the esophageal carcinoma tissue of patients. In addition, the potential role of peri-esophageal carcinoma in the ELD of iDCs is also unknown. In the present study, we showed that the tumor microenvironment derived from esophageal carcinoma homogenate promoted iDCs to differentiate from the DC pathway toward endothelial cells, while the peri-esophageal carcinoma homogenate did not have this function. During the course of ELD, ERK signaling pathway and CREB were activated. Blocking MEK, both the phosphorylation of ERK and CREB, and the ELD of iDCs were inhibited. These data suggest that esophageal carcinoma tissue, not peri-esophageal carcinoma tissue, can drive iDCs to differentiate into endothelial-like cells, instead of differentiation into mature DCs, thereby losing the ability of antigen presentation. PMID:23708958

  11. Transcranial random noise stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

    PubMed Central

    Chaieb, Leila; Antal, Andrea; Paulus, Walter

    2015-01-01

    Background: Application of transcranial random noise stimulation (tRNS) between 0.1 and 640 Hz of the primary motor cortex (M1) for 10 min induces a persistent excitability increase lasting for at least 60 min. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS) was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1 mA for 10 min stimulation duration and a pharmacological agent (or sham) on eight healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency toward inhibiting MEPs 5–60 min poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0–20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS. Conclusions: In contrast to transcranial direct current stimulation (tDCS), aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms. PMID:25914617

  12. Bihemispheric-tDCS and Upper Limb Rehabilitation Improves Retention of Motor Function in Chronic Stroke: A Pilot Study

    PubMed Central

    Goodwill, Alicia M.; Teo, Wei-Peng; Morgan, Prue; Daly, Robin M.; Kidgell, Dawson J.

    2016-01-01

    Background: Single sessions of bihemispheric transcranial direct-current stimulation (bihemispheric-tDCS) with concurrent rehabilitation improves motor function in stroke survivors, which outlasts the stimulation period. However few studies have investigated the behavioral and neurophysiological adaptations following a multi-session intervention of bihemispheric-tDCS concurrent with rehabilitation. Objective: This pilot study explored the immediate and lasting effects of 3-weeks of bihemispheric-tDCS and upper limb (UL) rehabilitation on motor function and corticospinal plasticity in chronic stroke survivors. Methods: Fifteen chronic stroke survivors underwent 3-weeks of UL rehabilitation with sham or real bihemispheric-tDCS. UL motor function was assessed via the Motor Assessment Scale (MAS), Tardieu Scale and grip strength. Corticospinal plasticity was indexed by motor evoked potentials (MEPs), cortical silent period (CSP) and short-interval intracortical inhibition (SICI) recorded from the paretic and non-paretic ULs, using transcranial magnetic stimulation (TMS). Measures were taken at baseline, 48 h post and 3-weeks following (follow-up) the intervention. Results: MAS improved following both real-tDCS (62%) and sham-tDCS (43%, P < 0.001), however at 3-weeks follow-up, the real-tDCS condition retained these newly regained motor skills to a greater degree than sham-tDCS (real-tDCS 64%, sham-tDCS 21%, P = 0.002). MEP amplitudes from the paretic UL increased for real-tDCS (46%: P < 0.001) and were maintained at 3-weeks follow-up (38%: P = 0.03), whereas no changes were observed with sham-tDCS. No changes in MEPs from the non-paretic nor SICI from the paretic UL were observed for either group. SICI from the non-paretic UL was greater at follow-up, for real-tDCS (27%: P = 0.04). CSP from the non-paretic UL increased by 33% following the intervention for real-tDCS compared with sham-tDCS (P = 0.04), which was maintained at 3-weeks follow-up (24%: P = 0

  13. Bidirectional interactions between neuronal and hemodynamic responses to transcranial direct current stimulation (tDCS): challenges for brain-state dependent tDCS

    PubMed Central

    Dutta, Anirban

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical neural activity. During neural activity, the electric currents from excitable membranes of brain tissue superimpose in the extracellular medium and generate a potential at scalp, which is referred as the electroencephalogram (EEG). Respective neural activity (energy demand) has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose (energy supply) via neurovascular coupling. The hemodynamic response can be captured by near-infrared spectroscopy (NIRS), which enables continuous monitoring of cerebral oxygenation and blood volume. This neurovascular coupling phenomenon led to the concept of neurovascular unit (NVU) that consists of the endothelium, glia, neurons, pericytes, and the basal lamina. Here, recent works suggest NVU as an integrated system working in concert using feedback mechanisms to enable proper brain homeostasis and function where the challenge remains in capturing these mostly nonlinear spatiotemporal interactions within NVU for brain-state dependent tDCS. In principal accordance, we propose EEG-NIRS-based whole-head monitoring of tDCS-induced neuronal and hemodynamic alterations during tDCS. PMID:26321925

  14. Bidirectional interactions between neuronal and hemodynamic responses to transcranial direct current stimulation (tDCS): challenges for brain-state dependent tDCS.

    PubMed

    Dutta, Anirban

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical neural activity. During neural activity, the electric currents from excitable membranes of brain tissue superimpose in the extracellular medium and generate a potential at scalp, which is referred as the electroencephalogram (EEG). Respective neural activity (energy demand) has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose (energy supply) via neurovascular coupling. The hemodynamic response can be captured by near-infrared spectroscopy (NIRS), which enables continuous monitoring of cerebral oxygenation and blood volume. This neurovascular coupling phenomenon led to the concept of neurovascular unit (NVU) that consists of the endothelium, glia, neurons, pericytes, and the basal lamina. Here, recent works suggest NVU as an integrated system working in concert using feedback mechanisms to enable proper brain homeostasis and function where the challenge remains in capturing these mostly nonlinear spatiotemporal interactions within NVU for brain-state dependent tDCS. In principal accordance, we propose EEG-NIRS-based whole-head monitoring of tDCS-induced neuronal and hemodynamic alterations during tDCS.

  15. Bidirectional interactions between neuronal and hemodynamic responses to transcranial direct current stimulation (tDCS): challenges for brain-state dependent tDCS.

    PubMed

    Dutta, Anirban

    2015-01-01

    Transcranial direct current stimulation (tDCS) has been shown to modulate cortical neural activity. During neural activity, the electric currents from excitable membranes of brain tissue superimpose in the extracellular medium and generate a potential at scalp, which is referred as the electroencephalogram (EEG). Respective neural activity (energy demand) has been shown to be closely related, spatially and temporally, to cerebral blood flow (CBF) that supplies glucose (energy supply) via neurovascular coupling. The hemodynamic response can be captured by near-infrared spectroscopy (NIRS), which enables continuous monitoring of cerebral oxygenation and blood volume. This neurovascular coupling phenomenon led to the concept of neurovascular unit (NVU) that consists of the endothelium, glia, neurons, pericytes, and the basal lamina. Here, recent works suggest NVU as an integrated system working in concert using feedback mechanisms to enable proper brain homeostasis and function where the challenge remains in capturing these mostly nonlinear spatiotemporal interactions within NVU for brain-state dependent tDCS. In principal accordance, we propose EEG-NIRS-based whole-head monitoring of tDCS-induced neuronal and hemodynamic alterations during tDCS. PMID:26321925

  16. Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

    PubMed Central

    Pina, Adriana; Frank de Araujo, Eliseu; Felonato, Maíra; Loures, Flávio V.; Feriotti, Claudia; Bernardino, Simone; Barbuto, José Alexandre M.

    2013-01-01

    The protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response to Paracoccidioides brasiliensis infection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified that P. brasiliensis infection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis. PMID:23340311

  17. Clinical Research with Transcranial Direct Current Stimulation (tDCS): Challenges and Future Directions

    PubMed Central

    Brunoni, Andre Russowsky; Nitsche, Michael A.; Bolognini, Nadia; Bikson, Marom; Wagner, Tim; Merabet, Lotfi; Edwards, Dylan J.; Valero-Cabre, Antoni; Rotenberg, Alexander; Pascual-Leone, Alvaro; Ferrucci, Roberta; Priori, Alberto; Boggio, Paulo; Fregni, Felipe

    2011-01-01

    Background Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past ten years, tDCS physiological mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodological, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. Methods We convened a workgroup of researchers in the field to review, discuss and provide updates and key challenges of neuromodulation use for clinical research. Main Findings/Discussion We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (i) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (ii) methodological aspects related to the clinical research of tDCS as divided according to study phase (i.e., preclinical, phase I, phase II and phase III studies); (iii) ethical and regulatory concerns; (iv) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS. PMID:22037126

  18. Phenotypic and functional alterations of pDCs in lupus-prone mice

    PubMed Central

    Zhou, Zhenyuan; Ma, Jianyang; Xiao, Chunyuan; Han, Xiao; Qiu, Rong; Wang, Yan; Zhou, Yingying; Wu, Li; Huang, Xinfang; Shen, Nan

    2016-01-01

    Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied. To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.NZMSle1/2/3, MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice. Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice. The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice. Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively. As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice. In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice. PMID:26879679

  19. Novel diazabicycloalkane delta opioid agonists.

    PubMed

    Loriga, Giovanni; Lazzari, Paolo; Manca, Ilaria; Ruiu, Stefania; Falzoi, Matteo; Murineddu, Gabriele; Bottazzi, Mirko Emilio Heiner; Pinna, Giovanni; Pinna, Gérard Aimè

    2015-09-01

    Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(αR)-α((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80). In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,7) mixtures. All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80.

  20. Streptococcal preparation OK-432 promotes the capacity of dendritic cells (DCs) to prime carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocyte responses induced with genetically modified DCs that express CEA.

    PubMed

    Ojima, Toshiyasu; Iwahashi, Makoto; Nakamura, Masaki; Matsuda, Kenji; Nakamori, Mikihito; Ueda, Kentaro; Naka, Teiji; Katsuda, Masahiro; Miyazawa, Motoki; Iida, Takeshi; Yamaue, Hiroki

    2008-02-01

    Cancer immunotherapy using dendritic cells (DCs) adenovirally transduced with the whole tumor-associated antigen (TAA) gene is an effective approach. Streptococcal preparation OK-432 is useful for stimulating DCs in terms of maturation. In this study, we established carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes (CTLs) using in vitro stimulation with adenovirally modified human DCs that express CEA. We investigated whether OK-432 stimulation could be more effective in inducing CEA-specific CTLs compared with other typical stimuli. DCs adenovirally transduced with the CEA gene were cultured under various conditions with tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), or OK-432. A cytotoxicity assay using peripheral blood mononuclear cell (PBMC)-derived CTLs was performed in a 4 h-51Cr release assay. OK-432 stimulated immature DCs to acquire a mature phenotype and to produce significant amounts of T-helper 1 cytokines. In all groups (immature DCs, TNF-alpha/DCs, LPS/DCs, OK-432/DCs), CEA-specific CTLs were generated. OK-432-stimulated DCs (HLA-A24) induced the most potent cytotoxic activity against CEA-expressing targets (A24) but not against controls. OK-432/DCs were able to induce markedly potent CTLs specific to target cells pulsed with CEA652 peptide (HLA-A24-restricted peptide), although others failed to induce potent CTLs. In conclusion, the CTL induction protocol using adenovirally modified DCs that express CEA after maturation with OK-432 showed a potent antitumor activity against CEA-expressing target cells, and is therefore promising for clinical applications as a cancer vaccine therapy.

  1. Prefrontal tDCS Decreases Pain in Patients with Multiple Sclerosis

    PubMed Central

    Ayache, Samar S.; Palm, Ulrich; Chalah, Moussa A.; Al-Ani, Tarik; Brignol, Arnaud; Abdellaoui, Mohamed; Dimitri, Dalia; Sorel, Marc; Créange, Alain; Lefaucheur, Jean-Pascal

    2016-01-01

    Background: In the last few years, transcranial direct current stimulation (tDCS) has emerged as an appealing therapeutic option to improve brain functions. Promising data support the role of prefrontal tDCS in augmenting cognitive performance and ameliorating several neuropsychiatric symptoms, namely pain, fatigue, mood disturbances, and attentional impairment. Such symptoms are commonly encountered in patients with multiple sclerosis (MS). Objective: The main objective of the current work was to evaluate the tDCS effects over the left dorsolateral prefrontal cortex (DLPFC) on pain in MS patients.Our secondary outcomes were to study its influence on attention, fatigue, and mood. Materials and Methods: Sixteen MS patients with chronic neuropathic pain were enrolled in a randomized, sham-controlled, and cross-over study.Patients randomly received two anodal tDCS blocks (active or sham), each consisting of three consecutive daily tDCS sessions, and held apart by 3 weeks. Evaluations took place before and after each block. To evaluate pain, we used the Brief Pain Inventory (BPI) and the Visual Analog Scale (VAS). Attention was assessed using neurophysiological parameters and the Attention Network Test (ANT). Changes in mood and fatigue were measured using various scales. Results: Compared to sham, active tDCS yielded significant analgesic effects according to VAS and BPI global scales.There were no effects of any block on mood, fatigue, or attention. Conclusion: Based on our results, anodal tDCS over the left DLPFC appears to act in a selective manner and would ameliorate specific symptoms, particularly neuropathic pain. Analgesia might have occurred through the modulation of the emotional pain network. Attention, mood, and fatigue were not improved in this work. This could be partly attributed to the short protocol duration, the small sample size, and the heterogeneity of our MS cohort. Future large-scale studies can benefit from comparing the tDCS effects over

  2. Improving Interference Control in ADHD Patients with Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Breitling, Carolin; Zaehle, Tino; Dannhauer, Moritz; Bonath, Björn; Tegelbeckers, Jana; Flechtner, Hans-Henning; Krauel, Kerstin

    2016-01-01

    The use of transcranial direct current stimulation (tDCS) in patients with attention deficit hyperactivity disorder (ADHD) has been suggested as a promising alternative to psychopharmacological treatment approaches due to its local and network effects on brain activation. In the current study, we investigated the impact of tDCS over the right inferior frontal gyrus (rIFG) on interference control in 21 male adolescents with ADHD and 21 age matched healthy controls aged 13–17 years, who underwent three separate sessions of tDCS (anodal, cathodal, and sham) while completing a Flanker task. Even though anodal stimulation appeared to diminish commission errors in the ADHD group, the overall analysis revealed no significant effect of tDCS. Since participants showed a considerable learning effect from the first to the second session, performance in the first session was separately analyzed. ADHD patients receiving sham stimulation in the first session showed impaired interference control compared to healthy control participants whereas ADHD patients who were exposed to anodal stimulation, showed comparable performance levels (commission errors, reaction time variability) to the control group. These results suggest that anodal tDCS of the right inferior frontal gyrus could improve interference control in patients with ADHD. PMID:27147964

  3. Anodal tDCS targeting the right orbitofrontal cortex enhances facial expression recognition.

    PubMed

    Willis, Megan L; Murphy, Jillian M; Ridley, Nicole J; Vercammen, Ans

    2015-12-01

    The orbitofrontal cortex (OFC) has been implicated in the capacity to accurately recognise facial expressions. The aim of the current study was to determine if anodal transcranial direct current stimulation (tDCS) targeting the right OFC in healthy adults would enhance facial expression recognition, compared with a sham condition. Across two counterbalanced sessions of tDCS (i.e. anodal and sham), 20 undergraduate participants (18 female) completed a facial expression labelling task comprising angry, disgusted, fearful, happy, sad and neutral expressions, and a control (social judgement) task comprising the same expressions. Responses on the labelling task were scored for accuracy, median reaction time and overall efficiency (i.e. combined accuracy and reaction time). Anodal tDCS targeting the right OFC enhanced facial expression recognition, reflected in greater efficiency and speed of recognition across emotions, relative to the sham condition. In contrast, there was no effect of tDCS to responses on the control task. This is the first study to demonstrate that anodal tDCS targeting the right OFC boosts facial expression recognition. This finding provides a solid foundation for future research to examine the efficacy of this technique as a means to treat facial expression recognition deficits, particularly in individuals with OFC damage or dysfunction.

  4. Facilitative effects of bi-hemispheric tDCS in cognitive deficits of Parkinson disease patients.

    PubMed

    Leite, Jorge; Gonçalves, Oscar F; Carvalho, Sandra

    2014-02-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily characterized by motor symptoms such as tremor, rigidity, bradykinesia, stiffness, slowness and impaired equilibrium. Although the motor symptoms have been the focus in PD, slight cognitive deficits are commonly found in non-demented and non-depressed PD patients, even in early stages of the disease, which have been linked to the subsequent development of pathological dementia. Thus, strongly reducing the quality of life (QoL). Both levodopa therapy and deep brain stimulation (DBS) have yield controversial results concerning the cognitive symptoms amelioration in PD patients. That does not seems to be the case with transcranial direct current stimulation (tDCS), although better stimulation parameters are needed. Therefore we hypothesize that simultaneously delivering cathodal tDCS (or ctDCS), over the right prefrontal cortex delivered with anodal tDCS (or atDCS) to left prefrontal cortex could be potentially beneficial for PD patients, either by mechanisms of homeostatic plasticity and by increases in the extracellular dopamine levels over the striatum.

  5. Silencing c-Kit expression in human DCs suppresses Th2, Th17 response but enhances Th1 response

    PubMed Central

    Yang, Bin; Yang, Qin; Huang, Qianchuan; Yan, Hongbo; Sun, Ting; Tong, Hui

    2015-01-01

    Dendritic cells (DCs) are integral to the differentiation of T helper cells into T helper type 1 TH1, TH2 and TH17 subsets. RNA interference (RNAi), which causes the degradation of any RNA in a sequence specific manner, is a posttranscriptional gene silencing mechanism. Targeting the c-Kit in DCs has been used as an approach to enhance antitumor immunity. Here, we shwed that transfection of DCs with siRNA specific for c-Kit gene can significantly knock down c-Kit. When exposed to TNF-α, immature DCs transfected with c-Kit siRNA can differentiate into mature DCs without reducing viability or IL-12p70 production. The c-Kit siRNA-treated DCs exhibited an increased allostimulatory capacity in a lymphocyte proliferation assay. Furthermore, c-Kit siRNA-transfected DCs enhanced TH1 responses by increasing IFN-γ and decreasing IL-4 production, and much stronger cytotoxic activity was observed when DCs were co-transfected with c-Kit siRNA and an endogenous tumor antigen in vitro. Our findings indicate that silencing the c-Kit gene in DCs with siRNA may offer a potential approach to enhance antitumor immunotherapy. PMID:26550451

  6. Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS)

    NASA Astrophysics Data System (ADS)

    Alam, Mahtab; Truong, Dennis Q.; Khadka, Niranjan; Bikson, Marom

    2016-06-01

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability—enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm2) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring’s diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation (\

  7. The Integration of DCS I/O to an Existing PLC

    NASA Technical Reports Server (NTRS)

    Sadhukhan, Debashis; Mihevic, John

    2013-01-01

    At the NASA Glenn Research Center (GRC), Existing Programmable Logic Controller (PLC) I/O was replaced with Distributed Control System (DCS) I/O, while keeping the existing PLC sequence Logic. The reason for integration of the PLC logic and DCS I/O, along with the evaluation of the resulting system is the subject of this paper. The pros and cons of the old system and new upgrade are described, including operator workstation screen update times. Detail of the physical layout and the communication between the PLC, the DCS I/O and the operator workstations are illustrated. The complex characteristics of a central process control system and the plan to remove the PLC processors in future upgrades is also discussed.

  8. Testing the involvement of the prefrontal cortex in lucid dreaming: a tDCS study.

    PubMed

    Stumbrys, Tadas; Erlacher, Daniel; Schredl, Michael

    2013-12-01

    Recent studies suggest that lucid dreaming (awareness of dreaming while dreaming) might be associated with increased brain activity over frontal regions during rapid eye movement (REM) sleep. By applying transcranial direct current stimulation (tDCS), we aimed to manipulate the activation of the dorsolateral prefrontal cortex (DLPFC) during REM sleep to increase dream lucidity. Nineteen participants spent three consecutive nights in a sleep laboratory. On the second and third nights they randomly received either 1 mA tDCS for 10 min or sham stimulation during each REM period starting with the second one. According to the participants' self-ratings, tDCS over the DLPFC during REM sleep increased lucidity in dreams. The effects, however, were not strong and found only in frequent lucid dreamers. While this indicates some preliminary support for the involvement of the DLPFC in lucid dreaming, further research, controlling for indirect effects of stimulation and including other brain regions, is needed. PMID:24021850

  9. Testing the involvement of the prefrontal cortex in lucid dreaming: a tDCS study.

    PubMed

    Stumbrys, Tadas; Erlacher, Daniel; Schredl, Michael

    2013-12-01

    Recent studies suggest that lucid dreaming (awareness of dreaming while dreaming) might be associated with increased brain activity over frontal regions during rapid eye movement (REM) sleep. By applying transcranial direct current stimulation (tDCS), we aimed to manipulate the activation of the dorsolateral prefrontal cortex (DLPFC) during REM sleep to increase dream lucidity. Nineteen participants spent three consecutive nights in a sleep laboratory. On the second and third nights they randomly received either 1 mA tDCS for 10 min or sham stimulation during each REM period starting with the second one. According to the participants' self-ratings, tDCS over the DLPFC during REM sleep increased lucidity in dreams. The effects, however, were not strong and found only in frequent lucid dreamers. While this indicates some preliminary support for the involvement of the DLPFC in lucid dreaming, further research, controlling for indirect effects of stimulation and including other brain regions, is needed.

  10. Understanding public (mis)understanding of tDCS for enhancement

    PubMed Central

    Cabrera, Laura Y.; Reiner, Peter B.

    2015-01-01

    In order to gain insight into the public’s perspective on using the minimally invasive technique transcranial direct current stimulation (tDCS) as an enhancement tool, we analyzed and compared online comments in key popular press articles from two different periods (pre-commercialization and post-commercialization). The main conclusion drawn from this exploratory investigation is that public perception regarding tDCS has shifted from misunderstanding to cautionary realism. This change in attitude can be explained as moving from a focus on an emergent technology to a focus on its applications, benefits, and risks as the technology becomes more grounded within the public domain. Future governance of tDCS should include the concerns and enthusiasms of the public. PMID:25964748

  11. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  12. Neuroimaging correlates of pharmacological and psychological treatments for specific phobia.

    PubMed

    Linares, Ila M; Chags, Marcos H N; Machado-de-Sousa, João P; Crippa, José A S; Hallak, Jaime E C

    2014-01-01

    Specific phobia is an anxiety disorder characterized by irrational fear and avoidance of specific things or situations, interfering significantly with the patients' daily life. Treatment for the disorder consists of both pharmacological and psychological approaches, mainly cognitive behavioral therapy (CBT). Neuroimaging techniques have been used in an attempt to improve our understanding of the neurobiology of SP and of the effects of treatment options available. This review describes the design and results of eight articles investigating the neuroimaging correlates of pharmacological and psychological treatments for SP. The studies show that CBT is effective in SP, leading to a reduction of anxiety symptoms that is accompanied by functional alterations in the brain. The results of pharmacological interventions for SP are less uniform, but suggest that the partial agonist of the NMDA (N-methyl D-aspartate) receptor DCS (D-cycloserine) can be used in combination with psychotherapy techniques for the achievement of quicker treatment response and that DCS modulates the function of structures implicated in the neurobiology of SP. Further research should explore the augmentation of CBT treatment with DCS in controlled trials.

  13. Monitoring cognitive function and need with the automated neuropsychological assessment metrics in Decompression Sickness (DCS) research

    NASA Technical Reports Server (NTRS)

    Nesthus, Thomas E.; Schiflett, Sammuel G.

    1993-01-01

    Hypobaric decompression sickness (DCS) research presents the medical monitor with the difficult task of assessing the onset and progression of DCS largely on the basis of subjective symptoms. Even with the introduction of precordial Doppler ultrasound techniques for the detection of venous gas emboli (VGE), correct prediction of DCS can be made only about 65 percent of the time according to data from the Armstrong Laboratory's (AL's) hypobaric DCS database. An AL research protocol concerned with exercise and its effects on denitrogenation efficiency includes implementation of a performance assessment test battery to evaluate cognitive functioning during a 4-h simulated 30,000 ft (9144 m) exposure. Information gained from such a test battery may assist the medical monitor in identifying early signs of DCS and subtle neurologic dysfunction related to cases of asymptomatic, but advanced, DCS. This presentation concerns the selection and integration of a test battery and the timely graphic display of subject test results for the principal investigator and medical monitor. A subset of the Automated Neuropsychological Assessment Metrics (ANAM) developed through the Office of Military Performance Assessment Technology (OMPAT) was selected. The ANAM software provides a library of simple tests designed for precise measurement of processing efficiency in a variety of cognitive domains. For our application and time constraints, two tests requiring high levels of cognitive processing and memory were chosen along with one test requiring fine psychomotor performance. Accuracy, speed, and processing throughout variables as well as RMS error were collected. An automated mood survey provided 'state' information on six scales including anger, happiness, fear, depression, activity, and fatigue. An integrated and interactive LOTUS 1-2-3 macro was developed to import and display past and present task performance and mood-change information.

  14. Simultaneous tDCS-fMRI Identifies Resting State Networks Correlated with Visual Search Enhancement

    PubMed Central

    Callan, Daniel E.; Falcone, Brian; Wada, Atsushi; Parasuraman, Raja

    2016-01-01

    This study uses simultaneous transcranial direct current stimulation (tDCS) and functional MRI (fMRI) to investigate tDCS modulation of resting state activity and connectivity that underlies enhancement in behavioral performance. The experiment consisted of three sessions within the fMRI scanner in which participants conducted a visual search task: Session 1: Pre-training (no performance feedback), Session 2: Training (performance feedback given), Session 3: Post-training (no performance feedback). Resting state activity was recorded during the last 5 min of each session. During the 2nd session one group of participants underwent 1 mA tDCS stimulation and another underwent sham stimulation over the right posterior parietal cortex. Resting state spontaneous activity, as measured by fractional amplitude of low frequency fluctuations (fALFF), for session 2 showed significant differences between the tDCS stim and sham groups in the precuneus. Resting state functional connectivity from the precuneus to the substantia nigra, a subcortical dopaminergic region, was found to correlate with future improvement in visual search task performance for the stim over the sham group during active stimulation in session 2. The after-effect of stimulation on resting state functional connectivity was measured following a post-training experimental session (session 3). The left cerebellum Lobule VIIa Crus I showed performance related enhancement in resting state functional connectivity for the tDCS stim over the sham group. The ability to determine the relationship that the relative strength of resting state functional connectivity for an individual undergoing tDCS has on future enhancement in behavioral performance has wide ranging implications for neuroergonomic as well as therapeutic, and rehabilitative applications. PMID:27014014

  15. Antioxidants, endothelial dysfunction, and DCS: in vitro and in vivo study.

    PubMed

    Wang, Qiong; Mazur, Aleksandra; Guerrero, François; Lambrechts, Kate; Buzzacott, Peter; Belhomme, Marc; Theron, Michaël

    2015-12-15

    Reactive oxygen species (ROS) production is a well-known effect in individuals after an undersea dive. This study aimed to delineate the links between ROS, endothelial dysfunction, and decompression sickness (DCS) through the use of antioxidants in vitro and in vivo. The effect of N-acetylcysteine (NAC) on superoxide and peroxynitrite, nitric oxide (NO) generation, and cell viability during in vitro diving simulation were analyzed. Also analyzed was the effect of vitamin C and NAC on plasma glutathione thiol and thiobarbituric acid reactive substances (TBARS), plasma angiotensin-converting enzyme (ACE) activity, and angiotensin-II and DCS morbidity during in vivo diving simulation. During an in vitro diving simulation, vascular endothelial cells showed overproduction of superoxide and peroxynitrite, obvious attenuation of NO generation, and promotion of cell death, all of which were reversed by NAC treatment. After in vivo diving simulation, plasma ACE activity and angiotensin-II level were not affected. The plasma level of glutathione thiol was downregulated after the dive, which was attenuated partially by NAC treatment. Plasma TBARS level was upregulated; however, either NAC or vitamin C treatment failed to prevent DCS morbidity. During in vitro simulation, endothelial superoxide and peroxynitrite-mediated oxidative stress were involved in the attenuation of NO availability and cell death. This study is the first attempt to link oxidative stress and DCS occurrence, and the link could not be confirmed in vivo. Even in the presence of antioxidants, ROS and bubbles generated during diving and/or decompression might lead to embolic or biochemical stress and DCS. Diving-induced oxidative stress might not be the only trigger of DCS morbidity. PMID:26472863

  16. Antioxidants, endothelial dysfunction, and DCS: in vitro and in vivo study.

    PubMed

    Wang, Qiong; Mazur, Aleksandra; Guerrero, François; Lambrechts, Kate; Buzzacott, Peter; Belhomme, Marc; Theron, Michaël

    2015-12-15

    Reactive oxygen species (ROS) production is a well-known effect in individuals after an undersea dive. This study aimed to delineate the links between ROS, endothelial dysfunction, and decompression sickness (DCS) through the use of antioxidants in vitro and in vivo. The effect of N-acetylcysteine (NAC) on superoxide and peroxynitrite, nitric oxide (NO) generation, and cell viability during in vitro diving simulation were analyzed. Also analyzed was the effect of vitamin C and NAC on plasma glutathione thiol and thiobarbituric acid reactive substances (TBARS), plasma angiotensin-converting enzyme (ACE) activity, and angiotensin-II and DCS morbidity during in vivo diving simulation. During an in vitro diving simulation, vascular endothelial cells showed overproduction of superoxide and peroxynitrite, obvious attenuation of NO generation, and promotion of cell death, all of which were reversed by NAC treatment. After in vivo diving simulation, plasma ACE activity and angiotensin-II level were not affected. The plasma level of glutathione thiol was downregulated after the dive, which was attenuated partially by NAC treatment. Plasma TBARS level was upregulated; however, either NAC or vitamin C treatment failed to prevent DCS morbidity. During in vitro simulation, endothelial superoxide and peroxynitrite-mediated oxidative stress were involved in the attenuation of NO availability and cell death. This study is the first attempt to link oxidative stress and DCS occurrence, and the link could not be confirmed in vivo. Even in the presence of antioxidants, ROS and bubbles generated during diving and/or decompression might lead to embolic or biochemical stress and DCS. Diving-induced oxidative stress might not be the only trigger of DCS morbidity.

  17. Applying anodal tDCS during tango dancing in a patient with Parkinson's disease.

    PubMed

    Kaski, D; Allum, J H; Bronstein, A M; Dominguez, R O

    2014-05-01

    Gait disturbance in patients with Parkinson's disease remains a therapeutic challenge, given its poor response to levodopa. Dance therapy is of recognised benefit in these patients, particularly partnered dance forms such as the tango. In parallel, non-invasive brain stimulation has begun to show promise for the rehabilitation of patients with Parkinson's disease, although effects on gait, compared to upper limbs, have been less well defined. We applied transcranial direct current stimulation (tDCS) in a 79 year old male patient with moderate Parkinson's disease during tango dancing to assess its effect on trunk motion and balance. The patient performed a total of four dances over two days, two 'tango+tDCS' and two 'tango+sham' in a randomised double-blind fashion. In a separate experimental session we also assessed the isolated effect of tDCS (and sham) on gait without tango dancing. For the dance session, trunk peak velocity during tango was significantly greater during tDCS compared to sham stimulation. In the gait experiments we observed a modest but significant reduction in the time taken to complete the 3m 'timed up and go' and 6m walk, and an increase in overall gait velocity and peak pitch trunk velocity with tDCS compared to sham. Our findings suggest that tDCS may be a useful adjunct to gait rehabilitation for patients with PD, although studies in a larger group of patients are needed to evaluate the therapeutic use of non-invasive brain stimulation during dance therapy.

  18. Bilateral tDCS on Primary Motor Cortex: Effects on Fast Arm Reaching Tasks

    PubMed Central

    Arias, Pablo; Corral-Bergantiños, Yoanna; Robles-García, Verónica; Madrid, Antonio; Oliviero, Antonio; Cudeiro, Javier

    2016-01-01

    Background The effects produced by transcranial direct current stimulation (tDCS) applied to the motor system have been widely studied in the past, chiefly focused on primary motor cortex (M1) excitability. However, the effects on functional tasks are less well documented. Objective This study aims to evaluate the effect of tDCS-M1 on goal-oriented actions (i.e., arm-reaching movements; ARM), in a reaction-time protocol. Methods 13 healthy subjects executed dominant ARM as fast as possible to one of two targets in front of them while surface EMG was recorded. Participants performed three different sessions. In each session they first executed ARM (Pre), then received tDCS, and finally executed Post, similar to Pre. Subjects received three different types of tDCS, one per session: In one session the anode was on right-M1 (AR), and the cathode on the left-M1 (CL), thus termed AR-CL; AL-CR reversed the montage; and Sham session was applied likewise. Real stimulation was 1mA-10min while subjects at rest. Three different variables and their coefficients of variation (CV) were analyzed: Premotor times (PMT), reaction-times (RT) and movement-times (MT). Results triceps-PMT were significantly increased at Post-Sham, suggesting fatigue. Results obtained with real tDCS were not different depending on the montage used, in both cases PMT were significantly reduced in all recorded muscles. RT and MT did not change for real or sham stimulation. RT-CV and PMT-CV were reduced after all stimulation protocols. Conclusion tDCS reduces premotor time and fatigability during the execution of fast motor tasks. Possible underlying mechanisms are discussed. PMID:27490752

  19. Cathodal HD-tDCS on the right V5 improves motion perception in humans.

    PubMed

    Zito, Giuseppe A; Senti, Theresa; Cazzoli, Dario; Müri, René M; Mosimann, Urs P; Nyffeler, Thomas; Nef, Tobias

    2015-01-01

    Brain lesions in the visual associative cortex are known to impair visual perception, i.e., the capacity to correctly perceive different aspects of the visual world, such as motion, color, or shapes. Visual perception can be influenced by non-invasive brain stimulation such as transcranial direct current stimulation (tDCS). In a recently developed technique called high definition (HD) tDCS, small HD-electrodes are used instead of the sponge electrodes in the conventional approach. This is believed to achieve high focality and precision over the target area. In this paper we tested the effects of cathodal and anodal HD-tDCS over the right V5 on motion and shape perception in a single blind, within-subject, sham controlled, cross-over trial. The purpose of the study was to prove the high focality of the stimulation only over the target area. Twenty one healthy volunteers received 20 min of 2 mA cathodal, anodal and sham stimulation over the right V5 and their performance on a visual test was recorded. The results showed significant improvement in motion perception in the left hemifield after cathodal HD-tDCS, but not in shape perception. Sham and anodal HD-tDCS did not affect performance. The specific effect of influencing performance of visual tasks by modulating the excitability of the neurons in the visual cortex might be explained by the complexity of perceptual information needed for the tasks. This provokes a "noisy" activation state of the encoding neuronal patterns. We speculate that in this case cathodal HD-tDCS may focus the correct perception by decreasing global excitation and thus diminishing the "noise" below threshold.

  20. Modulating behavioral inhibition by tDCS combined with cognitive training.

    PubMed

    Ditye, Thomas; Jacobson, Liron; Walsh, Vincent; Lavidor, Michal

    2012-06-01

    Cognitive training is an effective tool to improve a variety of cognitive functions, and a small number of studies have now shown that brain stimulation accompanying these training protocols can enhance their effects. In the domain of behavioral inhibition, little is known about how training can affect this skill. As for transcranial direct current stimulation (tDCS), it was previously found that stimulation over the right inferior frontal gyrus (rIFG) facilitates behavioral inhibition performance and modulates its electrophysiological correlates. This study aimed to investigate this behavioral facilitation in the context of a learning paradigm by giving tDCS over rIFG repetitively over four consecutive days of training on a behavioral inhibition task (stop signal task (SST)). Twenty-two participants took part; ten participants were assigned to receive anodal tDCS (1.5 mA, 15 min), 12 were assigned to receive training but not active stimulation. There was a significant effect of training on learning and performance in the SST, and the integration of the training and rIFG-tDCS produced a more linear learning slope. Better performance was also found in the active stimulation group. Our findings show that tDCS-combined cognitive training is an effective tool for improving the ability to inhibit responses. The current study could constitute a step toward the use of tDCS and cognitive training as a therapeutic tool for cognitive control impairments in conditions such as attention-deficit hyperactivity disorder (ADHD) or schizophrenia. PMID:22532165

  1. Investigating the cortical regions involved in MEP modulation in tDCS

    PubMed Central

    Salvador, Ricardo; Wenger, Cornelia; Miranda, Pedro C.

    2015-01-01

    Transcranial magnetic stimulation (TMS) is used in several studies to evaluate cortical excitability changes induced by transcranial direct current stimulation (tDCS) of the primary motor cortex. Interpretation of these results, however, is hindered by the very different spatial distribution of the electric field (E-field) induced by the two techniques and by the different target neurons that they might act upon. In this study we used the finite element method to calculate the E-field distribution induced by TMS and tDCS in a realistically shaped model of a human head. A model of a commercially available figure-8 coil was placed over a position above the identified hand knob (HK) region. We also modeled two configurations of bipolar tDCS montages with one of the electrodes placed over the HK and a return electrode over the contralateral orbital region. The electrodes over the HK were either rectangular in shape, with an area of 35 cm2 or cylindrical with an area of π cm2 (1 cm radius). To compare the E-field distribution in TMS and the two tDCS models, average values of the E-field's magnitude as well as the polar and azimuthal angle were investigated in the HK region and premotor areas. The results show that both techniques induce fields with different magnitudes and directions in the HK: the field in tDCS is predominantly perpendicular to the cortical surface, contrary to what happens in TMS where the field is mostly parallel to it. In the premotor areas, the magnitude of the E-field induced in TMS was well below the accepted threshold for MEP generation, 100 V/m. In tDCS, the magnitude of the field in these areas was comparable to that induced at the HK with a significant component perpendicular to the cortical surface. These results indicate that tDCS and TMS target preferentially different neuronal structures at the HK. Besides, they show that premotor areas may play a role in the tDCS-induced after effects on motor cortex excitability. PMID:26528134

  2. Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test.

    PubMed

    Sellers, Kristin K; Mellin, Juliann M; Lustenberger, Caroline M; Boyle, Michael R; Lee, Won Hee; Peterchev, Angel V; Fröhlich, Flavio

    2015-09-01

    Transcranial direct current stimulation (tDCS) modulates excitability of motor cortex. However, there is conflicting evidence about the efficacy of this non-invasive brain stimulation modality to modulate performance on cognitive tasks. Previous work has tested the effect of tDCS on specific facets of cognition and executive processing. However, no randomized, double-blind, sham-controlled study has looked at the effects of tDCS on a comprehensive battery of cognitive processes. The objective of this study was to test if tDCS had an effect on performance on a comprehensive assay of cognitive processes, a standardized intelligence quotient (IQ) test. The study consisted of two substudies and followed a double-blind, between-subjects, sham-controlled design. In total, 41 healthy adult participants were included in the final analysis. These participants completed the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) as a baseline measure. At least one week later, participants in substudy 1 received either bilateral tDCS (anodes over both F4 and F3, cathode over Cz, 2 mA at each anode for 20 min) or active sham tDCS (2 mA for 40 s), and participants in substudy 2 received either right or left tDCS (anode over either F4 or F3, cathode over Cz, 2 mA for 20 min). In both studies, the WAIS-IV was immediately administered following stimulation to assess for performance differences induced by bilateral and unilateral tDCS. Compared to sham stimulation, right, left, and bilateral tDCS reduced improvement between sessions on Full Scale IQ and the Perceptual Reasoning Index. This demonstration that frontal tDCS selectively degraded improvement on specific metrics of the WAIS-IV raises important questions about the often proposed role of tDCS in cognitive enhancement.

  3. Transcranial direct current stimulation (tDCS) of frontal cortex decreases performance on the WAIS-IV intelligence test.

    PubMed

    Sellers, Kristin K; Mellin, Juliann M; Lustenberger, Caroline M; Boyle, Michael R; Lee, Won Hee; Peterchev, Angel V; Fröhlich, Flavio

    2015-09-01

    Transcranial direct current stimulation (tDCS) modulates excitability of motor cortex. However, there is conflicting evidence about the efficacy of this non-invasive brain stimulation modality to modulate performance on cognitive tasks. Previous work has tested the effect of tDCS on specific facets of cognition and executive processing. However, no randomized, double-blind, sham-controlled study has looked at the effects of tDCS on a comprehensive battery of cognitive processes. The objective of this study was to test if tDCS had an effect on performance on a comprehensive assay of cognitive processes, a standardized intelligence quotient (IQ) test. The study consisted of two substudies and followed a double-blind, between-subjects, sham-controlled design. In total, 41 healthy adult participants were included in the final analysis. These participants completed the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) as a baseline measure. At least one week later, participants in substudy 1 received either bilateral tDCS (anodes over both F4 and F3, cathode over Cz, 2 mA at each anode for 20 min) or active sham tDCS (2 mA for 40 s), and participants in substudy 2 received either right or left tDCS (anode over either F4 or F3, cathode over Cz, 2 mA for 20 min). In both studies, the WAIS-IV was immediately administered following stimulation to assess for performance differences induced by bilateral and unilateral tDCS. Compared to sham stimulation, right, left, and bilateral tDCS reduced improvement between sessions on Full Scale IQ and the Perceptual Reasoning Index. This demonstration that frontal tDCS selectively degraded improvement on specific metrics of the WAIS-IV raises important questions about the often proposed role of tDCS in cognitive enhancement. PMID:25934490

  4. The anodal tDCS over the left posterior parietal cortex enhances attention toward a focus word in a sentence.

    PubMed

    Minamoto, Takehiro; Azuma, Miyuki; Yaoi, Ken; Ashizuka, Aoi; Mima, Tastuya; Osaka, Mariko; Fukuyama, Hidenao; Osaka, Naoyuki

    2014-01-01

    The posterior parietal cortex (PPC) has two attentional functions: top-down attentional control and stimulus-driven attentional processing. Using the focused version of the reading span test (RST), in which the target word to be remembered is the critical word for comprehending a sentence (focused word) or a non-focused word, we examined the effect of tDCS on resolution of distractor interference by the focused word in the non-focus condition (top-down attentional control) and on augmented/shrunk attentional capture by the focused word in both the focus and non-focus conditions (stimulus-driven attentional processing). Participants were divided into two groups: anodal tDCS (atDCS) and cathodal tDCS (ctDCS). Online stimulation was given while participants performed the RST. A post-hoc recognition task was also administered in which three kinds of words were presented: target words in the RST, distractor words in the RST, and novel words. atDCS augmented the effect of the focused word by increasing differences in performance between the focus and non-focus conditions. Such an effect was not observed in the ctDCS group. As for the recognition task, atDCS again produced the augmented effect of the focused words in the distractor recognition. On the other hand, ctDCS brought less recognition of non-focused target words in comparison to sham. The results indicate that atDCS promotes stimulus-driven attentional processing, possibly by affecting neural firing in the inferior parietal regions. In contrast, ctDCS appears to prevent retrieval of less important information from episodic memory, which may require top-down attentional processing. PMID:25538609

  5. The anodal tDCS over the left posterior parietal cortex enhances attention toward a focus word in a sentence

    PubMed Central

    Minamoto, Takehiro; Azuma, Miyuki; Yaoi, Ken; Ashizuka, Aoi; Mima, Tastuya; Osaka, Mariko; Fukuyama, Hidenao; Osaka, Naoyuki

    2014-01-01

    The posterior parietal cortex (PPC) has two attentional functions: top-down attentional control and stimulus-driven attentional processing. Using the focused version of the reading span test (RST), in which the target word to be remembered is the critical word for comprehending a sentence (focused word) or a non-focused word, we examined the effect of tDCS on resolution of distractor interference by the focused word in the non-focus condition (top-down attentional control) and on augmented/shrunk attentional capture by the focused word in both the focus and non-focus conditions (stimulus-driven attentional processing). Participants were divided into two groups: anodal tDCS (atDCS) and cathodal tDCS (ctDCS). Online stimulation was given while participants performed the RST. A post-hoc recognition task was also administered in which three kinds of words were presented: target words in the RST, distractor words in the RST, and novel words. atDCS augmented the effect of the focused word by increasing differences in performance between the focus and non-focus conditions. Such an effect was not observed in the ctDCS group. As for the recognition task, atDCS again produced the augmented effect of the focused words in the distractor recognition. On the other hand, ctDCS brought less recognition of non-focused target words in comparison to sham. The results indicate that atDCS promotes stimulus-driven attentional processing, possibly by affecting neural firing in the inferior parietal regions. In contrast, ctDCS appears to prevent retrieval of less important information from episodic memory, which may require top-down attentional processing. PMID:25538609

  6. tDCS over left M1 or DLPFC does not improve learning of a bimanual coordination task

    PubMed Central

    Vancleef, Kathleen; Meesen, Raf; Swinnen, Stephan P.; Fujiyama, Hakuei

    2016-01-01

    Previously, transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has resulted in improved performance in simple motor tasks. For a complex bimanual movement, studies using functional magnetic resonance imaging and transcranial magnetic stimulation indicated the involvement of the left dorsolateral prefrontal cortex (DLPFC) as well as left M1. Here we investigated the relative effect of up-regulating the cortical function in left DLPFC and left M1 with tDCS. Participants practised a complex bimanual task over four days while receiving either of five stimulation protocols: anodal tDCS applied over M1, anodal tDCS over DLPFC, sham tDCS over M1, sham tDCS over DLPFC, or no stimulation. Performance was measured at the start and end of each training day to make a distinction between acquisition and consolidation. Although task performance improved over days, no significant difference between stimulation protocols was observed, suggesting that anodal tDCS had little effect on learning the bimanual task regardless of the stimulation sites and learning phase (acquisition or consolidation). Interestingly, cognitive performance as well as corticomotor excitability did not change following stimulation. Accordingly, we found no evidence for behavioural or neurophysiological changes following tDCS over left M1 or left DLPFC in learning a complex bimanual task. PMID:27779192

  7. Impact of tDCS on Performance and Learning of Target Detection: Interaction with Stimulus Characteristics and Experimental Design

    ERIC Educational Resources Information Center

    Coffman, B. A.; Trumbo, M. C.; Flores, R. A.; Garcia, C. M.; van der Merwe, A. J.; Wassermann, E. M.; Weisend, M. P.; Clark, V. P.

