Joshua William Buckholtz

All Publications

• Distinct Developmental Trajectories for Risky and Impulsive Decision-Making in Chimpanzees JOURNAL OF EXPERIMENTAL PSYCHOLOGY-GENERAL Rosati, A. G., Thompson, M., Atencia, R., Buckholtz, J. W. 2023

  Abstract

  Human adolescence is characterized by a suite of changes in decision-making and emotional regulation that promote risky and impulsive behavior. Accumulating evidence suggests that behavioral and physiological shifts seen in human adolescence are shared by some primates, yet it is unclear if the same cognitive mechanisms are recruited. We examined developmental changes in risky choice, intertemporal choice, and emotional responses to decision outcomes in chimpanzees, our closest-living relatives. We found that adolescent chimpanzees were more risk-seeking than adults, as in humans. However, chimpanzees showed no developmental change in intertemporal choice, unlike humans, although younger chimpanzees did exhibit elevated emotional reactivity to waiting compared to adults. Comparisons of cortisol and testosterone indicated robust age-related variation in these biomarkers, and patterns of individual differences in choices, emotional reactivity, and hormones also supported a developmental dissociation between risk and choice impulsivity. These results show that some but not all core features of human adolescent decision-making are shared with chimpanzees. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

  View details for DOI 10.1037/xge0001347

  View details for Web of Science ID 000920219900001

  View details for PubMedID 36689365

• Characterizing mood disorders in the AFFECT study: a large, longitudinal, and phenotypically rich genetic cohort in the US TRANSLATIONAL PSYCHIATRY Dalby, M., Vitezic, M., Plath, N., Hammer-Helmich, L., Jiang, Y., Tian, C., Dhamija, D., Wilson, C. H., Hinds, D., Sullivan, P. F., Buckholtz, J. W., Smoller, J. W., 23andMe Res Team 2022; 12 (1): 121

  Abstract

  There has recently been marked progress in identifying genetic risk factors for major depression (MD) and bipolar disorder (BD); however, few systematic efforts have been made to elucidate heterogeneity that exists within and across these diagnostic taxa. The Affective disorders, Environment, and Cognitive Trait (AFFECT) study presents an opportunity to identify and associate the structure of cognition and symptom-level domains across the mood disorder spectrum in a prospective study from a diverse US population.Participants were recruited from the 23andMe, Inc research participant database and through social media; self-reported diagnosis of MD or BD by a medical professional and medication status data were used to enrich for mood-disorder cases. Remote assessments were used to acquire an extensive range of phenotypes, including mood state, transdiagnostic symptom severity, task-based measures of cognition, environmental exposures, personality traits. In this paper we describe the study design, and the demographic and clinical characteristics of the cohort. In addition we report genetic ancestry, SNP heritability, and genetic correlations with other large cohorts of mood disorders.A total of 48,467 participants were enrolled: 14,768 with MD, 9864 with BD, and 23,835 controls. Upon enrollment, 47% of participants with MD and 27% with BD indicated being in an active mood episode. Cases reported early ages of onset (mean = 13.2 and 14.3 years for MD and BD, respectively), and high levels of recurrence (78.6% and 84.9% with >5 episodes), psychotherapy, and psychotropic medication use. SNP heritability on the liability scale for the ascertained MD participants (0.19-0.21) was consistent with the high level of disease severity in this cohort, while BD heritability estimates (0.16-0.22) were comparable to reports in other large scale genomic studies of mood disorders. Genetic correlations between the AFFECT cohort and other large-scale cohorts were high for MD but not for BD. By incorporating transdiagnostic symptom assessments, repeated measures, and genomic data, the AFFECT study represents a unique resource for dissecting the structure of mood disorders across multiple levels of analysis. In addition, the fully remote nature of the study provides valuable insights for future virtual and decentralized clinical trials within mood disorders.

  View details for DOI 10.1038/s41398-022-01877-2

  View details for Web of Science ID 000773248600001

  View details for PubMedID 35338122

  View details for PubMedCentralID PMC8956583

• Chimpanzee Cooperation Is Fast and Independent From Self-Control PSYCHOLOGICAL SCIENCE Rosati, A. G., DiNicola, L. M., Buckholtz, J. W. 2018; 29 (11): 1832-1845

  Abstract

  Large-scale cooperation is a hallmark of our species and appears to be unique among primates. Yet the evolutionary mechanisms that drove the emergence of humanlike patterns of cooperation remain unclear. Studying the cognitive processes underlying cooperative behavior in apes, our closest living relatives, can help identify these mechanisms. Accordingly, we employed a novel test battery to assess the willingness of 40 chimpanzees to donate resources, instrumentally help others, and punish a culpable thief. We found that chimpanzees were faster to make prosocial than selfish choices and that more prosocial individuals made the fastest responses. Further, two measures of self-control did not predict variation in prosocial responding, and individual performance across cooperative tasks did not covary. These results show that chimpanzees and humans share key cognitive processes for cooperation, despite differences in the scope of their cooperative behaviors.

  View details for DOI 10.1177/0956797618800042

  View details for Web of Science ID 000450308600009

  View details for PubMedID 30295562

• Disrupted Prefrontal Regulation of Striatal Subjective Value Signals in Psychopathy NEURON Hosking, J. G., Kastman, E. K., Dorfman, H. M., Samanez-Larkin, G. R., Baskin-Sommers, A., Kiehl, K. A., Newman, J. P., Buckholtz, J. W. 2017; 95 (1): 221-+

  Abstract

  Psychopathy is a personality disorder with strong links to criminal behavior. While research on psychopathy has focused largely on socio-affective dysfunction, recent data suggest that aberrant decision making may also play an important role. Yet, the circuit-level mechanisms underlying maladaptive decision making in psychopathy remain unclear. Here, we used a multi-modality functional imaging approach to identify these mechanisms in a population of adult male incarcerated offenders. Psychopathy was associated with stronger subjective value-related activity within the nucleus accumbens (NAcc) during inter-temporal choice and with weaker intrinsic functional connectivity between NAcc and ventromedial prefrontal cortex (vmPFC). NAcc-vmPFC connectivity strength was negatively correlated with NAcc subjective value-related activity; however, this putative regulatory pattern was abolished as psychopathy severity increased. Finally, weaker cortico-striatal regulation predicted more frequent criminal convictions. These data suggest that cortico-striatal circuit dysregulation drives maladaptive decision making in psychopathy, supporting the notion that reward system dysfunction comprises an important neurobiological risk factor.

