Study protocol for a randomised controlled trial investigating the effects of Mindfulness Based Stress Reduction on stress regulation and associated neurocognitive mechanisms in stressed university students: the MindRest study.

BACKGROUND: Stress-related disorders are a growing public health concern. While stress is a natural and adaptive process, chronic exposure to stressors can lead to dysregulation and take a cumulative toll on physical and mental well-being. One approach to coping with stress and building resilience is through Mindfulness-Based Stress Reduction (MBSR). By understanding the neural mechanisms of MBSR, we can gain insight into how it reduces stress and what drives individual differences in treatment outcomes. This study aims to establish the clinical effects of MBSR on stress regulation in a population that is susceptible to develop stress-related disorders (i.e., university students with mild to high self-reported stress), to assess the role of large-scale brain networks in stress regulation changes induced by MBSR, and to identify who may benefit most from MBSR. METHODS: This study is a longitudinal two-arm randomised, wait-list controlled trial to investigate the effects of MBSR on a preselected, Dutch university student population with elevated stress levels. Clinical symptoms are measured at baseline, post-treatment, and three months after training. Our primary clinical symptom is perceived stress, with additional measures of depressive and anxiety symptoms, alcohol use, stress resilience, positive mental health, and stress reactivity in daily life. We investigate the effects of MBSR on stress regulation in terms of behaviour, self-report measures, physiology, and brain activity. Repetitive negative thinking, cognitive reactivity, emotional allowance, mindfulness skills, and self-compassion will be tested as potential mediating factors for the clinical effects of MBSR. Childhood trauma, personality traits and baseline brain activity patterns will be tested as potential moderators of the clinical outcomes. DISCUSSION: This study aims to provide valuable insights into the effectiveness of MBSR in reducing stress-related symptoms in a susceptible student population and crucially, to investigate its effects on stress regulation, and to identify who may benefit most from the intervention. TRIAL REGISTRATION: Registered on September 15, 2022, at clinicaltrials.gov, NCT05541263 .

Effect of striatal dopamine on Pavlovian bias. A large [¹8F]-DOPA PET study.

Interaction between Pavlovian and instrumental control systems is key for adaptive motivated behavior, but also plays an important role in various neuropsychiatric disorders, including depression, addiction, and anxiety. Here, we employed the flouorodopa positron emission tomography ([¹8F]-DOPA PET) in healthy participants (N = 100) to assess whether dopamine synthesis capacity (Ki), specifically in the ventral striatum, accounts for individual variation in Pavlovian-to-instrumental transfer (PIT). Surprisingly, this was not the case. Rather, the relationship of ventral striatal Ki with PIT depended on working memory (WM) capacity. Ventral striatal dopamine boosted the effects of Pavlovian cues on instrumental responding to a greater degree in participants with higher WM capacity. Caution is warranted to interpret this post hoc four-way interaction given the modest sample size. Nonetheless, these results chime with prior findings demonstrating that dopaminergic drugs boost Pavlovian biases to a greater degree in participants with greater WM capacity and highlight the importance of interactions between striatal dopamine and WM capacity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychopathic tendency in violent offenders is associated with reduced aversive Pavlovian inhibition of behavior and associated striatal BOLD signal.

Background: Violent offenders with psychopathic tendencies are characterized by instrumental, i.e., planned, callous, and unemotional (aggressive) behavior and have been shown to exhibit abnormal aversive processing. However, the consequences of abnormal aversive processing for instrumental action and associated neural mechanisms are unclear. Materials and methods: Here we address this issue by using event-related functional magnetic resonance imaging (fMRI) in 15 violent offenders with high psychopathic tendencies and 18 matched controls during the performance of an aversive Pavlovian-to-instrumental transfer paradigm. This paradigm allowed us to assess the degree to which aversive Pavlovian cues affect instrumental action and associated neural signaling. Results: Psychopathic tendency scores were associated with an attenuation of aversive Pavlovian inhibition of instrumental action. Moreover, exploratory analyses revealed an anomalous positive association between aversive inhibition of action and aversive inhibition of BOLD signal in the caudate nucleus of violent offenders with psychopathic tendencies. In addition, psychopathic tendency also correlated positively with amygdala reactivity during aversive versus neutral cues in Pavlovian training. Conclusion: These findings strengthen the hypothesis that psychopathic tendencies in violent offenders are related to abnormal impact of aversive processing on instrumental behavior. The neural effects raise the possibility that this reflects deficient transfer of aversive Pavlovian inhibitory biases onto neural systems that implement instrumental action, including the caudate nucleus.