    2012-01-01

    We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential…

  8. Potentials and limits to enhance cognitive functions in healthy and pathological aging by tDCS

    PubMed Central

    Prehn, Kristin; Flöel, Agnes

    2015-01-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that is increasingly used in research and clinical settings to enhance the effects of cognitive training. In our present review, we will first summarize studies using tDCS alone and in combination with cognitive training in older adults and patients with Alzheimer’s dementia (AD). We will also review one study (Meinzer et al., 2014c) that showed an improvement in cognitive performance during anodal tDCS over the left inferior frontal cortex in patients with mild cognitive impairment (MCI) which is regarded as a prodromal stage of AD. Although promising short-term results have been reported, evidence from randomized controlled trials (RCTs) with sufficient sample sizes is scarce. In addition, stimulation protocols (in terms of intensity, duration, and repetition of stimulation) that lead to sustained improvements in outcome measures relevant for daily life still remain to be established. Following, we will discuss modulating factors such as technical parameters as well as the question whether there are specific cognitive functions (e.g., learning, memory consolidation, executive control) which are more amenable to tDCS enhancement than others. Finally, we will highlight future directions and limitations in this field and emphasize the need to conduct RCTs to establish efficacy of interventions for activities of daily life for a given patient population. PMID:26441526

  9. Transcranial Brain Stimulation Techniques For Major Depression: Should We Extend TMS Lessons to tDCS?

    PubMed

    Dell'Osso, Bernardo; Altamura, A Carlo

    2014-01-01

    Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are non-invasive brain stimulation techniques that, by means of magnetic fields and low intensity electrical current, respectively, aim to interefere with and modulate cortical excitability, at the level of dorsolateral prefrontal cortex, in patients with major depression and poor response to standard antidepressants. While the clinical efficacy of TMS in major depression has been extensively investigated over the last 10 years, tDCS has attracted research interest only in the last years, with fewer randomized clinical trials (RCTs) in the field. Nevertheless, in spite of the different rationale and mechanism of action of the two techniques, tDCS recent acquisitions, in relation to the treatment of major depression, seem to parallel those previously obtained with TMS, in terms of treatment duration to achieve optimal benefit and patient's history of drug-resistance. After briefly introducing the two techniques, the article examines possible common pathways of clinical use for TMS and tDCS, emerging from recent RCTs and likely orienting future investigation with non invasive brain stimulation for the treatment of major depression.

  10. Transcranial modulation of brain oscillatory responses: A concurrent tDCS-MEG investigation.

    PubMed

    Hanley, Claire J; Singh, Krish D; McGonigle, David J

    2016-10-15

    Despite the increasing use of transcranial direct current stimulation (tDCS), the physiological mechanisms underlying its effects are still largely unknown. One approach to directly investigate the effects of the neuromodulation technique on the brain is to integrate tDCS with non-invasive neuroimaging in humans. To provide new insight into the neurobiology of the method, DC stimulation (1mA, 600s) was applied concurrently with Magnetoencephalography (MEG), while participants engaged in a visuomotor task before, during and after a period of tDCS. Responses in the motor beta band (15-30Hz) and visual gamma band (30-80Hz) were localised using Synthetic Aperture Magnetometry (SAM). The resulting induced and evoked oscillatory responses were subsequently analysed. A statistically significant reduction of average power in the visual gamma band was observed for anodal compared to sham stimulation. The magnitude of motor evoked responses was also found to be significantly modulated by anodal stimulation. These results demonstrate that MEG can be used to derive inferences on the cortical mechanisms of tDCS.

  11. tDCS selectively improves working memory in older adults with more education.

    PubMed

    Berryhill, Marian E; Jones, Kevin T

    2012-07-19

    Cognitive performance, including performance on working memory (WM) tasks declines with age. Changes in brain activations are one presumed contributor to WM decline in the healthy aging population. In particular, neuroimaging studies show that when older adults perform WM tasks there tends to be greater bilateral frontal activity than in younger adults. We hypothesized that stimulating the prefrontal cortex in healthy older adults would improve WM performance. To test this hypothesis we employed transcranial direct current stimulation (tDCS), a neurostimulation technique in which small amounts of electrical current are applied to the scalp with the intent of modulating the activity in underlying neurons. Across three testing sessions we applied sham stimulation or anodal tDCS to the left (F3) or right (F4) prefrontal cortex to healthy older adults as they performed trials of verbal and visual 2-back WM tasks. Surprisingly, tDCS was uniformly beneficial across site and WM task, but only in older adults with more education. In the less educated group, tDCS provided no benefit to verbal or visual WM performance. We interpret these findings as evidence for differential frontal recruitment as a function of strategy when older adults perform WM tasks.

  12. Multisession Anodal tDCS Protocol Improves Motor System Function in an Aging Population

    PubMed Central

    Dumel, G.; Bourassa, M.-E.; Desjardins, M.; Voarino, N.; Charlebois-Plante, C.; Doyon, J.; De Beaumont, Louis

    2016-01-01

    Objectives. The primary objective of this study was to investigate the effects of five consecutive, daily 20-minute sessions of M1 a-tDCS on motor learning in healthy, cognitively intact, aging adults. Design. A total of 23 participants (51 to 69 years old) performed five consecutive, daily 20-minute sessions of a serial reaction time task (SRT task) concomitant with either anodal (n = 12) or sham (n = 11) M1 a-tDCS. Results. We found a significant group × training sessions interaction, indicating that whereas aging adults in the sham group exhibited little-to-no sequence-specific learning improvements beyond the first day of training, reproducible improvements in the ability to learn new motor sequences over 5 consecutive sessions were the net result in age-equivalent participants from the M1 a-tDCS group. A significant main effect of group on sequence-specific learning revealed greater motor learning for the M1 a-tDCS group when the five learning sessions were averaged. Conclusion. These findings raise into prominence the utility of multisession anodal TDCS protocols in combination with motor training to help prevent/alleviate age-associated motor function decline. PMID:26881118

  13. Efficient delivery of antigen to DCs using yeast-derived microparticles.

    PubMed

    Pan, Ying; Li, Xiaopeng; Kang, Tianyi; Meng, Hui; Chen, Zhouli; Yang, Li; Wu, Yang; Wei, Yuquan; Gou, Maling

    2015-01-01

    Some pathogens can be naturally recognized and internalized by antigen presentation cells (APCs) in vivo, providing a platform for efficient vaccine delivery. However, the biosafety concerns discourage the clinical applications of live pathogens. Here, yeast-derived microparticles were prepared for cancer vaccine delivery. By chemical treatment of bread yeast, capsular yeast shell (YS) microparticles were obtained. Ovalbumin (OVA), as a model antigen, was conjugated to the surface of YS. Results indicated that these YS microparticles with a uniform size of ~3.4 μm can be recognized and internalized by dendritic cells (DCs). The YS-mediated antigen delivery can enhance the cellular uptake of antigen by DCs, promote the maturation of DCs, and trigger DCs to release immune co-stimulatory molecules. Immunization with YS-mediated antigen can induce an effective immune response against tumor cells in vivo, with contributions from both humoral and cellular immunity. This work suggests that yeast shell microparticles as efficient vaccine delivery system has promising applications in cancer immunotherapy. PMID:26022399

  14. Beta-agonists and animal welfare

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The use of beta-agonists in animal feed is a high profile topic within the U.S. as consumers and activist groups continue to question its safety. The only beta-agonist currently available for use in swine is ractopamine hydrochloride (RAC). This is available as Paylean™ (Elanco Animal Health – FDA a...

  15. Enhancing vigilance in operators with prefrontal cortex transcranial direct current stimulation (tDCS).

    PubMed

    Nelson, Jeremy T; McKinley, R Andy; Golob, Edward J; Warm, Joel S; Parasuraman, Raja

    2014-01-15

    Sustained attention, often referred to as vigilance in humans, is the ability to maintain goal-directed behavior for extended periods of time and respond to intermittent targets in the environment. With greater time-on-task the ability to detect targets decreases and reaction time increases-a phenomenon termed the vigilance decrement. The purpose of this study was to examine the role of dorsolateral prefrontal cortex in the vigilance decrement. Subjects (n=19) received prefrontal transcranial direct current stimulation (tDCS) at one of two different time points during a vigilance task (early or late). The impact of tDCS was examined using measures of behavior, hemispheric blood flow velocity, and regional blood oxygenation relative to sham stimulation. In the sham condition greater time-on-task was accompanied by fewer target detections and slower reaction times, indicating a vigilance decrement, and decreased blood flow velocity. tDCS significantly altered baseline task-induced physiologic and behavioral changes, dependent on the time of stimulation administration and electrode configuration (determining polarity of stimulation). Compared to the sham condition, with more time-on-task blood flow velocity decreased less and cerebral oxygenation increased more in the tDCS condition. Behavioral measures showed a significant improvement in target detection performance with tDCS compared to the sham stimulation. Signal detection analysis revealed a significant change in operator discriminability and response bias with increased time-on-task, as well as interactions between time of stimulation administration and electrode configuration. Current density modeling of tDCS showed high densities in the medial prefrontal cortex and anterior cingulate cortex. These findings confirm that cerebral hemodynamic measures provide an index of resource utilization and point to the central role of the frontal cortex in vigilance. Further, they suggest that modulation of the frontal

  16. The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study.

    PubMed

    Jones, Kevin T; Gözenman, Filiz; Berryhill, Marian E

    2015-01-15

    Working memory (WM) capacity falls along a spectrum with some people demonstrating higher and others lower WM capacity. Efforts to improve WM include applying transcranial direct current stimulation (tDCS), in which small amounts of current modulate the activity of underlying neurons and enhance cognitive function. However, not everyone benefits equally from a given tDCS protocol. Recent findings revealed tDCS-related WM benefits for individuals with higher working memory (WM) capacity. Here, we test two hypotheses regarding those with low WM capacity to see if they too would benefit under more optimal conditions. We tested whether supplying a WM strategy (Experiment 1) or providing greater extrinsic motivation through incentives (Experiment 2) would restore tDCS benefit to the low WM capacity group. We also employed functional near infrared spectroscopy to monitor tDCS-induced changes in neural activity. Experiment 1 demonstrated that supplying a WM strategy improved the high WM capacity participants' accuracy and the amount of oxygenated blood levels following anodal tDCS, but it did not restore tDCS-linked WM benefits to the low WM capacity group. Experiment 2 demonstrated that financial motivation enhanced performance in both low and high WM capacity groups, especially after anodal tDCS. Here, only the low WM capacity participants showed a generalized increase in oxygenated blood flow across both low and high motivation conditions. These results indicate that ensuring that participants' incentives are high may expand cognitive benefits associated with tDCS. This finding is relevant for translational work using tDCS in clinical populations, in which motivation can be a concern. PMID:25462798

  17. Remotely-supervised transcranial direct current stimulation (tDCS) for clinical trials: guidelines for technology and protocols

    PubMed Central

    Charvet, Leigh E.; Kasschau, Margaret; Datta, Abhishek; Knotkova, Helena; Stevens, Michael C.; Alonzo, Angelo; Loo, Colleen; Krull, Kevin R.; Bikson, Marom

    2015-01-01

    The effect of transcranial direct current stimulation (tDCS) is cumulative. Treatment protocols typically require multiple consecutive sessions spanning weeks or months. However, traveling to clinic for a tDCS session can present an obstacle to subjects and their caregivers. With modified devices and headgear, tDCS treatment can be administered remotely under clinical supervision, potentially enhancing recruitment, throughput, and convenience. Here we propose standards and protocols for clinical trials utilizing remotely-supervised tDCS with the goal of providing safe, reproducible and well-tolerated stimulation therapy outside of the clinic. The recommendations include: (1) training of staff in tDCS treatment and supervision; (2) assessment of the user’s capability to participate in tDCS remotely; (3) ongoing training procedures and materials including assessments of the user and/or caregiver; (4) simple and fail-safe electrode preparation techniques and tDCS headgear; (5) strict dose control for each session; (6) ongoing monitoring to quantify compliance (device preparation, electrode saturation/placement, stimulation protocol), with corresponding corrective steps as required; (7) monitoring for treatment-emergent adverse effects; (8) guidelines for discontinuation of a session and/or study participation including emergency failsafe procedures tailored to the treatment population’s level of need. These guidelines are intended to provide a minimal level of methodological rigor for clinical trials seeking to apply tDCS outside a specialized treatment center. We outline indication-specific applications (Attention Deficit Hyperactivity Disorder, Depression, Multiple Sclerosis, Palliative Care) following these recommendations that support a standardized framework for evaluating the tolerability and reproducibility of remote-supervised tDCS that, once established, will allow for translation of tDCS clinical trials to a greater size and range of patient populations

  18. The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study

    PubMed Central

    Jones, Kevin T.; Gözenman, Filiz; Berryhill, Marian E.

    2014-01-01

    Working memory (WM) capacity falls along a spectrum with some people demonstrating higher and others lower WM capacity. Efforts to improve WM include applying transcranial direct current stimulation (tDCS), in which small amounts of current modulate the activity of underlying neurons and enhance cognitive function. However, not everyone benefits equally from a given tDCS protocol. Recent findings revealed tDCS-related WM benefits for individuals with higher working memory (WM) capacity. Here, we test two hypotheses regarding those with low WM capacity to see if they too would benefit under more optimal conditions. We tested whether supplying a WM strategy (Experiment 1) or providing greater extrinsic motivation through incentives (Experiment 2) would restore tDCS benefit to the low WM capacity group. We also employed functional near infrared spectroscopy to monitor tDCS-induced changes in neural activity. Experiment 1 demonstrated that supplying a WM strategy improved the high WM capacity participants’ accuracy and the amount of oxygenated blood levels following anodal tDCS, but it did not restore tDCS-linked WM benefits to the low WM capacity group. Experiment 2 demonstrated that financial motivation enhanced performance in both low and high WM capacity groups, especially after anodal tDCS. Here, only the low WM capacity participants showed a generalized increase in oxygenated blood flow across both low and high motivation conditions. These results indicate that ensuring that participants’ incentives are high may expand cognitive benefits associated with tDCS. This finding is relevant for translational work using tDCS in clinical populations, in which motivation can be a concern. PMID:25462798

  19. Human CD1c(+) DCs are critical cellular mediators of immune responses induced by immunogenic cell death.

    PubMed

    Di Blasio, Stefania; Wortel, Inge M N; van Bladel, Diede A G; de Vries, Laura E; Duiveman-de Boer, Tjitske; Worah, Kuntal; de Haas, Nienke; Buschow, Sonja I; de Vries, I Jolanda M; Figdor, Carl G; Hato, Stanleyson V

    2016-08-01

    Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1). Proper activation of the immune system relies on the integration of these signals by dendritic cells (DCs). Studies on the crucial role of DCs, in the context of ICD, have been performed using mouse models or human in vitro-generated monocyte-derived DCs (moDCs), which do not fully recapitulate the in vivo situation. Here, we explore the effect of platinum-induced ICD on phenotype and function of human blood circulating DCs. Tumor cells were treated with OXP or CDDP and induction of ICD was investigated. We show that both platinum drugs triggered translocation of calreticulin and HSP70, as well as the release of ATP and HMGB1. Platinum treatment increased phagocytosis of tumor fragments by human blood DCs and enhanced phenotypic maturation of blood myeloid and plasmacytoid DCs. Moreover, upon interaction with platinum-treated tumor cells, CD1c(+) DCs efficiently stimulated allogeneic proliferation of T lymphocytes. Together, our observations indicate that platinum-treated tumor cells may exert an active stimulatory effect on human blood DCs. In particular, these data suggest that CD1c(+) DCs are critical mediators of immune responses induced by ICD. PMID:27622063

  20. Human CD1c+ DCs are critical cellular mediators of immune responses induced by immunogenic cell death

    PubMed Central

    Di Blasio, Stefania; Wortel, Inge M. N.; van Bladel, Diede A. G.; de Vries, Laura E.; Duiveman-de Boer, Tjitske; Worah, Kuntal; de Haas, Nienke; Buschow, Sonja I.; de Vries, I. Jolanda M.; Figdor, Carl G.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1). Proper activation of the immune system relies on the integration of these signals by dendritic cells (DCs). Studies on the crucial role of DCs, in the context of ICD, have been performed using mouse models or human in vitro-generated monocyte-derived DCs (moDCs), which do not fully recapitulate the in vivo situation. Here, we explore the effect of platinum-induced ICD on phenotype and function of human blood circulating DCs. Tumor cells were treated with OXP or CDDP and induction of ICD was investigated. We show that both platinum drugs triggered translocation of calreticulin and HSP70, as well as the release of ATP and HMGB1. Platinum treatment increased phagocytosis of tumor fragments by human blood DCs and enhanced phenotypic maturation of blood myeloid and plasmacytoid DCs. Moreover, upon interaction with platinum-treated tumor cells, CD1c+ DCs efficiently stimulated allogeneic proliferation of T lymphocytes. Together, our observations indicate that platinum-treated tumor cells may exert an active stimulatory effect on human blood DCs. In particular, these data suggest that CD1c+ DCs are critical mediators of immune responses induced by ICD.

  1. Transcranial direct current stimulation (tDCS) of left parietal cortex facilitates gesture processing in healthy subjects.

    PubMed

    Weiss, Peter H; Achilles, Elisabeth I S; Moos, Katharina; Hesse, Maike D; Sparing, Roland; Fink, Gereon R

    2013-12-01

    Gesture processing deficits constitute a key symptom of apraxia, a disorder of motor cognition frequently observed after left-hemispheric stroke. The clinical relevance of apraxia stands in stark contrast to the paucity of therapeutic options available. Transcranial direct current stimulation (tDCS) is a promising tool for modulating disturbed network function after stroke. Here, we investigate the effect of parietal tDCS on gesture processing in healthy human subjects. Neuropsychological and imaging studies suggest that the imitation and matching of hand gestures involve the left inferior parietal lobe (IPL). Using neuronavigation based on cytoarchitectonically defined anatomical probability maps, tDCS was applied over left IPL-areas PF, PFm, or PG in healthy participants (n = 26). Before and after tDCS, subjects performed a gesture matching task and a person discrimination task for control. Changes in error rates and reaction times were analyzed for the effects of anodal and cathodal tDCS (compared with sham tDCS). Matching of hand gestures was specifically facilitated by anodal tDCS applied over the cytoarchitectonically defined IPL-area PFm, whereas tDCS over IPL-areas PF and PG did not elucidate significant effects. Taking into account tDCS electrode size and the central position of area PFm within IPL, it can be assumed that the observed effect is rather the result of a combined stimulation of the supramarginal and angular gyrus than an isolated PFm stimulation. Our data confirm the pivotal role of the left IPL in gesture processing. Furthermore, anatomically guided tDCS of the left IPL may constitute a promising approach to neurorehabilitation of apraxic patients with gesture processing deficits. PMID:24305816

  2. Human CD1c+ DCs are critical cellular mediators of immune responses induced by immunogenic cell death

    PubMed Central

    Di Blasio, Stefania; Wortel, Inge M. N.; van Bladel, Diede A. G.; de Vries, Laura E.; Duiveman-de Boer, Tjitske; Worah, Kuntal; de Haas, Nienke; Buschow, Sonja I.; de Vries, I. Jolanda M.; Figdor, Carl G.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Chemotherapeutics, including the platinum compounds oxaliplatin (OXP) and cisplatin (CDDP), are standard care of treatment for cancer. Although chemotherapy has long been considered immunosuppressive, evidence now suggests that certain cytotoxic agents can efficiently stimulate antitumor responses, through the induction of a form of apoptosis, called immunogenic cell death (ICD). ICD is characterized by exposure of calreticulin and heat shock proteins (HSPs), secretion of ATP and release of high-mobility group box 1 (HMGB1). Proper activation of the immune system relies on the integration of these signals by dendritic cells (DCs). Studies on the crucial role of DCs, in the context of ICD, have been performed using mouse models or human in vitro-generated monocyte-derived DCs (moDCs), which do not fully recapitulate the in vivo situation. Here, we explore the effect of platinum-induced ICD on phenotype and function of human blood circulating DCs. Tumor cells were treated with OXP or CDDP and induction of ICD was investigated. We show that both platinum drugs triggered translocation of calreticulin and HSP70, as well as the release of ATP and HMGB1. Platinum treatment increased phagocytosis of tumor fragments by human blood DCs and enhanced phenotypic maturation of blood myeloid and plasmacytoid DCs. Moreover, upon interaction with platinum-treated tumor cells, CD1c+ DCs efficiently stimulated allogeneic proliferation of T lymphocytes. Together, our observations indicate that platinum-treated tumor cells may exert an active stimulatory effect on human blood DCs. In particular, these data suggest that CD1c+ DCs are critical mediators of immune responses induced by ICD. PMID:27622063

  3. [Adrenergic beta-agonist intoxication].

    PubMed

    Carrola, Paulo; Devesa, Nuno; Silva, José Manuel; Ramos, Fernando; Alexandrino, Mário B; Moura, José J

    2003-01-01

    The authors describe two clinical cases (father and daughter), observed in the Hospital Urgency with distal tremors, anxiety, palpitations, nausea, headaches and dizziness, two hours after ingestión of cow liver. They also had leucocytosis (with neutrophylia), hypokalemia and hyperglycaemia. After treatment with potassium i.v. and propranolol, the symptoms disappeared. The symptoms recurred at home because the patients didn't take the prescribed medication and persisted for five days, with spontaneous disappearance. The serum of both patients revealed the presence of clenbuterol (65 hg/ml - father and 58 hg/ml - daughter). The animal's liver had a concentration of 1,42 mg/kg. Clenbuterol is a ß-adrenergic agonist with low specificity, with some veterinary indications. However, this substance has been illegally used as a growth's promotor. We intend to alert doctors for this problem, particularly those that work in the Urgency.

  4. β2-agonist therapy in lung disease.

    PubMed

    Cazzola, Mario; Page, Clive P; Rogliani, Paola; Matera, M Gabriella

    2013-04-01

    β2-Agonists are effective bronchodilators due primarily to their ability to relax airway smooth muscle (ASM). They exert their effects via their binding to the active site of β2-adrenoceptors on ASM, which triggers a signaling cascade that results in a number of events, all of which contribute to relaxation of ASM. There are some differences between β2-agonists. Traditional inhaled short-acting β2-agonists albuterol, fenoterol, and terbutaline provide rapid as-needed symptom relief and short-term prophylactic protection against bronchoconstriction induced by exercise or other stimuli. The twice-daily β2-agonists formoterol and salmeterol represent important advances. Their effective bronchodilating properties and long-term improvement in lung function offer considerable clinical benefits to patients. More recently, a newer β2-agonist (indacaterol) with a longer pharmacodynamic half-life has been discovered, with the hopes of achieving once-daily dosing. In general, β2-agonists have an acceptable safety profile, although there is still controversy as to whether long-acting β2-agonists may increase the risk of asthma mortality. In any case, they can induce adverse effects, such as increased heart rate, palpitations, transient decrease in PaO2, and tremor. Desensitization of β2-adrenoceptors that occurs during the first few days of regular use of β2-agonist treatment may account for the commonly observed resolution of the majority of these adverse events after the first few doses. Nevertheless, it can also induce tolerance to bronchoprotective effects of β2-agonists and has the potential to reduce bronchodilator sensitivity to them. Some novel once-daily β2-agonists (olodaterol, vilanterol, abediterol) are under development, mainly in combination with an inhaled corticosteroid or a long-acting antimuscarinic agent. PMID:23348973

  5. The evolution of beta2-agonists.

    PubMed

    Sears, M R

    2001-08-01

    Beta-agonists have been widely used in the treatment of asthma for many years Although concerns have been expressed over their safety based largely upon epidemics of increased mortality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterol in the 1970s and 1980s, the specific beta2-agonists are vital drugs in asthma management. The short-acting beta2-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting beta2-agonists and regular or frequent use can increase the severity of the condition. The development of beta2-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting beta-agonists, such as prolonged bronchodilation, reduced day- and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting beta2-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater mprovement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.

  6. Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified aromatic-turmerone (AR).

    PubMed

    Yonggang, Tan; Yiming, Meng; Heying, Zhang; Cheng, Sun; Qiushi, Wang; Xianghong, Yang; Wei, Zheng; Huawei, Zhou; Shan, Fengping

    2012-10-01

    The aim of this work is to evaluate the effects of purified aromatic-turmerone (ar-turmerione, AR) on murine dendritic cells (DCs). These impacts of AR on DCs from bone marrow derived DCs(BMDCs) were assessed with use of conventional scanning electron microscopy (SEM), fluorescence activated cell sorting (FACS), transmission electron microscopy (TEM), cytochemistry assay, FITC-dextran, bio-assay and enzyme linked immunosorbent assay (ELISA). We found that AR induced phenotypic maturation as evidenced by increased expression of CD86, CD40, CD83, CD80 and major histocompatibility complex II (MHC II). The functional tests showed the activity of acidic phosphatase (ACP) inside the DCs were downregulated after treatment with AR (which occurs when phagocytosis of DCs were decreased). Finally, we proved that AR increased the production of IL-12 and tumor necrosis factor α (TNF-α). These data suggested that AR could promote phenotypic and functional maturation of DCs and this adjuvant-like activity may have potential therapeutic value. It is therefore concluded that AR could exert positive modulation on murine DCs.

  7. Neonatal Plasmacytoid Dendritic Cells (pDCs) Display Subset Variation but Can Elicit Potent Anti-Viral Innate Responses

    PubMed Central

    Zhang, Xiaoming; Lepelley, Alice; Azria, Elie; Lebon, Pierre; Roguet, Gwenaelle; Schwartz, Olivier; Launay, Odile; Leclerc, Claude; Lo-Man, Richard

    2013-01-01

    Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV) or herpes-simplex virus (HSV) by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses. PMID:23326320

  8. Efficacy of HBV-pulsed DCs in combination with entecavir in patients with chronic hepatitis B infection.

    PubMed

    Wei, Mei-Juan; Pan, Xing-Nan; Wei, Kai-Peng; Li, Xu-Hong; Liu, Xiao-Long; Zhang, Xiao-Man; Jiang, Ya-Ling; Zhang, Chun-Yu; Shen, Jian-Kun

    2015-08-01

    Dendritic cells (DCs) are multifunctional cells that initiate adaptive immune responses. Patients with chronic hepatitis B virus (HBV) infection have reduced numbers of DCs which may be functionally impaired, a defect that may contribute to viral persistence. Autologous DC-based immunotherapy is considered to be a treatment option for chronic HBV infection (CHB). We evaluated the therapeutic efficacy of HBV-pulsed DCs in combination with the antiviral drug entecavir in patients with CHB. Eighty patients were divided into four groups: HBV-pulsed DCs only, HBV-pulsed DCs plus entecavir, entecavir only, and an untreated control group. Patients on combination therapy exhibited greater antiviral responses than patients on either monotherapy. The combination of HBV-pulsed DCs and entecavir resulted in the largest reduction in serum viral DNA levels and the highest percentage of virologic response. In addition, combination therapy resulted in viral e antigen (HBeAg) loss and seroconversion. These results suggest that the combination of HBV-pulsed autologous DCs and entecavir could be therapeutically advantageous for patients with CHB.

  9. MIF Promotes Classical Activation and Conversion of Inflammatory Ly6Chigh Monocytes into TipDCs during Murine Toxoplasmosis

    PubMed Central

    Ruiz-Rosado, Juan de Dios; Olguín, Jonadab E.; Juárez-Avelar, Imelda; Saavedra, Rafael; Terrazas, Luis I.; Robledo-Avila, Frank H.; Vazquez-Mendoza, Alicia; Fernández, Jacquelina; Satoskar, Abhay R.; Partida-Sánchez, Santiago; Rodriguez-Sosa, Miriam

    2016-01-01

    Macrophage migration inhibitory factor (MIF) mediates immunity against Toxoplasma gondii infection by inducing inflammatory cytokines required to control the parasite replication. However, the role of this inflammatory mediator in the cell-mediated immune response against this infection is still poorly understood. Here, we used T. gondii-infected WT and Mif−/− mice to analyze the role of MIF in the maturation of CD11b+ and CD8α+ dendritic cells (DCs). We found that MIF promotes maturation of CD11b+ but not CD8α+ DCs, by inducing IL-12p70 production and CD86 expression. Infected Mif−/− mice showed significantly lower numbers of TNF and inducible nitric oxide synthase- (iNOS-) producing DCs (TipDCs) compared to infected WT mice. The adoptive transfer of Ly6Chigh monocytes into infected WT or Mif−/− mice demonstrated that MIF participates in the differentiation of Ly6Chigh monocytes into TipDCs. In addition, infected Mif−/− mice display a lower percentage of IFN-γ-producing natural killer (NK) cells compared to WT mice, which is associated with reducing numbers of TipDCs in Mif−/− mice. Furthermore, administration of recombinant MIF (rMIF) into T. gondii-infected Mif−/− mice restored the numbers of TipDCs and reversed the susceptible phenotype of Mif−/− mice. Collectively, these results demonstrate an important role for MIF inducing cell-mediated immunity to T. gondii infection. PMID:27057101

  10. [Induction of amnesia induced by disturbance of memory consolidation by antagonists of glutamate or serotonin receptors will be suppressed by the protein synthesis inhibitor].

    PubMed

    Solntseva, S V; Nikitin, V P

    2010-12-01

    We have previously found two stages of amnesia evoked by disruption of memory reconsolidation with MK-801 (NMDA glutamate receptors antagonists) application in food aversion conditioned snails. Repeated conditioning restored the food aversion at early stage of amnesia development (<10 days), whereas repeated conditioning 10 days after MK-801 application did not restore the food aversion. In present work, amnesia was induced with MK-801/reminding 24 hours after food aversion conditioning, and antiamnestic effects of NMDA receptor glycine site agonist d-cycloserine were studied at early (3rd day) or late (12th day) stages of amnesia development. D-cycloserine injection and reminding restored memory only 3 days after amnesia induction whereas d-cycloserine injection without reminding was ineffective. D-cycloserine injection and reminding as well as repeated learning 12 days after amnesia induction were also ineffective in memory restoration. Thus, for the first time, it is revealed that NMDA receptor agonist d-cycloserine influences the memory restoration processes only at early but not the later stages of amnesia development.

  11. Aspirin metabolites are GPR35 agonists.

    PubMed

    Deng, Huayun; Fang, Ye

    2012-07-01

    Aspirin is widely used as an anti-inflammatory, anti-platelet, anti-pyretic, and cancer-preventive agent; however, the molecular mode of action is unlikely due entirely to the inhibition of cyclooxygenases. Here, we report the agonist activity of several aspirin metabolites at GPR35, a poorly characterized orphan G protein-coupled receptor. 2,3,5-Trihydroxybenzoic acid, an aspirin catabolite, was found to be the most potent GPR35 agonist among aspirin metabolites. Salicyluric acid, the main metabolite of aspirin, was also active. These results suggest that the GPR35 agonist activity of certain aspirin metabolites may contribute to the clinical features of aspirin. PMID:22526472

  12. Microbial Carriage State of Peripheral Blood Dendritic cells (DCs) in Chronic Periodontitis Influences DC Differentiation, Atherogenic Potential†

    PubMed Central

    Carrion, Julio; Scisci, Elizabeth; Miles, Brodie; Sabino, Gregory J.; Zeituni, Amir E; Gu, Ying; Bear, Adam; Genco, Caroline A; Brown, David L.; Cutler, Christopher W

    2012-01-01

    The low grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. Here, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19−BDCA-1+DC-SIGN+ blood myeloid DCs (mDCs) were analyzed in CP subjects with, or without existing acute coronary syndrome (ACS) and in healthy controls (CTL). FACS analysis revealed a significant increase in blood mDCs in the following order: CTLDCs; moreover, mDCs secreted high levels of MMP-9 and upregulated C1q, HSP60, HSP-70, CCR2 and CXCL16 transcripts in response to P. gingivalis in a fimbriae-dependent manner. Moreover, the survival of the anaerobe P. gingivalis under aerobic conditions was enhanced when within mDCs. Immunofluorescence analysis of oral mucosa and atherosclerotic plaques demonstrate infiltration with mDCs, colocalized with P. gingivalis. Our results suggest a role for blood mDCs in harboring and disseminating pathogens from oral mucosa to atherosclerosis plaques, which may provide key signals for mDC differentiation and atherogenic conversion. PMID:22891282

  13. The Effects of tDCS Across the Spatial Frequencies and Orientations that Comprise the Contrast Sensitivity Function

    PubMed Central

    Richard, Bruno; Johnson, Aaron P.; Thompson, Benjamin; Hansen, Bruce C.

    2015-01-01

    Transcranial Direct Current Stimulation (tDCS) has recently been employed in traditional psychophysical paradigms in an effort to measure direct manipulations on spatial frequency channel operations in the early visual system. However, the effects of tDCS on contrast sensitivity have only been measured at a single spatial frequency and orientation. Since contrast sensitivity is known to depend on spatial frequency and orientation, we ask how the effects of anodal and cathodal tDCS may vary according to these dimensions. We measured contrast sensitivity with sinusoidal gratings at four different spatial frequencies (0.5, 4, 8, and 12 cycles/°), two orientations (45° Oblique and Horizontal), and for two stimulus size conditions [fixed size (3°) and fixed period (1.5 cycles)]. Only contrast sensitivity measured with a 45° oblique grating with a spatial frequency of 8 cycles/° (period = 1.5 cycles) demonstrated clear polarity specific effects of tDCS, whereby cathodal tDCS increased and anodal tDCS decreased contrast sensitivity. Overall, effects of tDCS were largest for oblique stimuli presented at high spatial frequencies (i.e., 8 and 12 cycles/°), and were small or absent at lower spatial frequencies, other orientations and stimulus size. Thus, the impact of tDCS on contrast sensitivity, and therefore on spatial frequency channel operations, is opposite in direction to other behavioral effects of tDCS, and only measurable in stimuli that generally elicit lower contrast sensitivity (e.g., oblique gratings with period of 1.5 cycles at spatial frequencies above the peak of the contrast sensitivity function). PMID:26640448

  14. Intensity dependent effects of tDCS on corticospinal excitability in chronic Spinal Cord Injury

    PubMed Central

    Murray, Lynda M; Edwards, Dylan J; Ruffini, Giulio; Labar, Douglas; Stampas, Argyrios; Pascual-Leone, Alvaro; Cortes, Mar

    2014-01-01

    Objective To investigate the effects of anodal transcranial direct current stimulation (a-tDCS) intensity on corticospinal excitability and affected muscle activation in individuals with chronic spinal cord injury (SCI). Design Single blind, randomized, sham-controlled, crossover study. Setting Medical Research Institute and Rehabilitation Hospital. Participants Nine volunteers with chronic SCI and motor dysfunction in wrist extensor muscles. Intervention Three single session exposures to 20 minutes of a-tDCS (anode over the extensor carpi radialis (ECR) muscle representation on the left primary motor cortex, cathode over the right supraorbital area), using 1 mA, 2 mA or sham stimulation, delivered at rest, with at least one week between sessions. Outcome Measures Corticospinal excitability was assessed with motor evoked potentials (MEPs) from the ECR muscle using surface electromyography (EMG) following transcranial magnetic stimulation. Changes in spinal excitability, sensory threshold and muscle strength were also investigated. Results Mean MEP amplitude significantly increased by ~40% immediately following 2 mA a-tDCS (Pre 0.36±0.1 mV; Post 0.47±0.11 mV; p=0.001), but not with 1 mA or sham. Maximal voluntary EMG measures remained unaltered across all conditions. Sensory threshold significantly decreased over time following 1 mA (p=0.002) and 2 mA (p=0.039) a-tDCS, and did not change with sham. F-wave persistence showed a non-significant trend for increase (Pre: 32±12%; Post: 41±10%; Follow-up: 46±12%) following 2 mA stimulation. No adverse effects were reported with any of the experimental conditions. Conclusion Anodal-tDCS can transiently raise corticospinal excitability to affected muscles in chronic SCI patients following 2 mA stimulation. Sensory perception can improve with both 1 and 2 mA stimulation. This study gives support to the safe and effective use of a-tDCS using small electrodes in SCI patients, and highlights the importance of stimulation

  15. Building up analgesia in humans via the endogenous μ-opioid system by combining placebo and active tDCS: a preliminary report.

    PubMed

    DosSantos, Marcos F; Martikainen, Ilkka K; Nascimento, Thiago D; Love, Tiffany M; DeBoer, Misty D; Schambra, Heidi M; Bikson, Marom; Zubieta, Jon-Kar; DaSilva, Alexandre F

    2014-01-01

    Transcranial Direct Current Stimulation (tDCS) is a method of non-invasive brain stimulation that has been frequently used in experimental and clinical pain studies. However, the molecular mechanisms underlying tDCS-mediated pain control, and most important its placebo component, are not completely established. In this pilot study, we investigated in vivo the involvement of the endogenous μ-opioid system in the global tDCS-analgesia experience. Nine healthy volunteers went through positron emission tomography (PET) scans with [11C]carfentanil, a selective μ-opioid receptor (MOR) radiotracer, to measure the central MOR activity during tDCS in vivo (non-displaceable binding potential, BPND)--one of the main analgesic mechanisms in the brain. Placebo and real anodal primary motor cortex (M1/2mA) tDCS were delivered sequentially for 20 minutes each during the PET scan. The initial placebo tDCS phase induced a decrease in MOR BPND in the periaqueductal gray matter (PAG), precuneus, and thalamus, indicating activation of endogenous μ-opioid neurotransmission, even before the active tDCS. The subsequent real tDCS also induced MOR activation in the PAG and precuneus, which were positively correlated to the changes observed with placebo tDCS. Nonetheless, real tDCS had an additional MOR activation in the left prefrontal cortex. Although significant changes in the MOR BPND occurred with both placebo and real tDCS, significant analgesic effects, measured by improvements in the heat and cold pain thresholds, were only observed after real tDCS, not the placebo tDCS. This study gives preliminary evidence that the analgesic effects reported with M1-tDCS, can be in part related to the recruitment of the same endogenous MOR mechanisms induced by placebo, and that such effects can be purposely optimized by real tDCS. PMID:25029273

  16. Combined stimulation of the glycine and polyamine sites of the NMDA receptor attenuates NMDA blockade-induced learning deficits of rats in a 14-unit T-maze.

    PubMed

    Meyer, R C; Knox, J; Purwin, D A; Spangler, E L; Ingram, D K

    1998-02-01

    The present study examined the effects of multi-site activation of the glycine and polyamine sites of the NMDA receptor on memory formation in rats learning a 14-unit T-maze task. The competitive NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP, 9 mg/kg), was used to impair learning. The objectives were two-fold: (1) to investigate the effects of independent stimulation of the strychnine-insensitive glycine site or the polyamine site; (2) to investigate the effects of simultaneous activation of these two sites. Male, Fischer-344 rats were pretrained to a criterion of 13 out of 15 shock avoidances in a straight runway, and 24 h later were trained in a 14-unit T-maze that also required shock avoidance. Prior to maze training, rats received intraperitoneal (i.p.) injections of saline, saline plus CPP, CPP plus the glycine agonist, D-cycloserine (DCS, 30 or 40 mg/kg), CPP plus the polyamine agonist, spermine (SPM, 2.5 or 5 mg/kg), or CPP plus a combination of DCS (7.5 mg/kg) and SPM (0.625 mg/kg). Individual administration of either DCS or SPM attenuated the CPP-induced maze learning impairment in a dose-dependent manner. However, the combined treatment with both DCS and SPM completely reversed the learning deficit at doses five-fold less than either drug given alone. These findings provide additional evidence that the glycine and polyamine modulatory sites of the NMDA receptor are involved in memory formation. Furthermore, the potent synergistic effect resulting from combined activation of the glycine and polyamine sites would suggest a stronger interaction between these two sites than previously considered, and might provide new therapeutic approaches for enhancing glutamatergic function. PMID:9498733

  17. Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS).