  View details for DOI 10.1016/j.neuron.2017.06.030

  View details for Web of Science ID 000404876500022

  View details for PubMedID 28683266

  View details for PubMedCentralID PMC5796650

• Psychopathic individuals exhibit but do not avoid regret during counterfactual decision making PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Baskin-Sommers, A., Stuppy-Sullivan, A. M., Buckholtz, J. W. 2016; 113 (50): 14438-14443

  Abstract

  Psychopathy is associated with persistent antisocial behavior and a striking lack of regret for the consequences of that behavior. Although explanatory models for psychopathy have largely focused on deficits in affective responsiveness, recent work indicates that aberrant value-based decision making may also play a role. On that basis, some have suggested that psychopathic individuals may be unable to effectively use prospective simulations to update action value estimates during cost-benefit decision making. However, the specific mechanisms linking valuation, affective deficits, and maladaptive decision making in psychopathy remain unclear. Using a counterfactual decision-making paradigm, we found that individuals who scored high on a measure of psychopathy were as or more likely than individuals low on psychopathy to report negative affect in response to regret-inducing counterfactual outcomes. However, despite exhibiting intact affective regret sensitivity, they did not use prospective regret signals to guide choice behavior. In turn, diminished behavioral regret sensitivity predicted a higher number of prior incarcerations, and moderated the relationship between psychopathy and incarceration history. These findings raise the possibility that maladaptive decision making in psychopathic individuals is not a consequence of their inability to generate or experience negative emotions. Rather, antisocial behavior in psychopathy may be driven by a deficit in the generation of forward models that integrate information about rules, costs, and goals with stimulus value representations to promote adaptive behavior.

  View details for DOI 10.1073/pnas.1609985113

  View details for Web of Science ID 000389696700075

  View details for PubMedID 27911790

  View details for PubMedCentralID PMC5167137

• Social norms, self-control, and the value of antisocial behavior CURRENT OPINION IN BEHAVIORAL SCIENCES Buckholtz, J. W. 2015; 3: 122-129

  View details for DOI 10.1016/j.cobeha.2015.03.004

  View details for Web of Science ID 000218442000023

• Promises, promises for neuroscience and law CURRENT BIOLOGY Buckholtz, J. W., Faigman, D. L. 2014; 24 (18): R861-R867

  Abstract

  Stunning technical advances in the ability to image the human brain have provoked excited speculation about the application of neuroscience to other fields. The 'promise' of neuroscience for law has been touted with particular enthusiasm. Here, we contend that this promise elides fundamental conceptual issues that limit the usefulness of neuroscience for law. Recommendations for overcoming these challenges are offered.

  View details for DOI 10.1016/j.cub.2014.07.057

  View details for Web of Science ID 000342396900015

  View details for PubMedID 25247363

• Psychopathology and the Human Connectome: Toward a Transdiagnostic Model of Risk For Mental Illness NEURON Buckholtz, J. W., Meyer-Lindenberg, A. 2012; 74 (6): 990-1004

  Abstract

  The panoply of cognitive, affective, motivational, and social functions that underpin everyday human experience requires precisely choreographed patterns of interaction between networked brain regions. Perhaps not surprisingly, diverse forms of psychopathology are characterized by breakdowns in these interregional relationships. Here, we discuss how functional brain imaging has provided insights into the nature of brain dysconnectivity in mental illness. Synthesizing work to date, we propose that genetic and environmental risk factors impinge upon systems-level circuits for several core dimensions of cognition, producing transdiagnostic symptoms. We argue that risk-associated disruption of these circuits mediates susceptibility to broad domains of psychopathology rather than discrete disorders.

  View details for DOI 10.1016/j.neuron.2012.06.002

  View details for Web of Science ID 000305659700006

  View details for PubMedID 22726830

• The roots of modern justice: cognitive and neural foundations of social norms and their enforcement NATURE NEUROSCIENCE Buckholtz, J. W., Marois, R. 2012; 15 (5): 655-661

  Abstract

  Among animals, Homo sapiens is unique in its capacity for widespread cooperation and prosocial behavior among large and genetically heterogeneous groups of individuals. This ultra-sociality figures largely in our success as a species. It is also an enduring evolutionary mystery. There is considerable support for the hypothesis that this facility is a function of our ability to establish, and enforce through sanctions, social norms. Third-party punishment of norm violations ("I punish you because you harmed him") seems especially crucial for the evolutionary stability of cooperation and is the cornerstone of modern systems of criminal justice. In this commentary, we outline some potential cognitive and neural processes that may underlie the ability to learn norms, to follow norms and to enforce norms through third-party punishment. We propose that such processes depend on several domain-general cognitive functions that have been repurposed, through evolution's thrift, to perform these roles.

  View details for DOI 10.1038/nn.3087

  View details for Web of Science ID 000303270200006

  View details for PubMedID 22534578

• Dopaminergic Network Differences in Human Impulsivity SCIENCE Buckholtz, J. W., Treadway, M. T., Cowan, R. L., Woodward, N. D., Li, R., Ansari, M., Baldwin, R. M., Schwartzman, A. N., Shelby, E. S., Smith, C. E., Kessler, R. M., Zald, D. H. 2010; 329 (5991): 532

  Abstract

  Dopamine (DA) has long been implicated in impulsivity, but the precise mechanisms linking human variability in DA signaling to differences in impulsive traits remain largely unknown. By using a dual-scan positron emission tomography approach in healthy human volunteers with amphetamine and the D2/D3 ligand [18F]fallypride, we found that higher levels of trait impulsivity were predicted by diminished midbrain D2/D3 autoreceptor binding and greater amphetamine-induced DA release in the striatum, which was in turn associated with stimulant craving. Path analysis confirmed that the impact of decreased midbrain D2/D3 autoreceptor availability on trait impulsivity is mediated in part through its effect on stimulated striatal DA release.

  View details for DOI 10.1126/science.1185778

  View details for Web of Science ID 000280483500026

  View details for PubMedID 20671181

  View details for PubMedCentralID PMC3161413

• Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits NATURE NEUROSCIENCE Buckholtz, J. W., Treadway, M. T., Cowan, R. L., Woodward, N. D., Benning, S. D., Li, R., Ansari, M., Baldwin, R. M., Schwartzman, A. N., Shelby, E. S., Smith, C. E., Cole, D., Kessler, R. M., Zald, D. H. 2010; 13 (4): 419-421

  Abstract

  Psychopathy is a personality disorder that is strongly linked to criminal behavior. Using [(18)F]fallypride positron emission tomography and blood oxygen level-dependent functional magnetic resonance imaging, we found that impulsive-antisocial psychopathic traits selectively predicted nucleus accumbens dopamine release and reward anticipation-related neural activity in response to pharmacological and monetary reinforcers, respectively. These findings suggest that neurochemical and neurophysiological hyper-reactivity of the dopaminergic reward system may comprise a neural substrate for impulsive-antisocial behavior and substance abuse in psychopathy.