Amygdala response predicts clinical symptom reduction in patients with borderline personality disorder: A pilot fMRI study.

Borderline personality disorder (BPD) is a prevalent, devastating, and heterogeneous psychiatric disorder. Treatment success is highly variable within this patient group. A cognitive neuroscientific approach to BPD might contribute to precision psychiatry by identifying neurocognitive factors that predict who will benefit from a specific treatment. Here, we build on observations that BPD is accompanied by the enhanced impact of the aversive effect on behavior and abnormal neural signaling in the amygdala. We assessed whether BPD is accompanied by abnormal aversive regulation of instrumental behavior and associated neural signaling, in a manner that is predictive of symptom reduction after therapy. We tested a clinical sample of 15 female patients with BPD, awaiting dialectical behavior therapy (DBT), and 16 matched healthy controls using fMRI and an aversive Pavlovian-to-instrumental transfer (PIT) task that assesses how instrumental behaviors are influenced by aversive Pavlovian stimuli. Patients were assessed 1 year after the start of DBT to quantify changes in BPD symptom severity. At baseline, behavioral aversive PIT and associated neural signaling did not differ between groups. However, the BOLD signal in the amygdala measured during aversive PIT was associated with symptom reduction at 1-year follow-up: higher PIT-related aversive amygdala signaling before treatment was associated with reduced clinical improvement at follow-up. Thus, within the evaluated group of BPD patients, the BOLD signal in the amygdala before treatment was related to clinical symptom reduction 1 year after the start of treatment. The results suggest that less PIT-related responsiveness of the amygdala increases the chances of treatment success. We note that the relatively small sample size is a limitation of this study and that replication is warranted.

Aversive Pavlovian inhibition in adult attention-deficit/hyperactivity disorder and its restoration by mindfulness-based cognitive therapy.

Background: Control over the tendency to make or withhold responses guided by contextual Pavlovian information plays a key role in understanding impulsivity and hyperactivity. Here we set out to assess (1) the understudied relation between contextual Pavlovian inhibitory control and hyperactivity/impulsivity in adults with ADHD and (2) whether this inhibition can be enhanced by mindfulness based cognitive therapy (MBCT). Methods: Within the framework of a randomized controlled trial 50 Adult ADHD patients were assessed before and after 8 weeks of treatment as usual (TAU) with (n = 24) or without (n = 26) MBCT. We employed a well-established behavioral Pavlovian-to-instrumental transfer task that quantifies Pavlovian inhibitory control over instrumental behavior. Results: Task results revealed (1) less aversive Pavlovian inhibition in ADHD patients with clinically relevant hyperactivity/impulsivity than in those without; and (2) enhanced Pavlovian inhibition across all ADHD patients after TAU+MBCT compared with TAU. Conclusion: These findings offer new insights in the neurocognitive mechanisms of hyperactivity/impulsivity in ADHD and its treatment: We reveal a role for Pavlovian inhibitory mechanisms in understanding hyperactive/impulsive behaviors in ADHD and point toward MBCT as an intervention that might influence these mechanisms.

Mindfulness based cognitive therapy (MBCT) reduces depression-related self-referential processing in patients with bipolar disorder: an exploratory task-based study.

Negative self-referential processing has fruitfully been studied in unipolar depressed patients, but remarkably less in patients with bipolar disorder (BD). This exploratory study examines the relation between task-based self-referential processing and depressive symptoms in BD and their possible importance to the working mechanism of mindfulness-based cognitive therapy (MBCT) for BD. The study population consisted of a subsample of patients with BD (n = 49) participating in an RCT of MBCT for BD, who were assigned to MBCT + TAU (n = 23) or treatment as usual (TAU) (n = 26). Patients performed the self-referential encoding task (SRET), which measures (1) positive and (2) negative attributions to oneself as well as (3) negative self-referential memory bias, before and after MBCT + TAU or TAU. At baseline, all three SRET measures were significantly related to depressive symptoms in patients with BD. Moreover, repeated measures analyses of variance revealed that negative self-referential memory bias diminished over time in the MBCT + TAU group, compared with the TAU group. Given the preliminary nature of our findings, future research should explore the possibly mediating role of reducing negative self-referential memory bias in preventing and treating depressive symptoms in BD through MBCT.