    PubMed

    Alam, Mahtab; Truong, Dennis Q; Khadka, Niranjan; Bikson, Marom

    2016-06-21

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be

  18. Spatial and polarity precision of concentric high-definition transcranial direct current stimulation (HD-tDCS).

    PubMed

    Alam, Mahtab; Truong, Dennis Q; Khadka, Niranjan; Bikson, Marom

    2016-06-21

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies low amplitude current via electrodes placed on the scalp. Rather than directly eliciting a neuronal response, tDCS is believed to modulate excitability-enhancing or suppressing neuronal activity in regions of the brain depending on the polarity of stimulation. The specificity of tDCS to any therapeutic application derives in part from how electrode configuration determines the brain regions that are stimulated. Conventional tDCS uses two relatively large pads (>25 cm(2)) whereas high-definition tDCS (HD-tDCS) uses arrays of smaller electrodes to enhance brain targeting. The 4  ×  1 concentric ring HD-tDCS (one center electrode surrounded by four returns) has been explored in application where focal targeting of cortex is desired. Here, we considered optimization of concentric ring HD-tDCS for targeting: the role of electrodes in the ring and the ring's diameter. Finite element models predicted cortical electric field generated during tDCS. High resolution MRIs were segmented into seven tissue/material masks of varying conductivities. Computer aided design (CAD) model of electrodes, gel, and sponge pads were incorporated into the segmentation. Volume meshes were generated and the Laplace equation ([Formula: see text] · (σ [Formula: see text] V)  =  0) was solved for cortical electric field, which was interpreted using physiological assumptions to correlate with stimulation and modulation. Cortical field intensity was predicted to increase with increasing ring diameter at the cost of focality while uni-directionality decreased. Additional surrounding ring electrodes increased uni-directionality while lowering cortical field intensity and increasing focality; though, this effect saturated and more than 4 surround electrode would not be justified. Using a range of concentric HD-tDCS montages, we showed that cortical region of influence can be

  19. Monoterpenoid agonists of TRPV3

    PubMed Central

    Vogt-Eisele, A K; Weber, K; Sherkheli, M A; Vielhaber, G; Panten, J; Gisselmann, G; Hatt, H

    2007-01-01

    Background and purpose: Transient receptor potential (TRP) V3 is a thermosensitive ion channel expressed predominantly in the skin and neural tissues. It is activated by warmth and the monoterpene camphor and has been hypothesized to be involved in skin sensitization. A selection of monoterpenoid compounds was tested for TRPV3 activation to establish a structure-function relationship. The related channel TRPM8 is activated by cool temperatures and a number of chemicals, among them the monoterpene (-)-menthol. The overlap of the receptor pharmacology between the two channels was investigated. Experimental approach: Transfected HEK293 cells were superfused with the test substances. Evoked currents were measured in whole cell patch clamp measurements. Dose-response curves for the most potent agonists were obtained in Xenopus laevis oocytes. Key results: Six monoterpenes significantly more potent than camphor were identified: 6-tert-butyl-m-cresol, carvacrol, dihydrocarveol, thymol, carveol and (+)-borneol. Their EC50 is up to 16 times lower than that of camphor. All of these compounds carry a ring-located hydroxyl group and neither activates TRPM8 to a major extent. Conclusions and implications: Terpenoids have long been recognized as medically and pharmacologically active compounds, although their molecular targets have only partially been identified. TRPV3 activation may be responsible for several of the described effects of terpenoids. We show here that TRPV3 is activated by a number of monoterpenes and that a secondary hydroxyl-group is a structural requirement. PMID:17420775

  20. [Safety of beta-agonists in asthma].

    PubMed

    Oscanoa, Teodoro J

    2014-01-01

    Beta 2 agonist bronchodilators (β2A) are very important part in the pharmacotherapy of bronchial asthma, a disease that progresses in the world in an epidemic way. The β2A are prescribed to millions of people around the world, therefore the safety aspects is of public interest. Short-Acting β2 Agonists (SABAs), such as albuterol inhaler, according to current evidence, confirming its safety when used as a quick-relief or rescue medication. The long-acting β2 agonists (LABAs) The long-acting bronchodilators β2A (Long acting β2 Agonists or LABAs) are used associated with inhaled corticosteroids as controller drugs for asthma exacerbationsaccess, for safety reasons LABAs are not recommended for use as monotherapy.

  1. A comparison between block and smooth modeling in finite element simulations of tDCS.

    PubMed

    Indahlastari, Aprinda; Sadleir, Rosalind J

    2015-01-01

    Current density distributions in five selected structures, namely, anterior superior temporal gyrus (ASTG), hippocampus (HIP), inferior frontal gyrus (IFG), occipital lobe (OCC) and pre-central gyrus (PRC) were investigated as part of a comparison between electrostatic finite element models constructed directly from MRI-resolution data (block models), and smoothed tetrahedral finite element models (smooth models). Three electrode configurations were applied, mimicking different tDCS therapies. Smooth model simulations were found to require three times longer to complete. The percentage differences between mean and median current densities of each model type in arbitrarily chosen brain structures ranged from -33.33-48.08%. No clear relationship was found between structure volumes and current density differences between the two model types. Tissue regions nearby the electrodes demonstrated the least percentage differences between block and smooth models. Therefore, block models may be adequate to predict current density values in cortical regions presumed targeted by tDCS.

  2. Effect of tDCS on task relevant and irrelevant perceptual learning of complex objects.

    PubMed

    Van Meel, Chayenne; Daniels, Nicky; de Beeck, Hans Op; Baeck, Annelies

    2016-01-01

    During perceptual learning the visual representations in the brain are altered, but these changes' causal role has not yet been fully characterized. We used transcranial direct current stimulation (tDCS) to investigate the role of higher visual regions in lateral occipital cortex (LO) in perceptual learning with complex objects. We also investigated whether object learning is dependent on the relevance of the objects for the learning task. Participants were trained in two tasks: object recognition using a backward masking paradigm and an orientation judgment task. During both tasks, an object with a red line on top of it were presented in each trial. The crucial difference between both tasks was the relevance of the object: the object was relevant for the object recognition task, but not for the orientation judgment task. During training, half of the participants received anodal tDCS stimulation targeted at the lateral occipital cortex (LO). Afterwards, participants were tested on how well they recognized the trained objects, the irrelevant objects presented during the orientation judgment task and a set of completely new objects. Participants stimulated with tDCS during training showed larger improvements of performance compared to participants in the sham condition. No learning effect was found for the objects presented during the orientation judgment task. To conclude, this study suggests a causal role of LO in relevant object learning, but given the rather low spatial resolution of tDCS, more research on the specificity of this effect is needed. Further, mere exposure is not sufficient to train object recognition in our paradigm. PMID:27096945

  3. Effect of tDCS on task relevant and irrelevant perceptual learning of complex objects.

    PubMed

    Van Meel, Chayenne; Daniels, Nicky; de Beeck, Hans Op; Baeck, Annelies

    2016-01-01

    During perceptual learning the visual representations in the brain are altered, but these changes' causal role has not yet been fully characterized. We used transcranial direct current stimulation (tDCS) to investigate the role of higher visual regions in lateral occipital cortex (LO) in perceptual learning with complex objects. We also investigated whether object learning is dependent on the relevance of the objects for the learning task. Participants were trained in two tasks: object recognition using a backward masking paradigm and an orientation judgment task. During both tasks, an object with a red line on top of it were presented in each trial. The crucial difference between both tasks was the relevance of the object: the object was relevant for the object recognition task, but not for the orientation judgment task. During training, half of the participants received anodal tDCS stimulation targeted at the lateral occipital cortex (LO). Afterwards, participants were tested on how well they recognized the trained objects, the irrelevant objects presented during the orientation judgment task and a set of completely new objects. Participants stimulated with tDCS during training showed larger improvements of performance compared to participants in the sham condition. No learning effect was found for the objects presented during the orientation judgment task. To conclude, this study suggests a causal role of LO in relevant object learning, but given the rather low spatial resolution of tDCS, more research on the specificity of this effect is needed. Further, mere exposure is not sufficient to train object recognition in our paradigm.

  4. Effects of Transcranial Direct Current Stimulation (tDCS) on Human Memory.

    SciTech Connect

    Matzen, Laura E.; Trumbo, Michael Christopher Stefan

    2014-10-01

    Training a person in a new knowledge base or skill set is extremely time consuming and costly, particularly in highly specialized domains such as the military and the intelligence community. Recent research in cognitive neuroscience has suggested that a technique called transcranial direct current stimulation (tDCS) has the potential to revolutionize training by enabling learners to acquire new skills faster, more efficiently, and more robustly (Bullard et al., 2011). In this project, we tested the effects of tDCS on two types of memory performance that are critical for learning new skills: associative memory and working memory. Associative memory is memory for the relationship between two items or events. It forms the foundation of all episodic memories, so enhancing associative memory could provide substantial benefits to the speed and robustness of learning new information. We tested the effects of tDCS on associative memory, using a real-world associative memory task: remembering the links between faces and names. Working memory refers to the amount of information that can be held in mind and processed at one time, and it forms the basis for all higher-level cognitive processing. We investigated the degree of transfer between various working memory tasks (the N-back task as a measure of verbal working memory, the rotation-span task as a measure of visuospatial working memory, and Raven's progressive matrices as a measure of fluid intelligence) in order to determine if tDCS-induced facilitation of performance is task-specific or general.

  5. Dopamine receptor partial agonists and addiction.

    PubMed

    Moreira, Fabricio A; Dalley, Jeffrey W

    2015-04-01

    Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

  6. PPAR Agonists and Cardiovascular Disease in Diabetes.

    PubMed

    Calkin, Anna C; Thomas, Merlin C

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARalpha agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARgamma agonists, and more recently dual PPARalpha/gamma coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARgamma receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease.

  7. PPAR Agonists and Cardiovascular Disease in Diabetes

    PubMed Central

    Calkin, Anna C.; Thomas, Merlin C.

    2008-01-01

    Peroxisome proliferators activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostasis. To the extent that PPAR agonists improve diabetic dyslipidaemia and insulin resistance, these agents have been considered to reduce cardiovascular risk. However, data from murine models suggests that PPAR agonists also have independent anti-atherosclerotic actions, including the suppression of vascular inflammation, oxidative stress, and activation of the renin angiotensin system. Many of these potentially anti-atherosclerotic effects are thought to be mediated by transrepression of nuclear factor-kB, STAT, and activator protein-1 dependent pathways. In recent clinical trials, PPARα agonists have been shown to be effective in the primary prevention of cardiovascular events, while their cardiovascular benefit in patients with established cardiovascular disease remains equivocal. However, the use of PPARγ agonists, and more recently dual PPARα/γ coagonists, has been associated with an excess in cardiovascular events, possibly reflecting unrecognised fluid retention with potent agonists of the PPARγ receptor. Newer pan agonists, which retain their anti-atherosclerotic activity without weight gain, may provide one solution to this problem. However, the complex biologic effects of the PPARs may mean that only vascular targeted agents or pure transrepressors will realise the goal of preventing atherosclerotic vascular disease. PMID:18288280

  8. The use of tDCS and CVS as methods of non-invasive brain stimulation.

    PubMed

    Been, Gregory; Ngo, Trung T; Miller, Steven M; Fitzgerald, Paul B

    2007-12-01

    Transcranial direct current stimulation (tDCS) and caloric vestibular stimulation (CVS) are safe methods for selectively modulating cortical excitability and activation, respectively, which have recently received increased interest regarding possible clinical applications. tDCS involves the application of low currents to the scalp via cathodal and anodal electrodes and has been shown to affect a range of motor, somatosensory, visual, affective and cognitive functions. Therapeutic effects have been demonstrated in clinical trials of tDCS for a variety of conditions including tinnitus, post-stroke motor deficits, fibromyalgia, depression, epilepsy and Parkinson's disease. Its effects can be modulated by combination with pharmacological treatment and it may influence the efficacy of other neurostimulatory techniques such as transcranial magnetic stimulation. CVS involves irrigating the auditory canal with cold water which induces a temperature gradient across the semicircular canals of the vestibular apparatus. This has been shown in functional brain-imaging studies to result in activation in several contralateral cortical and subcortical brain regions. CVS has also been shown to have effects on a wide range of visual and cognitive phenomena, as well as on post-stroke conditions, mania and chronic pain states. Both these techniques have been shown to modulate a range of brain functions, and display potential as clinical treatments. Importantly, they are both inexpensive relative to other brain stimulation techniques such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS).

  9. tDCS Effects on Verbal Fluency: A Response to Vannorsdall et al (2016).

    PubMed

    Cattaneo, Zaira; Pisoni, Alberto; Gallucci, Marcello; Papagno, Costanza

    2016-09-01

    In a prior study (Cattaneo et al, 2011. Neuroscience. 183:64-70), we demonstrated that anodal transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus enhanced verbal fluency in healthy young adults. Although our data are in line with the results of other published studies, another research group recently failed to report anodal tDCS effects on verbal fluency using a paradigm similar to ours (Vannorsdall et al, 2016. Cogn Behav Neurol. 29:11-17). Here we discuss aspects of study design and interpretation of results that should be considered in replications, focusing particularly on homogeneity of procedures. Notwithstanding the possibility that our study may indeed not be replicable, we hypothesize that Vannorsdall et al found an interesting modifier of the tDCS effects on verbal production by introducing a critical methodologic difference from our original study. We demonstrate this difference by presenting the results of an additional experiment. We believe that the sharing of data between research groups and constructive debate on possible differences in results should be encouraged because they help define the boundaries of applicability of an experimental paradigm. This is even more important for research findings that may have clinical implications, as is the case here. PMID:27662449

  10. Toward unraveling reading-related modulations of tDCS-induced neuroplasticity in the human visual cortex.

    PubMed

    Antal, Andrea; Ambrus, Géza Gergely; Chaieb, Leila

    2014-01-01

    Stimulation using weak electrical direct currents has shown to be capable of inducing polarity-dependent diminutions or elevations in motor and visual cortical excitability. The aim of the present study was to test if reading during transcranial direct current stimulation (tDCS) is able to modify stimulation-induced plasticity in the visual cortex. Phosphene thresholds (PTs) in 12 healthy subjects were recorded before and after 10 min of anodal, cathodal, and sham tDCS in combination with reading. Reading alone decreased PTs significantly, compared to the sham tDCS condition without reading. Interestingly, after both anodal and cathodal stimulation there was a tendency toward smaller PTs. Our results support the observation that tDCS-induced plasticity is highly dependent on the cognitive state of the subject during stimulation, not only in the case of motor cortex but also in the case of visual cortex stimulation.

  11. CD1c-Related DCs that Express CD207/Langerin, but Are Distinguishable from Langerhans Cells, Are Consistently Present in Human Tonsils

    PubMed Central

    De Monte, Anne; Olivieri, Charles-Vivien; Vitale, Sébastien; Bailleux, Sonanda; Castillo, Laurent; Giordanengo, Valérie; Maryanski, Janet L.; Segura, Elodie; Doglio, Alain

    2016-01-01

    Several subsets of dendritic cells (DCs) are present in the oropharyngeal tonsillar tissues and are thought to behave as major actors in development and regulation of immunity by acting as a first line of recognition for airborne and alimentary antigens. We previously discovered in human adult tonsils infected with Epstein–Barr virus (EBV), a subset of DCs that expressed langerin/CD207, a lectin usually recognized as a hallmark of epidermal Langerhans cells (LCs). In the present study, we analyzed the content of several child and adult tonsils in order to characterize in more detail the phenotype of these tonsillar CD207-expressing DCs (tCD207 DCs) and to compare it with that of other human DC subsets. We showed that all the human tonsils studied (n = 12) contained significant proportions of tCD207 DCs among tonsillar cells expressing HLA-DR. Moreover, the presence of tCD207 DCs in tonsils from young children free of EBV infection indicated that these cells could be established early in the tonsil independently of EBV infection. We also showed that tCD207 DCs, that were found mainly located within the tonsillar lymphoid stroma, were distinguishable from LCs by the level of expression of CD1a and EpCAM, and also from human inflammatory DCs by the lack of CD1a, CD206, and CD14 expression. Detailed analysis of cell surface DC markers showed that tCD207 DCs were unrelated to CD141+ DCs or macrophages, but defined a subtype of tonsillar DCs closely related to myeloid resident CD1c DCs. Since it was established that blood CD1c myeloid DCs exhibit plasticity and are capable of expressing CD207 notably in the presence of inflammatory cytokines, it is tempting to speculate that CD207+ CD1c+ DCs may play a specific immune role. PMID:27252701

  12. Cerebellar tDCS Does Not Improve Learning in a Complex Whole Body Dynamic Balance Task in Young Healthy Subjects

    PubMed Central

    Steiner, Katharina Marie; Enders, Anne; Thier, Wiebke; Batsikadze, Giorgi; Ludolph, Nicolas; Ilg, Winfried; Timmann, Dagmar

    2016-01-01

    Transcranial direct current stimulation (tDCS) of the cerebellum is of increasing interest as a non-invasive technique to modulate motor performance and learning in health and disease. Previous studies have shown that cerebellar tDCS facilitates reach adaptation and associative motor learning in healthy subjects. In the present study it was tested whether cerebellar tDCS improves learning of a complex whole body motor skill. Because this task involves learning of posture and balance likely including learning of a new motor sequence and cognitive strategies, cerebellar tDCS was applied over midline cerebellar structures and the posterolateral cerebellar hemispheres. 30 young and healthy subjects performed two days of balance training on a Lafayette Instrument 16030 stability platform®. Participants received either anodal, cathodal or sham cerebellar tDCS during training on day 1. The cerebellar electrode (7 cm width by 5 cm height) was centered 2 cm below the inion. Mean platform angle deviation and mean balance time were assessed. All subjects showed significant effects of learning. Learning rate was not different between the three modes of stimulation neither on day 1 nor on day 2. Cerebellar tDCS did not facilitate learning of a complex whole body dynamic balance task in young and healthy subjects. tDCS effects, however, may have been missed because of the small group size. Furthermore, it cannot be excluded that young and healthy subjects learned and performed already at a near optimal level with little room for further improvement. Future work has to evaluate potential benefits of cerebellar tDCS in elderly subjects and subjects with cerebellar deficits, whose motor control and motor learning network is not optimally tuned. PMID:27669151

  13. [Treatment of posttraumatic stress disorder and extinction learning of traumatic memory].

    PubMed

    Asukai, Nozomu

    2013-06-01

    Posttraumatic stress disorder (PTSD) is a debilitating psychological condition that develops following exposure to a traumatic event. The characteristic symptoms of PTSD are re-experience, avoidance, psychic numbing and hyper-arousal. The biological PTSD literature has been dramatically growing over the past three decades. PTSD symptoms related to re-experiencing the traumatic event may be conceptualized within a fear conditioning framework. Recent findings suggest that PTSD is associated with a failure of extinction learning of an acquired fear response. A fear-circuit model of PTSD posits that vmPFC fails to inhibit the amygdala, which has a crucial role in fear learning. Exposure therapy currently has the largest number of randomized clinical trials demonstrating its efficacy, and is recommended with substantial clinical confidence in treatment guidelines for PTSD. The efficacy of Prolonged Exposure (PE) was also shown for Japanese PTSD patients in a randomized controlled trial (Asukai et al., 2010). The emotional processing theory that accounts for the treatment mechanism of PE may be consistent with the hypothesis of a neurobiological mechanism in PTSD. D-cycloserine (DCS), an NMDA partial agonist, has been shown to facilitate extinction learning in animals and humans. Clinically, DCS has been shown to be a promising augmentation to PE, particularly for those who need longer treatment. PMID:25069244

  14. [Treatment of posttraumatic stress disorder and extinction learning of traumatic memory].

    PubMed

    Asukai, Nozomu

    2013-06-01

    Posttraumatic stress disorder (PTSD) is a debilitating psychological condition that develops following exposure to a traumatic event. The characteristic symptoms of PTSD are re-experience, avoidance, psychic numbing and hyper-arousal. The biological PTSD literature has been dramatically growing over the past three decades. PTSD symptoms related to re-experiencing the traumatic event may be conceptualized within a fear conditioning framework. Recent findings suggest that PTSD is associated with a failure of extinction learning of an acquired fear response. A fear-circuit model of PTSD posits that vmPFC fails to inhibit the amygdala, which has a crucial role in fear learning. Exposure therapy currently has the largest number of randomized clinical trials demonstrating its efficacy, and is recommended with substantial clinical confidence in treatment guidelines for PTSD. The efficacy of Prolonged Exposure (PE) was also shown for Japanese PTSD patients in a randomized controlled trial (Asukai et al., 2010). The emotional processing theory that accounts for the treatment mechanism of PE may be consistent with the hypothesis of a neurobiological mechanism in PTSD. D-cycloserine (DCS), an NMDA partial agonist, has been shown to facilitate extinction learning in animals and humans. Clinically, DCS has been shown to be a promising augmentation to PE, particularly for those who need longer treatment.

  15. On the relationship between cortical excitability and visual oscillatory responses - A concurrent tDCS-MEG study.

    PubMed

    Marshall, Tom R; Esterer, Sophie; Herring, Jim D; Bergmann, Til O; Jensen, Ole

    2016-10-15

    Neuronal oscillations in the alpha band (8-12Hz) in visual cortex are considered to instantiate 'attentional gating' via the inhibition of activity in regions representing task-irrelevant parts of space. In contrast, visual gamma-band activity (40-100Hz) is regarded as representing a bottom-up drive from incoming visual information, with increased synchronisation producing a stronger feedforward impulse for relevant information. However, little is known about the direct relationship between excitability of the visual cortex and these oscillatory mechanisms. In this study we used transcranial direct current stimulation (tDCS) in an Oz-Cz montage in order to stimulate visual cortex, concurrently recording whole-brain oscillatory activity using magnetoencephalography (MEG) whilst participants performed a visual task known to produce strong modulations of alpha- and gamma-band activity. We found that visual stimuli produced expected modulations of alpha and gamma - presenting a moving annulus stimulus led to a strong gamma increase and alpha decrease - and that this pattern was observable both during active (anodal and cathodal) tDCS and sham tDCS. However, tDCS did not seem to produce systematic alterations of these oscillatory responses. The present study thus demonstrates that concurrent tDCS/MEG of the visual system is a feasible tool for investigating visual neuronal oscillations, and we discuss potential reasons for the apparent inability of tDCS to effectively change the amplitude of visual stimulus induced oscillatory responses in the current study.

  16. Synergistic production of TNFα and IFNα by human pDCs incubated with IFNλ3 and IL-3.

    PubMed

    Finotti, Giulia; Tamassia, Nicola; Cassatella, Marco A

    2016-10-01

    In this study, we investigated whether IFNλ3 and IL-3 reciprocally influence their capacity to activate various functions of human plasmacytoid dendritic cells (pDCs). In fact, we preliminarily observed that IFNλ3 upregulates the expression of the IL-3Rα (CD123), while IL-3 augments the expression of IFNλR1 in pDCs. As a result, we found that combination of IFNλ3 and IL-3 induces a strong potentiation in the production of TNFα, IFNα, as well as in the expression of Interferon-Stimulated Gene (ISG) mRNAs by pDCs, as compared to either IFNλ3 or IL-3 alone. In such regard, we found that endogenous IFNα autocrinally promotes the expression of ISG mRNAs in IL-3-, but not in IFNλ3 plus IL-3-, treated pDCs. Moreover, we uncovered that the production of IFNα by IFNλ3 plus IL-3-treated pDCs is mostly dependent on endogenously produced TNFα. Altogether, our data demonstrate that IFNλ3 and IL-3 collaborate to promote, at maximal levels, discrete functional responses of human pDCs. PMID:27513213

  17. Effect of transcranial direct current stimulation (tDCS) on MMN-indexed auditory discrimination: a pilot study.

    PubMed

    Impey, Danielle; Knott, Verner

    2015-08-01

    Membrane potentials and brain plasticity are basic modes of cerebral information processing. Both can be externally (non-invasively) modulated by weak transcranial direct current stimulation (tDCS). Polarity-dependent tDCS-induced reversible circumscribed increases and decreases in cortical excitability and functional changes have been observed following stimulation of motor and visual cortices but relatively little research has been conducted with respect to the auditory cortex. The aim of this pilot study was to examine the effects of tDCS on auditory sensory discrimination in healthy participants (N = 12) assessed with the mismatch negativity (MMN) brain event-related potential (ERP). In a randomized, double-blind, sham-controlled design, participants received anodal tDCS over the primary auditory cortex (2 mA for 20 min) in one session and 'sham' stimulation (i.e., no stimulation except initial ramp-up for 30 s) in the other session. MMN elicited by changes in auditory pitch was found to be enhanced after receiving anodal tDCS compared to 'sham' stimulation, with the effects being evidenced in individuals with relatively reduced (vs. increased) baseline amplitudes and with relatively small (vs. large) pitch deviants. Additional studies are needed to further explore relationships between tDCS-related parameters, auditory stimulus features and individual differences prior to assessing the utility of this tool for treating auditory processing deficits in psychiatric and/or neurological disorders.

  18. Proposal of DCS-OFDM-PON upstream transmission with intensity modulator and collective self-coherent detection

    NASA Astrophysics Data System (ADS)

    Zhang, Jing; Yang, Heming; Zhao, Difu; Qiu, Kun

    2016-07-01

    We introduce digital coherent superposition (DCS) into optical access network and propose a DCS-OFDM-PON upstream transmission scheme using intensity modulator and collective self-coherent detection. The generated OFDM signal is real based on Hermitian symmetry, which can be used to estimate the common phase error (CPE) by complex conjugate subcarrier pairs without any pilots. In simulation, we transmit an aggregated 40 Gb/s optical OFDM signal from two ONUs. The transmission performance with DCS is slightly better after 25 km transmission without relative transmission time delay. The fiber distance for different ONUs to RN are not same in general and there is relative transmission time delay between ONUs, which causes inter-carrier-interference (ICI) power increasing and degrades the transmission performance. The DCS can mitigate the ICI power and the DCS-OFDM-PON upstream transmission outperforms the conventional OFDM-PON. The CPE estimation is by using two pairs of complex conjugate subcarriers without redundancy. The power variation can be 9 dB in DCS-OFDM-PON, which is enough to tolerate several kilometers fiber length difference between the ONUs.

  19. Rapid reconstitution of functionally active 6-sulfoLacNAc+ dendritic cells (slanDCs) of donor origin following allogeneic haematopoietic stem cell transplant

    PubMed Central

    Mimiola, E; Marini, O; Perbellini, O; Micheletti, A; Vermi, W; Lonardi, S; Costantini, C; Meneghelli, E; Andreini, A; Bonetto, C; Vassanelli, A; Cantini, M; Zoratti, E; Massi, D; Zamo', A; Leso, A; Quaresmini, G; Benedetti, F; Pizzolo, G; Cassatella, M A; Tecchio, C

    2014-01-01

    The role of dendritic cells (DCs) and macrophages in allogeneic haematopoietic stem cell transplant (HSCT) is critical in determining the extent of graft-versus-host response. The goal of this study was to analyse slanDCs, a subset of human proinflammatory DCs, in haematopoietic stem cell (HSC) sources, as well as to evaluate their 1-year kinetics of reconstitution, origin and functional capacities in peripheral blood (PB) and bone marrow (BM) of patients who have undergone HSCT, and their presence in graft-versus-host disease (GVHD) tissue specimens. slanDCs were also compared to myeloid (m)DCs, plasmacytoid (p)DCs and monocytes in HSC sources and in patients' PB and BM throughout reconstitution. slanDCs accounted for all HSC sources. In patients' PB and BM, slanDCs were identified from day +21, showing median frequencies comparable to healthy donors, donor origin and kinetics of recovery similar to mDCs, pDCs, and monocytes. Under cyclosporin treatment, slanDCs displayed a normal pattern of maturation, and maintained an efficient chemotactic activity and capacity of releasing tumour necrosis factor (TNF)-α upon lipopolysaccharide (LPS) stimulation. None the less, they were almost undetectable in GVHD tissue specimens, being present only in intestinal acute GVHD samples. slanDCs reconstitute early, being donor-derived and functionally competent. The absence of slanDCs from most of the GVHD-targeted tissue specimens seems to rule out the direct participation of these cells in the majority of the local reactions characterizing GVHD. PMID:24853271

  20. beta2-Agonists at the Olympic Games.

    PubMed

    Fitch, Kenneth D

    2006-01-01

    The different approaches that the International Olympic Committee (IOC) had adopted to beta2-agonists and the implications for athletes are reviewed by a former Olympic team physician who later became a member of the Medical Commission of the IOC (IOC-MC). Steadily increasing knowledge of the effects of inhaled beta2-agonists on health, is concerned with the fact that oral beta2-agonists may be anabolic, and rapid increased use of inhaled beta2-agonists by elite athletes has contributed to the changes to the IOC rules. Since 2001, the necessity for athletes to meet IOC criteria (i.e., that they have asthma and/or exercise-induced asthma [EIA]) has resulted in improved management of athletes. The prevalence of beta2-agonist use by athletes mirrors the known prevalence of asthma symptoms in each country, although athletes in endurance events have the highest prevalence. The age-of-onset of asthma/EIA in elite winter athletes may be atypical. Of the 193 athletes at the 2006 Winter Olympics who met th IOC's criteria, only 32.1% had childhood asthma and 48.7% of athletes reported onset at age 20 yr or older. These findings lead to speculation that years of intense endurance training may be a causative factor in bronchial hyperreactivity. The distinction between oral (prohibited in sports) and inhaled salbutamol is possible, but athletes must be warned that excessive use of inhaled salbutamol can lead to urinary concentrations similar to those observed after oral administration. This article provides justification that athletes should provide evidence of asthma or EIA before being permitted to use inhaled beta2-agonists. PMID:17085798

  1. The effects of 1 Hz rTMS preconditioned by tDCS on gait kinematics in Parkinson's disease.

    PubMed

    von Papen, Mitra; Fisse, Mirabell; Sarfeld, Anna-Sophia; Fink, Gereon R; Nowak, Dennis A

    2014-07-01

    Hypokinetic gait is a common and very disabling symptom of Parkinson's disease (PD). Repetitive transcranial magnetic stimulation (rTMS) over the motor cortex has been used with variable effectiveness to treat hypokinesia in PD. Preconditioning rTMS by transcranial direct current stimulation (tDCS) may enhance its effectiveness to treat hypokinetic gait in PD. Three-dimensional kinematic gait analysis was performed (1) prior to, (2) immediately after and (3) 30 min after low-frequency rTMS (1 Hz, 900 pulses, 80% of resting motor threshold) over M1 contralateral to the more affected body side preconditioned by (1) cathodal, (2) anodal or (3) sham tDCS (amperage: 1 mA, duration: 10 min) in ten subjects with PD (7 females, mean age 63 ± 9 years) and ten healthy subjects (four females, mean age 50 ± 11 years). The effects of tDCS-preconditioned rTMS on gait kinematics were assessed by the following parameters: number of steps, step length, stride length, double support time, cadence, swing and stance phases. Our data suggest a bilateral improvement of hypokinetic gait in PD after 1 Hz rTMS over M1 of the more affected body side preceded by anodal tDCS. In contrast, 1 Hz rTMS alone (preceded by sham tDCS) and 1 Hz rTMS preceded by cathodal tDCS were ineffective to improve gait kinematics in PD. In healthy subjects, gait kinematics was unaffected by either intervention. Preconditioning motor cortex rTMS by tDCS is a promising approach to treat hypokinetic gait in PD.

  2. Cerebellar Transcranial Direct Current Stimulation (ctDCS): A Novel Approach to Understanding Cerebellar Function in Health and Disease.

    PubMed

    Grimaldi, Giuliana; Argyropoulos, Georgios P; Bastian, Amy; Cortes, Mar; Davis, Nicholas J; Edwards, Dylan J; Ferrucci, Roberta; Fregni, Felipe; Galea, Joseph M; Hamada, Masahi; Manto, Mario; Miall, R Chris; Morales-Quezada, Leon; Pope, Paul A; Priori, Alberto; Rothwell, John; Tomlinson, S Paul; Celnik, Pablo

    2016-02-01

    The cerebellum is critical for both motor and cognitive control. Dysfunction of the cerebellum is a component of multiple neurological disorders. In recent years, interventions have been developed that aim to excite or inhibit the activity and function of the human cerebellum. Transcranial direct current stimulation of the cerebellum (ctDCS) promises to be a powerful tool for the modulation of cerebellar excitability. This technique has gained popularity in recent years as it can be used to investigate human cerebellar function, is easily delivered, is well tolerated, and has not shown serious adverse effects. Importantly, the ability of ctDCS to modify behavior makes it an interesting approach with a potential therapeutic role for neurological patients. Through both electrical and non-electrical effects (vascular, metabolic) ctDCS is thought to modify the activity of the cerebellum and alter the output from cerebellar nuclei. Physiological studies have shown a polarity-specific effect on the modulation of cerebellar-motor cortex connectivity, likely via cerebellar-thalamocortical pathways. Modeling studies that have assessed commonly used electrode montages have shown that the ctDCS-generated electric field reaches the human cerebellum with little diffusion to neighboring structures. The posterior and inferior parts of the cerebellum (i.e., lobules VI-VIII) seem particularly susceptible to modulation by ctDCS. Numerous studies have shown to date that ctDCS can modulate motor learning, and affect cognitive and emotional processes. Importantly, this intervention has a good safety profile; similar to when applied over cerebral areas. Thus, investigations have begun exploring ctDCS as a viable intervention for patients with neurological conditions. PMID:25406224

  3. Electric fields of motor and frontal tDCS in a standard brain space: A computer simulation study.

    PubMed

    Laakso, Ilkka; Tanaka, Satoshi; Mikkonen, Marko; Koyama, Soichiro; Sadato, Norihiro; Hirata, Akimasa

    2016-08-15

    The electric field produced in the brain is the main physical agent of transcranial direct current stimulation (tDCS). Inter-subject variations in the electric fields may help to explain the variability in the effects of tDCS. Here, we use multiple-subject analysis to study the strength and variability of the group-level electric fields in the standard brain space. Personalized anatomically-accurate models of 62 subjects were constructed from T1- and T2-weighted MRI. The finite-element method was used to computationally estimate the individual electric fields, which were registered to the standard space using surface based registration. Motor cortical and frontal tDCS were modelled for 16 electrode montages. For each electrode montage, the group-level electric fields had a consistent strength and direction in several brain regions, which could also be located at some distance from the electrodes. In other regions, the electric fields were more variable, and thus more likely to produce variable effects in each individual. Both the anode and cathode locations affected the group-level electric fields, both directly under the electrodes and elsewhere. For motor cortical tDCS, the electric fields could be controlled at the group level by moving the electrodes. However, for frontal tDCS, the group-level electric fields were more variable, and the electrode locations had only minor effects on the group average fields. Our results reveal the electric fields and their variability at the group level in the standard brain space, providing insights into the mechanisms of tDCS for plasticity induction. The data are useful for planning, analysing and interpreting tDCS studies. PMID:27188218

  4. PubMed Central

    Davis, Michael

    2011-01-01

    Based primarily on studies that employ Pavlovian fear conditioning, extinction of conditioned fear has been found to be mediated by N-methyl-D-aspartate (NMDA) receptors in the amygdala and medial prefrontal cortex. This led to the discovery that an NMDA partial agonist, D-cycloserine, could facilitate fear extinction when given systemically or locally into the amygdala. Because many forms of cognitive behavioral therapy depend on fear extinction, this led to the successful use of D-cycloserine as an adjunct to psychotherapy in patients with so-called simple phobias (fear of heights), social phobia, obsessive-compulsive behavior, and panic disorder. Data in support of these conclusions are reviewed, along with some of the possible limitations of D-cycloserine as an adjunct to psychotherapy. PMID:22275851

  5. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates

    NASA Astrophysics Data System (ADS)

    Wille-Reece, Ulrike; Flynn, Barbara J.; Loré, Karin; Koup, Richard A.; Kedl, Ross M.; Mattapallil, Joseph J.; Weiss, Walter R.; Roederer, Mario; Seder, Robert A.

    2005-10-01

    Induction and maintenance of antibody and T cell responses will be critical for developing a successful vaccine against HIV. A rational approach for generating such responses is to design vaccines or adjuvants that have the capacity to activate specific antigen-presenting cells. In this regard, dendritic cells (DCs) are the most potent antigen-presenting cells for generating primary T cell responses. Here, we report that Toll-like receptor (TLR) agonists and ligands that activate DCs in vitro influence the magnitude and quality of the cellular immune response in nonhuman primates (NHPs) when administered with HIV Gag protein. NHPs immunized with HIV Gag protein and a TLR7/8 agonist or a TLR9 ligand [CpG oligodeoxynucleotides (CpG ODN)] had significantly increased Gag-specific T helper 1 and antibody responses, compared with animals immunized with HIV Gag protein alone. Importantly, conjugating the HIV Gag protein to the TLR7/8 agonist (Gag-TLR7/8 conjugate) dramatically enhanced the magnitude and altered the quality of the T helper 1 response, compared with animals immunized with HIV Gag protein and the TLR7/8 agonist or CpG ODN. Furthermore, immunization with the Gag-TLR7/8 conjugate vaccine elicited Gag-specific CD8+ T responses. Collectively, our results show that conjugating HIV Gag protein to a TLR7/8 agonist is an effective way to elicit broad-based adaptive immunity in NHPs. This type of vaccine formulation should have utility in preventive or therapeutic vaccines in which humoral and cellular immunity is required. vaccine | dendritic cell | cross-presentation | cellular immunity

  6. Stimulating somatosensory psychophysics: a double-blind, sham-controlled study of the neurobiological mechanisms of tDCS

    PubMed Central

    Hanley, Claire J.; Tommerdahl, Mark; McGonigle, David J.

    2015-01-01

    The neuromodulation technique transcranial direct current stimulation (tDCS) is thought to produce its effects on behavior by altering cortical excitability. Although the mechanisms underlying the observed effects are thought to rely on the balance of excitatory and inhibitory neurotransmission, the physiological principles of the technique are not completely understood. In this study, we examine the influence of tDCS on vibrotactile adaptation, using a simple amplitude discrimination paradigm that has been shown to exhibit modifications in performance due to changes in inhibitory neurotransmission. Double-blind tDCS (Anodal/Sham) of 1 mA was delivered for 600 s to electrodes positioned in a somatosensory/contralateral orbit montage. Stimulation was applied as part of a pre/post design, between blocks of the behavioral tasks. In accordance with previous work, results obtained before the application of tDCS indicated that amplitude discrimination thresholds were significantly worsened during adaptation trials, compared to those achieved at baseline. However, tDCS failed to modify amplitude discrimination performance. Using a Bayesian approach, this finding was revealed to constitute substantial evidence for the null hypothesis. The failure of DC stimulation to alter vibrotactile adaptation thresholds is discussed in the context of several factors that may have confounded the induction of changes in cortical plasticity. PMID:26500499

  7. Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study.

    PubMed

    Smith, Robert C; Boules, Sylvia; Mattiuz, Sanela; Youssef, Mary; Tobe, Russell H; Sershen, Henry; Lajtha, Abel; Nolan, Karen; Amiaz, Revital; Davis, John M

    2015-10-01

    Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers. Thirty subjects provided evaluable data on the MATRICS Consensus Cognitive Battery (MCCB), with the primary outcome measure, the MCCB Composite score. Active compared to sham tDCS subjects showed significant improvements after the fifth tDCS session in MCCB Composite score (p=0.008) and on the MCCB Working Memory (p=0.002) and Attention-Vigilance (p=0.027) domain scores, with large effect sizes. MCCB Composite and Working Memory domain scores remained significant at Benjamini-Hochberg corrected significance levels (α=0.05). There were no statistically significant effects on secondary outcome measures of psychiatric symptoms (PANSS scores), hallucinations, cigarette craving, or cigarettes smoked. The positive effects of tDCS on cognitive performance suggest a potential efficacious treatment for cognitive deficits in partially recovered chronic schizophrenia outpatients that should be further investigated.

  8. A pilot study on effects of 4×1 high-definition tDCS on motor cortex excitability.

    PubMed

    Caparelli-Daquer, Egas M; Zimmermann, Trelawny J; Mooshagian, Eric; Parra, Lucas C; Rice, Justin K; Datta, Abhishek; Bikson, Marom; Wassermann, Eric M

    2012-01-01

    High-Definition transcranial Direct Current Stimulation (HD-tDCS) using specialized small electrodes has been proposed as a focal, non-invasive neuromodulatory technique. Here we provide the first evidence of a change in cortical excitability after HD-tDCS of the motor cortex, using TMS motor evoked potential (MEP) as the measure of excitability. Stimulation for 20 minutes at 1 mA with an anode centered over the hand area of the motor cortex and four surrounding return electrodes (anodal 4×1 montage) produced a significant increase in MEP amplitude and variability after stimulation, compared to sham stimulation. Stimulation was well tolerated by all subjects with adverse effects limited to transient sensation under the electrodes. A high-resolution computational model confirmed predictions of increased focality using the 4×1 HD tDCS montage compared to conventional tDCS. Simulations also indicated that variability in placement of the center electrode relative to the location of the target (central sulcus) could account for increasing variability. These results provide support for the careful use of this technique where focal tDCS is desired.

  9. Identification of Selective ERRγ Inverse Agonists.

    PubMed

    Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin

    2016-01-12

    GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  10. Multiple tyrosine metabolites are GPR35 agonists

    PubMed Central

    Deng, Huayun; Hu, Haibei; Fang, Ye

    2012-01-01

    Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism. PMID:22523636

  11. Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel

    PubMed Central

    Fregni, F; Nitsche, MA; Loo, C.K.; Brunoni, AR; Marangolo, P; Leite, J; Carvalho, S; Bolognini, N; Caumo, W; Paik, NJ; Simis, M; Ueda, K; Ekhitari, H; Luu, P; Tucker, DM; Tyler, WJ; Brunelin, J; Datta, A; Juan, CH; Venkatasubramanian, G; Boggio, PS; Bikson, M

    2014-01-01

    The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials. PMID:25983531

  12. Early adopters of the magical thinking cap: a study on do-it-yourself (DIY) transcranial direct current stimulation (tDCS) user community

    PubMed Central

    Jwa, Anita

    2015-01-01

    Among currently available technologies, transcranial direct current stimulation (tDCS) is one of the most promising neuroenhancements because it is relatively effective, safe, and affordable. Recently, lay people have begun to build—or purchase—the tDCS device to use it at home for treatment or as a cognitive enhancer. The tDCS device is currently not covered by the existing regulatory framework, but there are still significant potential risks of misusing this device, and its long-term effects on the brain have not been fully explored. Thus, researchers have argued the need for regulations or official guidelines for the personal use of tDCS. However, until now, no systematic research on the do-it-yourself (DIY) tDCS user community has been done. The present study explores the basic demographic characteristics of DIY tDCS users as well as why and how they are using this device through a questionnaire survey, in-depth interviews, and a content analysis of web postings on the use of tDCS. This preliminary but valuable picture of the DIY tDCS user community will shed light on future studies and policy analysis to craft sound regulations and official guidelines for the use of tDCS. PMID:27774197

  13. The effectiveness of ground level post-flight 100 percent oxygen breathing as therapy for pain-only altitude Decompression Sickness (DCS)

    NASA Technical Reports Server (NTRS)

    Demboski, John T.; Pilmanis, Andrew A.

    1994-01-01

    In both the aviation and space environments, decompression sickness (DCS) is an operational limitation. Hyperbaric recompression is the most efficacious treatment for altitude DCS. However, the inherent recompression of descent to ground level while breathing oxygen is in itself therapy for altitude DCS. If pain-only DCS occurs during a hypobaric exposure, and the symptoms resolver during descent, ground level post-flight breathing of 100% O2 for 2 hours (GLO2) is considered sufficient treatment by USAF Regulation 161-21. The effectiveness of the GLO2 treatment protocol is defined.

  14. BDCA1-positive dendritic cells (DCs) represent a unique human myeloid DC subset that induces innate and adaptive immune responses to Staphylococcus aureus Infection.