  View details for DOI 10.1038/nn.2510

  View details for Web of Science ID 000276073500010

  View details for PubMedID 20228805

  View details for PubMedCentralID PMC2916168

• Neural mechanisms of genetic risk for impulsivity and violence in humans PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Meyer-Lindenberg, A., Buckholtz, J. W., Kolachana, B., Hariri, A. R., Pezawas, L., Blasi, G., Wabnitz, A., Honea, R., Verchinski, B., Callicott, J. H., Egan, M., Mattay, Weinberger, D. R. 2006; 103 (16): 6269-6274

  Abstract

  Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.

  View details for DOI 10.1073/pnas.0511311103

  View details for Web of Science ID 000236999000039

  View details for PubMedID 16569698

  View details for PubMedCentralID PMC1458867

• MULTIPLE POLYGENIC SCORES AND INDIVIDUAL GENOMIC LOCI ASSOCIATE WITH SELF-REPORTED ANTIPSYCHOTIC USE, TREATMENT CESSATION, AND TREATMENT RESISTANCE IN AFFECTIVE DISORDERS Hellberg, K., Jiang, Y., Forsingdal, A., LaBianca, S., Dhamija, D., Hinds, D. A., Buckholtz, J. W., Smoller, J. W., Dalby, M., Schork, A., Vitezic, M., 23 Me Res Team ELSEVIER. 2023: S75

  View details for DOI 10.1016/j.euroneuro.2023.08.144

  View details for Web of Science ID 001089437400143

• GENETIC ARCHITECTURE OF COMPLEX COGNITIVE PROCESSES AND LINKS TO PSYCHOPATHOLOGY Tubbs, J., Mallard, T., Dalby, M., Choi, K., Plath, N., Hammer-Helmich, L., Jiang, Y., Smoller, J., Buckholtz, J., 23andMe Res Team ELSEVIER. 2023: S41-S42

  View details for DOI 10.1016/j.euroneuro.2023.08.085

  View details for Web of Science ID 001089437400085

• EMERGING APPROACHES TO GWAS PHENOTYPING: FROM SYNAPSE TO SYMPTOM Buckholtz, J., Mallard, T., Palmer, A. ELSEVIER. 2023: S41

  View details for DOI 10.1016/j.euroneuro.2023.08.084

  View details for Web of Science ID 001089437400084

• Examining tradeoffs between cognitive effort and relief among adults with self-injurious behavior JOURNAL OF AFFECTIVE DISORDERS Franz, P. J., Fortgang, R. G., Millner, A. J., Jaroszewski, A. C., Wittler, E. M., Alpert, J. E., Buckholtz, J. W., Nock, M. K. 2023; 321: 320-328

  Abstract

  People engage in nonsuicidal self-injury (NSSI) to reduce negative affect, but it is not clear why they engage in this harmful type of behavior instead of using healthier strategies. The primary goal of this study was to evaluate whether people choose NSSI to reduce negative affect because they perceive it to be less cognitively costly than other available strategies.In experiment one, 43 adults completed a novel, relief-based effort discounting task designed to index preferences about exerting cognitive effort to achieve relief. In experiment two, 149 adults, 52 % with a history of NSSI, completed our effort discounting task.Our main results suggest that people will accept less relief from an aversive experience if doing so requires expending less effort, i.e. they demonstrate effort discounting in the context of decisions about relief. We also found and that effort discounting is stronger among those with a history of NSSI, but this association became nonsignificant when simultaneously accounting for other conditions associated with aberrant effort tradeoffs.The use of a control group without NSSI or other potentially harmful relief-seeking behaviors limits our ability to draw specific conclusions about NSSI. The ecological validity of our task was limited by a modestly effective affect manipulation, and because participants made hypothetical choices.This study demonstrates that preferences about exerting cognitive effort may be a barrier to using healthier affect regulation strategies. Further, the preference not to exert cognitive effort, though present in NSSI, is likely not unique to NSSI. Instead, effort discounting may be a transdiagnostic mechanism promoting an array of harmful relief-seeking behaviors.

  View details for DOI 10.1016/j.jad.2022.10.029

  View details for Web of Science ID 000918974000009

  View details for PubMedID 36302491

• The association of impulsivity with effects of the ChooseWell 365 workplace nudge intervention on diet and weight TRANSLATIONAL BEHAVIORAL MEDICINE McCurley, J. L., Buckholtz, J. W., Roberto, C. A., Levy, D. E., Anderson, E. M., Chang, Y., Thorndike, A. N. 2022

  Abstract

  Impulsivity is associated with unhealthy food choices. Nudge interventions in the food environment may be particularly helpful for individuals with high impulsivity. To examine if trait, choice, and action impulsivity were associated with the effectiveness of a workplace-based nudge intervention to improve diet and weight. This was a planned secondary analysis of 487 participants of ChooseWell 365, a randomized controlled trial that tested a 12-month nudge intervention to improve cafeteria purchases among hospital employees. Trait impulsivity was measured with the Barratt Impulsiveness Scale. Choice and action impulsivity were assessed with delay discounting and response inhibition tasks, respectively. Tertiles were generated for each measure. Multivariable regression models examined the association of impulsivity with cafeteria purchases [Healthy Purchasing Score (HPS)] over 12 months, dietary intake [Healthy Eating Index-2015 (HEI) score], and body mass index (BMI) measured at 12 months. Interaction terms tested differences in intervention effect by level of impulsivity. Participants with higher trait (p = .02) and choice (p < .001) impulsivity had lower baseline HPS than those with lower impulsivity. Employees of all impulsivity levels increased healthy eating, but higher trait impulsivity was associated with smaller increase in HPS over 12 months (p = .03). In the highest action impulsivity tertile, 12-month BMI increased less for intervention vs. control participants (0.3 vs. 0.5 kg/m2; p-interaction = .04). There were no interaction effects for trait or choice impulsivity. A workplace nudge intervention improved food choices among employees of all impulsivity levels and attenuated weight gain in those with higher action impulsivity.