Neural correlates of repetitive negative thinking: Dimensional evidence across the psychopathological continuum.

Repetitive negative thinking (RNT) captures an important transdiagnostic factor that predisposes to a maladaptive stress response and contributes to diverse psychiatric disorders. Although RNT can best be seen as a continuous symptom dimension that cuts across boundaries from health to various psychiatric disorders, the neural mechanisms underlying RNT have almost exclusively been studied in health and stress-related disorders, such as depression and anxiety disorders. We set out to study RNT from a large-scale brain network perspective in a diverse population consisting of healthy subjects and patients with a broader range of psychiatric disorders. We studied 46 healthy subjects along with 153 patients with a stress-related and/or neurodevelopmental disorder. We focused on three networks, that are associated with RNT and diverse psychiatric disorders: the salience network, default mode network (DMN) and frontoparietal network (FPN). We investigated the relationship of RNT with both network connectivity strength at rest and with the stress-induced changes in connectivity. Across our whole sample, the level of RNT was positively associated with the connectivity strength of the left FPN at rest, but negatively associated with stress-induced changes in DMN connectivity. These findings may reflect an upregulation of the FPN in an attempt to divert attention away from RNT, while the DMN result may reflect a less flexible adaptation to stress, related to RNT. Additionally, we discuss how our findings fit into the non-invasive neurostimulation literature. Taken together, our results provide initial insight in the neural mechanisms of RNT across the spectrum from health to diverse psychiatric disorders.

Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders (MIND-SET): Protocol for a Cross-sectional Comorbidity Study From a Research Domain Criteria Perspective.

BACKGROUND: It is widely acknowledged that comorbidity between psychiatric disorders is common. Shared and diverse underpinnings of psychiatric disorders cannot be systematically understood based on symptom-based categories of mental disorders, which map poorly onto pathophysiological mechanisms. In the Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders (MIND-SET) study, we make use of current concepts of comorbidity that transcend the current diagnostic categories. We test this approach to psychiatric problems in patients with frequently occurring psychiatric disorders and their comorbidities (excluding psychosis). OBJECTIVE: The main aim of the MIND-SET project is to determine the shared and specific mechanisms of neurodevelopmental and stress-related psychiatric disorders at different observational levels. METHODS: This is an observational cross-sectional study. Data from different observational levels as defined in the Research Domain Criteria (genetics, physiology, neuropsychology, system-level neuroimaging, behavior, self-report, and experimental neurocognitive paradigms) are collected over four time points. Included are adult (aged ≥18 years), nonpsychotic, psychiatric patients with a clinical diagnosis of a stress-related disorder (mood disorder, anxiety disorder, or substance use disorder) or a neurodevelopmental disorder (autism spectrum disorder or attention-deficit/hyperactivity disorder). Individuals with no current or past psychiatric diagnosis are included as neurotypical controls. Data collection started in June 2016 with the aim to include a total of 650 patients and 150 neurotypical controls by 2021. The data collection procedure includes online questionnaires and three subsequent sessions with (1) standardized clinical examination, physical examination, and blood sampling; (2) psychological constructs, neuropsychological tests, and biological marker sampling; and (3) neuroimaging measures. RESULTS: We aim to include a total of 650 patients and 150 neurotypical control participants in the time period between 2016 and 2022. In October 2021, we are at 95% of our target. CONCLUSIONS: The MIND-SET study enables us to investigate the mechanistic underpinnings of nonpsychotic psychiatric disorders transdiagnostically. We will identify both shared and disorder-specific markers at different observational levels that can be used as targets for future diagnostic and treatment approaches.

Effects of methylphenidate on reinforcement learning depend on working memory capacity.