    PubMed

    Jin, Jun-O; Zhang, Wei; Du, Jiang-Yuan; Yu, Qing

    2014-11-01

    Staphylococcus aureus bloodstream infection (bacteremia) is a major cause of morbidity and mortality and places substantial cost burdens on health care systems. The role of peripheral blood dendritic cells (PBDCs) in the immune responses against S. aureus infection has not been well characterized. In this study, we demonstrated that BDCA1(+) myeloid DCs (mDCs) represent a unique PBDC subset that can induce immune responses against S. aureus infection. BDCA1(+) mDCs could engulf S. aureus and strongly upregulated the expression of costimulatory molecules and production of proinflammatory cytokines. Furthermore, BDCA1(+) mDCs expressed high levels of major histocompatibility complex (MHC) class I and II molecules in response to S. aureus and greatly promoted proliferation and gamma interferon (IFN-γ) production in CD4 and CD8 T cells. Moreover, BDCA1(+) mDCs expressed higher levels of Toll-like receptor 2 (TLR-2) and scavenger receptor A (SR-A) than those on CD16(+) and BDCA3(+) mDCs, and these two receptors were both required for the recognition of S. aureus and the subsequent activation of BDCA1(+) mDCs. Finally, BDCA1(+) mDC-mediated immune responses against S. aureus were dependent on MyD88 signaling pathways. These results demonstrate that human BDCA1(+) mDCs represent a unique subset of mDCs that can respond to S. aureus to undergo maturation and activation and to induce Th1 and Tc1 immune responses. PMID:25114114

  15. FXR agonist activity of conformationally constrained analogs of GW 4064

    SciTech Connect

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Navas, III, Frank; Parks, Derek J.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  16. FXR agonist activity of conformationally constrained analogs of GW 4064.

    PubMed

    Akwabi-Ameyaw, Adwoa; Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Navas, Frank; Parks, Derek J; Spearing, Paul K; Todd, Dan; Williams, Shawn P; Bruce Wisely, G

    2009-08-15

    Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.

  17. Cathodal tDCS over the left prefrontal cortex diminishes choice-induced preference change.

    PubMed

    Mengarelli, Flavia; Spoglianti, Silvia; Avenanti, Alessio; di Pellegrino, Giuseppe

    2015-05-01

    In everyday life, people often find themselves facing difficult decisions between options that are equally attractive. Cognitive dissonance theory states that after making a difficult choice between 2 equally preferred options, individuals no longer find the alternatives similarly desirable. Rather, they often change their existing preferences to align more closely with the choice they have just made. Despite the relevance of cognitive dissonance in modulating behavior, little is known about the brain processes crucially involved in choice-induced preference change. In the present study, we applied cathodal transcranial Direct Current Stimulation (tDCS) with the aim of downregulating the activity of the left or the right dorsolateral prefrontal cortex (DLPFC) during a revised version of Brehm's (in 1956. Post-decision changes in the desirability of alternatives. J Abnorm Soc Psychol. 52:384-389) free-choice paradigm. We found that cathodal tDCS over the left, but not over the right, DLPFC caused a reduction of the typical behavior-induced preference change relative to sham stimulation. Our findings highlight the role of prefrontal cortex in cognitive dissonance and provide evidence that left DLPFC plays a necessary role in the implementation of choice-induced preference change.

  18. Medial prefrontal cortex reacts to unfairness if this damages the self: a tDCS study

    PubMed Central

    Miniussi, Carlo; Rumiati, Raffaella I.

    2015-01-01

    Neural correlates of unfairness perception depend on who is the target of the unfair treatment. These previous findings suggest that the activation of medial prefrontal cortex (MPFC) is related to unfairness perception only when the subject of the measurement is also the person affected by the unfair treatment. We aim at demonstrating the specificity of MPFC involvement using transcranial direct current stimulation (tDCS), a technique that induces cortical excitability changes in the targeted region. We use a modified version of the Ultimatum Game, in which responders play both for themselves (myself—MS condition) and on behalf of an unknown third-party (TP condition), where they respond to unfairness without being the target of it. We find that the application of cathodal tDCS over MPFC decreases the probability of rejecting unfair offers in MS, but not in TP; conversely, the same stimulation increases the probability of rejecting fair offers in TP, but not in MS. We confirm the hypothesis that MPFC is specifically related to processing unfairness when the self is involved, and discuss possible explanations for the opposite effect of the stimulation in TP. PMID:25552567

  19. Polarity-Dependent Misperception of Subjective Visual Vertical during and after Transcranial Direct Current Stimulation (tDCS).

    PubMed

    Santos-Pontelli, Taiza E G; Rimoli, Brunna P; Favoretto, Diandra B; Mazin, Suleimy C; Truong, Dennis Q; Leite, Joao P; Pontes-Neto, Octavio M; Babyar, Suzanne R; Reding, Michael; Bikson, Marom; Edwards, Dylan J

    2016-01-01

    Pathologic tilt of subjective visual vertical (SVV) frequently has adverse functional consequences for patients with stroke and vestibular disorders. Repetitive transcranial magnetic stimulation (rTMS) of the supramarginal gyrus can produce a transitory tilt on SVV in healthy subjects. However, the effect of transcranial direct current stimulation (tDCS) on SVV has never been systematically studied. We investigated whether bilateral tDCS over the temporal-parietal region could result in both online and offline SVV misperception in healthy subjects. In a randomized, sham-controlled, single-blind crossover pilot study, thirteen healthy subjects performed tests of SVV before, during and after the tDCS applied over the temporal-parietal region in three conditions used on different days: right anode/left cathode; right cathode/left anode; and sham. Subjects were blind to the tDCS conditions. Montage-specific current flow patterns were investigated using computational models. SVV was significantly displaced towards the anode during both active stimulation conditions when compared to sham condition. Immediately after both active conditions, there were rebound effects. Longer lasting after-effects towards the anode occurred only in the right cathode/left anode condition. Current flow models predicted the stimulation of temporal-parietal regions under the electrodes and deep clusters in the posterior limb of the internal capsule. The present findings indicate that tDCS over the temporal-parietal region can significantly alter human SVV perception. This tDCS approach may be a potential clinical tool for the treatment of SVV misperception in neurological patients. PMID:27031726

  20. Polarity-Dependent Misperception of Subjective Visual Vertical during and after Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Santos-Pontelli, Taiza E. G.; Rimoli, Brunna P.; Favoretto, Diandra B.; Mazin, Suleimy C.; Truong, Dennis Q.; Leite, Joao P.; Pontes-Neto, Octavio M.; Babyar, Suzanne R.; Reding, Michael; Bikson, Marom; Edwards, Dylan J.

    2016-01-01

    Pathologic tilt of subjective visual vertical (SVV) frequently has adverse functional consequences for patients with stroke and vestibular disorders. Repetitive transcranial magnetic stimulation (rTMS) of the supramarginal gyrus can produce a transitory tilt on SVV in healthy subjects. However, the effect of transcranial direct current stimulation (tDCS) on SVV has never been systematically studied. We investigated whether bilateral tDCS over the temporal-parietal region could result in both online and offline SVV misperception in healthy subjects. In a randomized, sham-controlled, single-blind crossover pilot study, thirteen healthy subjects performed tests of SVV before, during and after the tDCS applied over the temporal-parietal region in three conditions used on different days: right anode/left cathode; right cathode/left anode; and sham. Subjects were blind to the tDCS conditions. Montage-specific current flow patterns were investigated using computational models. SVV was significantly displaced towards the anode during both active stimulation conditions when compared to sham condition. Immediately after both active conditions, there were rebound effects. Longer lasting after-effects towards the anode occurred only in the right cathode/left anode condition. Current flow models predicted the stimulation of temporal-parietal regions under the electrodes and deep clusters in the posterior limb of the internal capsule. The present findings indicate that tDCS over the temporal-parietal region can significantly alter human SVV perception. This tDCS approach may be a potential clinical tool for the treatment of SVV misperception in neurological patients. PMID:27031726

  1. tDCS-Induced Analgesia and Electrical Fields in Pain-Related Neural Networks in Chronic Migraine

    PubMed Central

    DaSilva, Alexandre F.; Mendonca, Mariana E.; Zaghi, Soroush; Lopes, Mariana; DosSantos, Marcos Fabio; Spierings, Egilius L.; Bajwa, Zahid; Datta, Abhishek; Bikson, Marom; Fregni, Felipe

    2014-01-01

    Objective We investigated in a sham-controlled trial the analgesic effects of a 4-week treatment of transcranial direct current stimulation (tDCS) over the primary motor cortex in chronic migraine. In addition, using a high-resolution tDCS computational model, we analyzed the current flow (electric field) through brain regions associated with pain perception and modulation. Methods Thirteen patients with chronic migraine were randomized to receive 10 sessions of active or sham tDCS for 20 minutes with 2 mA over 4 weeks. Data were collected during baseline, treatment and follow-up. For the tDCS computational analysis, we adapted a high-resolution individualized model incorporating accurate segmentation of cortical and subcortical structures of interest. Results There was a significant interaction term (time vs group) for the main outcome (pain intensity) and for the length of migraine episodes (ANOVA, P < .05 for both analyses). Post-hoc analysis showed a significant improvement in the follow-up period for the active tDCS group only. Our computational modeling studies predicted electric current flow in multiple cortical and subcortical regions associated with migraine pathophysiology. Significant electric fields were generated, not only in targeted cortical regions but also in the insula, cingulate cortex, thalamus, and brainstem regions. Conclusions Our findings give preliminary evidence that patients with chronic migraine have a positive, but delayed, response to anodal tDCS of the primary motor cortex. These effects may be related to electrical currents induced in pain-related cortical and subcortical regions. PMID:22512348

  2. Impact of tDCS on performance and learning of target detection: interaction with stimulus characteristics and experimental design.

    PubMed

    Coffman, B A; Trumbo, M C; Flores, R A; Garcia, C M; van der Merwe, A J; Wassermann, E M; Weisend, M P; Clark, V P

    2012-06-01

    We have previously found that transcranial direct current stimulation (tDCS) over right inferior frontal cortex (RIFC) enhances performance during learning of a difficult visual target detection task (Clark et al., 2012). In order to examine the cognitive mechanisms of tDCS that lead to enhanced performance, here we analyzed its differential effects on responses to stimuli that varied by repetition and target presence, differences related to expectancy by comparing performance in single- and double-blind task designs, and individual differences in skin stimulation and mood. Participants were trained for 1h to detect target objects hidden in a complex virtual environment, while anodal tDCS was applied over RIFC at 0.1 mA or 2.0 mA for the first 30 min. Participants were tested immediately before and after training and again 1h later. Higher tDCS current was associated with increased performance for all test stimuli, but was greatest for repeated test stimuli with the presence of hidden-targets. This finding was replicated in a second set of subjects using a double-blind task design. Accuracy for target detection discrimination sensitivity (d'; Z(hits)-Z(false alarms)) was greater for 2.0 mA current (1.77) compared with 0.1 mA (0.95), with no differences in response bias (β). Taken together, these findings indicate that the enhancement of performance with tDCS is sensitive to stimulus repetition and target presence, but not to changes in expectancy, mood, or type of blinded task design. The implications of these findings for understanding the cognitive mechanisms of tDCS are discussed.

  3. Controlling the Emotional Bias: Performance, Late Positive Potentials, and the Effect of Anodal Transcranial Direct Current Stimulation (tDCS)

    PubMed Central

    Faehling, Florian; Plewnia, Christian

    2016-01-01

    Cognitive control of emotional processing is essential for adaptive human behavior. Biased attention toward emotionally salient information is critically linked with affective disorders and is discussed as a promising treatment target. Anodal (activity enhancing) transcranial direct current stimulation (tDCS) has been shown to increase healthy and impaired cognitive control over emotional distraction and is therefore widely used for the investigation and experimental treatment of this disorder. In this study, event-related potential (ERP) were recorded parallel to tDCS to track its online effects. Healthy volunteers (n = 87) performed a delayed working memory paradigm with emotional salient and neutral distractors during stimulation with different intensities (sham, 0.5, 1, 1.5 mA). Measuring the late positive potential (LPP), an ERP that indexes attention allocation, we found that a valence-specific increase of the early portion of the LPP (eLPP, 250–500 ms) was associated with less emotional distraction in the sham group. Of note, stimulation with tDCS exerted an intensity related effect on this correlation. The later part of the LPP (lLPP, 500–1000 ms) was found to be correlated with reaction time, regardless of valence. General effect of tDCS on LPPs and task performance were not observed. These findings demonstrate that ERP recordings parallel to tDCS are feasible to investigate the neuronal underpinnings of stimulation effects on executive functions. Furthermore, they support the notion that the LPP induced by a distractive stimulus during a working memory task mirrors the additional allocation of neuronal resources with a specific sensitivity of the early LPP for highly arousing negative stimuli. Finally, together with the variable magnitude and direction of the emotional bias, the lack of systematic modulations of LPPs and behavior by tDCS further underlines the important influence of the individual brain activity patterns on stimulation effects both on

  4. Optimization of focality and direction in dense electrode array transcranial direct current stimulation (tDCS)

    NASA Astrophysics Data System (ADS)

    Guler, Seyhmus; Dannhauer, Moritz; Erem, Burak; Macleod, Rob; Tucker, Don; Turovets, Sergei; Luu, Phan; Erdogmus, Deniz; Brooks, Dana H.

    2016-06-01

    Objective. Transcranial direct current stimulation (tDCS) aims to alter brain function non-invasively via electrodes placed on the scalp. Conventional tDCS uses two relatively large patch electrodes to deliver electrical current to the brain region of interest (ROI). Recent studies have shown that using dense arrays containing up to 512 smaller electrodes may increase the precision of targeting ROIs. However, this creates a need for methods to determine effective and safe stimulus patterns as the number of degrees of freedom is much higher with such arrays. Several approaches to this problem have appeared in the literature. In this paper, we describe a new method for calculating optimal electrode stimulus patterns for targeted and directional modulation in dense array tDCS which differs in some important aspects with methods reported to date. Approach. We optimize stimulus pattern of dense arrays with fixed electrode placement to maximize the current density in a particular direction in the ROI. We impose a flexible set of safety constraints on the current power in the brain, individual electrode currents, and total injected current, to protect subject safety. The proposed optimization problem is convex and thus efficiently solved using existing optimization software to find unique and globally optimal electrode stimulus patterns. Main results. Solutions for four anatomical ROIs based on a realistic head model are shown as exemplary results. To illustrate the differences between our approach and previously introduced methods, we compare our method with two of the other leading methods in the literature. We also report on extensive simulations that show the effect of the values chosen for each proposed safety constraint bound on the optimized stimulus patterns. Significance. The proposed optimization approach employs volume based ROIs, easily adapts to different sets of safety constraints, and takes negligible time to compute. An in-depth comparison study gives

  5. Recent advances in the discovery of alpha1-adrenoceptor agonists.

    PubMed

    Bishop, Michael J

    2007-01-01

    The alpha(1) adrenoceptors are three of nine well-characterized receptors that are activated by epinephrine and norepinephrine. Agonists acting at the alpha(1) adrenoceptors produce numerous physiological effects, and are used therapeutically for several indications. Many known alpha(1) adrenoceptor agonists are alpha(1A) selective, but the discovery of highly selective alpha(1B) and alpha(1D) adrenoceptor agonists has proven to be an extremely difficult goal to achieve. This review will focus on recent advances in the discovery, development and clinical utility of subtype-specific alpha(1) agonists as well as contributions to our understanding of agonist-receptor interactions.

  6. Increased agonist affinity at the mu-opioid receptor induced by prolonged agonist exposure

    PubMed Central

    Birdsong, William T.; Arttamangkul, Seksiri; Clark, Mary J.; Cheng, Kejun; Rice, Kenner C.; Traynor, John R.; Williams, John T.

    2013-01-01

    Prolonged exposure to high-efficacy agonists results in desensitization of the mu opioid receptor (MOR). Desensitized receptors are thought to be unable to couple to G-proteins, preventing downstream signaling, however the changes to the receptor itself are not well characterized. In the current study, confocal imaging was used to determine whether desensitizing conditions cause a change in agonist-receptor interactions. Using rapid solution exchange, the binding kinetics of fluorescently labeled opioid agonist, dermorphin Alexa594 (derm A594), to MORs was measured in live cells. The affinity of derm A594 binding increased following prolonged treatment of cells with multiple agonists that are known to cause receptor desensitization. In contrast, binding of a fluorescent antagonist, naltrexamine Alexa 594, was unaffected by similar agonist pre-treatment. The increased affinity of derm A594 for the receptor was long-lived and partially reversed after a 45 min wash. Treatment of the cells with pertussis toxin did not alter the increase in affinity of the derm A594 for MOR. Likewise the affinity of derm A594 for MORs expressed in mouse embryonic fibroblasts derived from arrestin 1 and 2 knockout animals increased following treatment of the cells with the desensitization protocol. Thus, opioid receptors were “imprinted” with a memory of prior agonist exposure that was independent of G-protein activation or arrestin binding that altered subsequent agonist-receptor interactions. The increased affinity suggests that acute desensitization results in a long lasting but reversible conformational change in the receptor. PMID:23447620

  7. Agonistic and reproductive interactions in Betta splendens.

    PubMed

    Bronstein, P M

    1984-12-01

    Reproductive and agonistic behaviors in Siamese fighting fish were investigated in eight experiments, and some consequences and determinants of these sequences were isolated. First, fights and the formation of dominance-subordinancy relations were studied. Second, it was determined that large body size as well as males' prior residency in a tank produced an agonistic advantage; the magnitude of this advantage was positively related to the duration of residency. Third, the prior-residency effect in Bettas was determined by males' familiarity with visual and/or tactile cues in their home tanks. Fourth, dominant males had greater access to living space and were more likely to display at a mirror, build nests, and approach females than were subordinates. Finally, it was discovered that chemical cues associated with presumedly inert plastic tank dividers influence Bettas' social behavior.

  8. Three Phases of CD8 T Cell Response in the Lung Following H1N1 Influenza Infection and Sphingosine 1 Phosphate Agonist Therapy

    PubMed Central

    Matheu, Melanie P.; Teijaro, John R.; Walsh, Kevin B.; Greenberg, Milton L.; Marsolais, David; Parker, Ian; Rosen, Hugh; Oldstone, Michael B A.; Cahalan, Michael D.

    2013-01-01

    Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a ‘cytokine storm’, a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP+CD8+ T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c+ DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8+ T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit. PMID:23533579

  9. Imaging transcranial direct current stimulation (tDCS) of the prefrontal cortex-correlation or causality in stimulation-mediated effects?

    PubMed

    Wörsching, Jana; Padberg, Frank; Ertl-Wagner, Birgit; Kumpf, Ulrike; Kirsch, Beatrice; Keeser, Daniel

    2016-10-01

    Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs.

  10. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits. PMID:26832440

  11. Signal Use by Octopuses in Agonistic Interactions.

    PubMed

    Scheel, David; Godfrey-Smith, Peter; Lawrence, Matthew

    2016-02-01

    Cephalopods show behavioral parallels to birds and mammals despite considerable evolutionary distance [1, 2]. Many cephalopods produce complex body patterns and visual signals, documented especially in cuttlefish and squid, where they are used both in camouflage and a range of interspecific interactions [1, 3-5]. Octopuses, in contrast, are usually seen as solitary and asocial [6, 7]; their body patterns and color changes have primarily been interpreted as camouflage and anti-predator tactics [8-12], though the familiar view of the solitary octopus faces a growing list of exceptions. Here, we show by field observation that in a shallow-water octopus, Octopus tetricus, a range of visible displays are produced during agonistic interactions, and these displays correlate with the outcome of those interactions. Interactions in which dark body color by an approaching octopus was matched by similar color in the reacting octopus were more likely to escalate to grappling. Darkness in an approaching octopus met by paler color in the reacting octopus accompanied retreat of the paler octopus. Octopuses also displayed on high ground and stood with spread web and elevated mantle, often producing these behaviors in combinations. This study is the first to document the systematic use of signals during agonistic interactions among octopuses. We show prima facie conformity of our results to an influential model of agonistic signaling [13]. These results suggest that interactions have a greater influence on octopus evolution than has been recognized and show the importance of convergent evolution in behavioral traits.

  12. ERTS-1 DCS technical support provided by Wallops Station. [ground truth stations and DCP repair depot

    NASA Technical Reports Server (NTRS)

    Smith, R.

    1975-01-01

    Wallops Station accepted the tasks of providing ground truth to several ERTS investigators, operating a DCP repair depot, designing and building an airborne DCP Data Acquisition System, and providing aircraft underflight support for several other investigators. Additionally, the data bank is generally available for use by ERTS and other investigators that have a scientific interest in data pertaining to the Chesapeake Bay area. Working with DCS has provided a means of evaluating the system as a data collection device possibly applicable to ongoing Earth Resources Program activities in the Chesapeake Bay area as well as providing useful data and services to other ERTS investigators. The two areas of technical support provided by Wallops, ground truth stations and repair for DCPs, are briefly discussed.

  13. Bandwidth optimization of compact microstrip antenna for PCS/DCS/bluetooth application

    NASA Astrophysics Data System (ADS)

    Singh, Vinod; Ali, Zakir; Ayub, Shahanaz; Singh, Ashutosh

    2014-09-01

    A novel compact broadband microstrip patch antenna is presented for various wireless applications. The proposed antenna has been fabricated and the impedance bandwidth and radiation pattern are measured. The simulated and measured antenna characteristics along with radiation pattern and gain are presented. It is stated that the proposed designed antenna can completely cover the required band widths of Digital communication system (DCS 1.71-1.88 GHz), Personal communication system (PCS 1.85-1.88 GHz) and IEEE 802.11b/g (2.4-2.485 GHz) with satisfactory radiation characteristics. The Experimental result shows that the proposed antenna presents a bandwidth 60.25% covering the range of 1.431-2.665 GHz with the maximum radiation efficiency 90%.

  14. Monitoring of streamflow in the Verde River by ERTS-1 Data Collection System (DCS)

    NASA Technical Reports Server (NTRS)

    Schumann, H. H.

    1973-01-01

    The Verde River watershed in central Arizona furnishes municipal, industrial, and agricultural water to the Salt River Valley --an area that contains more than half of Arizona's population and about one-fourth of the State's irrigated land. Water-management decisions related to the operation of large multiple-use reservoirs require accurate and continuous monitoring of moisture conditions over large remote areas. The U.S. Geological Survey in cooperation with the Salt River Valley Water Users' Association installed a specially designed gaging station on the Verde River near the town of Camp Verde to evaluate near-real time streamflow data furnished by the ERTS-1 Data Collection System (DCS). On Nov. 3, 1972, the installation was equipped with a Stevens digital water-level recorder, modified for telemetry, and an ERTS-1 data collection platform operating in the digital-parallel mode.

  15. On the importance of electrode parameters for shaping electric field patterns generated by tDCS.

    PubMed

    Saturnino, Guilherme B; Antunes, André; Thielscher, Axel

    2015-10-15

    Transcranial direct current stimulation (tDCS) uses electrode pads placed on the head to deliver weak direct current to the brain and modulate neuronal excitability. The effects depend on the intensity and spatial distribution of the electric field. This in turn depends on the geometry and electric properties of the head tissues and electrode pads. Previous numerical studies focused on providing a reasonable level of detail of the head anatomy, often using simplified electrode models. Here, we explore via finite element method (FEM) simulations based on a high-resolution head model how detailed electrode modeling influences the calculated electric field in the brain. We take into account electrode shape, size, connector position and conductivities of different electrode materials (including saline solutions and electrode gels). These factors are systematically characterized to demonstrate their impact on the field distribution in the brain. The goals are to assess the effect of simplified electrode models; and to develop practical rules-of-thumb to achieve a stronger stimulation of the targeted brain regions underneath the electrode pads. We show that for standard rectangular electrode pads, lower saline and gel conductivities result in more homogeneous fields in the region of interest (ROI). Placing the connector at the center of the electrode pad or farthest from the second electrode substantially increases the field strength in the ROI. Our results highlight the importance of detailed electrode modeling and of having an adequate selection of electrode pads/gels in experiments. We also advise for a more detailed reporting of the electrode montages when conducting tDCS experiments, as different configurations significantly affect the results.

  16. tDCS in post-stroke aphasia: the role of stimulation parameters, behavioral treatment and patient characteristics.

    PubMed

    de Aguiar, Vânia; Paolazzi, Caterina Laura; Miceli, Gabriele

    2015-02-01

    Neurostimulation techniques have been recently adopted in aphasia rehabilitation. In several studies transcranial direct current stimulation (tDCS) was used to enhance treatment effects. The methodology adopted in different studies is characterized by a large variability, as concerns stimulation parameters (e.g., montage type, current intensity, session duration, number and frequency of treatment sessions), participant inclusion criteria (subacute vs chronic, selected vs general aphasia types) and characteristics of associated behavioral treatments (online vs offline treatment, focused on different underlying deficits). Group analyses report on positive results for most of the adopted paradigms. We review the available literature focusing on tDCS in the rehabilitation of stroke-related aphasia, with reference to the current views on tDCS's action mechanisms and on the factors that may influence the effects of stimulation. Even though our understanding of the mechanisms activated by neurostimulation techniques is still limited, available evidence already allows to propose methodological recommendations for studies intending to use tDCS as a treatment adjuvant. Where several options for a specific stimulation parameter seem suitable, we provide information to reach a knowledgeable decision.

  17. tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature

    PubMed Central

    van Dun, Kim; Bodranghien, Florian C. A. A.; Mariën, Peter; Manto, Mario U.

    2016-01-01

    Transcranial Direct Current Stimulation (tDCS) is an up-and-coming electrical neurostimulation technique increasingly used both in healthy subjects and in selected groups of patients. Due to the high density of neurons in the cerebellum, its peculiar anatomical organization with the cortex lying superficially below the skull and its diffuse connections with motor and associative areas of the cerebrum, the cerebellum is becoming a major target for neuromodulation of the cerebellocerebral networks. We discuss the recent studies based on cerebellar tDCS with a focus on the numerous technical and open issues which remain to be solved. Our current knowledge of the physiological impacts of tDCS on cerebellar circuitry is criticized. We provide a comparison with transcranial Alternating Current Stimulation (tACS), another promising transcranial electrical neurostimulation technique. Although both tDCS and tACS are becoming established techniques to modulate the cerebellocerebral networks, it is surprising that their impacts on cerebellar disorders remains unclear. A major reason is that the literature lacks large trials with a double-blind, sham-controlled, and cross-over experimental design in cerebellar patients. PMID:27242469

  18. tDCS of the Cerebellum: Where Do We Stand in 2016? Technical Issues and Critical Review of the Literature.

    PubMed

    van Dun, Kim; Bodranghien, Florian C A A; Mariën, Peter; Manto, Mario U

    2016-01-01

    Transcranial Direct Current Stimulation (tDCS) is an up-and-coming electrical neurostimulation technique increasingly used both in healthy subjects and in selected groups of patients. Due to the high density of neurons in the cerebellum, its peculiar anatomical organization with the cortex lying superficially below the skull and its diffuse connections with motor and associative areas of the cerebrum, the cerebellum is becoming a major target for neuromodulation of the cerebellocerebral networks. We discuss the recent studies based on cerebellar tDCS with a focus on the numerous technical and open issues which remain to be solved. Our current knowledge of the physiological impacts of tDCS on cerebellar circuitry is criticized. We provide a comparison with transcranial Alternating Current Stimulation (tACS), another promising transcranial electrical neurostimulation technique. Although both tDCS and tACS are becoming established techniques to modulate the cerebellocerebral networks, it is surprising that their impacts on cerebellar disorders remains unclear. A major reason is that the literature lacks large trials with a double-blind, sham-controlled, and cross-over experimental design in cerebellar patients. PMID:27242469

  19. Cerebellum as a forward but not inverse model in visuomotor adaptation task: a tDCS-based and modeling study.

    PubMed

    Yavari, Fatemeh; Mahdavi, Shirin; Towhidkhah, Farzad; Ahmadi-Pajouh, Mohammad-Ali; Ekhtiari, Hamed; Darainy, Mohammad

    2016-04-01

    Despite several pieces of evidence, which suggest that the human brain employs internal models for motor control and learning, the location of these models in the brain is not yet clear. In this study, we used transcranial direct current stimulation (tDCS) to manipulate right cerebellar function, while subjects adapt to a visuomotor task. We investigated the effect of this manipulation on the internal forward and inverse models by measuring two kinds of behavior: generalization of training in one direction to neighboring directions (as a proxy for inverse models) and localization of the hand position after movement without visual feedback (as a proxy for forward model). The experimental results showed no effect of cerebellar tDCS on generalization, but significant effect on localization. These observations support the idea that the cerebellum is a possible brain region for internal forward, but not inverse model formation. We also used a realistic human head model to calculate current density distribution in the brain. The result of this model confirmed the passage of current through the cerebellum. Moreover, to further explain some observed experimental results, we modeled the visuomotor adaptation process with the help of a biologically inspired method known as population coding. The effect of tDCS was also incorporated in the model. The results of this modeling study closely match our experimental data and provide further evidence in line with the idea that tDCS manipulates FM's function in the cerebellum.

  20. Self-Administered Domiciliary tDCS Treatment for Tinnitus: A Double-Blind Sham-Controlled Study

    PubMed Central

    Mäkitie, Antti; Aarnisalo, Antti A.

    2016-01-01

    Transcranial direct current stimulation (tDCS) has shown potential for providing tinnitus relief, although positive effects have usually been observed only during a short time period after treatment. In recent studies the focus has turned from one-session experiments towards multi-session treatment studies investigating long-term outcomes with double-blinded and sham-controlled study designs. Traditionally, tDCS has been administered in a clinical setting by a healthcare professional but in studies involving multiple treatment sessions, often a trade-off has to be made between sample size and the amount of labor needed to run the trial. Also, as the number of required visits to the clinic increases, the dropout rate is likely to rise proportionally.The aim of the current study was to find out if tDCS treatment for tinnitus could be patient-administered in a domiciliary setting and whether the results would be comparable to those from in-hospital treatment studies. Forty-three patients with chronic (> 6 months) tinnitus were involved in the study, and data on 35 out of these patients were included in final analysis. Patients received 20 minutes of left temporal area anodal (LTA) or bifrontal tDCS stimulation (2 mA) or sham stimulation (0.3 mA) for ten consecutive days. An overall reduction in the main outcome measure, Tinnitus Handicap Inventory (THI), was found (mean change −5.0 points, p < 0.05), but there was no significant difference between active and sham treatment outcomes. Patients found the tDCS treatment easy to administer and they all tolerated it well. In conclusion, self-administered domiciliary tDCS treatment for tinnitus was found safe and feasible and gave outcome results similar to recent randomized controlled long-term treatment trials. The results suggest better overall treatment response—as measured by THI—with domiciliary treatment than with in-hospital treatment, but this advantage is not related to the tDCS variant. The study protocol

  1. High-definition transcranial direct current stimulation induces both acute and persistent changes in broadband cortical synchronization: a simultaneous tDCS-EEG study.

    PubMed

    Roy, Abhrajeet; Baxter, Bryan; He, Bin

    2014-07-01

    The goal of this study was to develop methods for simultaneously acquiring electrophysiological data during high-definition transcranial direct current stimulation (tDCS) using high-resolution electroencephalography (EEG). Previous studies have pointed to the after-effects of tDCS on both motor and cognitive performance, and there appears to be potential for using tDCS in a variety of clinical applications. However, little is known about the real-time effects of tDCS on rhythmic cortical activity in humans due to the technical challenges of simultaneously obtaining electrophysiological data during ongoing stimulation. Furthermore, the mechanisms of action of tDCS in humans are not well understood. We have conducted a simultaneous tDCS-EEG study in a group of healthy human subjects. Significant acute and persistent changes in spontaneous neural activity and event-related synchronization (ERS) were observed during and after the application of high-definition tDCS over the left sensorimotor cortex. Both anodal and cathodal stimulation resulted in acute global changes in broadband cortical activity which were significantly different than the changes observed in response to sham stimulation. For the group of eight subjects studied, broadband individual changes in spontaneous activity during stimulation were apparent both locally and globally. In addition, we found that high-definition tDCS of the left sensorimotor cortex can induce significant ipsilateral and contralateral changes in event-related desynchronization and ERS during motor imagination following the end of the stimulation period. Overall, our results demonstrate the feasibility of acquiring high-resolution EEG during high-definition tDCS and provide evidence that tDCS in humans directly modulates rhythmic cortical synchronization during and after its administration.

  2. Can tDCS enhance item-specific effects and generalization after linguistically motivated aphasia therapy for verbs?

    PubMed Central

    de Aguiar, Vânia; Bastiaanse, Roelien; Capasso, Rita; Gandolfi, Marialuisa; Smania, Nicola; Rossi, Giorgio; Miceli, Gabriele

    2015-01-01

    Background: Aphasia therapy focusing on abstract properties of language promotes both item-specific effects and generalization to untreated materials. Neuromodulation with transcranial Direct Current Stimulation (tDCS) has been shown to enhance item-specific improvement, but its potential to enhance generalization has not been systematically investigated. Here, we test the efficacy of ACTION (a linguistically motivated protocol) and tDCS in producing item-specific and generalized improvement in aphasia. Method: Nine individuals with post-stroke aphasia participated in this study. Participants were pre-tested with a diagnostic language battery and a cognitive screening. Experimental tasks were administered over multiple baselines. Production of infinitives, of finite verbs and of full sentences were assessed before and after each treatment phase. Nonword repetition was used as a control measure. Each subject was treated in two phases. Ten daily 1-h treatment sessions were provided per phase, in a double-blind, cross-over design. Linguistically-motivated language therapy focusing on verb inflection and sentence construction was provided in both phases. Each session began with 20 min of real or sham tDCS. Stimulation site was determined individually, based on MRI scans. Results: Group data showed improved production of treated and untreated verbs, attesting the efficacy of behavioral treatment, and its potential to yield generalization. Each individual showed significant item-specific improvement. Generalization occurred in the first phase of treatment for all subjects, and in the second phase for two subjects. Stimulation effects at the group level were significant for treated and untreated verbs altogether, but a ceiling effect for Sham cannot be excluded, as scores between real tDCS and Sham differed only before treatment. Conclusion: Our data demonstrate the efficacy of ACTION and suggest that tDCS may enhance both item-specific effects and generalization. PMID

  3. Electrodes for high-definition transcutaneous DC stimulation for applications in drug delivery and electrotherapy, including tDCS.

    PubMed

    Minhas, Preet; Bansal, Varun; Patel, Jinal; Ho, Johnson S; Diaz, Julian; Datta, Abhishek; Bikson, Marom

    2010-07-15

    Transcutaneous electrical stimulation is applied in a range of biomedical applications including transcranial direct current stimulation (tDCS). tDCS is a non-invasive procedure where a weak direct current (<2 mA) is applied across the scalp to modulate brain function. High-definition tDCS (HD-tDCS) is a technique used to increase the spatial focality of tDCS by passing current across the scalp using <12 mm diameter electrodes. The purpose of this study was to design and optimize "high-definition" electrode-gel parameters for electrode durability, skin safety and subjective pain. Anode and cathode electrode potential, temperature, pH and subjective sensation over time were assessed during application of 2 mA direct current, for up to 22 min on agar gel or subject forearms. A selection of five types of solid-conductors (Ag pellet, Ag/AgCl pellet, rubber pellet, Ag/AgCl ring and Ag/AgCl disc) and seven conductive gels (Signa, Spectra, Tensive, Redux, BioGel, Lectron and CCNY-4) were investigated. The Ag/AgCl ring in combination with CCNY-4 gel resulted in the most favorable outcomes. Under anode stimulations, electrode potential and temperature rises were generally observed in all electrode-gel combinations except for Ag/AgCl ring and disc electrodes. pH remained constant for all solid-conductors except for both Ag and rubber pellet electrodes with Signa and CCNY-4 gels. Sensation ratings were independent of stimulation polarity. Ag/AgCl ring electrodes were found to be the most comfortable followed by Ag, rubber and Ag/AgCl pellet electrodes across all gels.

  4. Agonist-Directed Desensitization of the β2-Adrenergic Receptor

    PubMed Central

    Goral, Vasiliy; Jin, Yan; Sun, Haiyan; Ferrie, Ann M.; Wu, Qi; Fang, Ye

    2011-01-01

    The β2-adrenergic receptor (β2AR) agonists with reduced tachyphylaxis may offer new therapeutic agents with improved tolerance profile. However, receptor desensitization assays are often inferred at the single signaling molecule level, thus ligand-directed desensitization is poorly understood. Here we report a label-free biosensor whole cell assay with microfluidics to determine ligand-directed desensitization of the β2AR. Together with mechanistic deconvolution using small molecule inhibitors, the receptor desensitization and resensitization patterns under the short-term agonist exposure manifested the long-acting agonism of salmeterol, and differentiated the mechanisms of agonist-directed desensitization between a full agonist epinephrine and a partial agonist pindolol. This study reveals the cellular mechanisms of agonist-selective β2AR desensitization at the whole cell level. PMID:21541288

  5. Sports doping: emerging designer and therapeutic β2-agonists.

    PubMed

    Fragkaki, A G; Georgakopoulos, C; Sterk, S; Nielen, M W F

    2013-10-21

    Beta2-adrenergic agonists, or β2-agonists, are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptom-relievers and, in combination with inhaled corticosteroids, as disease-controllers. The use of β2-agonists is prohibited in sports by the World Anti-Doping Agency (WADA) due to claimed anabolic effects, and also, is prohibited as growth promoters in cattle fattening in the European Union. This paper reviews the last seven-year (2006-2012) literature concerning the development of novel β2-agonists molecules either by modifying the molecule of known β2-agonists or by introducing moieties producing indole-, adamantyl- or phenyl urea derivatives. New emerging β2-agonists molecules for future therapeutic use are also presented, intending to emphasize their potential use for doping purposes or as growth promoters in the near future.

  6. Modulation of Innate Immune Responses via Covalently Linked TLR Agonists

    PubMed Central

    2015-01-01

    We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines. PMID:26640818

  7. "If two witches would watch two watches, which witch would watch which watch?" tDCS over the left frontal region modulates tongue twister repetition in healthy subjects.

    PubMed

    Fiori, V; Cipollari, S; Caltagirone, C; Marangolo, P

    2014-01-01

    Recent studies have demonstrated that transcranial direct current stimulation (tDCS) modulates cortical activity in the human brain. In the language domain, it has already been shown that during a naming task tDCS reduces vocal reaction times in healthy individuals and speeds up the recovery process in left brain-damaged aphasic subjects. In this study, we wondered whether tDCS would influence the ability to articulate tongue twisters during a repetition task. Three groups of 10 healthy individuals were asked to repeat a list of tongue twisters in three different stimulation conditions: one group performed the task during anodal tDCS (atDCS) (20 min, 2 mA) over the left frontal region; a second group during cathodal tDCS delivered over the same region; and, in a third group, sham stimulation was applied. Accuracy and vocal reaction times in repeating each tongue twister before, during and 1h after the stimulation were recorded. Participants were more accurate and faster at repeating the stimuli during atDCS than at baseline, while cathodal tDCS significantly reduced their performance in terms of accuracy and reaction times. No significant differences were observed among the three time points during the sham condition. We believe that these data clearly confirm that the left frontal region is critically involved in the process of speech repetition. They are also in line with recent evidence suggesting that frontal tDCS might be used as a therapeutic tool in patients suffering from articulatory deficits.

  8. Functional improvement and neuroplastic effects of anodal transcranial direct current stimulation (tDCS) delivered 1 day vs. 1 week after cerebral ischemia in rats.

    PubMed

    Yoon, Kyung Jae; Oh, Byung-Mo; Kim, Dae-Yul

    2012-05-01

    Transcranial direct current stimulation (tDCS) is an emerging tool for improving recovery from stroke. However, there has been no trial to determine whether it has a therapeutic benefit in the early stage of cerebral ischemia, and there is no consensus on the optimal time window of stimulation. Here, we described the effects of anodal tDCS in early cerebral ischemia, assessing functional improvements and changes in neuronal plasticity, and identifying the optimal time window for delivering tDCS to maximize functional gains. Thirty rats were randomly assigned to three groups: sham (n=10); early tDCS (ET), receiving tDCS 1day after ischemia for 5 days (n=10), and late tDCS (LT), receiving tDCS 1 week after ischemia for 5 days (n=10). Both ET and LT groups showed improved Barnes maze performance and motor behavioral index scores. However, only the LT group exhibited improvement in beam balance test. Immunohistochemical stainings showed that the ET group reinforced notable MAP-2 expression and the LT group enhanced mainly the level of GAP-43 in both peri-lesional and contralesional cortex. These immunohistochemical results had significant correlation with behavioral and cognitive functions. However, brain MRI and (1)H MRS showed no significant differences among the three groups in ischemic volume and metabolic alteration. These results suggest that anodal tDCS has the potential to modulate neural plasticity around the ischemic penumbra and even in the contralesional area without aggravating infarction volume and metabolic alteration. The degree of functional improvement was slightly greater when tDCS was applied 1 week rather than 1 day after ischemic injury.

  9. Small Molecule Bax Agonists for Cancer Therapy

    PubMed Central

    Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K.; Sica, Gabriel L.; Corsino, Patrick E.; Zhou, Jia; Ding, Chunyong; White, Mark A.; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming

    2014-01-01

    Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here, we employed the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK program suite. Three compounds, small molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumor growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anti-cancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies. PMID:25230299

  10. A Toll-like receptor 2 agonist-fused antigen enhanced antitumor immunity by increasing antigen presentation and the CD8 memory T cells population

    PubMed Central

    Wu, Chiao-Chieh; Liu, Shih-Jen; Chen, Hsin-Wei; Shen, Kuan-Yin; Leng, Chih-Hsiang

    2016-01-01

    The induction of long-lived effector CD8+ T cells is key to the development of efficient cancer vaccines. In this study, we demonstrated that a Toll-like receptor 2 (TLR2) agonist-fused antigen increased antigen presentation via TLR2 signaling and induced effector memory-like CD8+ T cells against cancer after immunization. The N-terminus of ovalbumin (OVA) was biologically fused with a bacterial lipid moiety TLR2 agonist to produce a recombinant lipidated ovalbumin (rlipo-OVA). We demonstrated that rlipo-OVA activated bone marrow-derived dendritic cells (BM-DCs) maturation and increased antigen presentation by major histocompatibility complex (MHC) class I via TLR2. After immunization, rlipo-OVA skewed the immune response towards T helper (Th) 1 and induced OVA-specific cytotoxic T lymphocyte (CTL) responses. Moreover, immunization with rlipo-OVA induced higher numbers of effector memory (CD44+CD62L−) CD8+ T cells compared with recombinant ovalbumin (rOVA) alone or rOVA mixed with the TLR2 agonist Pam3CSK4. Accordingly, the CD27+CD43+ effector memory CD8+ T cells expressed high levels of the long-lived CD127 marker. The administration of rlipo-OVA could inhibit tumor growth, but the anti-tumor effects were lost after the depletion of CD8 or CD127 cells in vivo. These findings suggested that the TLR2 agonist-fused antigen induced long-lived memory CD8+ T cells for efficient cancer therapy. PMID:27127171

  11. Medical aspects of terrorist bombings - a focus on DCS and DCR.

    PubMed

    Mutafchiyski, Ventsislav M; Popivanov, Georgi I; Kjossev, Kirien C

    2014-01-01

    Although terrorist bombings have tormented the world for a long time, currently they have reached unprecedented levels and become a continuous threat without borders, race or age. Almost all of them are caused by improvised explosive devices. The unpredictability of the terrorist bombings, leading to simultaneous generation of a large number of casualties and severe "multidimensional" blast trauma require a constant vigilance and preparedness of every hospital worldwide. Approximately 1-2.6% of all trauma patients and 7% of the combat casualties require a massive blood transfusion. Coagulopathy is presented in 65% of them with mortality exceeding 50%. Damage control resuscitation is a novel approach, developed in the military practice for treatment of this subgroup of trauma patients. The comparison with the conventional approach revealed mortality reduction with 40-74%, lower frequency of abdominal compartment syndrome (8% vs. 16%), sepsis (9% vs. 20%), multiorgan failure (16% vs. 37%) and a significant reduction of resuscitation volumes, both crystalloids and blood products. DCS and DCR are promising new approaches, contributing for the mortality reduction among the most severely wounded patients. Despite the lack of consensus about the optimal ratio of the blood products and the possible influence of the survival bias, we think that DCR carries survival benefit and recommend it in trauma patients with exsanguinating bleeding.