  View details for DOI 10.1093/tbm/ibac103

  View details for Web of Science ID 000902379300001

  View details for PubMedID 36548448

• The origins of cognitive flexibility in chimpanzees DEVELOPMENTAL SCIENCE Cantwell, A., Buckholtz, J. W., Atencia, R., Rosati, A. G. 2022; 25 (5): e13266

  Abstract

  Cognitive flexibility is a core component of executive function, a suite of cognitive capacities that enables individuals to update their behavior in dynamic environments. Human executive functions are proposed to be enhanced compared to other species, but this inference is based primarily on neuroanatomical studies. To address this, we examined the nature and origins of cognitive flexibility in chimpanzees, our closest living relatives. Across three studies, we examined different components of cognitive flexibility using reversal learning tasks where individuals first learned one contingency and then had to shift responses when contingencies flipped. In Study 1, we tested n = 82 chimpanzees ranging from juvenility to adulthood on a spatial reversal task, to characterize the development of basic shifting skills. In Study 2, we tested how n = 24 chimpanzees use spatial versus arbitrary perceptual information to shift, a proposed difference between human and nonhuman cognition. In Study 3, we tested n = 40 chimpanzees on a probabilistic reversal task. We found an extended developmental trajectory for basic shifting and shifting in response to probabilistic feedback-chimpanzees did not reach mature performance until late in ontogeny. Additionally, females were faster to shift than males were. We also found that chimpanzees were much more successful when using spatial versus perceptual cues, and highly perseverative when faced with probabilistic versus consistent outcomes. These results identify both core features of chimpanzee cognitive flexibility that are shared with humans, as well as constraints on chimpanzee cognitive flexibility that may represent evolutionary changes in human cognitive development.

  View details for DOI 10.1111/desc.13266

  View details for Web of Science ID 000792776100001

  View details for PubMedID 35397187

  View details for PubMedCentralID PMC9841514

• Don't Ever Leave Me, You Disgusting Monster: Computational Insights Into Moral Inference Updating in Borderline Personality Disorder BIOLOGICAL PSYCHIATRY-COGNITIVE NEUROSCIENCE AND NEUROIMAGING Buckholtz, J. W. 2020; 5 (12): 1075-1076

  View details for DOI 10.1016/j.bpsc.2020.10.012

  View details for Web of Science ID 000599513300003

  View details for PubMedID 33288035

• Are suicide attempters more impulsive than suicide ideators? GENERAL HOSPITAL PSYCHIATRY Millner, A. J., Lee, M. D., Hoyt, K., Buckholtz, J. W., Auerbach, R. P., Nock, M. K. 2020; 63: 103-110

  Abstract

  For over 100 years impulsiveness has been cited as a key factor in why some people that think about killing themselves go on to attempt suicide. Yet prior studies are limited by not using experimental groups that can test this hypothesis and by treating impulsiveness as a unidimensional construct. To overcome these limitations, we compared suicide ideators and suicide attempters on several dimensions of impulsiveness.In Study 1 we compared inpatient suicide attempters who made an attempt within the prior two weeks (n = 30), current inpatient suicide ideators (n = 31), and community controls (n = 34) on several dimensions of impulsiveness using self-report and behavioral measures. In Study 2 (n = 346), we compared three similar groups based on lifetime and past year suicidal behaviors on several of the measures in Study 1.In Study 1, we found only that negative urgency was clearly elevated among attempters compared with ideators. In Study 2, there were no significant differences on any impulsiveness constructs, including negative urgency.Results from the two studies suggest that attempters may not have significantly elevated trait impulsiveness, compared to ideators; however, attempters may have higher impulsiveness when in a negative state.

  View details for DOI 10.1016/j.genhosppsych.2018.08.002

  View details for Web of Science ID 000522622700019

  View details for PubMedID 30097321

• Aberrant Cost-Benefit Integration During Effort-Based Decision Making Relates to Severity of Substance Use Disorders CLINICAL PSYCHOLOGICAL SCIENCE Stuppy-Sullivan, A. M., Buckholtz, J. W., Baskin-Sommers, A. 2020; 8 (1): 155-168

  View details for DOI 10.1177/2167702619868155

  View details for Web of Science ID 000496386200001

• The impact of chronic stress during adolescence on the development of aggressive behavior: A systematic review on the role of the dopaminergic system in rodents NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Tielbeek, J. J., Al-Itejawi, Z., Zijlmans, J., Polderman, T. C., Buckholtz, J. W., Popma, A. 2018; 91: 187-197

  Abstract

  Pathological aggression, frequently observed in psychiatric patients and criminal subjects, poses a major burden on the health care and criminal justice system, necessitating better aetiological models to inform targets for prevention and intervention. Emerging evidence suggests that adverse experiences during development can cause long-lasting brain alterations associated with maladaptive behaviors, such as aggression. The present review discusses, mainly based on studies in rodents, whether disruption of the mesocorticolimbic dopamine system through chronic stress-exposure during adolescence predisposes to adult aggression. Our findings suggest that chronic stress in adolescence induces prefrontal cortex (PFC) hyperdopaminergia and ultimately leads to blunted prefrontal dopamine transmission in adulthood. This, in turn, disrupts the ability of the PFC to guide adaptive, long-term focused action selection by regulating mesolimbic dopamine signaling. We propose that, especially during the dynamic and transitional period of adolescence, exposure to chronic stress could lead to excessive adaptive change, which may result in an increased vulnerability to maladaptive aggression in adulthood. We discuss how these findings in rodents may translate to humans.

  View details for DOI 10.1016/j.neubiorev.2016.10.009

  View details for Web of Science ID 000438179700015

  View details for PubMedID 27826069

• Predicting Violent Behavior: What Can Neuroscience Add? TRENDS IN COGNITIVE SCIENCES Poldrack, R. A., Monahan, J., Imrey, P. B., Reyna, V., Raichle, M. E., Faigman, D., Buckholtz, J. W. 2018; 22 (2): 111–23

  Abstract

  The ability to accurately predict violence and other forms of serious antisocial behavior would provide important societal benefits, and there is substantial enthusiasm for the potential predictive accuracy of neuroimaging techniques. Here, we review the current status of violence prediction using actuarial and clinical methods, and assess the current state of neuroprediction. We then outline several questions that need to be addressed by future studies of neuroprediction if neuroimaging and other neuroscientific markers are to be successfully translated into public policy.