RATIONALE: Brain catecholamines have long been implicated in reinforcement learning, exemplified by catecholamine drug and genetic effects on probabilistic reversal learning. However, the mechanisms underlying such effects are unclear. OBJECTIVES AND METHODS: Here we investigated effects of an acute catecholamine challenge with methylphenidate (20 mg, oral) on a novel probabilistic reversal learning paradigm in a within-subject, double-blind randomised design. The paradigm was designed to disentangle effects on punishment avoidance from effects on reward perseveration. Given the known large individual variability in methylphenidate's effects, we stratified our effects by working memory capacity and trait impulsivity, putatively modulating the effects of methylphenidate, in a large sample (n = 102) of healthy volunteers. RESULTS: Contrary to our prediction, methylphenidate did not alter performance in the reversal phase of the task. Our key finding is that methylphenidate altered learning of choice-outcome contingencies in a manner that depended on individual variability in working memory span. Specifically, methylphenidate improved performance by adaptively reducing the effective learning rate in participants with higher working memory capacity. CONCLUSIONS: This finding emphasises the important role of working memory in reinforcement learning, as reported in influential recent computational modelling and behavioural work, and highlights the dependence of this interplay on catecholaminergic function.

Putting mindfulness-based cognitive therapy to the test in routine clinical practice: A transdiagnostic panacea or a disorder specific intervention?

BACKGROUND: Over the past two decades there has been a growing number of randomized clinical trials supporting the efficacy of mindfulness-based cognitive therapy (MBCT) in the treatment of several psychiatric disorders. Since evidence for its effectiveness in routine clinical practice is lagging behind, we aimed to examine adherence, outcome and predictors of MBCT in a well-characterized, heterogeneous outpatient population in routine clinical practice. METHODS: Data were collected from a naturalistic uncontrolled cohort of 998 patients formally diagnosed with mainly depression, anxiety disorders, personality disorders, somatoform disorders and/or ADHD. Patients received protocolized MBCT and completed self-report questionnaires pre- and post-treatment on overall functioning (Outcome Questionnaire, primary outcome), depressive symptoms, worry, mindfulness skills and self-compassion. Pre-to post-treatment changes were analysed for the overall sample and each diagnostic category separately with paired sample t-tests, reliable change indices (only overall sample) and repeated measures ANOVA for groups with and without comorbidity. Multiple linear regression was carried out to assess possible predictors of adherence and change in overall functioning. RESULTS: Adherence was high (94%) but negatively affected by lower levels of education, more comorbidity and presence of ADHD. Outcome in terms of improvement in overall functioning was good in the overall sample (Cohen's d = 0.50, 30% showed reliable improvement vs. 3.5% reliable deterioration) and within each diagnostic category (Cohen's d range = 0.37-0.61). Worse overall functioning at baseline was the only predictor for a larger treatment effect. CONCLUSIONS: After MBCT, overall functioning improved in a large heterogeneous psychiatric outpatient population independent of diagnosis or comorbidity.

Mechanisms of Change in Mindfulness-Based Cognitive Therapy in Adults With ADHD.

Objective: Mindfulness-based cognitive therapy (MBCT) has been demonstrated to be effective in adults with ADHD. The aim of the current study was to examine its possible working mechanisms. Method: In the context of an randomized controlled trial (RCT), MBCT + TAU (treatment as usual) (n = 43) versus TAU (n = 51), we used mediation analyses to examine whether reduction of clinician-rated ADHD symptoms and improvement of positive mental health at 6-month follow-up had been mediated by change in mindfulness skills, self-compassion, and executive functioning over the course of MBCT. Results: Increase of self-compassion mediated improvement of positive mental health at 6-month follow-up. Improvement of mindfulness skills or self-compassion did not mediate the reduction in ADHD symptoms. Additional analyses suggest that self-reported inhibition did. Conclusion: The effect of MBCT on ADHD symptoms and positive mental health thus occurred via different mechanisms of change, that is, by improvements in inhibition and self-compassion, respectively.

The effectiveness of mindfulness-based cognitive therapy for major depressive disorder: evidence from routine outcome monitoring data.