  12. Direct current stimulation (tDCS) reveals parietal asymmetry in local/global and salience-based selection.

    PubMed

    Bardi, Lara; Kanai, Ryota; Mapelli, Daniela; Walsh, Vincent

    2013-03-01

    Data from neuropsychology and neuroimaging studies indicate hemispheric asymmetries in processing object's global form versus local parts. However the attentional mechanisms subtending visual selection of different levels of information are poorly understood. The classical left hemisphere/local-right hemisphere/global dichotomy has been recently challenged by studies linking the asymmetry of activation in the posterior parietal cortex (PPC) with the relative salience of the stimulus rather than with the local/global level. The present study aimed to assess hemispheric asymmetry in local-global and salience-based selection in hierarchical stimuli by using transcranial direct current stimulation (tDCS). To this end, tDCS has been applied to the PPC of both the hemispheres. Our data revealed that tDCS did affect the selection of the target on the basis of its relative salience in a manner that depended on the tDCS polarity applied to the two hemispheres. This result is in line with previous findings that the left PPC is critically involved in attention for low-salience stimuli in the presence of high-salience distractor information, while right PPC is involved in attending to more salient stimuli. Hemispheric asymmetries were also found in local/global selection. Overall the results suggest that neural activation in the PPC is related to both the salience and the level of stimulus representations mediating responses to hierarchical stimuli. The comparison of the results from Experiments 1 and 2 in local/global-based selection suggests that the effect of stimulation could be completely opposite depending on subtle differences in demands of attentional control (sustained attention vs task switching).

  13. Good alarm design plays a vital role in successful DCS implementation: Hard learned lessons from petrochemical applications

    SciTech Connect

    Wilson, C.; Rothenberg, D.

    2006-07-01

    Nuclear operators are eager to update their automation infrastructure, but are apprehensive due to the consequences of failure. The process industries have learned that alarm design is critical to a successful Distributed Control System (DCS) implementation. This paper shares valuable insight into how alarms play a key role in successful management of upsets, help focus operator attention, and supply critical information during periods of high stress. (authors)

  14. DCS: A Case Study of Identification of Knowledge and Disposition Gaps Using Principles of Continuous Risk Management

    NASA Technical Reports Server (NTRS)

    Norcross, Jason; Steinberg, Susan; Kundrot, Craig; Charles, John

    2011-01-01

    The Human Research Program (HRP) is formulated around the program architecture of Evidence-Risk-Gap-Task-Deliverable. Review of accumulated evidence forms the basis for identification of high priority risks to human health and performance in space exploration. Gaps in knowledge or disposition are identified for each risk, and a portfolio of research tasks is developed to fill them. Deliverables from the tasks inform the evidence base with the ultimate goal of defining the level of risk and reducing it to an acceptable level. A comprehensive framework for gap identification, focus, and metrics has been developed based on principles of continuous risk management and clinical care. Research towards knowledge gaps improves understanding of the likelihood, consequence or timeframe of the risk. Disposition gaps include development of standards or requirements for risk acceptance, development of countermeasures or technology to mitigate the risk, and yearly technology assessment related to watching developments related to the risk. Standard concepts from clinical care: prevention, diagnosis, treatment, monitoring, rehabilitation, and surveillance, can be used to focus gaps dealing with risk mitigation. The research plan for the new HRP Risk of Decompression Sickness (DCS) used the framework to identify one disposition gap related to establishment of a DCS standard for acceptable risk, two knowledge gaps related to DCS phenomenon and mission attributes, and three mitigation gaps focused on prediction, prevention, and new technology watch. These gaps were organized in this manner primarily based on target for closure and ease of organizing interim metrics so that gap status could be quantified. Additional considerations for the knowledge gaps were that one was highly design reference mission specific and the other gap was focused on DCS phenomenon.

  15. Human iNKT Cells Promote Protective Inflammation by Inducing Oscillating Purinergic Signaling in Monocyte-Derived DCs.

    PubMed

    Xu, Xuequn; Pocock, Ginger M; Sharma, Akshat; Peery, Stephen L; Fites, J Scott; Felley, Laura; Zarnowski, Robert; Stewart, Douglas; Berthier, Erwin; Klein, Bruce S; Sherer, Nathan M; Gumperz, Jenny E

    2016-09-20

    Invariant natural killer T (iNKT) cells are innate T lymphocytes that promote host defense against a variety of microbial pathogens. Whether microbial ligands are required for their protective effects remains unclear. Here, we show that iNKT cells stimulate human-monocyte-derived dendritic cells (DCs) to produce inflammatory mediators in a manner that does not require the presence of microbial compounds. Interleukin 2 (IL-2)-exposed iNKT cells selectively induced repeated cytoplasmic Ca(2+) fluxes in DCs that were dependent on signaling by the P2X7 purinergic receptor and mediated by ATP released during iNKT-DC interactions. Exposure to iNKT cells led to DC cyclooxygenase 2 (PTGS2) gene transcription, and release of PGE2 that was associated with vascular permeabilization in vivo. Additionally, soluble factors were released that induced neutrophil recruitment and activation and enhanced control of Candida albicans. These results suggest that sterile interactions between iNKT cells and monocyte-derived DCs lead to the production of non-redundant inflammatory mediators that promote neutrophil responses. PMID:27653689

  16. The Effect of tDCS on Cognition and Neurologic Recovery of Rats with Alzheimer’s Disease

    PubMed Central

    Yu, Seong Hun; Park, Seong Doo; Sim, Ki Chel

    2014-01-01

    [Purpose] This study examined the effect of the application of transcranial direct current stimulation (tDCS) on neurologic recovery and cognitive function of rats with Alzheimer-like dementia induced by scopolamine injections. [Subjects] To create a cognition dysfunction model, intraperitoneal injection of scopolamine was given to Sprague-Dawley rats that subsequently received tDCS for 4 weeks. [Methods] Changes in motor behavior were evaluated by conducting an open field test. Acetylcholine content in the cerebral cortex and hippocampus was examined for a biochemical assessment. [Results] With respect to changes in motor behavior, group II showed the most meaningful difference after scopolamine injection, followed by group III. In the biochemical assessment, the results of the examination of acetylcholine content in the tissue of the cerebral cortex and the hippocampus on the 14th and 28th days, respectively, showed the most significant increase in group II, followed by group III. [Conclusion] The above findings confirm that tDCS application after the onset of cognitive dysfunction caused by Alzheimer’s disease leads to a positive effect on motor behavior and biochemical changes, and this effect is maintained over a specific period of time. PMID:24648641

  17. Enhancing verbal creativity: modulating creativity by altering the balance between right and left inferior frontal gyrus with tDCS.

    PubMed

    Mayseless, N; Shamay-Tsoory, S G

    2015-04-16

    Creativity is the production of novel ideas that have value. Previous research indicated that while regions in the right hemisphere are implicated in the production of new ideas, damage to the left inferior frontal gyrus (IFG) is associated with increased creativity, indicating that the left IFG damage may have a "releasing" effect on creativity. To examine this, in the present study we used transcranial direct current stimulation (tDCS) to modulate activity of the right and the left IFG. In the first experiment we show that whereas anodal tDCS over the right IFG coupled with cathodal tDCS over the left IFG increases creativity as measured by a verbal divergent thinking task, the reverse stimulation does not affect creative production. To further confirm that only altering the balance between the two hemispheres is crucial in modulating creativity, in the second experiment we show that stimulation targeting separately the left IFG (cathodal stimulation) or the right IFG (anodal stimulation) did not result in changes in creativity as measured by verbal divergent thinking. These findings support the balance hypothesis, according to which verbal creativity requires a balance of activation between the right and the left frontal lobes, and more specifically, between the right and the left IFG.

  18. Enhancing verbal creativity: modulating creativity by altering the balance between right and left inferior frontal gyrus with tDCS.

    PubMed

    Mayseless, N; Shamay-Tsoory, S G

    2015-04-16

    Creativity is the production of novel ideas that have value. Previous research indicated that while regions in the right hemisphere are implicated in the production of new ideas, damage to the left inferior frontal gyrus (IFG) is associated with increased creativity, indicating that the left IFG damage may have a "releasing" effect on creativity. To examine this, in the present study we used transcranial direct current stimulation (tDCS) to modulate activity of the right and the left IFG. In the first experiment we show that whereas anodal tDCS over the right IFG coupled with cathodal tDCS over the left IFG increases creativity as measured by a verbal divergent thinking task, the reverse stimulation does not affect creative production. To further confirm that only altering the balance between the two hemispheres is crucial in modulating creativity, in the second experiment we show that stimulation targeting separately the left IFG (cathodal stimulation) or the right IFG (anodal stimulation) did not result in changes in creativity as measured by verbal divergent thinking. These findings support the balance hypothesis, according to which verbal creativity requires a balance of activation between the right and the left frontal lobes, and more specifically, between the right and the left IFG. PMID:25659343

  19. Physical Chemistry to the Rescue: Differentiating Nicotinic and Cholinergic Agonists

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    Researches suggest that two agonists can bind to the same binding site of an important transmembrane protein and elicit a biological response through strikingly different binding interactions. Evidence is provided which suggests two possible types of nicotinic acetylcholine receptor agonist binding like acetlycholine (cholinergic) or like nicotine…

  20. GLP-1 agonist treatment: implications for diabetic retinopathy screening.

    PubMed

    Varadhan, Lakshminarayanan; Humphreys, Tracy; Hariman, Christian; Walker, Adrian B; Varughese, George I

    2011-12-01

    Rapid improvement in glycaemic control induced by GLP-1 agonist therapy could be yet another illustration of transient or permanent progression of diabetic retinopathy, similar to documented examples such as pregnancy and continuous subcutaneous insulin infusion. Specific guidelines would be needed to monitor this paradoxical phenomenon during treatment with GLP-1 agonists. PMID:21906831

  1. TOXICITY OF AHR AGONISTS TO FISH EARLY LIFE STAGES

    EPA Science Inventory

    Fish early life stages are exceptionally sensitive to the lethal toxicity of chemicals that act as arylhydrocarbon receptor (AhR) agonists. Toxicity characterizations based on 2,3,7,8-tetrachlorodibenzo-p-dioxin, generally the most potent AhR agonist, support the toxicity equiva...

  2. Safety review of the DCS (Distributed Control System) controlled full scale SRAT/SME (Sludge Receipt Adjustment Tank/Slurry Mix Evaporator) for water runs

    SciTech Connect

    Hacker, B.A.

    1988-01-29

    This memorandum addresses safety concerns of the Full Scale Sludge Receipt Adjustment Tank/Slurry Mix Evaporator (SRAT/SME) resulting from the installation of the new Distributed Control System (DCS). The present configuration of the SRAT/SME with DCS has been determined to be safe for operational testing with water. Another memorandum will be written after experience has been gained during water runs for actual operation. Previous safety evaluations and process hazard reviews for this facility have addressed normal industrial safety hazards and hazards associated with formic acid handling and operation with organics in the feed. Process operation with the new DCS controls will be very similar to the earlier operation controlled by the Modicon programmable logic controller (PLC). The interlocks for the SRAT/SME that were in the PLC have been programmed into the new DCS and will be reviewed here. 6 refs.

  3. Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl.

    PubMed

    Maguire, David R; France, Charles P

    2016-08-01

    Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability. PMID:27184925

  4. Characterization and properties of biosurfactants produced by a newly isolated strain Bacillus methylotrophicus DCS1 and their applications in enhancing solubility of hydrocarbon.

    PubMed

    Jemil, Nawel; Ben Ayed, Hanen; Hmidet, Noomen; Nasri, Moncef

    2016-11-01

    Six biosurfactant-producing bacteria were isolated from hydrocarbon contaminated soils in Sfax, Tunisia. Isolates were screened for biosurfactant production by different conventional methods including hemolytic activity, surface tension reduction, drop-collapsing and oil displacement tests. All these screening tests show that all the isolates behave differently. Among the isolated bacteria, DCS1 strain was selected for further studies based on its highest activities and it was identified as Bacillus methylotrophicus DCS1. This strain was found to be a potent producer of biosurfactant when cultivated in mineral-salts medium supplemented with diesel oil (2 %, v/v) as a sole carbon source. Physicochemical properties and stability of biosurfactants synthesized by B. methylotrophicus DCS1 were investigated. The produced biosurfactants DCS1, from Landy medium, possess high surface activity that could lower the surface tension of water to a value of 31 from 72 mN m(-1) and have a critical micelle concentration (CMC) of 100 mg L(-1). Compared with SDS and Tween 80, biosurfactants showed excellent emulsification activities against different hydrocarbon substrates and high solubilization efficiency towards diesel oil. Biosurfactants DCS1 showed good stability in a wide range of temperature, pH and salinity. These results suggested that biosurfactants produced by B. methylotrophicus DCS1 could be an alternative to chemically synthesized surfactants for use in bioremediation processes to enhance the solubility of hydrophobic compounds. PMID:27628335

  5. In-vivo Imaging of Magnetic Fields Induced by Transcranial Direct Current Stimulation (tDCS) in Human Brain using MRI

    NASA Astrophysics Data System (ADS)

    Jog, Mayank V.; Smith, Robert X.; Jann, Kay; Dunn, Walter; Lafon, Belen; Truong, Dennis; Wu, Allan; Parra, Lucas; Bikson, Marom; Wang, Danny J. J.

    2016-10-01

    Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that applies mA currents at the scalp to modulate cortical excitability. Here, we present a novel magnetic resonance imaging (MRI) technique, which detects magnetic fields induced by tDCS currents. This technique is based on Ampere’s law and exploits the linear relationship between direct current and induced magnetic fields. Following validation on a phantom with a known path of electric current and induced magnetic field, the proposed MRI technique was applied to a human limb (to demonstrate in-vivo feasibility using simple biological tissue) and human heads (to demonstrate feasibility in standard tDCS applications). The results show that the proposed technique detects tDCS induced magnetic fields as small as a nanotesla at millimeter spatial resolution. Through measurements of magnetic fields linearly proportional to the applied tDCS current, our approach opens a new avenue for direct in-vivo visualization of tDCS target engagement.

  6. Characterization and properties of biosurfactants produced by a newly isolated strain Bacillus methylotrophicus DCS1 and their applications in enhancing solubility of hydrocarbon.

    PubMed

    Jemil, Nawel; Ben Ayed, Hanen; Hmidet, Noomen; Nasri, Moncef

    2016-11-01

    Six biosurfactant-producing bacteria were isolated from hydrocarbon contaminated soils in Sfax, Tunisia. Isolates were screened for biosurfactant production by different conventional methods including hemolytic activity, surface tension reduction, drop-collapsing and oil displacement tests. All these screening tests show that all the isolates behave differently. Among the isolated bacteria, DCS1 strain was selected for further studies based on its highest activities and it was identified as Bacillus methylotrophicus DCS1. This strain was found to be a potent producer of biosurfactant when cultivated in mineral-salts medium supplemented with diesel oil (2 %, v/v) as a sole carbon source. Physicochemical properties and stability of biosurfactants synthesized by B. methylotrophicus DCS1 were investigated. The produced biosurfactants DCS1, from Landy medium, possess high surface activity that could lower the surface tension of water to a value of 31 from 72 mN m(-1) and have a critical micelle concentration (CMC) of 100 mg L(-1). Compared with SDS and Tween 80, biosurfactants showed excellent emulsification activities against different hydrocarbon substrates and high solubilization efficiency towards diesel oil. Biosurfactants DCS1 showed good stability in a wide range of temperature, pH and salinity. These results suggested that biosurfactants produced by B. methylotrophicus DCS1 could be an alternative to chemically synthesized surfactants for use in bioremediation processes to enhance the solubility of hydrophobic compounds.

  7. Transcranial direct current stimulation (tDCS) in behavioral and food addiction: a systematic review of efficacy, technical, and methodological issues

    PubMed Central

    Sauvaget, Anne; Trojak, Benoît; Bulteau, Samuel; Jiménez-Murcia, Susana; Fernández-Aranda, Fernando; Wolz, Ines; Menchón, José M.; Achab, Sophia; Vanelle, Jean-Marie; Grall-Bronnec, Marie

    2015-01-01

    Objectives: Behavioral addictions (BA) are complex disorders for which pharmacological and psychotherapeutic treatments have shown their limits. Non-invasive brain stimulation, among which transcranial direct current stimulation (tDCS), has opened up new perspectives in addiction treatment. The purpose of this work is to conduct a critical and systematic review of tDCS efficacy, and of technical and methodological considerations in the field of BA. Methods: A bibliographic search has been conducted on the Medline and ScienceDirect databases until December 2014, based on the following selection criteria: clinical studies on tDCS and BA (namely eating disorders, compulsive buying, Internet addiction, pathological gambling, sexual addiction, sports addiction, video games addiction). Study selection, data analysis, and reporting were conducted according to the PRISMA guidelines. Results: Out of 402 potential articles, seven studies were selected. So far focusing essentially on abnormal eating, these studies suggest that tDCS (right prefrontal anode/left prefrontal cathode) reduces food craving induced by visual stimuli. Conclusions: Despite methodological and technical differences between studies, the results are promising. So far, only few studies of tDCS in BA have been conducted. New research is recommended on the use of tDCS in BA, other than eating disorders. PMID:26500478

  8. Prefrontal Transcranial Direct Current Stimulation Alters Activation and Connectivity in Cortical and Subcortical Reward Systems: A tDCS-fMRI Study

    PubMed Central

    Weber, Matthew J.; Messing, Samuel B.; Rao, Hengyi; Detre, John A.; Thompson-Schill, Sharon L.

    2014-01-01

    Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique used both experimentally and therapeutically to modulate regional brain function. However, few studies have directly measured the aftereffects of tDCS on brain activity or examined changes in task-related brain activity consequent to prefrontal tDCS. To investigate the neural effects of tDCS, we collected fMRI data from 22 human subjects, both at rest and while performing the Balloon Analog Risk Task (BART), before and after true or sham transcranial direct current stimulation. TDCS decreased resting blood perfusion in orbitofrontal cortex and the right caudate and increased task-related activity in the right dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) in response to losses but not wins or increasing risk. Network analysis showed that whole-brain connectivity of the right ACC correlated positively with the number of pumps subjects were willing to make on the BART, and that tDCS reduced connectivity between the right ACC and the rest of the brain. Whole-brain connectivity of the right DLPFC also correlated negatively with pumps on the BART, as prior literature would suggest. Our results suggest that tDCS can alter activation and connectivity in regions distal to the electrodes. PMID:24453107

  9. In-vivo Imaging of Magnetic Fields Induced by Transcranial Direct Current Stimulation (tDCS) in Human Brain using MRI

    PubMed Central

    Jog, Mayank V.; Smith, Robert X.; Jann, Kay; Dunn, Walter; Lafon, Belen; Truong, Dennis; Wu, Allan; Parra, Lucas; Bikson, Marom; Wang, Danny J. J.

    2016-01-01

    Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that applies mA currents at the scalp to modulate cortical excitability. Here, we present a novel magnetic resonance imaging (MRI) technique, which detects magnetic fields induced by tDCS currents. This technique is based on Ampere’s law and exploits the linear relationship between direct current and induced magnetic fields. Following validation on a phantom with a known path of electric current and induced magnetic field, the proposed MRI technique was applied to a human limb (to demonstrate in-vivo feasibility using simple biological tissue) and human heads (to demonstrate feasibility in standard tDCS applications). The results show that the proposed technique detects tDCS induced magnetic fields as small as a nanotesla at millimeter spatial resolution. Through measurements of magnetic fields linearly proportional to the applied tDCS current, our approach opens a new avenue for direct in-vivo visualization of tDCS target engagement. PMID:27698358

  10. Wearable functional near infrared spectroscopy (fNIRS) and transcranial direct current stimulation (tDCS): expanding vistas for neurocognitive augmentation

    PubMed Central

    McKendrick, Ryan; Parasuraman, Raja; Ayaz, Hasan

    2015-01-01

    Contemporary studies with transcranial direct current stimulation (tDCS) provide a growing base of evidence for enhancing cognition through the non-invasive delivery of weak electric currents to the brain. The main effect of tDCS is to modulate cortical excitability depending on the polarity of the applied current. However, the underlying mechanism of neuromodulation is not well understood. A new generation of functional near infrared spectroscopy (fNIRS) systems is described that are miniaturized, portable, and include wearable sensors. These developments provide an opportunity to couple fNIRS with tDCS, consistent with a neuroergonomics approach for joint neuroimaging and neurostimulation investigations of cognition in complex tasks and in naturalistic conditions. The effects of tDCS on complex task performance and the use of fNIRS for monitoring cognitive workload during task performance are described. Also explained is how fNIRS + tDCS can be used simultaneously for assessing spatial working memory. Mobile optical brain imaging is a promising neuroimaging tool that has the potential to complement tDCS for realistic applications in natural settings. PMID:25805976

  11. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  12. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  13. A TLR9 agonist enhances the anti-tumor immunity of peptide and lipopeptide vaccines via different mechanisms.

    PubMed

    Song, Ying-Chyi; Liu, Shih-Jen

    2015-01-01

    The toll-like receptor 9 (TLR9) agonists CpG oligodeoxynucleotides (CpG ODNs) have been recognized as promising adjuvants for vaccines against infectious diseases and cancer. However, the role of TLR9 signaling in the regulation of antigen uptake and presentation is not well understood. Therefore, to investigate the effects of TLR9 signaling, this study used synthetic peptides (IDG) and lipopeptides (lipoIDG), which are internalized by dendritic cells (DCs) via endocytosis-dependent and endocytosis-independent pathways, respectively. Our data demonstrated that the internalization of lipoIDG and IDG by bone marrow-derived dendritic cells (BMDCs) was not enhanced in the presence of CpG ODNs; however, CpG ODNs prolonged the co-localization of IDG with CpG ODNs in early endosomes. Surprisingly, CpG ODNs enhanced CD8(+) T cell responses, and the anti-tumor effects of IDG immunization were stronger than those of lipoIDG immunization. LipoIDG admixed with CpG ODNs induced low levels of CD8(+) T cells and partially inhibit tumor growth. Our findings suggest that CpG ODNs increase the retention of antigens in early endosomes, which is important for eliciting anti-tumor immunity. These results will facilitate the application of CpG adjuvants in the design of different vaccines.

  14. Antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists.

    PubMed

    Labrie, F; Bélanger, A; Kelly, P A; Séguin, C; Cusan, L; Lefebvre, F A; Reeves, J J; Lemay, A; Faure, N; Gourdeau, Y; Raynaud, J P

    1981-01-01

    This paper reviews the mechanisms responsible for the antifertility effects of luteinizing hormone-releasing hormone (LHRH) agonists. Large doses of the LHRH agonist LHRH-EA lead to a marked reduction of testicular and secondary sex organ weight, LH receptor levels, and plasma testosterone concentration. A marked inhibition of basal testicular and testosterone concentrations is obtained after daily administration of the LHRH agonists at doses greater than 10 ng. Treatment with low doses of the LHRH agonist can lead to an increased steroidogenic response to LH. Treatment with low doses of LHRH agonists could stimulate Leydig cell function while high doses are history. A study of the effects of longterm treatment with an LHRH agonsist on spermatogenesis revelaed that testis, prostate, and seminal vesicle weight decreased and plasma LH and FSH levels increased over 12 weeks. Comparison of the effects of increasing doses of LHRH agonist on testicular and ovarian gonadotropin receptors and steroidogenesis in male rats indicates that single or repeated administration of LHRH agonists can lead to loss of testicular LH receptors in the absence of the pituitary gland. The loss of ovarian gonadotropin receptors in female rats is also investigated. Antifertility effects of LHRH ethylamide are accompanied by a marked loss of LH/hCG and FSH receptors in ovarian tissue. The injection of 1,3, or 10 ng LHRH-EA in intact rats has no significant effect on ovarian LH receptor levels. A study of the direct action of LHRH agonists at the ovarian level demonstrates a close relationship between the binding activity of a large series of LHRH agonists and antagonists in the anterior pituitary gland and the ovary. Inhibition of testicular steroidogenesis in man by treatment with a potent LHRH agonist is also demonstrated. Intranasal administration of LHRH ethylamide has luteolytic effects in normal women. Daily administration of LHRH-EA inhibited ovulation in all but 2 of 89 treatment

  15. tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study.

    PubMed

    Kim, Soyoung; Stephenson, Mary C; Morris, Peter G; Jackson, Stephen R

    2014-10-01

    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and 'supervised' learning of internal 'forward' models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

  16. The effect of the interval-between-sessions on prefrontal transcranial direct current stimulation (tDCS) on cognitive outcomes: a systematic review and meta-analysis.

    PubMed

    Dedoncker, Josefien; Brunoni, Andre R; Baeken, Chris; Vanderhasselt, Marie-Anne

    2016-10-01

    Recently, there has been wide interest in the effects of transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) on cognitive functioning. However, many methodological questions remain unanswered. One of them is whether the time interval between active and sham-controlled stimulation sessions, i.e. the interval between sessions (IBS), influences DLPFC tDCS effects on cognitive functioning. Therefore, a systematic review and meta-analysis was performed of experimental studies published in PubMed, Science Direct, and other databases from the first data available to February 2016. Single session sham-controlled within-subject studies reporting the effects of tDCS of the DLPFC on cognitive functioning in healthy controls and neuropsychiatric patients were included. Cognitive tasks were categorized in tasks assessing memory, attention, and executive functioning. Evaluation of 188 trials showed that anodal vs. sham tDCS significantly decreased response times and increased accuracy, and specifically for the executive functioning tasks, in a sample of healthy participants and neuropsychiatric patients (although a slightly different pattern of improvement was found in analyses for both samples separately). The effects of cathodal vs. sham tDCS (45 trials), on the other hand, were not significant. IBS ranged from less than 1 h to up to 1 week (i.e. cathodal tDCS) or 2 weeks (i.e. anodal tDCS). This IBS length had no influence on the estimated effect size when performing a meta-regression of IBS on reaction time and accuracy outcomes in all three cognitive categories, both for anodal and cathodal stimulation. Practical recommendations and limitations of the study are further discussed.

  17. Computational Pipeline for NIRS-EEG Joint Imaging of tDCS-Evoked Cerebral Responses—An Application in Ischemic Stroke

    PubMed Central

    Guhathakurta, Debarpan; Dutta, Anirban

    2016-01-01

    Transcranial direct current stimulation (tDCS) modulates cortical neural activity and hemodynamics. Electrophysiological methods (electroencephalography-EEG) measure neural activity while optical methods (near-infrared spectroscopy-NIRS) measure hemodynamics coupled through neurovascular coupling (NVC). Assessment of NVC requires development of NIRS-EEG joint-imaging sensor montages that are sensitive to the tDCS affected brain areas. In this methods paper, we present a software pipeline incorporating freely available software tools that can be used to target vascular territories with tDCS and develop a NIRS-EEG probe for joint imaging of tDCS-evoked responses. We apply this software pipeline to target primarily the outer convexity of the brain territory (superficial divisions) of the middle cerebral artery (MCA). We then present a computational method based on Empirical Mode Decomposition of NIRS and EEG time series into a set of intrinsic mode functions (IMFs), and then perform a cross-correlation analysis on those IMFs from NIRS and EEG signals to model NVC at the lesional and contralesional hemispheres of an ischemic stroke patient. For the contralesional hemisphere, a strong positive correlation between IMFs of regional cerebral hemoglobin oxygen saturation and the log-transformed mean-power time-series of IMFs for EEG with a lag of about −15 s was found after a cumulative 550 s stimulation of anodal tDCS. It is postulated that system identification, for example using a continuous-time autoregressive model, of this coupling relation under tDCS perturbation may provide spatiotemporal discriminatory features for the identification of ischemia. Furthermore, portable NIRS-EEG joint imaging can be incorporated into brain computer interfaces to monitor tDCS-facilitated neurointervention as well as cortical reorganization. PMID:27378836

  18. Computational Pipeline for NIRS-EEG Joint Imaging of tDCS-Evoked Cerebral Responses-An Application in Ischemic Stroke.

    PubMed

    Guhathakurta, Debarpan; Dutta, Anirban

    2016-01-01

    Transcranial direct current stimulation (tDCS) modulates cortical neural activity and hemodynamics. Electrophysiological methods (electroencephalography-EEG) measure neural activity while optical methods (near-infrared spectroscopy-NIRS) measure hemodynamics coupled through neurovascular coupling (NVC). Assessment of NVC requires development of NIRS-EEG joint-imaging sensor montages that are sensitive to the tDCS affected brain areas. In this methods paper, we present a software pipeline incorporating freely available software tools that can be used to target vascular territories with tDCS and develop a NIRS-EEG probe for joint imaging of tDCS-evoked responses. We apply this software pipeline to target primarily the outer convexity of the brain territory (superficial divisions) of the middle cerebral artery (MCA). We then present a computational method based on Empirical Mode Decomposition of NIRS and EEG time series into a set of intrinsic mode functions (IMFs), and then perform a cross-correlation analysis on those IMFs from NIRS and EEG signals to model NVC at the lesional and contralesional hemispheres of an ischemic stroke patient. For the contralesional hemisphere, a strong positive correlation between IMFs of regional cerebral hemoglobin oxygen saturation and the log-transformed mean-power time-series of IMFs for EEG with a lag of about -15 s was found after a cumulative 550 s stimulation of anodal tDCS. It is postulated that system identification, for example using a continuous-time autoregressive model, of this coupling relation under tDCS perturbation may provide spatiotemporal discriminatory features for the identification of ischemia. Furthermore, portable NIRS-EEG joint imaging can be incorporated into brain computer interfaces to monitor tDCS-facilitated neurointervention as well as cortical reorganization. PMID:27378836

  19. Physiological and modeling evidence for focal transcranial electrical brain stimulation in humans: a basis for high-definition tDCS.

    PubMed

    Edwards, Dylan; Cortes, Mar; Datta, Abhishek; Minhas, Preet; Wassermann, Eric M; Bikson, Marom

    2013-07-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 × 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 × 1 montage (4 × cathode, surrounding a single central anode; montage radius ~3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 × 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 × 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 × 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 × 1-Ring montage for cortically targeted neuromodulation.

  20. Technique and considerations in the use of 4x1 ring high-definition transcranial direct current stimulation (HD-tDCS).

    PubMed

    Villamar, Mauricio F; Volz, Magdalena Sarah; Bikson, Marom; Datta, Abhishek; Dasilva, Alexandre F; Fregni, Felipe

    2013-07-14

    High-definition transcranial direct current stimulation (HD-tDCS) has recently been developed as a noninvasive brain stimulation approach that increases the accuracy of current delivery to the brain by using arrays of smaller "high-definition" electrodes, instead of the larger pad-electrodes of conventional tDCS. Targeting is achieved by energizing electrodes placed in predetermined configurations. One of these is the 4x1-ring configuration. In this approach, a center ring electrode (anode or cathode) overlying the target cortical region is surrounded by four return electrodes, which help circumscribe the area of stimulation. Delivery of 4x1-ring HD-tDCS is capable of inducing significant neurophysiological and clinical effects in both healthy subjects and patients. Furthermore, its tolerability is supported by studies using intensities as high as 2.0 milliamperes for up to twenty minutes. Even though 4x1 HD-tDCS is simple to perform, correct electrode positioning is important in order to accurately stimulate target cortical regions and exert its neuromodulatory effects. The use of electrodes and hardware that have specifically been tested for HD-tDCS is critical for safety and tolerability. Given that most published studies on 4x1 HD-tDCS have targeted the primary motor cortex (M1), particularly for pain-related outcomes, the purpose of this article is to systematically describe its use for M1 stimulation, as well as the considerations to be taken for safe and effective stimulation. However, the methods outlined here can be adapted for other HD-tDCS configurations and cortical targets.

  1. Modulating the Activity of Ventromedial Prefrontal Cortex by Anodal tDCS Enhances the Trustee’s Repayment through Altruism

    PubMed Central

    Zheng, Haoli; Huang, Daqiang; Chen, Shu; Wang, Siqi; Guo, Wenmin; Luo, Jun; Ye, Hang; Chen, Yefeng

    2016-01-01

    Trust and trustworthiness are essential to an efficient economy and play crucial roles in social life. Previous evidence from behavioral experiments has revealed that the trustworthiness of individuals is closely related with their altruistic preference. It has been demonstrated that the ventromedial prefrontal cortex (vmPFC) is associated with decisions involving trustworthiness. Moreover, vmPFC lesion patients showed less trustworthiness and altruism than control subjects, indicating the indispensable role of this specific brain area in human social interactions. However, the causal relationship between this neural area and trustworthiness, as well as altruism, has not been fully revealed. The potential neural basis behind the behavior of trustees’ repayment has also seldom been discussed. In the present study, we aimed to provide evidence of a direct link between the neural and behavioral results through the application of transcranial direct current stimulation (tDCS) over the vmPFC of our participants. We found that activating the vmPFC could promote both the trustworthiness and altruism of our participants. We also show that enhancing the excitability of the vmPFC using tDCS increased the trustworthiness of the participants, and this promoting effect might be attributable to the enhancement of individuals’ altruistic preference. In addition, we revealed that the enhancing effect in trustworthiness and altruism might be specific to the activation of the vmPFC by applying tDCS over another brain region within the prefrontal cortex as a control site. Crucially, our findings provide direct evidence supporting the critical role of the vmPFC in cooperative behaviors in economic interactions, especially the trustees’ repayment in the trust game and the dictators’ altruistic transfer in the dictator game. PMID:27713721

  2. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  3. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs.

  4. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-09-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25437461

  5. [Effects of GLP-1 receptor agonists on carbohydrate metabolism control].

    PubMed

    Fernández-García, José Carlos; Colomo, Natalia; Tinahones, Francisco José

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) receptor agonists are a new group of drugs for the treatment of type 2 diabetes mellitus (DM2). In the present article, we review the available evidence on the efficacy of GLP-1 receptor agonists as glucose-lowering agents, their place in therapeutic algorithms, and the clinical factors associated with a favorable treatment response. Finally, we describe the clinical characteristics of patients who may benefit from these drugs. PMID:25326839

  6. PPAR dual agonists: are they opening Pandora's Box?

    PubMed

    Balakumar, Pitchai; Rose, Madhankumar; Ganti, Subrahmanya S; Krishan, Pawan; Singh, Manjeet

    2007-08-01

    Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPARalpha, PPARgamma and PPARdelta/beta. Activation of PPARalpha reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPARgamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPARdelta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPARalpha and PPARgamma ligands in preventing the cardiovascular risks. The PPARalpha/gamma dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPARalpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPARdelta. Therefore, further studies are on the track to develop PPARalpha/delta and PPAR gamma/delta dual agonists and PPARalpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in

  7. Identification of M-CSF agonists and antagonists

    SciTech Connect

    Pandit, Jayvardhan; Jancarik, Jarmila; Kim, Sung-Hou; Koths, Kirston; Halenbeck, Robert; Fear, Anna Lisa; Taylor, Eric; Yamamoto, Ralph; Bohm, Andrew

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  8. Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine

    PubMed Central

    2013-01-01

    Background Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing. Objective To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention. Methods We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy. Results In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication

  9. Pharmacogenetics of beta2 adrenergic receptor agonists in asthma management.

    PubMed

    Ortega, V E

    2014-07-01

    Beta2 (β2) adrenergic receptor agonists (beta agonists) are a commonly prescribed treatment for asthma despite the small increase in risk for life-threatening adverse responses associated with long-acting beta agonist (LABA). The concern for life-threatening adverse effects associated with LABA and the inter-individual variability of therapeutic responsiveness to LABA-containing combination therapies provide the rationale for pharmacogenetic studies of beta agonists. These studies primarily evaluated genes within the β2-adrenergic receptor and related pathways; however, recent genome-wide studies have identified novel loci for beta agonist response. Recent studies have identified a role for rare genetic variants in determining beta agonist response and, potentially, the risk for rare, adverse responses to LABA. Before genomics research can be applied to the development of genetic profiles for personalized medicine, it will be necessary to continue adapting to the analysis of an increasing volume of genetic data in larger cohorts with a combination of analytical methods and in vitro studies.

  10. Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli.

    PubMed

    Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F; Diamond, Scott L

    2010-07-01

    Prediction of cellular response to multiple stimuli is central to evaluating patient-specific clinical status and to basic understanding of cell biology. Cross-talk between signaling pathways cannot be predicted by studying them in isolation and the combinatorial complexity of multiple agonists acting together prohibits an exhaustive exploration of the complete experimental space. Here we describe pairwise agonist scanning (PAS), a strategy that trains a neural network model based on measurements of cellular responses to individual and all pairwise combinations of input signals. We apply PAS to predict calcium signaling responses of human platelets in EDTA-treated plasma to six different agonists (ADP, convulxin, U46619, SFLLRN, AYPGKF and PGE(2)) at three concentrations (0.1, 1 and 10 x EC(50)). The model predicted responses to sequentially added agonists, to ternary combinations of agonists and to 45 different combinations of four to six agonists (R = 0.88). Furthermore, we use PAS to distinguish between the phenotypic responses of platelets from ten donors. Training neural networks with pairs of stimuli across the dose-response regime represents an efficient approach for predicting complex signal integration in a patient-specific disease milieu. PMID:20562863

  11. State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control

    PubMed Central

    DaSilva, Alexandre F.; Truong, Dennis Q.; DosSantos, Marcos F.; Toback, Rebecca L.; Datta, Abhishek; Bikson, Marom

    2015-01-01

    Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes’ placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10–20 or 10–10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder. PMID

  12. State-of-art neuroanatomical target analysis of high-definition and conventional tDCS montages used for migraine and pain control.

    PubMed

    DaSilva, Alexandre F; Truong, Dennis Q; DosSantos, Marcos F; Toback, Rebecca L; Datta, Abhishek; Bikson, Marom

    2015-01-01

    Although transcranial direct current stimulation (tDCS) studies promise to modulate cortical regions associated with pain, the electric current produced usually spreads beyond the area of the electrodes' placement. Using a forward-model analysis, this study compared the neuroanatomic location and strength of the predicted electric current peaks, at cortical and subcortical levels, induced by conventional and High-Definition-tDCS (HD-tDCS) montages developed for migraine and other chronic pain disorders. The electrodes were positioned in accordance with the 10-20 or 10-10 electroencephalogram (EEG) landmarks: motor cortex-supraorbital (M1-SO, anode and cathode over C3 and Fp2, respectively), dorsolateral prefrontal cortex (PFC) bilateral (DLPFC, anode over F3, cathode over F4), vertex-occipital cortex (anode over Cz and cathode over Oz), HD-tDCS 4 × 1 (one anode on C3, and four cathodes over Cz, F3, T7, and P3) and HD-tDCS 2 × 2 (two anodes over C3/C5 and two cathodes over FC3/FC5). M1-SO produced a large current flow in the PFC. Peaks of current flow also occurred in deeper brain structures, such as the cingulate cortex, insula, thalamus and brainstem. The same structures received significant amount of current with Cz-Oz and DLPFC tDCS. However, there were differences in the current flow to outer cortical regions. The visual cortex, cingulate and thalamus received the majority of the current flow with the Cz-Oz, while the anterior parts of the superior and middle frontal gyri displayed an intense amount of current with DLPFC montage. HD-tDCS montages enhanced the focality, producing peaks of current in subcortical areas at negligible levels. This study provides novel information regarding the neuroanatomical distribution and strength of the electric current using several tDCS montages applied for migraine and pain control. Such information may help clinicians and researchers in deciding the most appropriate tDCS montage to treat each pain disorder.

  13. Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity

    PubMed Central

    Gupta, Subhash C.; Yadav, Roopali; Pavuluri, Ratnamala; Morley, Barbara J.; Stairs, Dustin J.; Dravid, Shashank M.

    2015-01-01

    The glutamate delta-1 (GluD1) receptor is highly expressed in the forebrain. We have previously shown that loss of GluD1 leads to social and cognitive deficits in mice, however, its role in synaptic development and neurotransmission remains poorly understood. Here we report that GluD1 is enriched in the medial prefrontal cortex (mPFC) and GluD1 knockout mice exhibit a higher dendritic spine number, greater excitatory neurotransmission as well as higher number of synapses in mPFC. In addition abnormalities in the LIMK1-cofilin signaling, which regulates spine dynamics, and a lower ratio of GluN2A/GluN2B expression was observed in the mPFC in GluD1 knockout mice. Analysis of the GluD1 knockout CA1 hippocampus similarly indicated the presence of higher spine number and synapses and altered LIMK1-cofilin signaling. We found that systemic administration of an N-methyl-d-aspartate (NMDA) receptor partial agonist d-cycloserine (DCS) at a high-dose, but not at a low-dose, and a GluN2B-selective inhibitor Ro-25-6981 partially normalized the abnormalities in LIMK1-cofilin signaling and reduced excess spine number in mPFC. The molecular effects of high-dose DCS and GluN2B inhibitor correlated with their ability to reduce the higher stereotyped behavior and depression-like behavior in GluD1 knockout mice. Together these findings demonstrate a critical requirement for GluD1 in normal spine development in the cortex and hippocampus. Moreover, these results identify inhibition of GluN2Bcontaining receptors as a mechanism for reducing excess dendritic spines and stereotyped behavior which may have therapeutic value in certain neurodevelopmental disorders. PMID:25721396

  14. NMDA GluN2B receptors involved in the antidepressant effects of curcumin in the forced swim test.

    PubMed

    Zhang, Lin; Xu, Tianyuan; Wang, Shuang; Yu, Lanqing; Liu, Dexiang; Zhan, Renzhi; Yu, Shu Yan

    2013-01-10

    The antidepressant-like effect of curcumin, a major active component of Curcuma longa, has been previously demonstrated in the forced swimming test. However, the mechanism of this beneficial effect on immobility scores, which is used to evaluate antidepressants, remains largely uncharacterized. The present study attempts to investigate the effects of curcumin on depressive-like behavior with a focus upon the possible contribution of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in this antidepressant-like effect of curcumin. Male mice were pretreated with specific receptor antagonists to different NMDA receptor subtypes such as CPP, NVP-AAM077 and Ro25-6981 as well as to a partial NMDA receptor agonist, D-cycloserine (DCS), prior to administration of curcumin to observe the effects on depressive behavior as measured by immobility scores in the forced swim test. We found that pre-treatment of mice with CPP, a broad-spectrum competitive NMDA receptor antagonist, blocked the anti-immobility effect of curcumin, suggesting the involvement of the glutamate-NMDA receptors. While pretreatment with NVP-AAM077 (the GluN2A-preferring antagonist) did not affect the anti-immobility effect of curcumin, Ro25-6981 (the GluN2B-preferring antagonist) was found to prevent the effect of curcumin in the forced swimming test. Furthermore, pre-treatment with a sub-effective dose of DCS potentiated the anti-immobility effect of a sub-effective dose of curcumin in the forced swimming test. Taken together, these results suggest that curcumin shows antidepressant-like effects in mice and the activation of GluN2B-containing NMDARs is likely to play a predominate role in this beneficial effect. Therefore, the antidepressant-like effect of curcumin in the forced swim test may be mediated, at least in part, by the glutamatergic system.