  View details for PubMedID 29183655

  View details for PubMedCentralID PMC5794654

• Blunted Ambiguity Aversion During Cost-Benefit Decisions in Antisocial Individuals SCIENTIFIC REPORTS Buckholtz, J. W., Karmarkar, U., Ye, S., Brennan, G. M., Baskin-Sommers, A. 2017; 7: 2030

  Abstract

  Antisocial behavior is often assumed to reflect aberrant risk processing. However, many of the most significant forms of antisocial behavior, including crime, reflect the outcomes of decisions made under conditions of ambiguity rather than risk. While risk and ambiguity are formally distinct and experimentally dissociable, little is known about ambiguity sensitivity in individuals who engage in chronic antisocial behavior. We used a financial decision-making task in a high-risk community-based sample to test for associations between sensitivity to ambiguity, antisocial behavior, and arrest history. Sensitivity to ambiguity was lower in individuals who met diagnostic criteria for Antisocial Personality Disorder. Lower ambiguity sensitivity was also associated with higher externalizing (but not psychopathy) scores, and with higher levels of aggression (but not rule-breaking). Finally, blunted sensitivity to ambiguity also predicted a greater frequency of arrests. Together, these data suggest that alterations in cost-benefit decision-making under conditions of ambiguity may promote antisocial behavior.

  View details for DOI 10.1038/s41598-017-02149-6

  View details for Web of Science ID 000401511100037

  View details for PubMedID 28515474

  View details for PubMedCentralID PMC5435701

• Selective Mapping of Psychopathy and Externalizing to Dissociable Circuits for Inhibitory Self-Control CLINICAL PSYCHOLOGICAL SCIENCE Rodman, A. M., Kastman, E. K., Dorfman, H. M., Baskin-Sommers, A. R., Kiehl, K. A., Newman, J. P., Buckholtz, J. W. 2016; 4 (3): 559-571

  Abstract

  Antisociality is commonly conceptualized as a unitary construct, but there is considerable evidence for multidimensionality. In particular, two partially dissociable symptom clusters - psychopathy and externalizing - have divergent associations to clinical and forensic outcomes and are linked to unique patterns executive dysfunction. Here, we used fMRI in a sample of incarcerated offenders to map these dimensions of antisocial behavior to brain circuits underlying two aspects of inhibitory self-control: interference suppression and response inhibition. We found that psychopathy and externalizing are characterized by unique and task-selective patterns of dysfunction. While higher levels of psychopathy predicted increased activity within a distributed fronto-parietal network for interference suppression, externalizing did not predict brain activity during attentional control. By contrast, each dimension had opposite associations to fronto-parietal activity during response inhibition. These findings provide neurobiological evidence supporting the fractionation of antisocial behavior, and identify dissociable mechanisms through which different facets predispose dysfunction and impairment.

  View details for DOI 10.1177/2167702616631495

  View details for Web of Science ID 000408534000016

  View details for PubMedID 27453803

  View details for PubMedCentralID PMC4955633

• From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms NEURON Buckholtz, J. W., Martin, J. W., Treadway, M. T., Jan, K., Zald, D. H., Jones, O., Marois, R. 2015; 87 (6): 1369-1380

  Abstract

  The social welfare provided by cooperation depends on the enforcement of social norms. Determining blameworthiness and assigning a deserved punishment are two cognitive cornerstones of norm enforcement. Although prior work has implicated the dorsolateral prefrontal cortex (DLPFC) in norm-based judgments, the relative contribution of this region to blameworthiness and punishment decisions remains poorly understood. Here, we used repetitive transcranial magnetic stimulation (rTMS) and fMRI to determine the specific role of DLPFC function in norm-enforcement behavior. DLPFC rTMS reduced punishment for wrongful acts without affecting blameworthiness ratings, and fMRI revealed punishment-selective DLPFC recruitment, suggesting that these two facets of norm-based decision making are neurobiologically dissociable. Finally, we show that DLPFC rTMS affects punishment decision making by altering the integration of information about culpability and harm. Together, these findings reveal a selective, causal role for DLPFC in norm enforcement: representational integration of the distinct information streams used to make punishment decisions.

  View details for DOI 10.1016/j.neuron.2015.08.023

  View details for Web of Science ID 000363782200023

  View details for PubMedID 26386518

  View details for PubMedCentralID PMC5488876

• Social Behavior: A Penny for Your Shocks CURRENT BIOLOGY Dorfman, H. M., Buckholtz, J. W. 2015; 25 (14): R600-R601

  Abstract

  Antisocial behavior is an enormously costly social problem, but its origins are poorly understood. A new study shows that prosocial and antisocial behaviors arise from individual differences in how we represent the value of others' pain relative to our own potential gain, rather than from variability in the capacity for effortful inhibitory control.

  View details for DOI 10.1016/j.cub.2015.05.036

  View details for Web of Science ID 000358465600007

  View details for PubMedID 26196484

• Neurogenetics of antisocial aggression ROUTLEDGE INTERNATIONAL HANDBOOK OF BIOSOCIAL CRIMINOLOGY Dorfman, H. M., Buckholtz, J. W., DeLisi, M., Vaughn, M. G. 2015: 115-127

  View details for Web of Science ID 000437709600008

• Corticolimbic gating of emotion-driven punishment NATURE NEUROSCIENCE Treadway, M. T., Buckholtz, J. W., Martin, J. W., Jan, K., Asplund, C. L., Ginther, M. R., Jones, O. D., Marois, R. 2014; 17 (9): 1270-1275

  Abstract

  Determining the appropriate punishment for a norm violation requires consideration of both the perpetrator's state of mind (for example, purposeful or blameless) and the strong emotions elicited by the harm caused by their actions. It has been hypothesized that such affective responses serve as a heuristic that determines appropriate punishment. However, an actor's mental state often trumps the effect of emotions, as unintended harms may go unpunished, regardless of their magnitude. Using fMRI, we found that emotionally graphic descriptions of harmful acts amplify punishment severity, boost amygdala activity and strengthen amygdala connectivity with lateral prefrontal regions involved in punishment decision-making. However, this was only observed when the actor's harm was intentional; when harm was unintended, a temporoparietal-medial-prefrontal circuit suppressed amygdala activity and the effect of graphic descriptions on punishment was abolished. These results reveal the brain mechanisms by which evaluation of a transgressor's mental state gates our emotional urges to punish.

  View details for DOI 10.1038/nn.3781

  View details for Web of Science ID 000341125400022

  View details for PubMedID 25086609

• Neurobiological mechanisms for impulsive-aggression: the role of MAOA. Current topics in behavioral neurosciences Dorfman, H. M., Meyer-Lindenberg, A., Buckholtz, J. W. 2014; 17: 297-313

  Abstract

  Aggression may be present across a large part of the spectrum of psychopathology, and underlies costly criminal antisocial behaviors. Human aggression is a complex and underspecified construct, confounding scientific discovery. Nevertheless, some biologically tractable subtypes are apparent, and one in particular-impulsive (reactive) aggression-appears to account for many facets of aggression-related dysfunction in psychiatric illness. Impulsive-aggression is significantly heritable, suggesting genetic transmission. However, the specific neurobiological mechanisms that mediate genetic risk for impulsive-aggression remain unclear. Here, we review extant data on the genetics and neurobiology of individual differences in impulsive-aggression, with particular attention to the role of genetic variation in Monoamine Oxidase A (MAOA) and its impact on serotonergic signaling within corticolimbic circuitry.