BACKGROUND: Meta-analyses show efficacy of mindfulness-based cognitive therapy (MBCT) in terms of relapse prevention and depressive symptom reduction in patients with major depressive disorder (MDD). However, most studies have been conducted in controlled research settings. AIMS: We aimed to investigate the effectiveness of MBCT in patients with MDD presenting in real-world clinical practice. Moreover, we assessed whether guideline recommendations for MBCT allocation in regard to recurrence and remission status of MDD hold in clinical practice. METHOD: This study assessed a naturalistic cohort of patients with (recurrent) MDD, either current or in remission (n = 765), who received MBCT in a university hospital out-patient clinic in The Netherlands. Outcome measures were self-reported depressive symptoms, worry, mindfulness skills and self-compassion. Predictors were MDD recurrence and remission status, and clinical and sociodemographic variables. Outcome and predictor analyses were conducted with linear regression. RESULTS: MBCT adherence was high (94%). Patients with a lower level of education had a higher chance of non-adherence. Attending more sessions positively influenced improvement in depressive symptoms. Depressive symptoms significantly reduced from pre- to post-MBCT (Δ mean = 7.7, 95%CI = 7.0-8.5, Cohen's d = 0.75). Improvement of depressive symptoms was independent from MDD recurrence and remission status. Unemployed patients showed less favourable outcomes. Worry, mindfulness skills and self-compassion all significantly improved. These improvements were related to changes in depressive symptoms. CONCLUSIONS: Previous efficacy results in controlled research settings are maintained in clinical practice. Results illustrate that MBCT is effective in routine clinical practice for patients suffering from MDD, irrespective of MDD recurrence and remission status.

Intact corticostriatal control of goal-directed action in Alcohol Use Disorder: a Pavlovian-to-instrumental transfer and outcome-devaluation study.

Deficits in instrumental, goal-directed control, combined with the influence of drug-associated Pavlovian-conditioned stimuli, are thought to influence the development and maintenance of addiction. However, direct evidence has mainly come from animal studies. We sought to establish whether alcohol use disorder (AUD) is characterized by behavioral or neurobiological deficits in (i) the integration of Pavlovian and instrumental values and (ii) goal-directed control; and (iii) whether duration or severity of AUD is associated with such deficits. The influence of cues predicting food rewards on instrumental action was assessed in a Pavlovian-to-instrumental transfer (PIT) test, measuring both specific and general PIT, and goal-directed behavior in an outcome-devaluation test. Brain activity was measured using functional MRI in 38 abstinent individuals with AUD and 22 matched healthy control individuals (HCs). We found significant specific and general PIT and outcome-devaluation effects across groups indicating goal-directed control, mediated by distinct corticostriatal signals, but no significant differences between individuals with AUD and healthy controls. Bayesian analyses provided substantial-to-strong evidence for the absence of group differences for these effects, or any relationship with duration or severity of AUD. These results suggest intact ability to integrate action-outcome associations on specific and general PIT and goal-directed learning in AUD during abstinence.

Catecholaminergic modulation of the avoidance of cognitive control.

The catecholamines have long been associated with cognitive control and value-based decision-making. More recently, we proposed that the catecholamines might modulate value-based decision-making about whether or not to engage in cognitive control. We test this hypothesis by assessing effects of a catecholamine challenge in a large sample of young, healthy adults (n = 100) on the avoidance of a cognitively demanding control process: task switching. Prolonging catecholamine transmission by blocking reuptake with methylphenidate altered the avoidance, but not the execution of cognitive control. Crucially, these effects could be isolated by taking into account individual differences in trait impulsivity, so that participants with higher trait impulsivity became more avoidant of cognitive control, despite faster task performance. One implication of these findings is that performance-enhancing effects of methylphenidate may be accompanied by an undermining effect on the willingness to exert cognitive control. Taken together, these findings integrate hitherto segregated literatures on catecholamines' roles in value-based learning/choice and cognitive control. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