  15. Perception of specific trigeminal chemosensory agonists

    PubMed Central

    Frasnelli, J; Albrecht, J; Bryant, B; Lundström, JN

    2011-01-01

    The intranasal trigeminal system is a third chemical sense in addition to olfaction and gustation. As opposed to smell and taste, we still lack knowledge on the relationship between receptor binding and perception for the trigeminal system. We therefore investigated the sensitivity of the intranasal trigeminal system towards agonists of the trigeminal receptors TRPM8 and TRPA1 by assessing subjects’ ability to identify which nostril has been stimulated in a monorhinal stimulation design. We summed the number of correct identifications resulting in a lateralization score. Stimuli were menthol (activating TRPM8 receptors), eucalyptol (TRPM8), mustard oil (TRPA1) and two mixtures thereof (menthol/eucalyptol and menthol/mustard oil). In addition, we examined the relationship between intensity and lateralization scores and investigated whether intensity evaluation and lateralization scores of the mixtures show additive effects. All stimuli were correctly lateralized significantly above chance. Across subjects the lateralization scores for single compounds activating the same receptor showed a stronger correlation than stimuli activating different receptors. Although single compounds were isointense, the mixture of menthol and eucalyptol (activating only TRPM8) was perceived as weaker and was lateralized less accurately than the mixture of menthol and mustard oil (activating both TRPM8 and TRPA1) suggesting suppression effects in the former mixture. In conclusion, sensitivity of different subpopulations of trigeminal sensory neurons seems to be related, but only to a certain degree. The large coherence in sensitivity between various intranasal trigeminal stimuli suggests that measuring sensitivity to one single trigeminal chemical stimulus may be sufficient to generally assess the trigeminal system’s chemosensitivity. Further, for stimuli activating the same receptor a mixture suppression effect appears to occur similar to that observed in the other chemosensory

  16. Applications of ERTS-1 Data Collection System (DCS) in the Arizona Regional Ecological Test Site (ARETS). [water management, streamflow rates, flood control

    NASA Technical Reports Server (NTRS)

    Schumann, H. H. (Principal Investigator)

    1973-01-01

    The author has identified the following significant results. The DCS water-stage data from the USGS streamflow gaging station on the Verde River near Camp Verde furnished information sufficient for the accurate computation of daily mean streamflow rates during the first 2 months of operation. Daily mean flow rates computed from the DCS data agreed with those computed from the digital recorder data within + or - 5% during periods of stable or slowly changing flow and within + or - 10% during periods of rapidly changing high flow. The SRP was furnished near-real time DCS information on snow moisture content and streamflow rates for use in the management and operation of the multiple-use reservoir system. The SRP, by prudent water management and the use of near-real time hydrologic data furnished by microwave and ERTS DCS telemetry, was successful in anticipating the amount of flow into the Salt and Verde Rivers and in the subsequent release of water at rates that did not create flooding in metropolitan Phoenix. Only minor flooding occurred along the Gila River west of Phoenix. According to the Maricopa County Civil Defense agency, wage and salary losses of about $11,400,000 resulted from closing of roads across the Salt River in the winter and spring of 1972-73; however, the number and duration of the closing were minimized by use of DCS data.

  17. A BTLA-mediated bait and switch strategy permits Listeria expansion in CD8α(+) DCs to promote long-term T cell responses.

    PubMed

    Yang, Xuanming; Zhang, Xunmin; Sun, Yonglian; Tu, Tony; Fu, May Lynne; Miller, Mendy; Fu, Yang-Xin

    2014-07-01

    Listeria monocytogenes infected CD8α(+) DCs in the spleen are essential for CD8(+) T cell generation. CD8α(+) DCs are also necessary for Listeria expansion and dissemination within the host. The mechanisms that regulate CD8α(+) DCs to allow Listeria expansion are unclear. We find that activating the B and T lymphocyte attenuator (BTLA), a coinhibitory receptor for T cells, suppresses, while blocking BTLA enhances, both the primary and memory CD8 T cell responses against Listeria. Btla(-/-) mice have lower effector and memory CD8(+) T cells while paradoxically also being more resistant to Listeria. Although bacterial entry into Btla(-/-) CD8α(+) DCs is unaffected, Listeria fails to expand within these cells. BTLA signaling limits Fas/FasL-mediated suppression of Listeria expansion within CD8α(+) DCs to more effectively alert adaptive immune cells. This study uncovers a BTLA-mediated strategy used by the host that permits Listeria proliferation to enable increasing T cell responses for long-term protection.

  18. Dissociable effects of anodal and cathodal tDCS reveal distinct functional roles for right parietal cortex in the detection of single and competing stimuli.

    PubMed

    Filmer, Hannah L; Dux, Paul E; Mattingley, Jason B

    2015-07-01

    Spatial attention can be used to direct neural processing resources to a subset of task-relevant or otherwise salient items within the environment. Such selective processes are particularly important for resolving competition between multiple stimuli. Deficits in processing single stimuli can arise after damage to parietal, frontal and temporal brain regions, as is typical in patients with contralesional spatial neglect. By contrast, deficits in processing multiple competing stimuli may arise specifically following lesions of the posterior parietal cortex (PPC), as occurs in the disorder of spatial extinction. It remains unclear, however, whether mechanisms involved in selecting single and competing stimuli reflect the same or dissociable neural operations within the PPC. To address this issue, in separate sessions, we applied transcranial direct current stimulation (tDCS) to the left or right PPC and measured the effect on detecting and discriminating single and competing visual stimulus events. Our results revealed reliable tDCS modulations of stimulus processing, specific to the right PPC, as well as a dissociation in the detection of single and competing stimuli. For the right PPC only, single stimuli presented to the left (contralateral) visual field were affected selectively by anodal tDCS, whereas competing stimuli across the two visual fields were affected by both anodal and cathodal tDCS. These contrasting effects of anodal and cathodal tDCS on perception of single and competing stimuli suggest dissociable neural coding properties within the right PPC.

  19. Dissociable effects of anodal and cathodal tDCS reveal distinct functional roles for right parietal cortex in the detection of single and competing stimuli.

    PubMed

    Filmer, Hannah L; Dux, Paul E; Mattingley, Jason B

    2015-07-01

    Spatial attention can be used to direct neural processing resources to a subset of task-relevant or otherwise salient items within the environment. Such selective processes are particularly important for resolving competition between multiple stimuli. Deficits in processing single stimuli can arise after damage to parietal, frontal and temporal brain regions, as is typical in patients with contralesional spatial neglect. By contrast, deficits in processing multiple competing stimuli may arise specifically following lesions of the posterior parietal cortex (PPC), as occurs in the disorder of spatial extinction. It remains unclear, however, whether mechanisms involved in selecting single and competing stimuli reflect the same or dissociable neural operations within the PPC. To address this issue, in separate sessions, we applied transcranial direct current stimulation (tDCS) to the left or right PPC and measured the effect on detecting and discriminating single and competing visual stimulus events. Our results revealed reliable tDCS modulations of stimulus processing, specific to the right PPC, as well as a dissociation in the detection of single and competing stimuli. For the right PPC only, single stimuli presented to the left (contralateral) visual field were affected selectively by anodal tDCS, whereas competing stimuli across the two visual fields were affected by both anodal and cathodal tDCS. These contrasting effects of anodal and cathodal tDCS on perception of single and competing stimuli suggest dissociable neural coding properties within the right PPC. PMID:25637773

  20. Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

    PubMed Central

    Schmidt, Philipp; Ritscher, Lars; Dong, Elizabeth N.; Hermsdorf, Thomas; Cöster, Maxi; Wittkopf, Doreen; Meiler, Jens

    2013-01-01

    The ADP receptor P2Y12 belongs to the superfamily of G protein–coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y12 and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y12. The potency at P2Y12 was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y12, with Y105, E188, R256, Y259, and K280 playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3′-OH of the 2′-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y12 and half of the constitutive active P2Y12 mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y12 but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID:23093496

  1. Transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex affects stimulus conflict but not response conflict.

    PubMed

    Zmigrod, S; Zmigrod, L; Hommel, B

    2016-05-13

    When the human brain encounters a conflict, performance is often impaired. Two tasks that are widely used to induce and measure conflict-related interference are the Eriksen flanker task, whereby the visual target stimulus is flanked by congruent or incongruent distractors, and the Simon task, where the location of the required spatial response is either congruent or incongruent with the location of the target stimulus. Interestingly, both tasks share the characteristic of inducing response conflict but only the flanker task induces stimulus conflict. We used a non-invasive brain stimulation technique to explore the role of the right dorsolateral prefrontal cortex (DLPFC) in dealing with conflict in the Eriksen flanker and Simon tasks. In different sessions, participants received anodal, cathodal, or sham transcranial direct current stimulation (tDCS) (2 mA, 20 min) on the right DLPFC while performing these tasks. The results indicate that cathodal tDCS over the right DLPFC increased the flanker interference effect while having no impact on the Simon effect. This finding provides empirical support for the role of the right DLPFC in stimulus-stimulus rather than stimulus-response conflict, which suggests the existence of multiple, domain-specific control mechanisms underlying conflict resolution. In addition, methodologically, the study also demonstrates the way in which brain stimulation techniques can reveal subtle yet important differences between experimental paradigms that are often assumed to tap into a single process. PMID:26924018

  2. Potential confusion of contaminating CD16+ mDCs with anergic CD16+ NK cells in chimpanzees

    PubMed Central

    Reeves, R. Keith; Evans, Tristan I.; Fultz, Patricia N.; Johnson, R. Paul

    2011-01-01

    Precise identification of natural killer (NK) cell populations in humans and nonhuman primates has been confounded by imprecise phenotypic definitions. A common definition used in nonhuman primates, including chimpanzees, is CD3− CD8α+CD16+, and this is the dominant NK cell phenotype in peripheral blood. However, recent data suggests that in chimpanzees a rare CD8α−CD16+ population also exists. Herein we present evidence validating the existence of this rare subset in chimpanzee peripheral blood, but also demonstrating that gating on CD3−CD8α−CD16+ cells can inadvertently include a large number of CD16+ myeloid dendritic cells (mDCs). We confirmed the inclusion of mDCs in CD3−CD8α−CD16+ gated cells by demonstrating high expression of CD11c, BDCA-1 and HLA-DR, and by lack of expression of NKp46 and intracellular perforin. We also functionally validated the CD8α−NK cell and mDC populations by mutually exclusive responsiveness to a classical NK cell stimulus, MHC class I-deficient cells, and a protypic mDC stimulus, poly I:C, respectively. Overall, these data demonstrate common problems with gating of NK cells that can lead to erroneous conclusions and highlight a critical need for consensus protocols for NK cell phenotyping. PMID:21360701

  3. Association between psychosocial job characteristics and sickness absence due to low back symptoms using combined DCS and ERI models

    PubMed Central

    Yu, Shanfa; Lu, Ming-Lun; Gu, Guizhen; Zhou, Wenhui; He, Lihua; Wang, Sheng

    2015-01-01

    Objective To evaluate the combined demand-control-support (DCS) and effort-reward-overcommitment (ERI-OC) stress models in association with sickness absence due to low back symptoms (SA-LBS). Methods A total of 2,737 blue-collar workers recruited from 13 companies in the most populous province (Henan) of China were included in the study. Personal and physical job characteristics, psychosocial scales of the stress models, and SA-LBS data in the preceding year were collected by a self-reported questionnaire and analyzed by a multivariable logistic regression model. Tertile exposure levels (low, medium and high) were constructed to discriminate a risk level. Odds ratios (OR) with 95% confidence intervals (CI) were used as the association with SA-LBS. Results A large percentage (84.5%) of the Chinese workers did not take sick leave after reporting low back symptoms during the preceding year. High job demand or medium–high reward was associated with SA-LBS. The association of the combined stress models and SA-LBS was not evident. Conclusions The ERI-OC model appeared to be more predictive of SA-LBS than the DCS model in the study population. The advantage of using combined stress models for predicting SA-LBS is not evident. PMID:24939110

  4. RXR Partial Agonist CBt-PMN Exerts Therapeutic Effects on Type 2 Diabetes without the Side Effects of RXR Full Agonists

    PubMed Central

    2012-01-01

    Treating insulin resistance and type 2 diabetes in rodents, currently known retinoid X receptor (RXR) agonists induce significant adverse effects. Here we introduce a novel RXR partial agonist CBt-PMN (11b), which shows a potent glucose-lowering effect and improvements of insulin secretion and glucose tolerance without the serious adverse effects caused by RXR full agonists. We suggest that RXR partial agonists may be a new class of antitype 2 diabetes drug candidates. PMID:24900488

  5. Dihydrocodeine/Agonists for Alcohol Dependents

    PubMed Central

    Ulmer, Albrecht; Müller, Markus; Frietsch, Bernhard

    2012-01-01

    Objective: Alcohol addiction too often remains insufficiently treated. It shows the same profile as severe chronic diseases, but no comparable, effective basic treatment has been established up to now. Especially patients with repeated relapses, despite all therapeutic approaches, and patients who are not able to attain an essential abstinence to alcohol, need a basic medication. It seems necessary to acknowledge that parts of them need any agonistic substance, for years, possibly lifelong. For >14 years, we have prescribed such substances with own addictive character for these patients. Methods: We present a documented best possible practice, no designed study. Since 1997, we prescribed Dihydrocodeine (DHC) to 102 heavily alcohol addicted patients, later, also Buprenorphine, Clomethiazole (>6 weeks), Baclofen, and in one case Amphetamine, each on individual indication. This paper focuses on the data with DHC, especially. The Clomethiazole-data has been submitted to a German journal. The number of treatments with the other substances is still low. Results: The 102 patients with the DHC treatment had 1367 medically assisted detoxifications and specialized therapies before! The 4 years-retention rate was 26.4%, including 2.8% successfully terminated treatments. In our 12-steps scale on clinical impression, we noticed a significant improvement from mean 3.7 to 8.4 after 2 years. The demand for medically assisted detoxifications in the 2 years remaining patients was reduced by 65.5%. Mean GGT improved from 206.6 U/l at baseline to 66.8 U/l after 2 years. Experiences with the other substances are similar but different in details. Conclusion: Similar to the Italian studies with GHB and Baclofen, we present a new approach, not only with new substances, but also with a new setting and much more trusting attitude. We observe a huge improvement, reaching an almost optimal, stable, long term status in around 1/4 of the patients already. Many further

  6. Canine recombinant adenovirus vector induces an immunogenicity-related gene expression profile in skin-migrated CD11b⁺ -type DCs.

    PubMed

    Contreras, Vanessa; Urien, Céline; Jouneau, Luc; Bourge, Mickael; Bouet-Cararo, Coraline; Bonneau, Michel; Zientara, Stephan; Klonjkowski, Bernard; Schwartz-Cornil, Isabelle

    2012-01-01

    Gene expression profiling of the blood cell response induced early after vaccination has previously been demonstrated to predict the immunogenicity of vaccines. In this study, we evaluated whether the analysis of the gene expression profile of skin-migrated dendritic cells (DCs) could be informative for the in vitro prediction of immunogenicity of vaccine, using canine adenovirus serotype 2 (CAV2) as vaccine vector. CAV2 has been shown to induce immunity to transgenes in several species including sheep and is an interesting alternative to human adenovirus-based vectors, based on the safety records of the parental strain in dogs and the lack of pre-existing immunity in non-host species. Skin-migrated DCs were collected from pseudo-afferent lymph in sheep. Both the CD11b(+) -type and CD103(+) -type skin-migrated DCs were transduced by CAV2. An analysis of the global gene response to CAV2 in the two skin DC subsets showed that the gene response in CD11b(+) -type DCs was far higher and broader than in the CD103(+) -type DCs. A newly released integrative analytic tool from Ingenuity systems revealed that the CAV2-modulated genes in the CD11b(+) -type DCs clustered in several activated immunogenicity-related functions, such as immune response, immune cell trafficking and inflammation. Thus gene profiling in skin-migrated DC in vitro indicates that the CD11b(+) DC type is more responsive to CAV2 than the CD103(+) DC type, and provides valuable information to help in evaluating and possibly improving viral vector vaccine effectiveness. PMID:23300693

  7. Canine Recombinant Adenovirus Vector Induces an Immunogenicity-Related Gene Expression Profile in Skin-Migrated CD11b+ -Type DCs

    PubMed Central

    Jouneau, Luc; Bourge, Mickael; Bouet-Cararo, Coraline; Bonneau, Michel; Zientara, Stephan; Klonjkowski, Bernard; Schwartz-Cornil, Isabelle

    2012-01-01

    Gene expression profiling of the blood cell response induced early after vaccination has previously been demonstrated to predict the immunogenicity of vaccines. In this study, we evaluated whether the analysis of the gene expression profile of skin-migrated dendritic cells (DCs) could be informative for the in vitro prediction of immunogenicity of vaccine, using canine adenovirus serotype 2 (CAV2) as vaccine vector. CAV2 has been shown to induce immunity to transgenes in several species including sheep and is an interesting alternative to human adenovirus-based vectors, based on the safety records of the parental strain in dogs and the lack of pre-existing immunity in non-host species. Skin-migrated DCs were collected from pseudo-afferent lymph in sheep. Both the CD11b+ -type and CD103+ -type skin-migrated DCs were transduced by CAV2. An analysis of the global gene response to CAV2 in the two skin DC subsets showed that the gene response in CD11b+ -type DCs was far higher and broader than in the CD103+ -type DCs. A newly released integrative analytic tool from Ingenuity systems revealed that the CAV2-modulated genes in the CD11b+ -type DCs clustered in several activated immunogenicity-related functions, such as immune response, immune cell trafficking and inflammation. Thus gene profiling in skin-migrated DC in vitro indicates that the CD11b+ DC type is more responsive to CAV2 than the CD103+ DC type, and provides valuable information to help in evaluating and possibly improving viral vector vaccine effectiveness. PMID:23300693

  8. Self-assembling peptide for co-delivery of HIV-1 CD8+ T cells epitope and Toll-like receptor 7/8 agonists R848 to induce maturation of monocyte derived dendritic cell and augment polyfunctional cytotoxic T lymphocyte (CTL) response.

    PubMed

    Ding, Yong; Liu, Jun; Lu, Sheng; Igweze, Justice; Xu, Wen; Kuang, Da; Zealey, Chris; Liu, Daheng; Gregor, Alex; Bozorgzad, Ardalan; Zhang, Lei; Yue, Elizabeth; Mujib, Shariq; Ostrowski, Mario; Chen, P

    2016-08-28

    Peptide based vaccine that incorporates one or several highly conserved CD8+ T cells epitopes to induce potent cytotoxic T lymphocyte (CTL) response is desirable for some infectious diseases, such as HIV-1 (human immunodeficiency virus-1), and cancers. However, the CD8+ T cells epitope is often weakly immunogenic, and thus requires a specific adjuvant or delivery system to enhance the efficiency. Here we investigated the use of self-assembling peptide EAK16-II based platform to achieve the co-delivery of CD8+ T cells epitope and TLR7/8 agonists (R848 or R837) for augmenting DCs maturation and HIV-1 specific CTL response. HIV-1 CTL epitope SL9 was conjugated with EAK16-II to obtain SL9-EAK16-II, which further spontaneously co-assembled with R848 or R837 in aqueous solution, forming co-assembled nanofibers. Fluorescence spectra and calorimetrical titration revealed the interaction between SL9-EAK16-II assemblies and R848 or R837 via hydrogen bonding and hydrophobic interaction, with the binding affinity (dissociation constant Kd) of 0.62μM or 0.53μM, respectively. Ex vivo generated DCs from HIV-1+ patients pulsed with the SL9-EAK16-II/R848 nanofibers stimulated significantly more polyfunctional SL9 specific CTLs, compared to the DCs pulsed with SL9 alone or the mixture of SL9 and TLR agonist. Furthermore, the nanofibers elicited stronger SL9 specific CTL response in vaccinated mice. Our findings suggest the self-assembling peptide EAK16-II might be used as a new delivery system for peptide based vaccines. PMID:27297778

  9. Honokiol: A non-adipogenic PPARγ agonist from nature☆

    PubMed Central

    Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela; Malainer, Clemens; Vuorinen, Anna; Noha, Stefan M.; Schwaiger, Stefan; Rollinger, Judith M.; Schuster, Daniela; Stuppner, Hermann; Dirsch, Verena M.; Heiss, Elke H.

    2013-01-01

    Background Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. PMID:23811337

  10. Modification of opiate agonist binding by pertussis toxin

    SciTech Connect

    Abood, M.E.; Lee, N.M.; Loh, H.H.

    1986-03-05

    Opiate agonist binding is decreased by GTP, suggesting the possible involvement of GTP binding proteins in regulation of opiate receptor binding. This possibility was addressed by asking whether pertussis toxin treatment, which results in ADP-ribosylation and modification of G proteins, would alter opiate agonist binding. The striatum was chosen for the initial brain area to be studied, since regulation of opiate action in this area had been shown to be modified by pertussis toxin. Treatment of striatal membranes with pertussis toxin results in up to a 55% decrease in /sup 3/(H)-DADLE binding as compared with membranes treated identically without toxin. This corresponds to a near complete ADP-ribosylation of both G proteins in the striatal membrane. The decrease in agonist binding appears to be due to an altered affinity of the receptor for agonist as opposed to a decrease in the number of sites. This effect of pertussis toxin on opiate agonist binding demonstrates the actual involvement of G proteins in regulation of opiate receptor binding.

  11. Sound production during agonistic behavior of male Drosophila melanogaster

    PubMed Central

    Jonsson, Thorin; Kravitz, Edward A

    2011-01-01

    Male Drosophila fruit flies acquire and defend territories in order to attract females for reproduction. Both, male-directed agonistic behavior and female-directed courtship consist of series of recurrent stereotypical components. Various studies demonstrated the importance of species-specific sound patterns generated by wing vibration as being critical for male courtship success. In this study we analyzed the patterns and importance of sound signals generated during agonistic interactions of male Drosophila melanogaster. In contrast to acoustic courtship signals that consist of sine and pulse patterns and are generated by one extended wing, agonistic signals lack sine-like components and are generally produced by simultaneous movements of both wings. Though intra-pulse oscillation frequencies (carrier frequency) are identical, inter-pulse intervals are twice as long and more variable in aggression signals than in courtship songs, where their precise temporal pattern serves species recognition. Acoustic signals accompany male agonistic interactions over their entire course but occur particularly often after tapping behavior which is a major way to identify the gender of the interaction partner. Since similar wing movements may either be silent or generate sound and wing movements with sound have a greater impact on the subsequent behavior of a receiver, sound producing wing movements seem to be generated intentionally to serve as a specific signal during fruit fly agonistic encounters. PMID:20953152

  12. Radiation therapy generates platelet-activating factor agonists

    PubMed Central

    Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.

    2016-01-01

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  13. Radiation therapy generates platelet-activating factor agonists.

    PubMed

    Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan; Murphy, Robert C; Konger, Raymond L; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston, Michael Edward; Dynlacht, Joseph R; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F; Travers, Jeffrey B

    2016-04-12

    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens. PMID:26959112

  14. Tolerance with beta 2-adrenoceptor agonists: time for reappraisal.

    PubMed Central

    Grove, A; Lipworth, B J

    1995-01-01

    1. In spite of the widespread use of beta 2-adrenoceptor agonists in the treatment of asthma controversy continues regarding their possible role in increasing asthma mortality and morbidity. There is however no evidence available to suggest that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. 2. There is no conclusive evidence to suggest that tolerance develops to the bronchodilator effects of short-acting beta 2-adrenoceptor agonists. Tolerance does however appear to develop to the anti-bronchoconstrictor effects of these drugs. 3. With regard to the long-acting beta 2-adrenoceptor agonists, there is evidence to suggest that tolerance develops both to their anti-bronchoconstrictor, and bronchodilator effects. Tolerance was however demonstrated in the presence of improved symptom control, therefore the clinical relevance of this phenomenon is uncertain. 4. Systemic corticosteroids can modulate lymphocyte beta 2-adrenoceptor function both preventing, and reversing tolerance. The situation regarding the effects of systemic or inhaled corticosteroids on modulating bronchodilator responses in asthmatics is less clear. There is some evidence to suggest that inhaled corticosteroids are unable to prevent bronchodilator or systemic tolerance to long-acting beta 2-adrenoceptor agonists. 5. On the basis of the current evidence, the British Thoracic Society guidelines for the management of asthma appear appropriate with regard to their recommendations for the use of long-acting beta 2-adrenoceptor agonists. PMID:7742147

  15. Current issues with beta2-adrenoceptor agonists: historical background.

    PubMed

    Tattersfield, Anne E

    2006-01-01

    The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

  16. Confounding of the Comparative Safety of Prenatal Opioid Agonist Therapy

    PubMed Central

    Brogly, Susan B; Hahn, Kristen A; Diaz, Sonia Hernandez; Werler, Martha

    2016-01-01

    Prenatal opioid agonist therapy with methadone or buprenorphine prevents maternal illicit opioid use and withdrawal and improves pregnancy outcomes compared to heroin use alone. Historically, methadone has been the first-line opioid agonist therapy for pregnant opioid dependent women; in recent years buprenorphine has become first-line treatment for some opioid dependent pregnant women. While there is some evidence of better outcomes in neonates exposed to buprenorphine vs. methadone, the effect of confounding from differences in women who use buprenorphine and methadone has not been carefully examined in most studies. This review explores mechanisms by which confounding can arise in measuring associations between prenatal buprenorphine vs. methadone exposure on neonatal outcomes using a graphical approach, directed acyclic graphs. The goal of this paper is to facilitate better understanding of the factors influencing neonatal abstinence syndrome and accurate assessment of the comparative safety of opioid agonist therapies on the neonate. PMID:27547489

  17. Adenosine receptor agonists for promotion of dermal wound healing

    PubMed Central

    Valls, María D.; Cronstein, Bruce N.; Montesinos, M. Carmen

    2009-01-01

    Wound healing is a dynamic and complex process that involves a well coordinated, highly regulated series of events including inflammation, tissue formation, revascularization and tissue remodeling. However, this orderly sequence is impaired in certain pathophysiological conditions such as diabetes mellitus, venous insufficiency, chronic glucocorticoid use, aging and malnutrition. Together with proper wound care, promotion of the healing process is the primary objective in the management of chronic poorly healing wounds. Recent studies have demonstrated that A2A adenosine receptor agonists promote wound healing in normal and diabetic animals and one such agonist, Sonedenoson, is currently being evaluated as a prospective new therapy of diabetic foot ulcers. We will review the mechanisms by which adenosine receptor activation affects the function of the cells and tissues that participate in wound healing, emphasizing the potential beneficial impact of adenosine receptor agonists in diabetic impaired healing. PMID:19041853

  18. Design, evaluation, and comparison of ghrelin receptor agonists and inverse agonists as suitable radiotracers for PET imaging.

    PubMed

    Chollet, Constance; Bergmann, Ralf; Pietzsch, Jens; Beck-Sickinger, Annette G

    2012-04-18

    Ghrelin agonist and inverse agonist radiotracers, suitable for positron emission tomography (PET), were developed to study the behavior of ghrelin receptor ligands in vivo and for further design of druggable peptides. The target peptides were synthesized on solid support and conjugated to the bifunctional chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), which is known to form a stable complex with Ga(3+). Complexation with (68)Ga could be achieved under mild conditions and led to radiotracers with high radiochemical purity and specific activity. The biological activity of the radiotracers was evaluated in vitro by an inositol phosphate turnover assay. Pharmacokinetic profile and metabolic stability of the (68)Ga-NODAGA-radiotracers were investigated by small animal PET in rodent. Ghrelin derived agonists presented very high kidney accumulation, negligible tissue distribution, fast blood clearance, and poor stability in blood. Contrarily, the inverse agonist radiotracer exhibited very high stability in blood, large diffusion in tissues, reasonable kidney and liver metabolism, and slow blood clearance. This pharmacokinetic profile makes the ghrelin inverse agonist motif KwFwLL-CONH(2) suitable for further development of radiotracers and a promising lead to design peptide-based therapeutics against obesity. PMID:22372770

  19. A novel rabies virus lipopeptide provides a better protection by improving the magnitude of DCs activation and T cell responses.

    PubMed

    Liu, Rui; Wang, Jingbo; Yang, Yan; Khan, Inamullah; Dong, Yue; Zhu, Naishuo

    2016-08-01

    Besides rabies virus neutralizing antibody, non-neutralizing antibody to internal vital proteins, interferon, and possibly cell-mediated immunity also have a critical role in preventing the infection by rabies virus (RV). We identified novel CTL and Th epitopes which could induce lymphocyte proliferation and IFN-γ, IL-4 production, and designed linear and branched lipopeptides with these selected CTL and Th epitopes. Compared to linear construct, branched lipopeptides, especially Lipo C, stimulate stronger phenotypic and functional maturation of DCs, as well as more efficient CD8(+) T cell responses, evaluating by using FACS, G333-341 tetramer staining and specific CTL assay. Lipo C could also assist rabies vaccine to induce an instant rabies virus neutralizing antibody production, and better protection against rabies virus challenge at early stage. These data reveal that Lipo C could be a promising component for developing novel rabies vaccines. PMID:27182006

  20. Agonist treatment in opioid use: advances and controversy.

    PubMed

    Viswanath, Biju; Chand, Prabhat; Benegal, Vivek; Murthy, Pratima

    2012-06-01

    Opioid dependence is a chronic relapsing condition which requires comprehensive care; pharmacological agents form the mainstay of its long term treatment. The two most popular approaches are the harm reduction method using agonists and the complete abstinence method using antagonists. Currently, particularly from the harm minimization perspective and the low feasibility of an abstinence based approach, there is an increasing trend toward agonist treatment. The use of buprenorphine has gained popularity in view of its safety profile and the availability of the buprenorphine-naloxone combination has made it popular as a take-home treatment. This review outlines the pharmacological advances and controversies in this area. PMID:22813654

  1. Insect Nicotinic Receptor Agonists as Flea Adulticides in Small Animals

    PubMed Central

    Vo, Dai Tan; Hsu, Walter H.; Martin, Richard J.

    2013-01-01

    Fleas are significant ectoparasites of small animals. They can be a severe irritant to animals and serve as a vector for a number of infectious diseases. In this article, we discuss the pharmacological characteristics of four insect nicotinic acetylcholine receptor (nAChR) agonists used as fleacides in dogs and cats, which include three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) and spinosad. Insect nAChR agonists are one of the most important new classes of insecticides, which are used to control sucking insects both on plants and on companion animals. These new compounds provide a new approach for practitioners to safely and effectively eliminate fleas. PMID:20646191

  2. Beta2-agonist extraction procedures for chromatographic analysis.

    PubMed

    dos Ramos, F J

    2000-06-01

    Normally, different procedures were necessary to prepare sample matrices for chromatographic determination of beta2-agonists. The present review includes sampling, pre-treatment and extraction/purification for urine, plasma, liver, meat, feeds, hair and milk powder, as previous steps for chromatographic analysis of beta2-agonists. Six methodologies were especially revised for extraction/purification namely, liquid-liquid extraction, solid-phase extraction (SPE), matrix solid-phase dispersion, immunoaffinity chromatography, dialysis and supercritical fluid extraction. SPE was discussed in detail and five mechanisms were described: adsorption, apolar, polar, ion-exchange and mixed phase. A brief conclusion in this field was also outlined.

  3. Pulmonary Allergic Responses Augment IL-13 Secretion by Circulating Basophils yet Suppress IFN-alpha from Plasmacytoid DCs

    PubMed Central

    Schroeder, John T.; Bieneman, Anja P.; Chichester, Kristin L.; Breslin, Linda; Xiao, HuiQing; Liu, Mark C.

    2011-01-01

    Background Allergic inflammatory processes may have the capacity to propagate systemically through the actions of circulating leukocytes. Consequently, basophils from allergic individuals are often “primed”, as evidenced by their hyper-responsiveness in vitro. IFN-α, secreted predominately by plasmacytoid DCs, suppresses basophil priming for IL-13 production in vitro. Objective This study sought in vivo correlates, arising during experimental allergen challenge, that support an “axis-interplay” between basophils and pDCs. Methods Using segmental allergen challenge in the lung, the immune responses of both cell types from blood were investigated in volunteers (n=10) before and 24h after allergen exposure. These responses were then correlated with inflammatory parameters measured in bronchoalveolar lavage fluids. Results In blood, segmental allergen challenge significantly augmented IL-13 secretion by basophils induced by IL-3 (p=0.009) yet reduced IFN-α secreted by plasmacytoid dendritic cells stimulated with CpG (p=0.018). Both parameters were negatively correlated (p=0.0015), at least among those subjects secreting the latter. Circulating basophil IL-13 responses further correlated with post-segmental allergen challenge bronchoalveolar lavage parameters including IL-13 protein (p=0.04), basophil (p=0.051), eosinophil (p=0.0018) and total cell counts (p<0.003). Basophil and IL-13 levels in bronchoalveolar lavage likewise correlated (p=0.0002). Conclusions These results support a mechanism of immune regulation whereby allergen reduces innate immune responses and IFN-α production by plasmacytoid dendritic cells, resulting in enhanced inflammation and basophil cytokine production at sites of allergen exposure. PMID:20184608

  4. The combined effects of neurostimulation and priming on creative thinking. A preliminary tDCS study on dorsolateral prefrontal cortex

    PubMed Central

    Colombo, Barbara; Bartesaghi, Noemi; Simonelli, Luisa; Antonietti, Alessandro

    2015-01-01

    The role of prefrontal cortex (PFC) in influencing creative thinking has been investigated by many researchers who, while succeeding in proving an effective involvement of PFC, reported suggestive but sometimes conflicting results. In order to better understand the relationships between creative thinking and brain activation in a more specific area of the PFC, we explored the role of dorsolateral PFC (DLPFC). We devised an experimental protocol using transcranial direct-current stimulation (tDCS). The study was based on a 3 (kind of stimulation: anodal vs. cathodal vs. sham) × 2 (priming: divergent vs. convergent) design. Forty-five healthy adults were randomly assigned to one stimulation condition. Participants’ creativity skills were assessed using the Product Improvement subtest from the Torrance Tests of Creative Thinking (TTCT). After 20 min of tDCS stimulation, participants were presented with visual images of common objects. Half of the participants were instructed to visualize themselves using the object in an unusual way (divergent priming), whereas the other half were asked to visualize themselves while using the object in a common way (convergent priming). Priming was aimed at inducing participants to adopt different attitudes toward the creative task. Afterwards, participants were asked to describe all of the possible uses of the objects that were presented. Participants’ physiological activation was recorded using a biofeedback equipment. Results showed a significant effect of anodal stimulation that enhanced creative performance, but only after divergent priming. Participants showed lower skin temperature values after cathodal stimulation, a finding which is coherent with studies reporting that, when a task is not creative or creative thinking is not prompted, people show lower levels of arousal. Differences in individual levels of creativity as assessed by the Product Improvement test were not influential. The involvement of DLPFC in creativity

  5. Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

    PubMed Central

    Puri, Rohan; Hinder, Mark R.; Fujiyama, Hakuei; Gomez, Rapson; Carson, Richard G.; Summers, Jeffery J.

    2015-01-01

    The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations. PMID

  6. The effects of anodal-tDCS on corticospinal excitability enhancement and its after-effects: conventional vs. unihemispheric concurrent dual-site stimulation

    PubMed Central

    Vaseghi, Bita; Zoghi, Maryam; Jaberzadeh, Shapour

    2015-01-01

    Previous researchers have approved the ability of anodal transcranial direct current stimulation (a-tDCS) of the primary motor cortex (M1) to enhance corticospinal excitability (CSE). The primary aim of the current study was to investigate the effect of concurrent stimulation of M1 and a functionally connected cortical site of M1 on CSE modulation. This new technique is called unihemispheric concurrent dual-site a-tDCS (a-tDCSUHCDS). The secondary aim was to investigate the mechanisms underlying the efficacy of this new approach in healthy individuals. In a randomized crossover study, 12 healthy right-handed volunteers received a-tDCS under five conditions: a-tDCS of M1, a-tDCSUHCDS of M1-dorsolateral prefrontal cortex (DLPFC), a-tDCSUHCDS of M1-primary sensory cortex (S1), a-tDCSUHCDS of M1-primary visual cortex (V1), and sham a-tDCSUHCDS. Peak-to-peak amplitude of transcranial magnetic stimulation (TMS) induced MEPs, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were assessed before and four times after each condition. A-tDCSUHCDS conditions induced larger MEPs than conventional a-tDCS. The level of M1 CSE was significantly higher following a-tDCSUHCDS of M1-DLPFC than other a-tDCSUHCDS conditions (p < 0.001), and lasted for over 24 h. The paired-pulse TMS results after a-tDCS of M1-DLPFC showed significant facilitatory increase and inhibitory change. A-tDCSUHCDS of M1-DLPFC increases M1 CSE twofold that of conventional a-tDCS. A-tDCSUHCDS of M1-DLPFC enhances the activity of glutamergic mechanisms for at least 24 h. Such long-lasting M1 CSE enhancement induced by a-tDCSUHCDS of M1-DLPFC could be a valuable finding in clinical scenarios such as learning, motor performance, or pain management. The present study has been registered on the Australian New Zealand Clinical Trial at http://www.anzctr.org.au/ with registry number of ACTRN12614000817640. PMID:27242498

  7. Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training.

    PubMed

    Grecco, Luanda A Collange; Oliveira, Claudia Santos; Galli, Manuela; Cosmo, Camila; Duarte, Natália de Almeida Carvalho; Zanon, Nelci; Edwards, Dylan J; Fregni, Felipe

    2016-01-01

    The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. PMID:27486393

  8. Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training.

    PubMed

    Grecco, Luanda A Collange; Oliveira, Claudia Santos; Galli, Manuela; Cosmo, Camila; Duarte, Natália de Almeida Carvalho; Zanon, Nelci; Edwards, Dylan J; Fregni, Felipe

    2016-01-01

    The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics.

  9. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway.

    PubMed

    Anipindi, Varun C; Bagri, Puja; Roth, Kristy; Dizzell, Sara E; Nguyen, Philip V; Shaler, Christopher R; Chu, Derek K; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P; Stampfli, Martin R; Kaushic, Charu

    2016-05-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway.

  10. Complete elimination of established neuroblastoma by synergistic action of gamma-irradiation and DCs treated with rSeV expressing interferon-beta gene.

    PubMed

    Tatsuta, K; Tanaka, S; Tajiri, T; Shibata, S; Komaru, A; Ueda, Y; Inoue, M; Hasegawa, M; Suita, S; Sueishi, K; Taguchi, T; Yonemitsu, Y

    2009-02-01

    Dendritic cell (DC)-based immunotherapy has been investigated as a new therapeutic approach to intractable neuroblastomas; however, only limited clinical effect has been reported. To overcome the relatively low sensitivity of neuroblastomas against immunotherapy, we undertook a preclinical efficacy study to examine murine models to assess the combined effects of gamma-irradiation pretreatment and recombinant Sendai virus (ts-rSeV/dF)-mediated murine interferon-beta (mIFN-beta) gene transfer to DCs using established c1300 neuroblastomas. Similar to intractable neuroblastomas in the clinic, established c1300 tumors were highly resistant to monotherapy with either gamma-irradiation or DCs activated by ts-rSeV/dF without transgene (ts-rSeV/dF-null) that has been shown to be effective against other murine tumors, including B16F10 melanoma. In contrast, immunotherapy using DCs expressing mIFN-beta through ts-rSeV/dF (ts-rSeV/dF-mIFNbeta-DCs) effectively reduced tumor size, and its combination with gamma-irradiation pretreatment dramatically enhanced its antitumor effect, resulting frequently in the complete elimination of established c1300 tumors 7-9 mm in diameter, in a high survival rate among mice, and in the development of protective immunity in the mice against rechallenge by the tumor cells. These results indicate that the combination of ts-rSeV/dF-mIFNbeta-DCs with gamma-irradiation is a hopeful strategy for the treatment of intractable neuroblastomas, warranting further investigation in the clinical setting.

  11. Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions.