  View details for DOI 10.1007/7854_2013_272

  View details for PubMedID 24470068

• A Thalamocorticostriatal Dopamine Network for Psychostimulant-Enhanced Human Cognitive Flexibility BIOLOGICAL PSYCHIATRY Samanez-Larkin, G. R., Buckholtz, J. W., Cowan, R. L., Woodward, N. D., Li, R., Ansari, M., Arrington, C. M., Baldwin, R. M., Smith, C. E., Treadway, M. T., Kessler, R. M., Zald, D. H. 2013; 74 (2): 99-105

  Abstract

  Everyday life demands continuous flexibility in thought and behavior. We examined whether individual differences in dopamine function are related to variability in the effects of amphetamine on one aspect of flexibility: task switching.Forty healthy human participants performed a task-switching paradigm following placebo and oral amphetamine administration. [(18)F]fallypride was used to measure D2/D3 baseline receptor availability and amphetamine-stimulated dopamine release.The majority of the participants showed amphetamine-induced benefits through reductions in switch costs. However, such benefits were variable. Individuals with higher baseline thalamic and cortical receptor availability and striatal dopamine release showed greater reductions in switch costs following amphetamine than individuals with lower levels. The relationship between dopamine receptors and stimulant-enhanced flexibility was partially mediated by striatal dopamine release.These data indicate that the impact of the psychostimulant on cognitive flexibility is influenced by the status of dopamine within a thalamocorticostriatal network. Beyond demonstrating a link between this dopaminergic network and the enhancement in task switching, these neural measures accounted for unique variance in predicting the psychostimulant-induced cognitive enhancement. These results suggest that there may be measurable aspects of variability in the dopamine system that predispose certain individuals to benefit from and hence use psychostimulants for cognitive enhancement.

  View details for DOI 10.1016/j.biopsych.2012.10.032

  View details for Web of Science ID 000321108800006

  View details for PubMedID 23273721

  View details for PubMedCentralID PMC3615042

• Perceived stress predicts altered reward and loss feedback processing in medial prefrontal cortex FRONTIERS IN HUMAN NEUROSCIENCE Treadway, M. T., Buckholtz, J. W., Zald, D. H. 2013; 7: 180

  Abstract

  Stress is a significant risk factor for the development of psychopathology, particularly symptoms related to reward processing. Importantly, individuals display marked variation in how they perceive and cope with stressful events, and such differences are strongly linked to risk for developing psychiatric symptoms following stress exposure. However, many questions remain regarding the neural architecture that underlies inter-subject variability in perceptions of stressors. Using functional magnetic resonance imaging (fMRI) during a Monetary Incentive Delay (MID) paradigm, we examined the effects of self-reported perceived stress levels on neural activity during reward anticipation and feedback in a sample of healthy individuals. We found that subjects reporting more uncontrollable and overwhelming stressors displayed blunted neural responses in medial prefrontal cortex (mPFC) following feedback related to monetary gains as well monetary losses. This is consistent with preclinical models that implicate the mPFC as a key site of vulnerability to the noxious effects of uncontrollable stressors. Our data help translate these findings to humans, and elucidate some of the neural mechanisms that may underlie stress-linked risk for developing reward-related psychiatric symptoms.

  View details for DOI 10.3389/fnhum.2013.00180

  View details for Web of Science ID 000319329100001

  View details for PubMedID 23730277

  View details for PubMedCentralID PMC3657626

• Exaggerated attention blink response in prisoners with externalizing JOURNAL OF RESEARCH IN PERSONALITY Baskin-Sommers, A., Wolf, R., Buckholtz, J., Warren, C., Newman, J. 2012; 46 (6): 688-693

  Abstract

  The diverse phenotypic expressions of disinhibitory psychopathology are believed to reflect a common latent predisposing variable: externalizing. While deficiencies in executive functioning (i.e., cognitive/inhibitory control, working memory) and affective hyper-reactivity are commonly associated with externalizing, there is also evidence that externalizing is related to anomalous allocation of attention. In this study, we administered an attention blink task to a sample of male prisoners and assessed externalizing using the Impulsive-Antisociality scale (Benning, Patrick, Hicks, Blonigen, & Krueger, 2003). Individuals with high Impulsive-Antisociality displayed a significantly steeper attention blink (i.e., less accurate identification of a second target) than individuals with low Impulsive-Antisociality. Results provide new evidence that externalizers over-allocate attention to salient information and suggest a novel conceptualization of their disinhibitory psychopathology.

  View details for DOI 10.1016/j.jrp.2012.08.003

  View details for Web of Science ID 000312626100006

  View details for PubMedID 23180900

  View details for PubMedCentralID PMC3501747

• Dopaminergic Mechanisms of Individual Differences in Human Effort-Based Decision-Making JOURNAL OF NEUROSCIENCE Treadway, M. T., Buckholtz, J. W., Cowan, R. L., Woodward, N. D., Li, R., Ansari, M., Baldwin, R. M., Schwartzman, A. N., Kessler, R. M., Zald, D. H. 2012; 32 (18): 6170-6176

  Abstract

  Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

  View details for DOI 10.1523/JNEUROSCI.6459-11.2012

  View details for Web of Science ID 000303598900012

  View details for PubMedID 22553023

  View details for PubMedCentralID PMC3391699

• On the Use and Misuse of Genomic and Neuroimaging Science in Forensic Psychiatry: Current Roles and Future Directions CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Treadway, M. T., Buckholtz, J. W. 2011; 20 (3): 533-+

  Abstract

  Dramatic advances in the understanding of the neurobiological bases of human behavior have prompted excitement and controversy surrounding the ethical, legal, and social applications of this knowledge. The authors critically examine the promise and challenges of integrating genomic and neuroimaging techniques into legal settings. They suggest criteria for enhancing the viability of incorporating these data within a legal context and highlight several recent developments that may eventually allow genetic and neuroimaging evidence to meet these criteria and play a more prominent role in forensic science and law.