Fatigue Is Associated With Altered Monitoring and Preparation of Physical Effort in Patients With Chronic Fatigue Syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by disabling fatigue, which is suggested to be maintained by dysfunctional beliefs. Fatigue and its maintenance are recently conceptualized as arising from abnormally precise expectations about bodily inputs and from beliefs of diminished control over bodily states, respectively. This study used functional neuroimaging to identify the neural correlates of fatigue and its maintenance by beliefs during a physical effort task. METHODS: We isolated behavioral adjustments and cerebral activity during feedback processing and motor preparation, in the context of a task in which patients with CFS (n = 85) and healthy control subjects (n = 29) produced 30%, 50%, and 70% of their right-hand maximal voluntary contraction, and received directional feedback on performance (e.g., too little force). RESULTS: Patients with CSF showed an effort-dependent behavioral bias toward less effort investment in response to directional feedback for the highest effort level as compared with healthy control subjects. This bias was associated with reduced feedback-related activity in the dorsolateral prefrontal cortex. These effects were proportional to state-related fatigue and prior beliefs about CFS patients' ability to perform the task. Patients with CFS also showed higher activity in the supplementary motor area, proportional to their state-related fatigue, and reduced connectivity between the supplementary motor area and sensorimotor cortex during motor preparation as compared with control subjects. CONCLUSIONS: These findings link fatigue symptoms to alterations in behavioral choices on effort investment, prefrontal functioning, and supplementary motor area connectivity, with the dorsolateral prefrontal cortex being associated with prior beliefs about physical abilities.

Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome.

BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity). METHODS: We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls. RESULTS: The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups. CONCLUSIONS: CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS.

Neural connectivity during reward expectation dissociates psychopathic criminals from non-criminal individuals with high impulsive/antisocial psychopathic traits.

Criminal behaviour poses a big challenge for society. A thorough understanding of the neurobiological mechanisms underlying criminality could optimize its prevention and management. Specifically,elucidating the neural mechanisms underpinning reward expectation might be pivotal to understanding criminal behaviour. So far no study has assessed reward expectation and its mechanisms in a criminal sample. To fill this gap, we assessed reward expectation in incarcerated, psychopathic criminals. We compared this group to two groups of non-criminal individuals: one with high levels and another with low levels of impulsive/antisocial traits. Functional magnetic resonance imaging was used to quantify neural responses to reward expectancy. Psychophysiological interaction analyses were performed to examine differences in functional connectivity patterns of reward-related regions. The data suggest that overt criminality is characterized, not by abnormal reward expectation per se, but rather by enhanced communication between reward-related striatal regions and frontal brain regions. We establish that incarcerated psychopathic criminals can be dissociated from non-criminal individuals with comparable impulsive/antisocial personality tendencies based on the degree to which reward-related brain regions interact with brain regions that control behaviour. The present results help us understand why some people act according to their impulsive/antisocial personality while others are able to behave adaptively despite reward-related urges.

Amplified Striatal Responses to Near-Miss Outcomes in Pathological Gamblers.

Near-misses in gambling games are losing events that come close to a win. Near-misses were previously shown to recruit reward-related brain regions including the ventral striatum, and to invigorate gambling behavior, supposedly by fostering an illusion of control. Given that pathological gamblers are particularly vulnerable to such cognitive illusions, their persistent gambling behavior might result from an amplified striatal sensitivity to near-misses. In addition, animal studies have shown that behavioral responses to near-miss-like events are sensitive to dopamine, but this dopaminergic influence has not been tested in humans. To investigate these hypotheses, we recruited 22 pathological gamblers and 22 healthy controls who played a slot machine task delivering wins, near-misses and full-misses, inside an fMRI scanner. Each participant played the task twice, once under placebo and once under a dopamine D2 receptor antagonist (sulpiride 400 mg), in a double-blind, counter-balanced design. Participants were asked about their motivation to continue gambling throughout the task. Across all participants, near-misses elicited higher motivation to continue gambling and increased striatal responses compared with full-misses. Crucially, pathological gamblers showed amplified striatal responses to near-misses compared with controls. These group differences were not observed following win outcomes. In contrast to our hypothesis, sulpiride did not induce any reliable modulation of brain responses to near-misses. Together, our results demonstrate that pathological gamblers have amplified brain responses to near-misses, which likely contribute to their persistent gambling behavior. However, there is no evidence that these responses are influenced by dopamine. These results have implications for treatment and gambling regulation.

Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.

In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.