    PubMed

    Herrmann, Martin J; Beier, Jennifer S; Simons, Bibiane; Polak, Thomas

    2016-01-01

    Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F (2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t (24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders. PMID:27462211

  12. Beta Band Transcranial Alternating (tACS) and Direct Current Stimulation (tDCS) Applied After Initial Learning Facilitate Retrieval of a Motor Sequence

    PubMed Central

    Krause, Vanessa; Meier, Anna; Dinkelbach, Lars; Pollok, Bettina

    2016-01-01

    The primary motor cortex (M1) contributes to the acquisition and early consolidation of a motor sequence. Although the relevance of M1 excitability for motor learning has been supported, the significance of M1 oscillations remains an open issue. This study aims at investigating to what extent retrieval of a newly learned motor sequence can be differentially affected by motor-cortical transcranial alternating (tACS) and direct current stimulation (tDCS). Alpha (10 Hz), beta (20 Hz) or sham tACS was applied in 36 right-handers. Anodal or cathodal tDCS was applied in 30 right-handers. Participants learned an eight-digit serial reaction time task (SRTT; sequential vs. random) with the right hand. Stimulation was applied to the left M1 after SRTT acquisition at rest for 10 min. Reaction times were analyzed at baseline, end of acquisition, retrieval immediately after stimulation and reacquisition after eight further sequence repetitions. Reaction times during retrieval were significantly faster following 20 Hz tACS as compared to 10 Hz and sham tACS indicating a facilitation of early consolidation. tDCS yielded faster reaction times, too, independent of polarity. No significant differences between 20 Hz tACS and tDCS effects on retrieval were found suggesting that 20 Hz effects might be associated with altered motor-cortical excitability. Based on the behavioral modulation yielded by tACS and tDCS one might speculate that altered motor-cortical beta oscillations support early motor consolidation possibly associated with neuroplastic reorganization. PMID:26834593

  13. Transcranial Direct Current Stimulation (tDCS) of the Right Inferior Frontal Gyrus Attenuates Skin Conductance Responses to Unpredictable Threat Conditions

    PubMed Central

    Herrmann, Martin J.; Beier, Jennifer S.; Simons, Bibiane; Polak, Thomas

    2016-01-01

    Patients with panic and post-traumatic stress disorders seem to show increased psychophysiological reactions to conditions of unpredictable (U) threat, which has been discussed as a neurobiological marker of elevated levels of sustained fear in these disorders. Interestingly, a recent study found that the right inferior frontal gyrus (rIFG) is correlated to the successful regulation of sustained fear during U threat. Therefore this study aimed to examine the potential use of non-invasive brain stimulation to foster the rIFG by means of anodal transcranial direct current stimulation (tDCS) in order to reduce psychophysiological reactions to U threat. Twenty six participants were randomly assigned into an anodal and sham stimulation group in a double-blinded manner. Anodal and cathodal electrodes (7 * 5 cm) were positioned right frontal to target the rIFG. Stimulation intensity was I = 2 mA applied for 20 min during a task including U threat conditions (NPU-task). The effects of the NPU paradigm were measured by assessing the emotional startle modulation and the skin conductance response (SCR) at the outset of the different conditions. We found a significant interaction effect of condition × tDCS for the SCR (F(2,48) = 6.3, p < 0.01) without main effects of condition and tDCS. Post hoc tests revealed that the increase in SCR from neutral (N) to U condition was significantly reduced in verum compared to the sham tDCS group (t(24) = 3.84, p < 0.001). Our results emphasize the causal role of rIFG for emotional regulation and the potential use of tDCS to reduce apprehension during U threat conditions and therefore as a treatment for anxiety disorders. PMID:27462211

  14. Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training

    PubMed Central

    Grecco, Luanda A. Collange; Oliveira, Claudia Santos; Galli, Manuela; Cosmo, Camila; Duarte, Natália de Almeida Carvalho; Zanon, Nelci; Edwards, Dylan J.; Fregni, Felipe

    2016-01-01

    The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non-respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double-blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. PMID:27486393

  15. Estradiol Enhances CD4+ T-Cell Anti-Viral Immunity by Priming Vaginal DCs to Induce Th17 Responses via an IL-1-Dependent Pathway

    PubMed Central

    Anipindi, Varun C.; Dizzell, Sara E.; Nguyen, Philip V.; Shaler, Christopher R.; Chu, Derek K.; Jiménez-Saiz, Rodrigo; Liang, Hong; Swift, Stephanie; Nazli, Aisha; Kafka, Jessica K.; Bramson, Jonathan; Xing, Zhou; Jordana, Manel; Wan, Yonghong; Snider, Denis P.; Stampfli, Martin R.; Kaushic, Charu

    2016-01-01

    Clinical and experimental studies have shown that estradiol (E2) confers protection against HIV and other sexually transmitted infections. Here, we investigated the underlying mechanism. Better protection in E2-treated mice, immunized against genital HSV-2, coincided with earlier recruitment and higher proportions of Th1 and Th17 effector cells in the vagina post-challenge, compared to placebo-treated controls. Vaginal APCs isolated from E2-treated mice induced 10-fold higher Th17 and Th1 responses, compared to APCs from progesterone-treated, placebo-treated, and estradiol-receptor knockout mice in APC-T cell co-cultures. CD11c+ DCs in the vagina were the predominant APC population responsible for priming these Th17 responses, and a potent source of IL-6 and IL-1β, important factors for Th17 differentiation. Th17 responses were abrogated in APC-T cell co-cultures containing IL-1β KO, but not IL-6 KO vaginal DCs, showing that IL-1β is a critical factor for Th17 induction in the genital tract. E2 treatment in vivo directly induced high expression of IL-1β in vaginal DCs, and addition of IL-1β restored Th17 induction by IL-1β KO APCs in co-cultures. Finally, we examined the role of IL-17 in anti-HSV-2 memory T cell responses. IL-17 KO mice were more susceptible to intravaginal HSV-2 challenge, compared to WT controls, and vaginal DCs from these mice were defective at priming efficient Th1 responses in vitro, indicating that IL-17 is important for the generation of efficient anti-viral memory responses. We conclude that the genital mucosa has a unique microenvironment whereby E2 enhances CD4+ T cell anti-viral immunity by priming vaginal DCs to induce Th17 responses through an IL-1-dependent pathway. PMID:27148737

  16. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents. PMID:27194194

  17. Systemic cancer immunotherapy with Toll-like receptor 7 agonists

    PubMed Central

    Hotz, Christian; Bourquin, Carole

    2012-01-01

    Toll-like receptor (TLR) 7 agonists represent a promising strategy for the immunotherapy of cancer. We have recently investigated the influence of TLR tolerance on the efficacy of systemic tumor treatment with TLR7 ligands. We propose that considering the kinetics of receptor sensitivity highly improves the outcome of cancer immunotherapy. PMID:22720251

  18. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants. PMID:27476423

  19. The emerging therapeutic roles of κ-opioid agonists.

    PubMed

    Jones, Mark R; Kaye, Alan D; Kaye, Aaron J; Urman, Richard D

    2016-01-01

    The current practice of μ-opioid receptor agonists such as morphine as the primary means of acute and chronic pain relief has several dangerous consequences that limit their effectiveness, including respiratory depression, gastrointestinal motility inhibition, addiction, tolerance, and abuse. Several other opioid receptors, notably the μ-opioid (KOP) receptor, have long been known to play a role in pain relief. Recent discoveries and advancements in laboratory techniques have allowed significant developments of KOP agonists as potential novel therapies for pain relief and other pathological processes. These drugs exhibit none of the classic opioid adverse effects and have displayed pronounced analgesia in several different scenarios. New formulations since 2014 have unveiled increased oral bioavailability, exceptional peripheral versus central selectivity, and a positive safety profile. Continued refinements of established μ-opioid agonist formulations have virtually eliminated the centrally mediated side effects of dysphoria and sedation that limited the applicability of previous KOP agonists. Further research is required to better elucidate the potential of these compounds in pain management, as well as in the mediation or modulation of other complex pathophysiological processes as therapeutic agents.

  20. Synthesis and immunostimulatory activity of substituted TLR7 agonists.

    PubMed

    Akinbobuyi, Babatope; Wang, Lei; Upchurch, Katherine C; Byrd, Matthew R; Chang, Charles A; Quintana, Jeremy M; Petersen, Rachel E; Seifert, Zacharie J; Boquin, José R; Oh, SangKon; Kane, Robert R

    2016-09-01

    Fifteen new substituted adenines were synthesized as potential TLR7 agonists. These compounds, along with 9 previously reported compounds, were analyzed for TLR7 activity and for the selective stimulation of B cell proliferation. Several functionalized derivatives exhibit significant activity, suggesting their potential for use as vaccine adjuvants.

  1. Activation of endplate nicotinic acetylcholine receptors by agonists.

    PubMed

    Auerbach, Anthony

    2015-10-15

    The interaction of a small molecule made in one cell with a large receptor made in another is the signature event of cell signaling. Understanding the structure and energy changes associated with agonist activation is important for engineering drugs, receptors and synapses. The nicotinic acetylcholine receptor (AChR) is a ∼300kD ion channel that binds the neurotransmitter acetylcholine (ACh) and other cholinergic agonists to elicit electrical responses in the central and peripheral nervous systems. This mini-review is in two sections. First, general concepts of skeletal muscle AChR operation are discussed in terms of energy landscapes for conformational change. Second, adult vs. fetal AChRs are compared with regard to interaction energies between ACh and agonist-site side chains, measured by single-channel electrophysiology and molecular dynamics simulations. The five aromatic residues that form the core of each agonist binding site can be divided into two working groups, a triad (led by αY190) that behaves similarly at all sites and a coupled pair (led by γW55) that has a large influence on affinity only in fetal AChRs. Each endplate AChR has 5 homologous subunits, two of α(1) and one each of β, δ, and either γ (fetal) or ϵ (adult). These nicotinic AChRs have only 2 functional agonist binding sites located in the extracellular domain, at αδ and either αγ or αϵ subunit interfaces. The receptor undergoes a reversible, global isomerization between structures called C and O. The C shape does not conduct ions and has a relatively low affinity for ACh, whereas O conducts cations and has a higher affinity. When both agonist sites are empty (filled only with water) the probability of taking on the O conformation (PO) is low, <10(-6). When ACh molecules occupy the agonist sites the C→O opening rate constant and C↔O gating equilibrium constant increase dramatically. Following a pulse of ACh at the nerve-muscle synapse, the endplate current rises rapidly

  2. Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

    PubMed

    Craft, R M; Bernal, S A

    2001-08-01

    A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects. PMID:11418226

  3. Synthesis and structure-activity relationships of novel indazolyl glucocorticoid receptor partial agonists.

    PubMed

    Gilmore, John L; Sheppeck, James E; Wang, Jim; Dhar, T G Murali; Cavallaro, Cullen; Doweyko, Arthur M; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Nadler, Steven G; Dodd, John H; Somerville, John E; Barrish, Joel C

    2013-10-01

    SAR was used to further develop an indazole class of non-steroidal glucocorticoid receptor agonists aided by a GR LBD (ligand-binding domain)-agonist co-crystal structure described in the accompanying paper. Progress towards discovering a dissociated GR agonist guided by human in vitro assays biased the optimization of this compound series towards partial agonists that possessed excellent selectivity against other nuclear hormone receptors. PMID:23916594

  4. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

    SciTech Connect

    Washburn, David G.; Hoang, Tram H.; Campobasso, Nino; Smallwood, Angela; Parks, Derek J.; Webb, Christine L.; Frank, Kelly A.; Nord, Melanie; Duraiswami, Chaya; Evans, Christopher; Jaye, Michael; Thompson, Scott K.

    2009-03-27

    A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXR{alpha} will be disclosed.

  5. Agonists and partial agonists of rhodopsin: retinal polyene methylation affects receptor activation.

    PubMed

    Vogel, Reiner; Lüdeke, Steffen; Siebert, Friedrich; Sakmar, Thomas P; Hirshfeld, Amiram; Sheves, Mordechai

    2006-02-14

    Using Fourier transform infrared (FTIR) difference spectroscopy, we have studied the impact of sites and extent of methylation of the retinal polyene with respect to position and thermodynamic parameters of the conformational equilibrium between the Meta I and Meta II photoproducts of rhodopsin. Deletion of methyl groups to form 9-demethyl and 13-demethyl analogues, as well as addition of a methyl group at C10 or C12, shifted the Meta I/Meta II equilibrium toward Meta I, such that the retinal analogues behaved like partial agonists. This equilibrium shift resulted from an apparent reduction of the entropy gain of the transition of up to 65%, which was only partially offset by a concomitant reduction of the enthalpy increase. The analogues produced Meta II photoproducts with relatively small alterations, while their Meta I states were significantly altered, which accounted for the aberrant transitions to Meta II. Addition of a methyl group at C14 influenced the thermodynamic parameters but had little impact on the position of the Meta I/Meta II equilibrium. Neutralization of the residue 134 in the E134Q opsin mutant increased the Meta II content of the 13-demethyl analogue, but not of the 9-demethyl analogue, indicating a severe impairment of the allosteric coupling between the conserved cytoplasmic ERY motif involved in proton uptake and the Schiff base/Glu 113 microdomain in the 9-demethyl analogue. The 9-methyl group appears therefore essential for the correct positioning of retinal to link protonation of the cytoplasmic motif with protonation of Glu 113 during receptor activation.

  6. Illegal use of beta-adrenergic agonists: European Community.

    PubMed

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated

  7. Cell type and gene-specific activity of the retinoid inverse agonist AGN 193109: divergent effects from agonist at retinoic acid receptor gamma in human keratinocytes.

    PubMed

    Thacher, S M; Nagpal, S; Klein, E S; Arefieg, T; Krasinski, G; DiSepio, D; Agarwal, C; Johnson, A; Eckert, R L; Chandraratna, R A

    1999-04-01

    Retinoids are important regulators of epithelial differentiation. AGN 193109 is a high-affinity antagonist and inverse agonist for the nuclear retinoic acid receptors (RARs). Paradoxically, both AGN 193109 and retinoid agonists inhibit the expression of the differentiation marker MRP-8 in normal human keratinocytes (NHKs). TTNPB, an RAR agonist, and AGN 193109 mutually antagonize MRP-8 inhibition at both mRNA and protein levels. We find that this antagonism, which is greatest at an AGN 193109:TTNPB ratio of about 10:1, is absent when either compound is in significant excess. The potent RARalpha-specific agonist, AGN 193836, has no effect on MRP-8 regulation. These data indicate that inverse agonists and agonists suppress MRP-8 in NHKs through RARgamma using distinct and mutually inhibitory mechanisms. The activity of AGN 193109 on MRP-8 is cell type specific. In differentiating ECE16-1 cervical cells, TTNPB inhibits while AGN 193109 induces MRP-8 mRNA levels. The effect of AGN 193109 on genes inhibited by retinoid agonists in NHKs is also selective; expression of the differentiation markers transglutaminase 1 and keratin 6 is not down-regulated by AGN 193109 whereas stromelysin-1 expression is suppressed. These results show a complex gene and cell context-specific interplay between agonist and inverse agonist for the regulation of gene expression.

  8. Pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders across the lifespan

    PubMed Central

    Doyle, Carolyn A.; McDougle, Christopher J.

    2012-01-01

    This review outlines pharmacologic treatments for the behavioral symptoms associated with autism spectrum disorders (ASDs) in children, adolescents, and adults. Symptom domains include repetitive and stereotyped behaviors, irritability and aggression, hyperactivity and inattention, and social impairment. Medications covered include serotonin reuptake inhibitors (SRIs), mirtazapine, antipsychotics, psychostimulants, atomoxetine, α-2 agonists, D-cycloserine, and memantine. Overall, SRIs are less efficacious and more poorly tolerated in children with ASDs than in adults. Antipsychotics are the most efficacious drugs for the treatment of irritability in ASDs, and may be useful in the treatment of other symptoms. Psychostimulants demonstrate some benefit for the treatment of hyperactivity and inattention in individuals with ASDs, but are less efficacious and associated with more adverse effects compared with individuals with ADHD. D-cycloserine and memantine appear helpful in the treatment of social impairment, although further research is needed. PMID:23226952

  9. Agonist-antagonist combinations in opioid dependence: a translational approach

    PubMed Central

    Mannelli, P.

    2011-01-01

    Summary The potential therapeutic benefits of co-administering opiate agonist and antagonist agents remain largely to be investigated. This paper focuses on the mechanisms of very low doses of naltrexone that help modulate the effects of methadone withdrawal and review pharmacological properties of the buprenorphine/naltrexone combination that support its clinical investigation. The bench-to-bedside development of the very low dose naltrexone treatment can serve as a translational paradigm to investigate and treat drug addiction. Further research on putative mechanisms elicited by the use of opioid agonist-antagonist combinations may lead to effective pharmacological alternatives to the gold standard methadone treatment, also useful for the management of the abuse of non opioid drugs and alcohol. PMID:22448305

  10. Orvinols with Mixed Kappa/Mu Opioid Receptor Agonist Activity

    PubMed Central

    2013-01-01

    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [35S]GTPγS assay are predictive of the in vivo profile. PMID:23438330

  11. Orvinols with mixed kappa/mu opioid receptor agonist activity.

    PubMed

    Greedy, Benjamin M; Bradbury, Faye; Thomas, Mark P; Grivas, Konstantinos; Cami-Kobeci, Gerta; Archambeau, Ashley; Bosse, Kelly; Clark, Mary J; Aceto, Mario; Lewis, John W; Traynor, John R; Husbands, Stephen M

    2013-04-25

    Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [(35)S]GTPγS assay are predictive of the in vivo profile.

  12. Grooming, rank, and agonistic support in tufted capuchin monkeys.

    PubMed

    Schino, Gabriele; Di Giuseppe, Francesca; Visalberghi, Elisabetta

    2009-02-01

    Studies investigating the relation between allogrooming and social rank in capuchin monkeys (genus Cebus) have yielded inconsistent results. In this study, we investigated the relation between grooming, agonistic support, aggression and social rank in a captive group of tufted capuchin monkeys (C. apella). Differently from most previous studies, we based our analyses on a relatively large database and studied a group with known genealogical relationships. Tufted capuchin females did not exchange grooming for rank-related benefits such as agonistic support or reduced aggression. Coherently with this picture, they did not groom up the hierarchy and did not compete for accessing high-ranking grooming partners. It is suggested that a small group size, coupled with a strong kin bias, may make the exchange of grooming for rank-related benefits impossible or unprofitable, thus eliminating the advantages of grooming up the hierarchy. We provide several possible explanations for the heterogeneity of results across capuchin studies that have addressed similar questions.

  13. Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics.

    PubMed

    Hämmerer, D; Bonaiuto, J; Klein-Flügge, M; Bikson, M; Bestmann, S

    2016-01-01

    During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition. PMID:27146700

  14. Software for the high-throughput collection of SAXS data using an enhanced Blu-Ice/DCS control system

    PubMed Central

    Classen, Scott; Rodic, Ivan; Holton, James; Hura, Greg L.; Hammel, Michal; Tainer, John A.

    2010-01-01

    Biological small-angle X-ray scattering (SAXS) provides powerful complementary data for macromolecular crystallography (MX) by defining shape, conformation and assembly in solution. Although SAXS is in principle the highest throughput technique for structural biology, data collection is limited in practice by current data collection software. Here the adaption of beamline control software, historically developed for MX beamlines, for the efficient operation and high-throughput data collection at synchrotron SAXS beamlines is reported. The Blu-Ice GUI and Distributed Control System (DCS) developed in the Macromolecular Crystallography Group at the Stanford Synchrotron Radiation Laboratory has been optimized, extended and enhanced to suit the specific needs of the biological SAXS endstation at the SIBYLS beamline at the Advanced Light Source. The customizations reported here provide a potential route for other SAXS beamlines in need of robust and efficient beamline control software. As a great deal of effort and optimization has gone into crystallographic software, the adaption and extension of crystallographic software may prove to be a general strategy to provide advanced SAXS software for the synchrotron community. In this way effort can be put into optimizing features for SAXS rather than reproducing those that have already been successfully implemented for the crystallographic community. PMID:20975223

  15. Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors

    PubMed Central

    Jin, Chuan; Yu, Di; Hillerdal, Victoria; Wallgren, AnnaCarin; Karlsson-Parra, Alex; Essand, Magnus

    2014-01-01

    Adoptive T-cell therapy of cancer is a treatment strategy where T cells are isolated, activated, in some cases engineered, and expanded ex vivo before being reinfused to the patient. The most commonly used T-cell expansion methods are either anti-CD3/CD28 antibody beads or the “rapid expansion protocol” (REP), which utilizes OKT-3, interleukin (IL)-2, and irradiated allogeneic feeder cells. However, REP-expanded or bead-expanded T cells are sensitive to the harsh tumor microenvironment and often short-lived after reinfusion. Here, we demonstrate that when irradiated and preactivated allosensitized allogeneic lymphocytes (ASALs) are used as helper cells to license OKT3-armed allogeneic mature dendritic cells (DCs), together they expand target T cells of high quality. The ASAL/DC combination yields an enriched Th1-polarizing cytokine environment (interferon (IFN)-γ, IL-12, IL-2) and optimal costimulatory signals for T-cell stimulation. When genetically engineered antitumor T cells were expanded by this coculture system, they showed better survival and cytotoxic efficacy under oxidative stress and immunosuppressive environment, as well as superior proliferative response during tumor cell killing compared to the REP protocol. Our result suggests a robust ex vivo method to expand T cells with improved quality for adoptive cancer immunotherapy. PMID:26015949

  16. Selective alteration of human value decisions with medial frontal tDCS is predicted by changes in attractor dynamics

    PubMed Central

    Hämmerer, D.; Bonaiuto, J.; Klein-Flügge, M.; Bikson, M.; Bestmann, S.

    2016-01-01

    During value-based decision making, ventromedial prefrontal cortex (vmPFC) is thought to support choices by tracking the expected gain from different outcomes via a competition-based process. Using a computational neurostimulation approach we asked how perturbing this region might alter this competition and resulting value decisions. We simulated a perturbation of neural dynamics in a biophysically informed model of decision-making through in silico depolarization at the level of neuronal ensembles. Simulated depolarization increased baseline firing rates of pyramidal neurons, which altered their susceptibility to background noise, and thereby increased choice stochasticity. These behavioural predictions were compared to choice behaviour in healthy participants performing similar value decisions during transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique. We placed the soma depolarizing electrode over medial frontal PFC. In line with model predictions, this intervention resulted in more random choices. By contrast, no such effect was observed when placing the depolarizing electrode over lateral PFC. Using a causal manipulation of ventromedial and lateral prefrontal function, these results provide support for competition-based choice dynamics in human vmPFC, and introduce computational neurostimulation as a mechanistic assay for neurostimulation studies of cognition. PMID:27146700

  17. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site.

  18. Dopamine Agonists and the Suppression of Impulsive Motor Actions in Parkinson’s Disease

    PubMed Central

    Wylie, S.A.; Claassen, D.O.; Huizenga, H.M.; Schewel, K.D.; Ridderinkhof, K.R.; Bashore, T.R.; van den Wildenberg, W.P.M.

    2012-01-01

    The suppression of spontaneous motor impulses is an essential facet of cognitive control that is linked to frontal-basal ganglia circuitry. Basal ganglia dysfunction caused by Parkinson’s disease (PD) disrupts the proficiency of action suppression, but how pharmacotherapy for PD impacts impulsive motor control is poorly understood. Dopamine agonists improve motor symptoms of PD, but can also provoke impulsive-compulsive behaviors (ICB). We investigated whether dopamine agonist medication has a beneficial or detrimental effect on impulsive action control in thirty-eight PD patients, half of whom had current ICB. Participants performed the Simon conflict task, which measures susceptibility to acting on spontaneous action impulses as well as the proficiency of suppressing these impulses. Compared to an off agonist state, patients on their agonist were no more susceptible to reacting impulsively, but were less proficient at suppressing the interference from the activation of impulsive actions. Importantly, agonist effects depended on baseline performance in the off agonist state; more proficient suppressors off agonist experienced a reduction in suppression on agonist, whereas less proficient suppressors off agonist showed improved suppression on agonist. Patients with active ICB were actually less susceptible to making fast, impulsive response errors than patients without ICB, suggesting that behavioral problems in this subset of patients may be less related to impulsivity in motor control. Our findings provide further evidence that dopamine agonist medication impacts specific cognitive control processes and that the direction of its effects depends on individual differences in performance off medication. PMID:22571461

  19. Ligand Binding Ensembles Determine Graded Agonist Efficacies at a G Protein-coupled Receptor.

    PubMed

    Bock, Andreas; Bermudez, Marcel; Krebs, Fabian; Matera, Carlo; Chirinda, Brian; Sydow, Dominique; Dallanoce, Clelia; Holzgrabe, Ulrike; De Amici, Marco; Lohse, Martin J; Wolber, Gerhard; Mohr, Klaus

    2016-07-29

    G protein-coupled receptors constitute the largest family of membrane receptors and modulate almost every physiological process in humans. Binding of agonists to G protein-coupled receptors induces a shift from inactive to active receptor conformations. Biophysical studies of the dynamic equilibrium of receptors suggest that a portion of receptors can remain in inactive states even in the presence of saturating concentrations of agonist and G protein mimetic. However, the molecular details of agonist-bound inactive receptors are poorly understood. Here we use the model of bitopic orthosteric/allosteric (i.e. dualsteric) agonists for muscarinic M2 receptors to demonstrate the existence and function of such inactive agonist·receptor complexes on a molecular level. Using all-atom molecular dynamics simulations, dynophores (i.e. a combination of static three-dimensional pharmacophores and molecular dynamics-based conformational sampling), ligand design, and receptor mutagenesis, we show that inactive agonist·receptor complexes can result from agonist binding to the allosteric vestibule alone, whereas the dualsteric binding mode produces active receptors. Each agonist forms a distinct ligand binding ensemble, and different agonist efficacies depend on the fraction of purely allosteric (i.e. inactive) versus dualsteric (i.e. active) binding modes. We propose that this concept may explain why agonist·receptor complexes can be inactive and that adopting multiple binding modes may be generalized also to small agonists where binding modes will be only subtly different and confined to only one binding site. PMID:27298318

  20. Mixed Kappa/Mu Opioid Receptor Agonists: The 6β-Naltrexamines

    PubMed Central

    Cami-Kobeci, Gerta; Neal, Adrian P.; Bradbury, Faye A.; Purington, Lauren C.; Aceto, Mario D.; Harris, Louis S.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.

    2011-01-01

    Ligands from the naltrexamine series have consistently demonstrated agonist activity at kappa opioid receptors (KOR), with varying activity at the mu opioid receptor (MOR). Various 6β-cinnamoylamino derivatives were made with the aim of generating ligands with a KOR agonist/MOR partial agonist profile, as ligands with this activity may be of interest as treatment agents for cocaine abuse. The ligands all displayed the desired high affinity, non-selective binding in vitro and in the functional assays were high efficacy KOR agonists with some partial agonist activity at MOR. Two of the new ligands (12a, 12b) have been evaluated in vivo, with 12a acting as a KOR agonist, and therefore somewhat similar to the previously evaluated analogues 3–6, while 12b displayed predominant MOR agonist activity. PMID:19253970

  1. Octopaminergic agonists for the cockroach neuronal octopamine receptor

    PubMed Central

    Hirashima, Akinori; Morimoto, Masako; Kuwano, Eiichi; Eto, Morifusa

    2003-01-01

    The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor. Abbreviation: AEA arylethanolamine AII 2-(arylimino)imidazolidine AIO 2-(arylimino)oxazolidine AIT 2-(arylimino)thiazolidine APAT 2-(α-phenylethylamino)-2-thiazoline BPAT 2-(β-phenylethylamino)-2-thiazoline CAO 2-(3-chlorobenzylamino)-2-oxazoline DCAO 2-(3,5-dichlorobenzylamino)-2-oxazoline DET5 2-(2,6-diethylphenylimino)-5-methylthiazolidine DET6 2-(2,6-diethylphenylimino)thiazine EGTA ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid GFA genetic function approximation G/PLS genetic partial least squares IND 2-aminomethyl-2-indanol LAH lithium aluminum hydride MCSG maximum common subgroup MCT6 2-(2-methyl-4-chlorophenylimino)thiazine OA octopamine PLS partial least squares QSAR quantitative structure-activity relationship SBAT 2-(substituted benzylamino)-2-thiazoline SD the sum of squared deviations of the dependent variable values from their mean SPIT 3-(substituted phenyl)imidazolidine-2-thione THI 2-amino-1-(2-thiazoyl)ethanol TMS tetramethyl silane PMID:15841226

  2. Newspapers and newspaper ink contain agonists for the ah receptor.

    PubMed

    Bohonowych, Jessica E S; Zhao, Bin; Timme-Laragy, Alicia; Jung, Dawoon; Di Giulio, Richard T; Denison, Michael S

    2008-04-01

    Ligand-dependent activation of the aryl hydrocarbon receptor (AhR) pathway leads to a diverse array of biological and toxicological effects. The best-studied ligands for the AhR include polycyclic and halogenated aromatic hydrocarbons, the most potent of which is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, as new AhR ligands are identified and characterized, their structural and physiochemical diversity continues to expand. Our identification of AhR agonists in crude extracts from diverse materials raises questions as to the magnitude and extent of human exposure to AhR ligands through normal daily activities. We have found that solvent extracts of newspapers from countries around the world stimulate the AhR signaling pathway. AhR agonist activity was observed for dimethyl sulfoxide (DMSO), ethanol, and water extracts of printed newspaper, unprinted virgin paper, and black printing ink, where activation of luciferase reporter gene expression was transient, suggesting that the AhR active chemical(s) was metabolically labile. DMSO and ethanol extracts also stimulated AhR transformation and DNA binding, and also competed with [(3)H]TCDD for binding to the AhR. In addition, DMSO extracts of printed newspaper induced cytochrome P450 1A associated 7-ethoxyresorufin-O-deethylase activity in zebrafish embryos in vivo. Although the responsible bioactive chemical(s) remain to be identified, our results demonstrate that newspapers and printing ink contain relatively potent metabolically labile agonists of the AhR. Given the large amount of recycling and reprocessing of newspapers throughout the world, release of these easily extractable AhR agonists into the environment should be examined and their potential effects on aquatic organisms assessed. PMID:18203687

  3. Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1.

    PubMed

    Aliouane, Lucie; Chao, Sovy; Brizuela, Leyre; Pfund, Emmanuel; Cuvillier, Olivier; Jean, Ludovic; Renard, Pierre-Yves; Lequeux, Thierry

    2014-09-01

    The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported.

  4. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide.

  5. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.

  6. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  7. Antipsychotic Induced Symptomatic Hyperprolactinemia: Are Dopamine Agonists Safe?

    PubMed Central

    Lertxundi, Unax; Domingo-Echaburu, Saioa; Peral, Javier; García, Montserrat

    2011-01-01

    Published literature shows that dopamine agonists can reverse antipsychotic-induced hyperprolactinemia without worsening psychotic symptoms in the majority of schizophrenic patients. However, psychiatrists have been reluctant to use drugs with dopaminergic properties for fear of exacerbating psychiatric symptoms. There are reported cases of psychosis worsening published for both cabergoline and bromocriptine. Cabergoline has proven to be more effective and safe when used to treat hyperprolactinemia, but whether cabergoline is also safer than bromocriptine in antipsychotic induced hyperprolactinemia remains unproven.

  8. A human platelet calcium calculator trained by pairwise agonist scanning.

    PubMed

    Lee, Mei Yan; Diamond, Scott L

    2015-02-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  9. Improving the developability profile of pyrrolidine progesterone receptor partial agonists

    SciTech Connect

    Kallander, Lara S.; Washburn, David G.; Hoang, Tram H.; Frazee, James S.; Stoy, Patrick; Johnson, Latisha; Lu, Qing; Hammond, Marlys; Barton, Linda S.; Patterson, Jaclyn R.; Azzarano, Leonard M.; Nagilla, Rakesh; Madauss, Kevin P.; Williams, Shawn P.; Stewart, Eugene L.; Duraiswami, Chaya; Grygielko, Eugene T.; Xu, Xiaoping; Laping, Nicholas J.; Bray, Jeffrey D.; Thompson, Scott K.

    2010-09-17

    The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.

  10. A Human Platelet Calcium Calculator Trained by Pairwise Agonist Scanning

    PubMed Central

    Lee, Mei Yan; Diamond, Scott L.

    2015-01-01

    Since platelet intracellular calcium mobilization [Ca(t)]i controls granule release, cyclooxygenase-1 and integrin activation, and phosphatidylserine exposure, blood clotting simulations require prediction of platelet [Ca(t)]i in response to combinatorial agonists. Pairwise Agonist Scanning (PAS) deployed all single and pairwise combinations of six agonists (ADP, convulxin, thrombin, U46619, iloprost and GSNO used at 0.1, 1, and 10xEC50; 154 conditions including a null condition) to stimulate platelet P2Y1/P2Y12 GPVI, PAR1/PAR4, TP, IP receptors, and guanylate cyclase, respectively, in Factor Xa-inhibited (250 nM apixaban), diluted platelet rich plasma that had been loaded with the calcium dye Fluo-4 NW. PAS of 10 healthy donors provided [Ca(t)]i data for training 10 neural networks (NN, 2-layer/12-nodes) per donor. Trinary stimulations were then conducted at all 0.1x and 1xEC50 doses (160 conditions) as was a sampling of 45 higher ordered combinations (four to six agonists). The NN-ensemble average was a calcium calculator that accurately predicted [Ca (t)]i beyond the single and binary training set for trinary stimulations (R = 0.924). The 160 trinary synergy scores, a normalized metric of signaling crosstalk, were also well predicted (R = 0.850) as were the calcium dynamics (R = 0.871) and high-dimensional synergy scores (R = 0.695) for the 45 higher ordered conditions. The calculator even predicted sequential addition experiments (n = 54 conditions, R = 0.921). NN-ensemble is a fast calcium calculator, ideal for multiscale clotting simulations that include spatiotemporal concentrations of ADP, collagen, thrombin, thromboxane, prostacyclin, and nitric oxide. PMID:25723389

  11. Gonadotropin-releasing hormone agonist-induced pituitary apoplexy

    PubMed Central

    Keane, Fergus; Navin, Patrick; Brett, Francesca; Dennedy, Michael C

    2016-01-01

    Summary Pituitary apoplexy represents an uncommon endocrine emergency with potentially life-threatening consequences. Drug-induced pituitary apoplexy is a rare but important consideration when evaluating patients with this presentation. We describe an unusual case of a patient with a known pituitary macroadenoma presenting with acute-onset third nerve palsy and headache secondary to tumour enlargement and apoplexy. This followed gonadotropin-releasing hormone (GNRH) agonist therapy used to treat metastatic prostate carcinoma. Following acute management, the patient underwent transphenoidal debulking of his pituitary gland with resolution of his third nerve palsy. Subsequent retrospective data interpretation revealed that this had been a secretory gonadotropinoma and GNRH agonist therapy resulted in raised gonadotropins and testosterone. Hence, further management of his prostate carcinoma required GNRH antagonist therapy and external beam radiotherapy. This case demonstrates an uncommon complication of GNRH agonist therapy in the setting of a pituitary macroadenoma. It also highlights the importance of careful, serial data interpretation in patients with pituitary adenomas. Finally, this case presents a unique insight into the challenges of managing a hormonal-dependent prostate cancer in a patient with a secretory pituitary tumour. Learning points While non-functioning gonadotropinomas represent the most common form of pituitary macroadenoma, functioning gonadotropinomas are exceedingly rare. Acute tumour enlargement, with potential pituitary apoplexy, is a rare but important adverse effect arising from GNRH agonist therapy in the presence of both functioning and non-functioning pituitary gonadotropinomas. GNRH antagonist therapy represents an alternative treatment option for patients with hormonal therapy-requiring prostate cancer, who also have diagnosed with a pituitary gonadotropinoma. PMID:27284452

  12. The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women.

    PubMed

    Strickler, Howard D; Martinson, Jeffrey; Desai, Seema; Xie, Xianhong; Burk, Robert D; Anastos, Kathryn; Massad, L Stewart; Minkoff, Howard; Xue, Xiaonan; D'Souza, Gypsyamber; Levine, Alexandra M; Colie, Christine; Watts, D Heather; Palefsky, Joel M; Landay, Alan

    2014-02-01

    Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.

  13. Increased flow precedes remote arteriolar dilations for some microapplied agonists.

    PubMed

    Frame, M D

    2000-04-01

    This study asks which occurs first in time for remote responses: a dilation or a remote change in flow. Arteriolar diameter (approximately 20 microm) and fluorescently labeled red blood cell (RBC) velocity were measured in the cremaster muscle of anesthetized (pentobarbital sodium, 70 mg/kg) hamsters (n = 51). Arterioles were locally stimulated for 60 s with micropipette-applied 10 microg/ml LM-609 (alpha(v)beta(3)-integrin agonist), 10(-3) M adenosine, or 10(-3) M 3-morpholinosydnonimine (SIN-1, nitric oxide donor) as remote response agonists or with 10(-3) M papaverine, which dilates only locally. Observations were made at a remote site 1,200 microm upstream. With LM-609 or adenosine, the RBC velocity increased first (within 5 s), and the remote dilation followed 5-7 s later. N-nitro-L-arginine (100 microM) blocked the LM-609 (100%) and adenosine (60%) remote dilations. SIN-1 induced a concurrent remote dilation and decrease in RBC velocity (approximately 10 s), suggesting the primary signal was to dilate. Papaverine had no remote effects. This study suggests that, although remote responses to some agonists are induced by primary signals to dilate, additionally, network changes in flow can stimulate extensive remote changes in diameter.

  14. Suppression of atherosclerosis by synthetic REV-ERB agonist

    SciTech Connect

    Sitaula, Sadichha; Billon, Cyrielle; Kamenecka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2015-05-08

    The nuclear receptors for heme, REV-ERBα and REV-ERBβ, play important roles in the regulation of metabolism and inflammation. Recently it was demonstrated that reduced REV-ERBα expression in hematopoetic cells in LDL receptor null mice led to increased atherosclerosis. We sought to determine if synthetic REV-ERB agonists that we have developed might have the ability to suppress atherosclerosis in this model. A previously characterized synthetic REV-ERB agonist, SR9009, was used to determine if activation of REV-ERB activity would affect atherosclerosis in LDL receptor deficient mice. Atherosclerotic plaque size was significantly reduced (p < 0.05) in mice administered SR9009 (100 mg/kg) for seven weeks compared to control mice (n = 10 per group). SR9009 treatment of bone marrow-derived mouse macrophages (BMDM) reduced the polarization of BMDMs to proinflammatory M1 macrophage while increasing the polarization of BMDMs to anti-inflammatory M2 macrophages. Our results suggest that pharmacological targeting of REV-ERBs may be a viable therapeutic option for treatment of atherosclerosis. - Highlights: • Synthetic REV-ERB agonist treatment reduced atherosclerosis in a mouse model. • Pharmacological activation of REV-ERB decreased M1 macrophage polarization. • Pharmacological activation of REV-ERB increased M2 macrophage polarization.

  15. Emerging strategies for exploiting cannabinoid receptor agonists as medicines.

    PubMed

    Pertwee, Roger G

    2009-02-01

    Medicines that activate cannabinoid CB(1) and CB(2) receptor are already in the clinic. These are Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol) and Sativex (Delta(9)-tetrahydrocannabinol with cannabidiol). The first two of these medicines can be prescribed to reduce chemotherapy-induced nausea and vomiting. Marinol can also be prescribed to stimulate appetite, while Sativex is prescribed for the symptomatic relief of neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic treatment for adult patients with advanced cancer. One challenge now is to identify additional therapeutic targets for cannabinoid receptor agonists, and a number of potential clinical applications for such agonists are mentioned in this review. A second challenge is to develop strategies that will improve the efficacy and/or the benefit-to-risk ratio of a cannabinoid receptor agonist. This review focuses on five strategies that have the potential to meet either or both of these objectives. These are strategies that involve: (i) targeting cannabinoid receptors located outside the blood-brain barrier; (ii) targeting cannabinoid receptors expressed by a particular tissue; (iii) targeting up-regulated cannabinoid receptors; (iv) targeting cannabinoid CB(2) receptors; or (v) 'multi-targeting'. Preclinical data that justify additional research directed at evaluating the clinical importance of each of these strategies are also discussed. PMID:19226257

  16. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes. PMID:24038158

  17. Structure of the agonist-bound neurotensin receptor.

    PubMed

    White, Jim F; Noinaj, Nicholas; Shibata, Yoko; Love, James; Kloss, Brian; Xu, Feng; Gvozdenovic-Jeremic, Jelena; Shah, Priyanka; Shiloach, Joseph; Tate, Christopher G; Grisshammer, Reinhard

    2012-10-25

    Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

  18. Molecular impact of juvenile hormone agonists on neonatal Daphnia magna.

    PubMed

    Toyota, Kenji; Kato, Yasuhiko; Miyakawa, Hitoshi; Yatsu, Ryohei; Mizutani, Takeshi; Ogino, Yukiko; Miyagawa, Shinichi; Watanabe, Hajime; Nishide, Hiroyo; Uchiyama, Ikuo; Tatarazako, Norihisa; Iguchi, Taisen

    2014-05-01

    Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to understand better the responses to pollutants in aquatic organisms, including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists: methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb) and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical-specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes were clustered as JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for the classification of JH analogs and identification of JH-responsive genes.

  19. Activation of antigen-exposed iMC-DCs at the "right place" and "right time" promotes potent anti-tumor immunity.

    PubMed

    Spencer, David M

    2012-05-01

    To better control the "licensing" of pro-Th1 dendritic cells (DCs), Spencer and colleagues have developed a synthetic ligand-inducible chimeric receptor, iMyD88/CD40 (iMC), incorporating synergistic Toll-like receptor (TLR) and costimulatory signaling elements, permitting DC regulation in vivo within the context of an immunological synapse. This novel technology results in potent anti-cancer activity.

  20. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice.

    PubMed

    Poleszak, Ewa; Wlaź, Piotr; Szewczyk, Bernadeta; Wlaź, Aleksandra; Kasperek, Regina; Wróbel, Andrzej; Nowak, Gabriel

    2011-11-01

    Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and D: -cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and D: -cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or D: -cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and D: -cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by D: -serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.

  1. Combining Exosomes Derived from Immature DCs with Donor Antigen-Specific Treg Cells Induces Tolerance in a Rat Liver Allograft Model.

    PubMed

    Ma, Ben; Yang, Jing-Yue; Song, Wen-Jie; Ding, Rui; Zhang, Zhuo-Chao; Ji, Hong-Chen; Zhang, Xuan; Wang, Jian-Lin; Yang, Xi-Sheng; Tao, Kai-Shan; Dou, Ke-Feng; Li, Xiao

    2016-01-01

    Allograft tolerance is the ultimate goal in the field of transplantation immunology. Immature dendritic cells (imDCs) play an important role in establishing tolerance but have limitations, including potential for maturation, short lifespan in vivo and short storage times in vitro. However, exosomes (generally 30-100 nm) from imDCs (imDex) retain many source cell properties and may overcome these limitations. In previous reports, imDex prolonged the survival time of heart or intestine allografts. However, tolerance or long-term survival was not achieved unless immune suppressants were used. Regulatory T cells (Tregs) can protect allografts from immune rejection, and our previous study showed that the effects of imDex were significantly associated with Tregs. Therefore, we incorporated Tregs into the treatment protocol to further reduce or avoid suppressant use. We defined the optimal exosome dose as approximately 20 μg (per treatment before, during and after transplantation) in rat liver transplantation and the antigen-specific role of Tregs in protecting liver allografts. In the co-treatment group, recipients achieved long-term survival, and tolerance was induced. Moreover, imDex amplified Tregs, which required recipient DCs and were enhanced by IL-2. Fortunately, the expanded Tregs retained their regulatory ability and donor-specificity. Thus, imDex and donor-specific Tregs can collaboratively induce graft tolerance. PMID:27640806

  2. Combining Exosomes Derived from Immature DCs with Donor Antigen-Specific Treg Cells Induces Tolerance in a Rat Liver Allograft Model

    PubMed Central

    Ma, Ben; Yang, Jing-Yue; Song, Wen-jie; Ding, Rui; Zhang, Zhuo-chao; Ji, Hong-chen; Zhang, Xuan; Wang, Jian-lin; Yang, Xi-sheng; Tao, Kai-shan; Dou, Ke-feng; Li, Xiao

    2016-01-01

    Allograft tolerance is the ultimate goal in the field of transplantation immunology. Immature dendritic cells (imDCs) play an important role in establishing tolerance but have limitations, including potential for maturation, short lifespan in vivo and short storage times in vitro. However, exosomes (generally 30–100 nm) from imDCs (imDex) retain many source cell properties and may overcome these limitations. In previous reports, imDex prolonged the survival time of heart or intestine allografts. However, tolerance or long-term survival was not achieved unless immune suppressants were used. Regulatory T cells (Tregs) can protect allografts from immune rejection, and our previous study showed that the effects of imDex were significantly associated with Tregs. Therefore, we incorporated Tregs into the treatment protocol to further reduce or avoid suppressant use. We defined the optimal exosome dose as approximately 20 μg (per treatment before, during and after transplantation) in rat liver transplantation and the antigen-specific role of Tregs in protecting liver allografts. In the co-treatment group, recipients achieved long-term survival, and tolerance was induced. Moreover, imDex amplified Tregs, which required recipient DCs and were enhanced by IL-2. Fortunately, the expanded Tregs retained their regulatory ability and donor-specificity. Thus, imDex and donor-specific Tregs can collaboratively induce graft tolerance. PMID:27640806

  3. Intradermal immunization in the ear with cholera toxin and its non-toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs.