  View details for DOI 10.1016/j.chc.2011.03.012

  View details for Web of Science ID 000292858300011

  View details for PubMedID 21683918

  View details for PubMedCentralID PMC5530871

• A unique role for the human amygdala in novelty detection NEUROIMAGE Blackford, J., Buckholtz, J. W., Avery, S. N., Zald, D. H. 2010; 50 (3): 1188-1193

  Abstract

  Previous research indicates that the amygdala and hippocampus are sensitive to novelty; however, two types of novelty can be distinguished - stimuli that are ordinary, but novel in the current context, and stimuli that are unusual. Using functional magnetic resonance imaging, we examined blood oxygen dependent level (BOLD) response of the human amygdala and hippocampus to novel, commonly seen objects versus novel unusual objects. When presented with the novel common stimuli, the BOLD signal increased significantly in both the amygdala and hippocampus. However, for the novel unusual stimuli, only the amygdala showed an increased response compared to the novel common stimuli. These findings suggest that the amygdala is distinctly responsive to novel unusual stimuli, making a unique contribution to the novelty detection circuit.

  View details for DOI 10.1016/j.neuroimage.2009.12.083

  View details for Web of Science ID 000275408200032

  View details for PubMedID 20045069

  View details for PubMedCentralID PMC2830341

• Worth the 'EEfRT'? The Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia PLOS ONE Treadway, M. T., Buckholtz, J. W., Schwartzman, A. N., Lambert, W. E., Zald, D. H. 2009; 4 (8)

  View details for DOI 10.1371/journal.pone.0006598

  View details for Web of Science ID 000268935900012

• The Neural Correlates of Third-Party Punishment NEURON Buckholtz, J. W., Asplund, C. L., Dux, P. E., Zald, D. H., Gore, J. C., Jones, O. D., Marois, R. 2008; 60 (5): 930-940

  Abstract

  Legal decision-making in criminal contexts includes two essential functions performed by impartial "third parties:" assessing responsibility and determining an appropriate punishment. To explore the neural underpinnings of these processes, we scanned subjects with fMRI while they determined the appropriate punishment for crimes that varied in perpetrator responsibility and crime severity. Activity within regions linked to affective processing (amygdala, medial prefrontal and posterior cingulate cortex) predicted punishment magnitude for a range of criminal scenarios. By contrast, activity in right dorsolateral prefrontal cortex distinguished between scenarios on the basis of criminal responsibility, suggesting that it plays a key role in third-party punishment. The same prefrontal region has previously been shown to be involved in punishing unfair economic behavior in two-party interactions, raising the possibility that the cognitive processes supporting third-party legal decision-making and second-party economic norm enforcement may be supported by a common neural mechanism in human prefrontal cortex.

  View details for DOI 10.1016/j.neuron.2008.10.016

  View details for Web of Science ID 000261746700021

  View details for PubMedID 19081385

• COMT genetic variation affects fear processing: Psychophysiological evidence BEHAVIORAL NEUROSCIENCE Montag, C., Hartmann, P., Buckholtz, J. W., Merz, M., Burk, C., Hennig, J., Reuter, M. 2008; 122 (4): 901-909

  Abstract

  Emotional dysregulation is a core characteristic of many psychiatric diseases, including the anxiety disorders. Although heritable influences account for a significant degree of variation in risk for such disorders, relatively few candidate susceptibility factors have been identified. A coding variant in one such gene, encoding the dopamine catabolic enzyme catechol-O-methyltransferase (COMT Val158Met), has previously been associated with anxiety and with anxiety-related temperament and altered neural responses to affective stimuli in healthy individuals. In 96 healthy women recruited from a sample of 800 participants according to genotype, the authors tested for an association between the DRD2/ANKK1 Taq Ia, the COMT Val158Met, and a psychophysiological measure of emotion processing, the acoustic affective startle reflex modulation (ASRM) paradigm, and found that COMT genotype significantly affected startle reflex modulation by aversive stimuli, with Met158 homozygotes exhibiting a markedly potentiated startle reflex compared with Val158 carriers. A trait measure of anxiety (Gray's Behavioral Inhibition System; J. A. Gray & N. McNaughton, 2000) was also associated with ASRM. The functional polymorphism in the dopamine D2 receptor (DRD2/ANKK1 Taq Ia) had no effect on startle modulation. The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation.

  View details for DOI 10.1037/0735-7044.122.4.901

  View details for Web of Science ID 000258080000018

  View details for PubMedID 18729643

• MAOA and the neurogenetic architecture of human aggression TRENDS IN NEUROSCIENCES Buckholtz, J. W., Meyer-Lindenberg, A. 2008; 31 (3): 120-129

  Abstract

  Antisocial aggression is a widespread and expensive social problem. Although aggressive behaviors and temperament are highly heritable, clinical and trait associations for the most promising candidate gene for aggression, MAOA, have been largely inconsistent. We suggest that limitations inherent to that approach might be overcome by using multimodal neuroimaging to characterize neural mechanisms of genetic risk. Herein, we detail functional, structural and connectivity findings implicating the low-expressing allele of the MAOA u-VNTR (MAOA-L) in adversely prejudicing information processing within a corticolimbic circuit composed of amygdala, rostral cingulate and medial prefrontal cortex. We propose that the MAOA-L, by causing an ontogenic excess of 5-hydroxytryptamine, labilizes critical neural circuitry for social evaluation and emotion regulation (the 'socioaffective scaffold'), thereby amplifying the effects of adverse early-life experience and creating deleterious sociocognitive biases. Our construct provides a neurobiologically consistent model for gene-environment interactions in impulsive aggression.

  View details for DOI 10.1016/j.tins.2007.12.006

  View details for Web of Science ID 000255104700002

  View details for PubMedID 18258310

• Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in human personality MOLECULAR PSYCHIATRY Buckholtz, J. W., Callicott, J. H., Kolachana, B., Hariri, A. R., Goldberg, T. E., Genderson, M., Egan, M. F., Mattay, V. S., Weinberger, D. R., Meyer-Lindenberg, A. 2008; 13 (3): 313-324

  Abstract

  Little is known about neural mechanisms underlying human personality and temperament, despite their considerable importance as highly heritable risk mediators for somatic and psychiatric disorders. To identify these circuits, we used a combined genetic and imaging approach focused on Monoamine Oxidase A (MAOA), encoding a key enzyme for monoamine metabolism previously associated with temperament and antisocial behavior. Male carriers of a low-expressing genetic variant exhibited dysregulated amygdala activation and increased functional coupling with ventromedial prefrontal cortex (vmPFC). Stronger coupling predicted increased harm avoidance and decreased reward dependence scores, suggesting that this circuitry mediates a part of the association of MAOA with these traits. We utilized path analysis to parse the effective connectivity within this system, and provide evidence that vmPFC regulates amygdala indirectly by influencing rostral cingulate cortex function. Our data implicate a neural circuit for variation in human personality under genetic control, provide an anatomically consistent mechanism for vmPFC-amygdala interactions underlying this variation, and suggest a role for vmPFC as a superordinate regulatory area for emotional arousal and social behavior.

  View details for DOI 10.1038/sj.mp.4002020

  View details for Web of Science ID 000253238600012

  View details for PubMedID 17519928

• FMRI evidence for functional epistasis between COMT and RGS4 MOLECULAR PSYCHIATRY Buckholtz, J. W., Sust, S., Tan, H. Y., Mattay, V. S., Straub, R. E., Meyer-Lindenberg, A., Weinberger, D. R., Callicott, J. H. 2007; 12 (10): 893-895

  View details for DOI 10.1038/sj.mp.4002008

  View details for Web of Science ID 000249920500003

  View details for PubMedID 17895922

• Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proceedings of the National Academy of Sciences of the United States of America Tan, H. Y., Chen, Q., Sust, S., Buckholtz, J. W., Meyers, J. D., Egan, M. F., Mattay, V. S., Meyer-Lindenberg, A., Weinberger, D. R., Callicott, J. H. 2007; 104 (30): 12536-41

  Abstract

  Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signal-to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.

  View details for DOI 10.1073/pnas.0610125104

  View details for PubMedID 17636131

  View details for PubMedCentralID PMC1920538

• Allelic variation in RGS4 impacts functional and structural connectivity in the human brain. The Journal of neuroscience : the official journal of the Society for Neuroscience Buckholtz, J. W., Meyer-Lindenberg, A., Honea, R. A., Straub, R. E., Pezawas, L., Egan, M. F., Vakkalanka, R., Kolachana, B., Verchinski, B. A., Sust, S., Mattay, V. S., Weinberger, D. R., Callicott, J. H. 2007; 27 (7): 1584-93

  Abstract

  Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness.

  View details for DOI 10.1523/JNEUROSCI.5112-06.2007

  View details for PubMedID 17301167

  View details for PubMedCentralID PMC6673752

• Dysfunctional prefrontal regional specialization and compensation in schizophrenia. The American journal of psychiatry Tan, H. Y., Sust, S., Buckholtz, J. W., Mattay, V. S., Meyer-Lindenberg, A., Egan, M. F., Weinberger, D. R., Callicott, J. H. 2006; 163 (11): 1969-77

  Abstract

  It has been suggested that in healthy persons higher-order cognitive processing engaged by incremental working memory load hierarchically employs more dorsal than ventral prefrontal resources in healthy individuals. Given that working memory performance is impaired in schizophrenia, especially at higher executive loads, the authors investigated how this prefrontal functional organization might be altered in disease, independent of performance deficits.Using N-back working memory functional magnetic resonance imaging (fMRI) data, the authors studied 15 patients with schizophrenia and 26 healthy comparison subjects. Subgroups based on median performance accuracy at 2-back were analyzed; high performers included eight schizophrenia patients and 14 comparison subjects, and low performers included seven patients and 12 comparison subjects.High-performing but not low-performing comparison subjects responded to incremental working memory executive load with disproportionately greater dorsal but not ventral prefrontal cortex activation, which also predicted performance accuracy. In the high- and low-performing patient groups, incremental working memory load caused a disproportionate increase in ventral but not dorsal prefrontal cortex activation relative to the respective comparison group, which also correlated with accuracy. Functional connectivity between the ventral prefrontal cortex and posterior parietal cortex was relatively greater in patients, whereas comparison subjects had greater functional connectivity between the dorsal prefrontal cortex and posterior parietal cortex.The hierarchical organization of the prefrontal cortex may be compromised in schizophrenia, resulting in loss of functional specialization and integration at the dorsal prefrontal cortex and in compensatory activation from the ventral prefrontal cortex, which may ultimately affect working memory and executive cognition.

  View details for DOI 10.1176/ajp.2006.163.11.1969

  View details for PubMedID 17074949

• Impact of complex genetic variation in COMT on human brain function MOLECULAR PSYCHIATRY Meyer-Lindenberg, A., Nichols, T., Callicott, J. H., Ding, J., Kolachana, B., Buckholtz, J., Mattay, V. S., Egan, M., Weinberger, D. R. 2006; 11 (9): 867-877

  Abstract

  Catechol-O-methyltransferase (COMT) has been shown to be critical for prefrontal dopamine flux, prefrontal cortex-dependent cognition and activation. Several potentially functional variants in the gene have been identified, but considerable controversy exists regarding the contribution of individual alleles and haplotypes to risk for schizophrenia, partly because clinical phenotypes are ill-defined and preclinical studies are limited by lack of adequate models. Here, we propose a neuroimaging approach to overcome these limitations by characterizing the functional impact of ambiguous haplotypes on a neural system-level intermediate phenotype in humans. Studying 126 healthy control subjects during a working-memory paradigm, we find that a previously described risk variant in a functional Val158Met (rs4680) polymorphism interacts with a P2 promoter region SNP (rs2097603) and an SNP in the 3' region (rs165599) in predicting inefficient prefrontal working memory response. We report evidence that the nonlinear response of prefrontal neurons to dopaminergic stimulation is a neural mechanism underlying these nonadditive genetic effects. This work provides an in vivo approach to functional validation in brain of the biological impact of complex genetic variations within a gene that may be critical for its clinical association.

  View details for DOI 10.1038/sj.mp.4001860

  View details for Web of Science ID 000240043100010

  View details for PubMedID 16786032

• Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans NEUROPSYCHOPHARMACOLOGY Bonson, K. R., Buckholtz, J. W., Murphy, D. L. 1996; 14 (6): 425-436

  Abstract

  This study investigates the possible interactions of antidepressant agents and hallucinogens in humans through structured interviews using a standardized questionnaire. Volunteer subjects recruited through announcements placed on the Internet or other sources were asked to describe the somatic, hallucinatory, and psychological effects of self-administered LSD prior to and during chronic administration of an antidepressant. Twenty-eight out of 32 subjects (88%) who had taken an antidepressant with inhibitory effects on serotonin (5-HT) reuptake (fluoxetine, paroxetine, sertraline, trazodone) for over 3 weeks had a subjective decrease or virtual elimination of their responses to LSD. An additional subject who had taken fluoxetine for only 1 week had an increased response to LSD. These data are in contrast to our previous study that reported increased responses to LSD during chronic administration of tricyclic antidepressants or lithium. Possible mechanisms of action for the effects from serotonergic antidepressants involve 5-HT2 and 5-HT1A receptors, changes in extracellular brain serotonin concentrations, and changes in brain catecholamine systems.

  View details for DOI 10.1016/0893-133X(95)00145-4

  View details for Web of Science ID A1996UL72800002

  View details for PubMedID 8726753