    PubMed

    Meza-Sánchez, David; Pérez-Montesinos, Gibrán; Sánchez-García, Javier; Moreno, José; Bonifaz, Laura C

    2011-10-01

    The nature of CD4(+) T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4(+) T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic β CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-γ and IL-17 by CD4(+) T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4(+) T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-γ activity. These results indicate that both CT and CTB induce an efficient CD4(+) T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.

  4. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A2, S/N 108, 08

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A2, S/N 108, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  5. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 109

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 109, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  6. Integrated Advanced Microwave Sounding Unit-A (AMSU-A). Engineering Test Report: Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1, S/N 108 2

    NASA Technical Reports Server (NTRS)

    Valdez, A.

    2000-01-01

    This is the Engineering Test Report, Radiated Emissions and SARR, SARP, DCS Receivers, Link Frequencies EMI Sensitive Band Test Results, AMSU-A1 SIN 108, for the Integrated Advanced Microwave Sounding Unit-A (AMSU-A).

  7. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR.

    PubMed

    Huang, Wendong; Zhang, Jun; Wei, Ping; Schrader, William T; Moore, David D

    2004-10-01

    The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine (m) and human (h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP)2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. PMID:15272053

  8. Additive antinociceptive effects of mixtures of the κ-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats.

    PubMed

    Maguire, David R; France, Charles P

    2016-02-01

    Pain is a significant clinical problem, and there is a need for pharmacotherapies that are more effective with fewer adverse effects than currently available medications. Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists; it is unclear whether they impact the effects of agonists acting at other opioid receptors. κ-Opioid receptor agonists have antinociceptive effects, but their clinical use is precluded by adverse effects; however, their therapeutic potential might be realized if antinociceptive effects could be selectively enhanced. In this study, the antinociceptive effects of the cannabinoid receptor agonist CP55940 and the κ-opioid receptor agonist spiradoline, alone and in combination, were studied in rats (n=7) using a warm water tail-withdrawal procedure. When administered alone, CP55940 (0.032-1.0 mg/kg) and spiradoline (1.0-32.0 mg/kg) increased tail-withdrawal latency, and mixtures of CP55940 and spiradoline (ratios of 1 : 3, 1 : 1, and 3 : 1) produced additive effects. It remains to be determined whether this additive interaction between a κ-opioid receptor agonist and a cannabinoid receptor agonist is selective for antinociception and whether it can be generalized to other drugs. PMID:26292184

  9. No Effect of 2 mA Anodal tDCS Over the M1 on Performance and Practice Effect on Grooved Pegboard Test and Trail Making Test B1,2,3

    PubMed Central

    Freili, Janita L.; Danielsen, Therese L.; Aslaksen, Per M.

    2015-01-01

    Abstract Previous studies suggest that transcranial direct current stimulation (tDCS) can facilitate motor performance and learning. In this double-blind experiment, 60 healthy human subjects (29 females) were randomized into three groups (active tDCS, sham tDCS, and no-treatment control group) in order to investigate the effect of a 20 min session of 2 mA tDCS over the motor cortex contralateral to the dominant hand on practice effect and performance on the Grooved Pegboard Test (GPT) and Trail Making Test (TMT). Performance was operationalized as the time to complete the tests before, during, and after stimulation. The practice effect was termed as the difference in time to complete the tests from pretest to post-test. Data on body mass index (BMI), head circumference, sleep status, interelectrode impedance, and caffeine and nicotine use were sampled to control for the influence of individual differences on the effect of tDCS. Adverse effects were registered using a standardized form. The results indicated no effect of tDCS on performance and practice effects on the GPT and TMT. For all groups, BMI was a predictor for a practice effect on the TMT. In the active tDCS group, high caffeine intake and low impedance predicted a practice effect on the GPT for the dominant hand. The present results suggest that impedance levels in tDCS studies should be routinely reported in future studies, as it might not only provide valuable information on the efficacy of the blinding conditions and participant discomfort, but also correlate with individual differences that are relevant to the outcome of the stimulation. PMID:26465001

  10. No Effect of 2 mA Anodal tDCS Over the M1 on Performance and Practice Effect on Grooved Pegboard Test and Trail Making Test B(1,2,3).

    PubMed

    Fagerlund, Asbjørn J; Freili, Janita L; Danielsen, Therese L; Aslaksen, Per M

    2015-01-01

    Previous studies suggest that transcranial direct current stimulation (tDCS) can facilitate motor performance and learning. In this double-blind experiment, 60 healthy human subjects (29 females) were randomized into three groups (active tDCS, sham tDCS, and no-treatment control group) in order to investigate the effect of a 20 min session of 2 mA tDCS over the motor cortex contralateral to the dominant hand on practice effect and performance on the Grooved Pegboard Test (GPT) and Trail Making Test (TMT). Performance was operationalized as the time to complete the tests before, during, and after stimulation. The practice effect was termed as the difference in time to complete the tests from pretest to post-test. Data on body mass index (BMI), head circumference, sleep status, interelectrode impedance, and caffeine and nicotine use were sampled to control for the influence of individual differences on the effect of tDCS. Adverse effects were registered using a standardized form. The results indicated no effect of tDCS on performance and practice effects on the GPT and TMT. For all groups, BMI was a predictor for a practice effect on the TMT. In the active tDCS group, high caffeine intake and low impedance predicted a practice effect on the GPT for the dominant hand. The present results suggest that impedance levels in tDCS studies should be routinely reported in future studies, as it might not only provide valuable information on the efficacy of the blinding conditions and participant discomfort, but also correlate with individual differences that are relevant to the outcome of the stimulation.

  11. No Effect of 2 mA Anodal tDCS Over the M1 on Performance and Practice Effect on Grooved Pegboard Test and Trail Making Test B(1,2,3).

    PubMed

    Fagerlund, Asbjørn J; Freili, Janita L; Danielsen, Therese L; Aslaksen, Per M

    2015-01-01

    Previous studies suggest that transcranial direct current stimulation (tDCS) can facilitate motor performance and learning. In this double-blind experiment, 60 healthy human subjects (29 females) were randomized into three groups (active tDCS, sham tDCS, and no-treatment control group) in order to investigate the effect of a 20 min session of 2 mA tDCS over the motor cortex contralateral to the dominant hand on practice effect and performance on the Grooved Pegboard Test (GPT) and Trail Making Test (TMT). Performance was operationalized as the time to complete the tests before, during, and after stimulation. The practice effect was termed as the difference in time to complete the tests from pretest to post-test. Data on body mass index (BMI), head circumference, sleep status, interelectrode impedance, and caffeine and nicotine use were sampled to control for the influence of individual differences on the effect of tDCS. Adverse effects were registered using a standardized form. The results indicated no effect of tDCS on performance and practice effects on the GPT and TMT. For all groups, BMI was a predictor for a practice effect on the TMT. In the active tDCS group, high caffeine intake and low impedance predicted a practice effect on the GPT for the dominant hand. The present results suggest that impedance levels in tDCS studies should be routinely reported in future studies, as it might not only provide valuable information on the efficacy of the blinding conditions and participant discomfort, but also correlate with individual differences that are relevant to the outcome of the stimulation. PMID:26465001

  12. Different serotonin receptor agonists have distinct effects on sound-evoked responses in inferior colliculus.

    PubMed

    Hurley, Laura M

    2006-11-01

    The neuromodulator serotonin has a complex set of effects on the auditory responses of neurons within the inferior colliculus (IC), a midbrain auditory nucleus that integrates a wide range of inputs from auditory and nonauditory sources. To determine whether activation of different types of serotonin receptors is a source of the variability in serotonergic effects, four selective agonists of serotonin receptors in the serotonin (5-HT) 1 and 5-HT2 families were iontophoretically applied to IC neurons, which were monitored for changes in their responses to auditory stimuli. Different agonists had different effects on neural responses. The 5-HT1A agonist had mixed facilitatory and depressive effects, whereas 5-HT1B and 5-HT2C agonists were both largely facilitatory. Different agonists changed threshold and frequency tuning in ways that reflected their effects on spike count. When pairs of agonists were applied sequentially to the same neurons, selective agonists sometimes affected neurons in ways that were similar to serotonin, but not to other selective agonists tested. Different agonists also differentially affected groups of neurons classified by the shapes of their frequency-tuning curves, with serotonin and the 5-HT1 receptors affecting proportionally more non-V-type neurons relative to the other agonists tested. In all, evidence suggests that the diversity of serotonin receptor subtypes in the IC is likely to account for at least some of the variability of the effects of serotonin and that receptor subtypes fulfill specialized roles in auditory processing. PMID:16870843

  13. DCs Pulsed with Novel HLA-A2-Restricted CTL Epitopes against Hepatitis C Virus Induced a Broadly Reactive Anti-HCV-Specific T Lymphocyte Response

    PubMed Central

    Guo, Zhongsheng; Zhang, Henghui; Rao, Huiying; Jiang, Dong; Cong, Xu; Feng, Bo; Wang, Jianghua; Wei, Lai; Chen, Hongsong

    2012-01-01

    Objective To determine the capacity of dendritic cells (DCs) loaded with single or multiple-peptide mixtures of novel hepatitis C virus (HCV) epitopes to stimulate HCV-specific cytotoxic T lymphocyte (CTL) effector functions. Methods A bioinformatics approach was used to predict HLA-A2-restricted HCV-specific CTL epitopes, and the predicted peptides identified from this screen were synthesized. Subsequent IFN-γ ELISPOT analysis detected the stimulating function of these peptides in peripheral blood mononuclear cells (PBMCs) from both chronic and self-limited HCV infected subjects (subjects exhibiting spontaneous HCV clearance). Mature DCs, derived in vitro from CD14+ monocytes harvested from the study subjects by incubation with appropriate cytokine cocktails, were loaded with novel peptide or epitope peptide mixtures and co-cultured with autologous T lymphocytes. Granzyme B (GrB) and IFN-γ ELISPOT analysis was used to test for epitope-specific CTL responses. T-cell-derived cytokines contained in the co-cultured supernatant were detected by flow cytometry. Results We identified 7 novel HLA-A2-restricted HCV-specific CTL epitopes that increased the frequency of IFN-γ-producing T cells compared to other epitopes, as assayed by measuring spot forming cells (SFCs). Two epitopes had the strongest stimulating capability in the self-limited subjects, one found in the E2 and one in the NS2 region of HCV; five epitopes had a strong stimulating capacity in both chronic and self-limited HCV infection, but were stronger in the self-limited subjects. They were distributed in E2, NS2, NS3, NS4, and NS5 regions of HCV, respectively. We also found that mDCs loaded with novel peptide mixtures could significantly increase GrB and IFN-γ SFCs as compared to single peptides, especially in chronic HCV infection subjects. Additionally, we found that DCs pulsed with multiple epitope peptide mixtures induced a Th1-biased immune response. Conclusions Seven novel and strongly stimulating

  14. Cerebellar cathodal tDCS interferes with recalibration and spatial realignment during prism adaptation procedure in healthy subjects.

    PubMed

    Panico, Francesco; Sagliano, Laura; Grossi, Dario; Trojano, Luigi

    2016-06-01

    The aim of this study is to clarify the specific role of the cerebellum during prism adaptation procedure (PAP), considering its involvement in early prism exposure (i.e., in the recalibration process) and in post-exposure phase (i.e., in the after-effect, related to spatial realignment). For this purpose we interfered with cerebellar activity by means of cathodal transcranial direct current stimulation (tDCS), while young healthy individuals were asked to perform a pointing task on a touch screen before, during and after wearing base-left prism glasses. The distance from the target dot in each trial (in terms of pixels) on horizontal and vertical axes was recorded and served as an index of accuracy. Results on horizontal axis, that was shifted by prism glasses, revealed that participants who received cathodal stimulation showed increased rightward deviation from the actual position of the target while wearing prisms and a larger leftward deviation from the target after prisms removal. Results on vertical axis, in which no shift was induced, revealed a general trend in the two groups to improve accuracy through the different phases of the task, and a trend, more visible in cathodal stimulated participants, to worsen accuracy from the first to the last movements in each phase. Data on horizontal axis allow to confirm that the cerebellum is involved in all stages of PAP, contributing to early strategic recalibration process, as well as to spatial realignment. On vertical axis, the improving performance across the different stages of the task and the worsening accuracy within each task phase can be ascribed, respectively, to a learning process and to the task-related fatigue. PMID:27031676

  15. Defining Nicotinic Agonist Binding Surfaces through Photoaffinity Labeling†

    PubMed Central

    Tomizawa, Motohiro; Maltby, David; Medzihradszky, Katalin F.; Zhang, Nanjing; Durkin, Kathleen A.; Presley, Jack; Talley, Todd T.; Taylor, Palmer; Burlingame, Alma L.; Casida, John E.

    2016-01-01

    Nicotinic acetylcholine (ACh) receptor (nAChR) agonists are potential therapeutic agents for neurological dysfunction. In the present study, the homopentameric mollusk ACh binding protein (AChBP), used as a surrogate for the extracellular ligand-binding domain of the nAChR, was specifically derivatized by the highly potent agonist azidoepibatidine (AzEPI) prepared as a photoaffinity probe and radioligand. One EPI-nitrene photoactivated molecule was incorporated in each subunit interface binding site based on analysis of the intact derivatized protein. Tryptic fragments of the modified AChBP were analyzed by collision-induced dissociation and Edman sequencing of radiolabeled peptides. Each specific EPI-nitrene-modified site involved either Tyr195 of loop C on the principal or (+)-face or Met116 of loop E on the complementary or (−)-face. The two derivatization sites were observed in similar frequency, providing evidence of the reactivity of the azido/nitrene probe substituent and close proximity to both residues. [3H]AzEPI binds to the α4β2 nAChR at a single high-affinity site and photoaffinity-labels only the α4 subunit, presumably modifying Tyr225 spatially corresponding to Tyr195 of AChBP. Phe137 of the β2 nAChR subunit, equivalent to Met116 of AChBP, conceivably lacks sufficient reactivity with the nitrene generated from the probe. The present photoaffinity labeling in a physiologically relevant condition combined with the crystal structure of AChBP allows development of precise structural models for the AzEPI interactions with AChBP and α4β2 nAChR. These findings enabled us to use AChBP as a structural surrogate to define the nAChR agonist site. PMID:17614369

  16. [Combination of TLR7 agonist T7-ethacrynic acid conjugate with ROR1 has a stronger anti-breast cancer effect].

    PubMed

    Zhang, Na; Jin, Guangyi; Jin, Zhenchao; Liu, Bing; Peng, Boya; Gao, Ningning; Hu, Yunlong; Tang, Li

    2016-07-01

    Objective To investigate the synergistic anti-breast cancer effect of Toll-like receptor 7 agonist T7-ethacrynic acid conjugate (T7-EA) in combination with receptor-tyrosine-kinase-like orphan receptor 1 (ROR1). Methods ROR1 cytotoxic T lymphocyte (CTL) epitope was predicted using Syfpeithi online software. Mouse spleen lymphocytes and bone marrow dendritic cells (DCs) were separately stimulated with 4 μmol/L T7-EA and 4 μmol/L ROR1 alone or in combination. ELISA assay was used to measure the levels of interferon-γ (IFN-γ), interleukin 12 (IL-12) and tumor necrosis factor-α (TNF-α). Xenograft model was established via subcutaneous injection of mouse breast cancer 4T1 cells. The mice were weekly treated through intraperitoneal administration of 3 mg/kg T7-EA, 15 mg/kg ROR1 or the combination of T7-EA and ROR1. After four rounds of treatment, tumor tissues were weighed. Serum level of anti-4T1 tumor protein IgG was measured by ELISA. Specific CTL activity was detected by lactate dehydrogenase (LDH) assay. Results The peptide PYCDETSSV was chosen as an antigen epitope of breast cancer. The T7-EA highly activated in vitro lymphocytes in a dose-dependent manner, which wasn't affected by other relevant peptides. The combination of T7-EA and ROR1 stimulated the secretion of IFN-γ and IL-12 by lymphocytes and TNF-α by bone marrow DCs. The growth of tumor in vivo was significantly inhibited by T7-EA combined with ROR1 compared with T7-EA or ROR1 alone. The specific CTL activity triggered by T7-EA combined with ROR1 was much stronger than that triggered by T7-EA or ROR1 alone. The titer of anti-4T1 tumor protein IgG induced by T7-EA combined with ROR1 was higher than that induced by T7-EA or ROR1. Conclusion The combination of T7-EA and ROR1 has a better killing effect on breast cancer. PMID:27363264

  17. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight.

  18. Narrow SAR in odorant sensing Orco receptor agonists.

    PubMed

    Romaine, Ian M; Taylor, Robert W; Saidu, Samsudeen P; Kim, Kwangho; Sulikowski, Gary A; Zwiebel, Laurence J; Waterson, Alex G

    2014-06-15

    The systematic exploration of a series of triazole-based agonists of the cation channel insect odorant receptor is reported. The structure-activity relationships of independent sections of the molecules are examined. Very small changes to the compound structure were found to exert a large impact on compound activity. Optimal substitutions were combined using a 'mix-and-match' strategy to produce best-in-class compounds that are capable of potently agonizing odorant receptor activity and may form the basis for the identification of a new mode of insect behavior modification. PMID:24813736

  19. Clenbuterol, a beta(2)-agonist, retards atrophy in denervated muscles

    NASA Technical Reports Server (NTRS)

    Zeman, Richard J.; Ludemann, Robert; Etlinger, Joseph D.

    1987-01-01

    The effects of a beta(2) agonist, clenbuterol, on the protein content as well as on the contractile strength and the muscle fiber cross-sectional area of various denervated muscles from rats were investigated. It was found that denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, of rats treated for 2-3 weeks with clenbuterol contained 95-110 percent more protein than denervated controls. The twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area.

  20. INSIGHT AGONISTES: A READING OF SOPHOCLES'S OEDIPUS THE KING.

    PubMed

    Mahon, Eugene J

    2015-07-01

    In this reading of Sophocles's Oedipus the King, the author suggests that insight can be thought of as the main protagonist of the tragedy. He personifies this depiction of insight, calling it Insight Agonistes, as if it were the sole conflicted character on the stage, albeit masquerading at times as several other characters, including gods, sphinxes, and oracles. This psychoanalytic reading of the text lends itself to an analogy between psychoanalytic process and Sophocles's tragic hero. The author views insight as always transgressing against, always at war with a conservative, societal, or intrapsychic chorus of structured elements. A clinical vignette is presented to illustrate this view of insight. PMID:26198605

  1. Induction of depersonalization by the serotonin agonist meta-chlorophenylpiperazine.

    PubMed

    Simeon, D; Hollander, E; Stein, D J; DeCaria, C; Cohen, L J; Saoud, J B; Islam, N; Hwang, M

    1995-09-29

    Sixty-seven subjects, including normal volunteers and patients with obsessive-compulsive disorder, social phobia, and borderline personality disorder, received ratings of depersonalization after double-blind, placebo-controlled challenges with the partial serotonin agonist meta-chlorophenylpiperazine (m-CPP). Challenge with m-CPP induced depersonalization significantly more than did placebo. Subjects who became depersonalized did not differ in age, sex, or diagnosis from those who did not experience depersonalization. There was a significant correlation between the induction of depersonalization and increase in panic, but not nervousness, anxiety, sadness, depression, or drowsiness. This report suggests that serotonergic dysregulation may in part underlie depersonalization.

  2. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  3. Discovery of a potent and selective GPR120 agonist.

    PubMed

    Shimpukade, Bharat; Hudson, Brian D; Hovgaard, Christine Kiel; Milligan, Graeme; Ulven, Trond

    2012-05-10

    GPR120 is a receptor of unsaturated long-chain fatty acids reported to mediate GLP-1 secretion, insulin sensitization, anti-inflammatory, and anti-obesity effects and is therefore emerging as a new potential target for treatment of type 2 diabetes and metabolic diseases. Further investigation is however hindered by the lack of suitable receptor modulators. Screening of FFA1 ligands provided a lead with moderate activity on GPR120 and moderate selectivity over FFA1. Optimization led to the discovery of the first potent and selective GPR120 agonist.

  4. Contamination with retinoic acid receptor agonists in two rivers in the Kinki region of Japan.

    PubMed

    Inoue, Daisuke; Nakama, Koki; Sawada, Kazuko; Watanabe, Taro; Takagi, Mai; Sei, Kazunari; Yang, Min; Hirotsuji, Junji; Hu, Jianying; Nishikawa, Jun-ichi; Nakanishi, Tsuyoshi; Ike, Michihiko

    2010-04-01

    This study was conducted to investigate the agonistic activity against human retinoic acid receptor (RAR) alpha in the Lake Biwa-Yodo River and the Ina River in the Kinki region of Japan. To accomplish this, a yeast two-hybrid assay was used to elucidate the spatial and temporal variations and potential sources of RARalpha agonist contamination in the river basins. RARalpha agonistic activity was commonly detected in the surface water samples collected along two rivers at different periods, with maximum all-trans retinoic acid (atRA) equivalents of 47.6 ng-atRA/L and 23.5 ng-atRA/L being observed in Lake Biwa-Yodo River and Ina River, respectively. The results indicated that RARalpha agonists are always present and widespread in the rivers. Comparative investigation of RARalpha and estrogen receptor alpha agonistic activities at 20 stations along each river revealed that the spatial variation pattern of RARalpha agonist contamination was entirely different from that of the estrogenic compound contamination. This suggests that the effluent from municipal wastewater treatment plants, a primary source of estrogenic compounds, seemed not to be the cause of RARalpha agonist contamination in the rivers. Fractionation using high performance liquid chromatography (HPLC) directed by the bioassay found two bioactive fractions from river water samples, suggesting the presence of at least two RARalpha agonists in the rivers. Although a trial conducted to identify RARalpha agonists in the major bioactive fraction was not completed as part of this study, comparison of retention times in HPLC analysis and quantification with liquid chromatography-mass spectrometry analysis revealed that the major causative contaminants responsible for the RARalpha agonistic activity were not RAs (natural RAR ligands) and 4-oxo-RAs, while 4-oxo-RAs were identified as the major RAR agonists in sewage in Beijing, China. These findings suggest that there are unknown RARalpha agonists with high

  5. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

    SciTech Connect

    Bass, Jonathan Y.; Caldwell, Richard D.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, Aaron B.; Parks, Derek J.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

    2010-09-27

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  6. Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064.

    PubMed

    Bass, Jonathan Y; Caldwell, Richard D; Caravella, Justin A; Chen, Lihong; Creech, Katrina L; Deaton, David N; Madauss, Kevin P; Marr, Harry B; McFadyen, Robert B; Miller, Aaron B; Parks, Derek J; Todd, Dan; Williams, Shawn P; Wisely, G Bruce

    2009-06-01

    Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.

  7. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.

    PubMed

    Sheppeck, James E; Gilmore, John L; Xiao, Hai-Yun; Dhar, T G Murali; Nirschl, David; Doweyko, Arthur M; Sack, Jack S; Corbett, Martin J; Malley, Mary F; Gougoutas, Jack Z; Mckay, Lorraine; Cunningham, Mark D; Habte, Sium F; Dodd, John H; Nadler, Steven G; Somerville, John E; Barrish, Joel C

    2013-10-01

    Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure. PMID:23953070

  8. In vitro and in vivo efficacy of a potent opioid receptor agonist, biphalin, compared to subtype-selective opioid receptor agonists for stroke treatment

    PubMed Central

    Yang, Li; Islam, Mohammad R; Karamyan, Vardan T.; Abbruscato, Thomas J.

    2015-01-01

    To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10 nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10 nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype. PMID:25801116

  9. Effects of LAAM and methadone utilization in an opiate agonist treatment program.

    PubMed

    Valdivia, J F; Khattak, S

    2000-01-01

    The development and approval of levo-alpha-acetylmethadol (LAAM) as a pharmacotherapeutic agent in opioid agonist therapy provided an alternative to methadone. Clinicians recognized the potential benefits that LAAM, a synthetic mu agonist with pharmacological properties which differ from those of methadone,could have in the treatment management of addicts in opioid agonist therapy. We report our experience utilizing LAAM from 1995 to 1999 at the Hines VA opioid agonist therapy clinic. The addition of LAAM to the clinic's treatment armamentarium has resulted in management options that have improved the areas of patient recruitment, patient retention, patient traffic, take-home medication, detoxification, and treatment outcomes.

  10. Trial Watch: Immunostimulation with Toll-like receptor agonists in cancer therapy

    PubMed Central

    Iribarren, Kristina; Bloy, Norma; Buqué, Aitziber; Cremer, Isabelle; Eggermont, Alexander; Fridman, Wolf Hervé; Fucikova, Jitka; Galon, Jérôme; Špíšek, Radek; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2016-01-01

    ABSTRACT Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy. PMID:27141345

  11. Dopamine agonist-induced substance addiction: the next piece of the puzzle.

    PubMed

    Evans, Andrew

    2011-02-01

    Traditional antiparkinson treatment strategies strive to balance the antiparkinson effects of dopaminergic drugs with the avoidance of motor response complications. Dopamine agonists have an established role in delaying the emergence of motor response complications or reducing motor "off" periods. The recent recognition of a range of "behavioural addictions" that are linked to dopamine agonist use has highlighted the role of dopamine in brain reward function and addiction disorders in general. Dopamine agonists have now even been linked occasionally to new substance addictions. The challenge now for the Parkinsonologist is to also balance the net benefits of using dopamine agonists for their motor effects with avoiding the harm from behavioural compulsions. PMID:20980151

  12. Analysis of agonist dissociation constants as assessed by functional antagonism in guinea pig left atria

    SciTech Connect

    Molenaar, P.; Malta, E.

    1986-04-01

    In electrically driven guinea pig left atria, positive inotropic responses to (-)-isoprenaline and the selective beta 1-adrenoceptor agonist RO363 were obtained in the absence and in the presence of the functional antagonists adenosine, carbachol, gallopamil, nifedipine, and Ro 03-7894. Each of the functional antagonists reduced the maximum response to both agonists and produced nonparallel rightward shifts in the cumulative concentration effect curves. For both agonists, dissociation constants (KA) were calculated using the equation described by Furchgott (1966) for irreversible antagonism. For RO363, which is a partial agonist with high agonist activity, the equations outlined for functional interaction by Mackay (1981) were also employed to calculate KA values. The KA values obtained by each method were compared with the dissociation constants (KD) for the two agonists determined from their ability to displace the radioligand (-)-(/sup 125/I)iodocyanopindolol from beta 1-adrenoceptors in guinea pig left atrial membrane preparations. The estimates of KA varied substantially from KD values. The KD values were taken as more accurate estimates of the true values for the dissociation constants because a high degree of correlation exists between pKD and pD2 values for a number of other beta-adrenoceptor agonists that behave as partial agonists and between pKD and pKB values for a number of beta-adrenoceptor antagonists. Thus, it appears that there are serious limitations in the current theory for using functional antagonism as a means of obtaining agonist dissociation constants.

  13. Structural complexes of the agonist, inverse agonist and antagonist bound C5a receptor: insights into pharmacology and signaling.

    PubMed

    Rana, Soumendra; Sahoo, Amita Rani; Majhi, Bharat Kumar

    2016-04-26

    The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. The study attempts to understand the pharmacology at the "orthosteric" site2 of C5aR rationally by generating a highly refined full-blown model structure of C5aR through advanced molecular modeling techniques, and further subjecting it to automated docking and molecular dynamics (MD) studies in the POPC bilayer. The first series of structural complexes of C5aR respectively bound to a linear native peptide agonist ((h)C5a-CT), a small molecule inverse agonist (NDT) and a cyclic peptide antagonist (PMX53) are reported, apparently establishing the unique pharmacological landscape of the "orthosteric" site2, which also illustrates an energetically distinct but coherent competitive chemistry ("cation-π" vs. "π-π" interactions) involved in distinguishing the established ligands known for targeting the "orthosteric" site2 of C5aR. Over a total of 1 μs molecular dynamics (MD) simulation in the POPC bilayer, it is evidenced that while the agonist prefers a "cation-π" interaction, the inverse agonist prefers a "cogwheel/L-shaped" interaction in contrast to the "edge-to-face/T-shaped" type π-π interactions demonstrated by the antagonist by engaging the F275(7.28) of the C5aR. In the absence of a NMR or crystallographically guided model structure of C5aR, the computational model complexes not only

  14. Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets

    SciTech Connect

    Schaechter, M.; Godfrey, P.P.; Minchin, M.C.W.; McClue, S.J.; Young, M.M.

    1985-10-28

    The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with (/sup 3/H)-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT/sub 2/ antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT/sub 2/ type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors. 30 references, 4 figures.

  15. Long-Acting Beta Agonists Enhance Allergic Airway Disease

    PubMed Central

    Knight, John M.; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O.; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A.; Milner, Joshua D.; Zhang, Yuan; Mandal, Pijus K.; Luong, Amber; Kheradmand, Farrah

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6. PMID:26605551

  16. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID:24752777

  17. Nicotinic acetylcholine receptor agonist attenuates ILC2-dependent airway hyperreactivity

    PubMed Central

    Galle-Treger, Lauriane; Suzuki, Yuzo; Patel, Nisheel; Sankaranarayanan, Ishwarya; Aron, Jennifer L.; Maazi, Hadi; Chen, Lin; Akbari, Omid

    2016-01-01

    Allergic asthma is a complex and chronic inflammatory disorder that is associated with airway hyperreactivity (AHR) and driven by Th2 cytokine secretion. Type 2 innate lymphoid cells (ILC2s) produce large amounts of Th2 cytokines and contribute to the development of AHR. Here, we show that ILC2s express the α7-nicotinic acetylcholine receptor (α7nAChR), which is thought to have an anti-inflammatory role in several inflammatory diseases. We show that engagement of a specific agonist with α7nAChR on ILC2s reduces ILC2 effector function and represses ILC2-dependent AHR, while decreasing expression of ILC2 key transcription factor GATA-3 and critical inflammatory modulator NF-κB, and reducing phosphorylation of upstream kinase IKKα/β. Additionally, the specific α7nAChR agonist reduces cytokine production and AHR in a humanized ILC2 mouse model. Collectively, our data suggest that α7nAChR expressed by ILC2s is a potential therapeutic target for the treatment of ILC2-mediated asthma. PMID:27752043

  18. A novel PPARgamma agonist monascin's potential application in diabetes prevention.

    PubMed

    Hsu, Wei-Hsuan; Pan, Tzu-Ming

    2014-07-25

    Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways.

  19. Mood disorders, circadian rhythms, melatonin and melatonin agonists.

    PubMed

    Quera Salva, M A; Hartley, S

    2012-01-01

    Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC). Melatonin (N-acetyl-5-hydroxytryptamine) is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD) and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light) or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.

  20. Pindolol--the pharmacology of a partial agonist.

    PubMed Central

    Clark, B J; Menninger, K; Bertholet, A

    1982-01-01

    1 Pindolol is a non-selective beta-adrenoceptor blocking agent; its affinity to adrenoceptors in guinea pig atria (beta 1) is not significantly different from that in guinea pig trachea (beta 1 + beta 2) and canine vascular smooth muscle (beta 2). 2 Pindolol displays a striking diversity of agonist activities in isolated tissues. Stimulant effects correspond to 40--50% of the maximum effects of isoprenaline in isolated kitten atria and guinea pig trachea and to only 10% in guinea pig atria. Effects in canine isolated mesenteric vessels are those of a full agonist, maximum responses equaling those of isoprenaline. These findings suggest that the stimulant effects of pindolol are exerted principally on beta 2-adrenoceptors. 3 Cardiac stimulation produced by pindolol in the dog is sufficient to compensate for the cardiac depression resulting from blockade of beta-adrenoceptors in the heart. Reductions in cardiac output and compensatory increases in total peripheral resistance do not occur or are much smaller than those produced by beta-adrenoceptor blocking agents lacking sympathomimetic activity. 4 Pindolol-induced relaxation of bronchial smooth muscle prevents or minimizes the bronchoconstrictor effects of injected spasmogens in the cat. 5 Pindolol has marked vasodilator activity, small doses reducing femoral and mesenteric vascular resistance by approximately 30%. Doses comparable to those used in hypertensive patients lower blood pressure by 20 mmHg in non-anaesthetized dogs. PMID:7049208

  1. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists. PMID:19832688

  2. Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

    PubMed

    Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

    2010-01-01

    For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

  3. Identification of agonists for a group of human odorant receptors

    PubMed Central

    Gonzalez-Kristeller, Daniela C.; do Nascimento, João B. P.; Galante, Pedro A. F.; Malnic, Bettina

    2015-01-01

    Olfaction plays a critical role in several aspects of the human life. Odorants are detected by hundreds of odorant receptors (ORs) which belong to the superfamily of G protein-coupled receptors. These receptors are expressed in the olfactory sensory neurons of the nose. The information provided by the activation of different combinations of ORs in the nose is transmitted to the brain, leading to odorant perception and emotional and behavioral responses. There are ~400 intact human ORs, and to date only a small percentage of these receptors (~10%) have known agonists. The determination of the specificity of the human ORs will contribute to a better understanding of how odorants are discriminated by the olfactory system. In this work, we aimed to identify human specific ORs, that is, ORs that are present in humans but absent from other species, and their corresponding agonists. To do this, we first selected 22 OR gene sequences from the human genome with no counterparts in the mouse, rat or dog genomes. Then we used a heterologous expression system to screen a subset of these human ORs against a panel of odorants of biological relevance, including foodborne aroma volatiles. We found that different types of odorants are able to activate some of these previously uncharacterized human ORs. PMID:25784876

  4. How does agonistic behaviour differ in albino and pigmented fish?

    PubMed Central

    Horký, Pavel; Wackermannová, Marie

    2016-01-01

    In addition to hypopigmentation of the skin and red iris colouration, albino animals also display distinct physiological and behavioural alterations. However, information on the social interactions of albino animals is rare and has mostly been limited to specially bred strains of albino rodents and animals from unique environments in caves. Differentiating between the effects of albinism and domestication on behaviour in rodents can be difficult, and social behaviour in cave fish changes according to species-specific adaptations to conditions of permanent darkness. The agonistic behaviours of albino offspring of pigmented parents have yet to be described. In this study, we observed agonistic behaviour in albino and pigmented juvenile Silurus glanis catfish. We found that the total number of aggressive interactions was lower in albinos than in pigmented catfish. The distance between conspecifics was also analysed, and albinos showed a tendency towards greater separation from their same-coloured conspecifics compared with pigmented catfish. These results demonstrate that albinism can be associated with lower aggressiveness and with reduced shoaling behaviour preference, as demonstrated by a tendency towards greater separation of albinos from conspecifics. PMID:27114883

  5. Grey Matter Density Predicts the Improvement of Naming Abilities After tDCS Intervention in Agrammatic Variant of Primary Progressive Aphasia.

    PubMed

    Cotelli, Maria; Manenti, Rosa; Paternicò, Donata; Cosseddu, Maura; Brambilla, Michela; Petesi, Michela; Premi, Enrico; Gasparotti, Roberto; Zanetti, Orazio; Padovani, Alessandro; Borroni, Barbara

    2016-09-01

    Agrammatic variant primary progressive aphasia is a neurodegenerative disorder specifically characterized by language deficits. A recent study has demonstrated a beneficial effect of transcranial direct current stimulation (tDCS) in combination with language training on naming accuracy in these patients. The aim of the study was to evaluate whether the improvement of naming accuracy after tDCS during language training was related to regional grey matter (GM) density. Eighteen avPPA patients underwent a brain magnetic resonance imaging before receiving a treatment that consisted of tDCS over the left dorsolateral prefrontal cortex during individualized language training (10 daily therapy sessions, 5 days per week from Monday to Friday). Performances on neuropsychological tests and naming of objects (treated and untreated) and actions were assessed at baseline, post-treatment  and 3 months after treatment. Correlations between individual changes after treatment on neuropsychological tests and on picture naming task and voxel-based GM volume at baseline were performed. We found that the improvement in the naming of treated objects was positively correlated with GM volume in the left fusiform, left middle temporal, and right inferior temporal gyri whereas action naming change was related to GM density in the left middle temporal gyrus. In conclusion baseline density of GM in these brain regions was associated with greater treatment response on naming performances, suggesting that intervention in early disease stages might be most successful. These findings have implication for designing future rehabilitation protocols in language variants of frontotemporal dementia. PMID:27194245

  6. Measurement of CD8+ and CD4+ T Cell Frequencies Specific for EBV LMP1 and LMP2a Using mRNA-Transfected DCs.

    PubMed

    Sohn, Dae-Hee; Sohn, Hyun-Jung; Lee, Hyun-Joo; Lee, Seon-Duk; Kim, Sueon; Hyun, Seung-Joo; Cho, Hyun-Il; Cho, Seok-Goo; Lee, Suk-Kyeong; Kim, Tai-Gyu

    2015-01-01

    An EBV-specific cellular immune response is associated with the control of EBV-associated malignancies and lymphoproliferative diseases, some of which have been successfully treated by adoptive T cell therapy. Therefore, many methods have been used to measure EBV-specific cellular immune responses. Previous studies have mainly used autologous EBV-transformed B-lymphoblastoid cell lines (B-LCLs), recombinant viral vectors transfected or peptide pulsed dendritic cells (DCs) as stimulators of CD8(+) and CD4(+) T lymphocytes. In the present study, we used an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay by using isolated CD8(+) and CD4(+) T cells stimulated with mRNA-transfected DCs. The frequency of latent membrane protein 1 (LMP1)-specific IFN-γ producing CD4(+) T cells was significantly higher than that of LMP2a. The frequency of IFN-γ producing CD4(+) T cells was significantly correlated with that of CD8(+) T cells in LMP1-specific immune responses (r = 0.7187, Pc < 0.0001). To determine whether there were changes in LMP1- or LMP2a-specific immune responses, subsequent peripheral blood mononuclear cells (PBMCs) samples were analyzed. Significant changes were observed in 5 of the 10 donors examined, and CD4(+) T cell responses showed more significant changes than CD8(+) T cell responses. CD8(+) and CD4(+) T cells from EBV-seropositive donors secreted only the Th1 cytokines IFN-γ, TNF-α, and IL-2, while Th2 (IL-4) and Th17 (IL-17a) cytokines were not detected. CD4(+) T cells secreted significantly higher cytokine levels than did CD8(+) T cells. Analysis of EBV-specific T cell responses using autologous DCs transfected with mRNA might provide a comprehensive tool for monitoring EBV infection and new insights into the pathogenesis of EBV-associated diseases. PMID:26023769

  7. Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification.

    PubMed

    Zaware, Pandurang; Shah, Shailesh R; Pingali, Harikishore; Makadia, Pankaj; Thube, Baban; Pola, Suresh; Patel, Darshit; Priyadarshini, Priyanka; Suthar, Dinesh; Shah, Maanan; Jamili, Jeevankumar; Sairam, Kalapatapu V V M; Giri, Suresh; Patel, Lala; Patel, Harilal; Sudani, Hareshkumar; Patel, Hiren; Jain, Mukul; Patel, Pankaj; Bahekar, Rajesh

    2011-01-15

    A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders. PMID:21195611

  8. Benzodiazepine Site Agonists Differentially Alter Acetylcholine Release in Rat Amygdala

    PubMed Central

    Hambrecht-Wiedbusch, Viviane S.; Mitchell, Melinda F.; Firn, Kelsie A.; Baghdoyan, Helen A.; Lydic, Ralph

    2014-01-01

    Background Agonist binding at the benzodiazepine site of γ-aminobutric acid type A receptors diminishes anxiety and insomnia by actions in the amygdala. The neurochemical effects of benzodiazepine-site agonists remain incompletely understood. Cholinergic neurotransmission modulates amygdala function, and in this study we tested the hypothesis that benzodiazepine-site agonists alter acetylcholine (ACh) release in the amygdala. Methods Microdialysis and high performance liquid chromatography quantified ACh release in the amygdala of Sprague-Dawley rats (n=33). ACh was measured before and after IV administration (3 mg/kg) of midazolam or eszopiclone, with and without anesthesia. ACh in isoflurane-anesthetized rats during dialysis with Ringer’s solution(control) was compared to ACh release during dialysis with Ringer’s solution containing (100 μM) midazolam, diazepam, eszopiclone, or zolpidem. Results In unanesthetized rats, ACh in the amygdala was decreased by IV midazolam (−51.1%; P=0.0029; 95% CI= −73.0% to −29.2%) and eszopiclone (−39.6%; P=0.0222; 95% CI= −69.8% to −9.3%). In anesthetized rats, ACh in the amygdala was decreased by IV administration of midazolam (−46.2%; P=0.0041; 95% CI= −67.9% to −24.5%) and eszopiclone (−34.0%; P=0.0009; 95% CI= −44.7% to −23.3%), and increased by amygdala delivery of diazepam (43.2%; P=0.0434; 95% CI= 2.1% to 84.3%), and eszopiclone (222.2%; P=0.0159; 95% CI= 68.5% to 375.8%). Conclusions ACh release in the amygdala was decreased by IV delivery of midazolam and eszopiclone. Dialysis delivery directly into the amygdala caused either increased (eszopiclone and diazepam) or likely no significant change (midazolam and zolpidem) in ACh release. These contrasting effects of delivery route on ACh release support the interpretation that systemically administered midazolam and eszopiclone decrease ACh release in the amygdala by acting on neuronal systems outside of the amygdala. PMID:24842176

  9. Discriminative stimulus properties of indorenate, a serotonin agonist.

    PubMed Central

    Velázquez-Martínez, D N; López Cabrera, M; Sánchez, H; Ramírez, J I; Hong, E

    1999-01-01

    OBJECTIVE: To determine whether indorenate, a serotonin-receptor agonist, can exert discriminative control over operant responses, to establish the temporal course of discriminative control and to compare its stimulus properties to a (5-HT)IA receptor agonist. [3H]-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT). DESIGN: Prospective animal study. ANIMALS: Ten male Wistar rats. INTERVENTIONS: Rats were trained to press either of 2 levers for sucrose solution according to a fixed ratio schedule, which was gradually increased. Rats were given injections of either indorenate or saline solution during discrimination training. Once they had achieved an 83% accuracy rate, rats underwent generalization tests after having received a different dose of indorenate, the training dose of indorenate at various intervals before the test, various doses of 8-OH-DPT, or NAN-190 administered before indorenate or 8-OH-DPAT. OUTCOME MEASURES: Distribution of responses between the 2 levers before the first reinforcer of the session, response rate for all the responses in the session, and a discrimination index that expressed the drug-appropriate responses as a proportion of the total responses. RESULTS: Indorenate administration resulted in discriminative control over operant responses, maintained at fixed ratio 10, at a dose of 10.0 mg/kg (but not 3.0 mg/kg). When the interval between the administration of indorenate and the start of the session was varied, the time course of its cue properties followed that of its described effects on 5-HT turnover. In generalization tests, the discrimination index was a function of the dose of indorenate employed; moreover, administration of 8-OH-DPAT (from 0.1 to 1.0 mg/kg) fully mimicked the stimulus properties of indorenate in a dose-dependent way. The (5-HT)IA antagonist NAN-190 prevented the stimulus generalization from indorenate to 8-OH-DPAT. Also, NAN-190 antagonized the stimulus control of indorenate when administered 45 minutes before

  10. Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

    PubMed Central

    Maguire, David R.

    2014-01-01

    Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of Δ9-THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6- and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4- and 19.6-fold, respectively. Δ9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4- and 7.9-fold, respectively, and the buprenorphine curve only 5.4- and 4.1-fold, respectively. Neither Δ9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency o