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Avoidance and heightened responses to perceived threats are key features of anxiety disorders. These disorders are characterised by inflexibility in dynamically updating behavioural and physiological responses to aversively conditioned cues or environmental contexts which are no longer objectively threatening, often manifesting in perseverative avoidance. However, less is known about how anxiety disorders might differ in adjusting to threat and safety shifts in the environment or how idiosyncratic avoidance responses are learned and persist. Twenty-eight patients with generalised anxiety disorder (GAD), without DSM co-morbidities, and 27 matched healthy controls were administered two previously established paradigms: Pavlovian threat reversal and shock avoidance habits through overtraining (assessed following devaluation with measures of perseverative responding). For both tasks we used subjective report scales and skin conductance responses (SCR). In the Pavlovian threat reversal task, patients with GAD showed a significantly overall higher SCR as well as a reduced differential SCR response compared to controls in the early but not late reversal phase. During the test of habitual avoidance responding, GAD patients did not differ from controls in task performance, habitual active avoidance responses during devaluation, or corresponding SCR during trials, but showed a trend toward more abstract confirmatory subjective justifications for continued avoidance following the task. GAD patients exhibited significantly greater skin conductance responses to signals of threat than controls, but did not exhibit the major deficits in reversal and safety signal learning shown previously by patients with OCD. Moreover, this patient group, again unlike OCD patients, did not show evidence of altered active avoidance learning or enhanced instrumental avoidance habits. Overall, these findings indicate no deficits in instrumental active avoidance or persistent avoidance habits, despite enhanced responses to Pavlovian threat cues in GAD. They suggest that GAD is characterised by passive, and not excessively rigid, avoidance styles., BJS receives funding from the Leverhulme Trust and the Lundbeck Foundation, and her research diagnostic Co-operative (MIC) and the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health theme. This research was funded by the Wellcome Trust (Grant 104631/Z/14/Z to TWR). For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Cross-species studies have identified an evolutionarily conserved role for serotonin in flexible behavior including reversal learning. The aim of the current study was to investigate the contribution of serotonin within the orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC) to visual discrimination and reversal learning. Male Lister Hooded rats were trained to discriminate between a rewarded (A+) and a nonrewarded (B−) visual stimulus to receive sucrose rewards in touchscreen operant chambers. Serotonin was depleted using surgical infusions of 5,7-dihydroxytryptamine (5,7-DHT), either globally by intracebroventricular (i.c.v.) infusions or locally by microinfusions into the OFC or mPFC. Rats that received i.c.v. infusions of 5,7-DHT before initial training were significantly impaired during both visual discrimination and subsequent reversal learning during which the stimulus–reward contingencies were changed (A− vs. B+). Local serotonin depletion from the OFC impaired reversal learning without affecting initial discrimination. After mPFC depletion, rats were unimpaired during reversal learning but slower to respond at the stimuli during all the stages; the mPFC group was also slower to learn during discrimination than the OFC group. These findings extend our understanding of serotonin in cognitive flexibility by revealing differential effects within two subregions of the prefrontal cortex in visual discrimination and reversal learning.

The involvement of serotonin in responses to negative feedback is well established. Acute serotonin reuptake inhibition has enhanced sensitivity to negative feedback (SNF), modelled by behaviour in probabilistic reversal learning (PRL) paradigms. Whilst experiments employing acute tryptophan depletion (ATD) in humans, to reduce serotonin synthesis, have shown no clear effect on SNF, sample sizes have been small. We studied a large sample of healthy volunteers, male and female, and found ATD had no effect on core behavioural measures in PRL. These results indicate that ATD effects can differ from other manipulations of serotonin expected to have a parallel or opposing action.

Maladaptive impulsivity manifests in a variety of disorders, including attention-deficit hyperactivity disorder (ADHD), depression, and substance use disorder. However, the etiological mechanisms of impulsivity remain poorly understood. In the present study, we used in-vivo proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolite content in the prefrontal cortex (PFC) and striatum of rats exhibiting low- versus high-impulsive (LI, HI) behavior on a visual attentional task. We validated our 1H-MRS findings using regionally resolved ex-vivo mass spectroscopy, transcriptomics, and site-directed RNA interference in the ventromedial PFC. We report a significant reduction in myoinositol levels in the PFC but not the striatum of HI rats compared with LI rats. Reduced myoinositol content was localized to the infralimbic (IL) cortex, where significant reductions in transcript levels of key proteins involved in the synthesis and recycling of myoinositol (IMPase1) were also present. Knockdown of IMPase1in the IL cortex increased impulsivity in nonimpulsive rats when the demand on inhibitory response control was increased. We conclude that diminished myoinositol levels in ventromedial PFC causally mediate a specific form of impulsivity linked to vulnerability for stimulant addiction in rodents. Myoinositol and related signaling substrates may thus offer novel opportunities for treating neuropsychiatric disorders comorbid with impulsive symptomology.

Background. The global COVID-19 pandemic has triggered a fundamental reexamination of how human psychological research can be conducted both safely and robustly in a new era of digital working and physical distancing. Online web-based testing has risen to the fore as a promising solution for rapid mass collection of cognitive data without requiring human contact. However, a long-standing debate exists over the data quality and validity of web-based studies. Here, we examine the opportunities and challenges afforded by the societal shift toward web-based testing, highlight an urgent need to establish a standard data quality assurance framework for online studies, and develop and validate a new supervised online testing methodology, remote guided testing (RGT). Methods. A total of 85 healthy young adults were tested on 10 cognitive tasks assessing executive functioning (flexibility, memory and inhibition) and learning. Tasks were administered either face-to-face in the laboratory (N=41) or online using remote guided testing (N=44), delivered using identical web-based platforms (CANTAB, Inquisit and i-ABC). Data quality was assessed using detailed trial-level measures (missed trials, outlying and excluded responses, response times), as well as overall task performance measures. Results. The results indicated that, across all measures of data quality and performance, RGT data was statistically-equivalent to data collected in person in the lab. Moreover, RGT participants out-performed the lab group on measured verbal intelligence, which could reflect test environment differences, including possible effects of mask-wearing on communication. Conclusions. These data suggest that the RGT methodology could help to ameliorate concerns regarding online data quality and - particularly for studies involving high-risk or rare cohorts - offer an alternative for collecting high-quality human cognitive data without requiring in-person physical attendance.

Background Obsessive–compulsive disorder (OCD) is a neuropsychiatric disorder which often proves refractory to current treatment approaches. Transcranial direct current stimulation (tDCS), a noninvasive form of neurostimulation, with potential for development as a self-administered intervention, has shown potential as a safe and efficacious treatment for OCD in a small number of trials. The two most promising stimulation sites are located above the orbitofrontal cortex (OFC) and the supplementary motor area (SMA). Methods The aim of this feasibility study is to inform the development of a definitive trial, focussing on the acceptability, safety of the intervention, feasibility of recruitment, adherence and tolerability to tDCS and study assessments and the size of the treatment effect. To this end, we will deliver a double-blind, sham-controlled, crossover randomised multicentre study in 25 adults with OCD. Each participant will receive three courses of tDCS (SMA, OFC and sham), randomly allocated and given in counterbalanced order. Each course comprises four 20-min stimulations, delivered over two consecutive days, separated by at least 4 weeks’ washout period. We will collect information about recruitment, study conduct and tDCS delivery. Blinded raters will assess clinical outcomes before, during and up to 4 weeks after stimulation using validated scales. We will include relevant objective neurocognitive tasks, testing cognitive flexibility, motor disinhibition, cooperation and habit learning. Discussion We will analyse the magnitude of the effect of the interventions on OCD symptoms alongside the standard deviation of the outcome measure, to estimate effect size and determine the optimal stimulation target. We will also measure the duration of the effect of stimulation, to provide information on spacing treatments efficiently. We will evaluate the usefulness and limitations of specific neurocognitive tests to determine a definitive test battery. Additionally, qualitative data will be collected from participants to better understand their experience of taking part in a tDCS intervention, as well as the impact on their overall quality of life. These clinical outcomes will enable the project team to further refine the methodology to ensure optimal efficiency in terms of both delivering and assessing the treatment in a full-scale trial. Trial registration ISRCTN17937049. (date applied 08/07/2019). Recruitment (ongoing) began 23rd July 2019 and is anticipated to complete 30th April 2021.

Funder: Information Technology Center of Zhejiang University, Funder: Shanghai Pujiang Program, Hemispheric lateralization constitutes a core architectural principle of human brain organization underlying cognition, often argued to represent a stable, trait-like feature. However, emerging evidence underlines the inherently dynamic nature of brain networks, in which time-resolved alterations in functional lateralization remain uncharted. Integrating dynamic network approaches with the concept of hemispheric laterality, we map the spatiotemporal architecture of whole-brain lateralization in a large sample of high-quality resting-state fMRI data (N = 991, Human Connectome Project). We reveal distinct laterality dynamics across lower-order sensorimotor systems and higher-order associative networks. Specifically, we expose 2 aspects of the laterality dynamics: laterality fluctuations (LF), defined as the standard deviation of laterality time series, and laterality reversal (LR), referring to the number of zero crossings in laterality time series. These 2 measures are associated with moderate and extreme changes in laterality over time, respectively. While LF depict positive association with language function and cognitive flexibility, LR shows a negative association with the same cognitive abilities. These opposing interactions indicate a dynamic balance between intra and interhemispheric communication, i.e., segregation and integration of information across hemispheres. Furthermore, in their time-resolved laterality index, the default mode and language networks correlate negatively with visual/sensorimotor and attention networks, which are linked to better cognitive abilities. Finally, the laterality dynamics are associated with functional connectivity changes of higher-order brain networks and correlate with regional metabolism and structural connectivity. Our results provide insights into the adaptive nature of the lateralized brain and new perspectives for future studies of human cognition, genetics, and brain disorders.

Funder: Fondation pour la Recherche M��dicale (Foundation for Medical Research in France); doi: https://doi.org/10.13039/501100002915, Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.

BACKGROUND: Impaired response inhibition in individuals with cocaine use disorder (CUD) is hypothesized to depend on deficient noradrenergic signaling in corticostriatal networks. Remediation of noradrenergic neurotransmission with selective norepinephrine reuptake inhibitors such as atomoxetine may therefore have clinical utility to improve response inhibitory control in CUD. METHODS: We carried out a randomized, double-blind, placebo-controlled, crossover study with 26 participants with CUD and 28 control volunteers investigating the neural substrates of stop-signal inhibitory control. The effects of a single dose of atomoxetine (40 mg) were compared with placebo on stop-signal reaction time performance and functional network connectivity using dynamic causal modeling. RESULTS: We found that atomoxetine speeded Go response times in both control participants and those with CUD. Improvements in stopping efficiency on atomoxetine were conditional on baseline (placebo) stopping performance and were directly associated with increased inferior frontal gyrus activation. Further, stopping performance, task-based brain activation, and effective connectivity were similar in the 2 groups. Dynamic causal modeling of effective connectivity of multiple prefrontal and basal ganglia regions replicated and extended previous models of network function underlying inhibitory control to CUD and control volunteers and showed subtle effects of atomoxetine on prefrontal-basal ganglia interactions. CONCLUSIONS: These findings demonstrate that atomoxetine improves response inhibition in a baseline-dependent manner in control participants and in those with CUD. Our results emphasize inferior frontal cortex function as a future treatment target owing to its key role in improving response inhibition in CUD.

Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

Background: Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesised to impair reinforcement learning. Computational modelling enables the investigation of the latent processes of reinforcement learning in SUD patients, which could elucidate the nature of their impairments. Methods: We investigated reinforcement learning in 44 SUD patients and 41 healthy control participants using a probabilistic reinforcement learning task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in reinforcement learning following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analysed task performance using computational modelling and hypothesised that reinforcement learning impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results: Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated reinforcement learning parameters differentially in both groups. Both amisulpride and pramipexole impaired reinforcement learning parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion: Our findings suggest that reinforcement learning impairments seen in SUD patients are associated with altered dopamine function.

Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and overactivated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC), and 14-25 (caudal ventromedial PFC) and the anteromedial caudate to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmoset monkeys. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32, or 14-25 had no effect. Overactivation of areas 11 and 24 impaired this response. These findings demonstrate the distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders, including obsessive-compulsive disorder.

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine D2 and 5-HT2A receptor blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed 2 and 3 response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5HT2A receptor blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. 3 Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared to fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance.

Background The balance between goal-directed behavior and habits has been hypothesized to be biased toward the latter in individuals with cocaine use disorder (CUD), suggesting possible neurochemical changes in the putamen, which may contribute to their compulsive behavior. Methods We assessed habitual behavior in 48 patients with CUD and 42 healthy control participants using a contingency degradation paradigm and the Creature of Habit Scale. In a subgroup of this sample (CUD: n = 21; control participants: n = 22), we also measured glutamate and glutamine concentrations in the left putamen using ultra-high-field (7T) magnetic resonance spectroscopy. We hypothesized that increased habitual tendencies in patients with CUD would be associated with abnormal glutamatergic metabolites in the putamen. Results Compared with their non–drug-using peers, patients with CUD exhibited greater habitual tendencies during contingency degradation, which correlated with increased levels of self-reported daily habits. We further identified a significant reduction in glutamate concentration and glutamate turnover (glutamate-to-glutamine ratio) in the putamen in patients with CUD, which was significantly related to the level of self-reported daily habits. Conclusions Patients with CUD exhibit enhanced habitual behavior, as assessed both by questionnaire and by a laboratory paradigm of contingency degradation. This automatic habitual tendency is related to a reduced glutamate turnover in the putamen, suggesting a dysregulation of habits caused by chronic cocaine use.

Evidence for pharmacological remediation of cognitive deficits in three major psychiatric disorders-attention deficit- hyperactivity disorder (ADHD), schizophrenia, and depression-is reviewed. ADHD is effectively treated with the stimulant medications methylphenidate and d-amphetamine, as well as nonstimulants such as atomoxetine, implicating cognitive enhancing effects mediated by noradrenaline and dopamine. However, the precise mechanisms underlying these effects remains unclear. Cognitive deficits in schizophrenia are less effectively treated, but attempts via a variety of neurotransmitter strategies are surveyed. The possibility of treating cognitive deficits in depression via antidepressant medication (eg, selective serotonin reuptake inhibitors) and by adjunctive drug treatment has only recently received attention because of confounding, or possibly interactive, effects on mood. Prospects for future advances in this important area may need to take into account transdiagnostic perspectives on cognition (including neurodegenerative diseases) as well as improvements in neuropsychological, neurobiological, and clinical trial design approaches to cognitive enhancement. .Se revisa la evidencia de la corrección farmacológica para los déficits cognitivos en tres trastornos psiquiátricos principales: trastorno por déficit de atención con hiperactividad (TDAH), esquizofrenia y depresión. El TDAH se trata eficazmente con medicamentos estimulantes como metilfenidato y d-anfetamina, y también con no estimulantes como la atomoxetina, lo que implica efectos de refuerzo cognitivo mediados por noradrenalina y dopamina. Sin embargo, los mecanismos subyacentes específicos a estos efectos aún no se han aclarado. Aunque los déficits cognitivos en la esquizofrenia tienen un tratamiento menos eficaz, se analizan algunos intentos a través de distintas estrategias de neurotransmisores. Sólo recientemente la posibilidad de tratar los déficits cognitivos en la depresión a través de medicamentos antidepresivos (p. ej. Inhibidores selectivos de la recaptura de serotonina) y mediante tratamiento farmacológico adyuvante ha recibido atención, debido a los efectos confusos o posiblemente a la interacción que se produce con el estado de ánimo. Es posible que los futuros avances en esta importante área tengan en cuenta las perspectivas transdiagnósticas sobre la cognición (incluidas las enfermedades neurodegenerativas), así como los progresos en los enfoques del diseño de ensayos neuropsicológicos, neurobiológicos y clínicos para la mejoría cognitiva.Des données probantes sur le traitement pharmacologique des déficits cognitifs dans trois troubles psychiatriques majeurs - le TDAH (trouble de l’attention et hyperactivité), la schizophrénie et la dépression - sont ici évaluées. Le méthylphénidate et la d-amphétamine, deux stimulants, sont efficaces sur le TDAH de même que l’atomoxétine, non stimulante, ce qui met en cause les effets de renforcement cognitif médiés par la noradrénaline et la dopamine. Néanmoins, les mécanismes précis sous-tendant ces effets sont mal compris. Les déficits cognitifs sont traités moins efficacement dans la schizophrénie mais des essais via de nombreux neurotransmetteurs sont à l’étude. Ce n’est que récemment que la possibilité de traiter des déficits cognitifs dans la dépression par un antidépresseur (par exemple des inhibiteurs sélectifs de la recapture de la sérotonine) et par un autre traitement médicamenteux, a été envisagée en raison d’effets confondants, et peut-être interactifs, sur l’humeur. Les perspectives transdiagnostiques sur la cognition (y compris les maladies neurodégénératives) ainsi que les améliorations dans les approches neurobiologiques, neuropsychologiques et les schémas d’essais cliniques pour l’amélioration cognitive pourraient servir les espoirs d’avancées futures dans ce domaine d’importance.

BACKGROUND: In obsessive-compulsive disorder (OCD), actions persist despite being inappropriate to the situation and without relationship to the overall goal. Dysfunctional beliefs have traditionally been postulated to underlie this condition. More recently, OCD has been characterized in terms of an imbalance between the goal-directed and the habit systems. To test these competing hypotheses, we used a novel experimental task designed to test subjective action-outcome knowledge of the effectiveness of actions (i.e., instrumental contingency), together with the balance between goal-directed and habitual responding. METHODS: Twenty-seven patients with OCD and 27 healthy control subjects were tested on a novel task involving the degradation of an action-outcome contingency. Sensitivity to instrumental contingency and the extent to which explicitly reported action-outcome knowledge guided behavior were probed by measuring response rate and subjectively reported judgments. RESULTS: Patients with OCD responded more than healthy control subjects in situations in which an action was less causally related to obtaining an outcome. However, patients showed intact explicit action-outcome knowledge, as assessed by self-report. In patients, the relationship between causality judgment and responding was altered; therefore, their actions were dissociated from explicit action-outcome knowledge. CONCLUSIONS: These findings indicate reduced sensitivity to instrumental contingency in OCD, reinforcing the notion of a deficient goal-directed system in this disorder. By showing a dissociation between subjectively reported action-outcome knowledge and behavior, the data provide experimental evidence for the ego-dystonic nature of OCD.

Fronto-striatal circuitry involving the orbitofrontal cortex has been identified as mediating successful reversal of stimulus-outcome contingencies. The region of the striatum that most contributes to reversal learning remains unclear, with studies in primates implicating both caudate nucleus and putamen. We trained four marmosets on a touchscreen-based serial reversal task and implanted each with cannulae targeting both putamen and caudate bilaterally. This allowed reversible inactivation of the two areas within the same monkeys, but across separate sessions, to directly investigate their respective contributions to reversal performance. Behavioral sensitivity to the GABAA agonist muscimol varied across subjects and between brain regions, so each marmoset received a range of doses. Intermediate doses of intra-putamen muscimol selectively impaired reversal performance, leaving the baseline discrimination phase unchanged. There was no effect of low doses and high doses were generally disruptive. By contrast, low doses of intra-caudate muscimol improved reversal performance, while high doses impaired both reversal and baseline discrimination performance. These data provide evidence for a specific role of the putamen in serial reversal learning, which may reflect the more habitual nature of repeated reversals using the same stimulus pair.

Novel psychoactive substances (NPS) are popular “club/party” drugs that first attracted attention in the UK in 2009 and remained legal until the 2016 Psychoactive Substances Act criminalized their distribution. Unlike “traditional” illicit drugs, very little is known about the influence of their analogs on neuropsychological functioning. We characterized the cognitive and emotional profile of NPS/polydrug users using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and EMOTICOM test battery in adult male (aged 20–49 years) recreational users without psychiatric comorbidities (n = 27; “psychonauts”), service users attending a UK specialist “Club Drug” Clinic for problematic use (n = 20) and healthy control volunteers without significant drug-taking histories (n = 35). Tasks were selected to distinguish “hot” cognitive processes that are highly influenced by emotion from “cold” cognitive processes that are largely independent of emotional influence. Both user groups reported significantly higher sensation-seeking traits compared with non-users. Recreational NPS users demonstrated more risk-taking behavior compared with controls and treatment-seeking NPS users showed poorer learning, episodic memory and response inhibition compared with the other two groups. These effects persisted, when controlling for age, intelligence, alcohol and cannabis use severity, nicotine dependence, trait anxiety, depression, childhood adversity, impulsivity, and sensation seeking. Overall, recreational NPS users showed elevated “hot” (emotion-laden) cognition in the absence of “cold” (non-emotional) cognitive deficits, whereas “cold” cognitive dysfunction was pronounced in individuals seeking treatment for problematic NPS use. High trait impulsivity and poor self-control may confer additional risk to NPS/polydrug use severity and separate those seeking treatment from those using NPS recreationally.

© 2020 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction Animal models have shown that chronic alcohol exposure is associated with persistent neuroadaptations in amygdala synaptic function, whereas human studies have consistently reported amygdala grey-matter volume (GMV) reductions in alcohol dependent patients (ADP). We hypothesised that chronic alcohol use associated with neuroadaptations may entail a reconfiguration of the amygdala's functional interactions and that these mechanisms may be affected by structural atrophy. We compared amygdala resting state functional connectivity (RSFC) using a whole brain seed-based approach and amygdala GMV in abstinent ADP (n = 20) and healthy controls (HC; n = 39), balanced for age, gender and levels of head motion. The potential moderating influence of age, cumulative alcohol exposure, abstinence length and head motion was further examined in the two groups separately using correlational analyses. We found increased amygdala RSFC with substantia nigra/ventral tegmental area (SN/VTA) in ADP compared with HC. As expected, amygdala GMV was lower in ADP. Multiple regression analyses of the ADP group showed that amygdala-SN/VTA RSFC increases were primarily associated with cumulative alcohol exposure rather than age, whereas amygdala GMV reductions were primarily associated with age rather than cumulative alcohol exposure. The same association between age and amygdala GMV was not observed amongst HC. Importantly, amygdala GMV and amygdala-SN/VTA RSFC were uncorrelated in ADP, and neither measure was correlated with abstinence length. These results suggest that chronic alcohol exposure is associated with persistent elevations in amygdala-SN/VTA RSFC and accelerated age-related grey-matter atrophy through potentially distinct mechanisms.

Funder: Zhangjiang Lab, Funder: the Shanghai AI Platform for Diagnosis and Treatment of Brain Diseases, Funder: the Project of Zhangjiang Hi-Tech District Management Committee, Funder: Shanghai (grant 2016-17), Funder: BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics); Grant(s): MR/N027558/1, Funder: Associazione Emma e Ernesto Rulfo per la Genetica Medica (IT), Funder: the Swedish Research Council FORMAS, Funder: the Medical Research Council, Funder: the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, Funder: the Human Brain Project (HBP SGA 2), Funder: the Fondation de France, the Fondation pour la Recherche Médicale, Funder: the Assistance-Publique-Hôpitaux-de-Paris and INSERM (interface grant), Funder: Paris Sud University IDEX 2012, Funder: cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, Background: Childhood trauma increases the risk for adult obesity through multiple complex pathways, and the neural substrates are yet to be determined. Methods: Participants from three population-based neuroimaging cohorts, including the IMAGEN cohort, the UK Biobank (UKB), and the Human Connectome Project (HCP), were recruited. Voxel-based morphometry analysis of both childhood trauma and body mass index (BMI) was performed in the longitudinal IMAGEN cohort; validation of the findings was performed in the UKB. White-matter connectivity analysis was conducted to study the structural connectivity between the identified brain region and subdivisions of the hypothalamus in the HCP. Results: In IMAGEN, a smaller frontopolar cortex (FPC) was associated with both childhood abuse (CA) (β = − .568, 95%CI − .942 to − .194; p = .003) and higher BMI (β = − .086, 95%CI − .128 to − .043; p < .001) in male participants, and these findings were validated in UKB. Across seven data collection sites, a stronger negative CA-FPC association was correlated with a higher positive CA-BMI association (β = − 1.033, 95%CI − 1.762 to − .305; p = .015). Using 7-T diffusion tensor imaging data (n = 156), we found that FPC was the third most connected cortical area with the hypothalamus, especially the lateral hypothalamus. A smaller FPC at age 14 contributed to higher BMI at age 19 in those male participants with a history of CA, and the CA-FPC interaction enabled a model at age 14 to account for some future weight gain during a 5-year follow-up (variance explained 5.8%). Conclusions: The findings highlight that a malfunctioning, top-down cognitive or behavioral control system, independent of genetic predisposition, putatively contributes to excessive weight gain in a particularly vulnerable population, and may inform treatment approaches.

BACKGROUND: Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. METHODS: We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR 0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR

BackgroundResponding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occurs in many psychiatric disorders including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and schizophrenia, where emotional responses can persist pathologically. Whilst there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does pharmacological lowering of serotonin affect the retention of conditioned threat memory?MethodsForty-seven healthy participants underwent threat conditioning on Day 1 followed by an extinction session. Emotional responding was assessed by the skin conductance response (SCR). On Day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind placebo-controlled randomized between-groups design. We then tested for the return of conditioned threat memory spontaneous recovery). We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression.ResultsThe expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion.ConclusionsThese results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.

High levels of intolerance of uncertainty (IU) could contribute to abnormal decision making in uncertain situations. Patients with Obsessive Compulsive Disorder (OCD) often report high IU, indecisiveness and the need to seek greater certainty before making decisions. The Beads task is a commonly used task assessing the degree of information gathering prior to making a decision and so would be predicted to show impairments in OCD patients. Results to date have found mixed support for this, possibility due to methodological issues. Here, a group of OCD patients (n = 50) with no comorbidities was compared with age, gender, and verbal-IQ matched controls (n = 50) on the most commonly used version of the Beads task. An independent sample of healthy volunteers with high versus low OC symptoms, and high versus low IU were also assessed (n = 125). There was no evidence that patients with OCD differed from control volunteers in the degree of information gathering prior to making a decision. Medication status and age did not appear to mediate performance. Similarly, there were no association in healthy volunteers between task performance and OC or IU characteristics. Additional measures examining the degree of certainty initially showed support for greater uncertainty in patients, but this was due to deviations from task instructions in a subset of patients. We conclude that despite the large sample size and good matching between groups, the Beads task in its most widely used form is not a useful measure of IU or of information gathering in OCD. The results argue against a robust behavioural difference in OCD when compared to controls. Recommendations for future studies employing the task are discussed.

Introduction Harmful behavior such as smoking may reflect a disturbance in the balance of goal-directed and habitual control. Animal models suggest that habitual control develops after prolonged substance use. In this study, we investigated whether smokers (N = 49) differ from controls (N = 46) in the regulation of goal-directed and habitual behavior. It was also investigated whether individual differences in nicotine dependence levels were associated with habitual responding. Methods We used two different multistage instrumental learning tasks that consist of an instrumental learning phase, subsequent outcome devaluation, and a testing phase to measure the balance between goal-directed and habitual responding. The testing phases of these tasks occurred after either appetitive versus avoidance instrumental learning. The appetitive versus aversive instrumental learning stages in the two different tasks modeled positive versus negative reinforcement, respectively. Results Smokers and nonsmoking controls did not differ on habitual versus goal-directed control in either task. Individual differences in nicotine dependence within the group of smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. Conclusions The current finding highlights the importance of individual differences within smokers. For future research, neuroimaging studies are suggested to further unravel the nature of the imbalance between goal-directed versus habitual control in severely dependent smokers by directly measuring activity in the corresponding brain systems. Implications Goal-directed versus habitual behavior in substance use and addiction is highly debated. This study investigated goal-directed versus habitual control in smokers. The findings suggest that smokers do not differ from controls in goal-directed versus habitual control. Individual differences in nicotine dependence within smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. These findings add to the ongoing debate on habitual versus goal-directed control in addiction and emphasize the importance of individual differences within smokers.

BackgroundObsessive-compulsive disorder (OCD) is a prevalent neuropsychiatric condition, with biological models implicating disruption of cortically mediated inhibitory control pathways, ordinarily serving to regulate our environmental responses and habits. The aim of this study was to evaluate inhibition-related cortical dysconnectivity as a novel candidate vulnerability marker of OCD.MethodsIn total, 20 patients with OCD, 18 clinically asymptomatic first-degree relatives of patients with OCD, and 20 control participants took part in a neuroimaging study comprising a functional magnetic resonance imaging stop signal task. Brain activations during the contrasts of interest were cluster thresholded, and a three-dimensional watershed algorithm was used to decompose activation maps into discrete clusters. Functional connections between these key neural nodes were examined using a generalized psychophysiological interaction model.ResultsThe three groups did not differ in terms of age, education level, gender, IQ, or behavioral task parameters. Patients with OCD exhibited hyperactivation of the bilateral occipital cortex during the task versus the other groups. Compared with control participants, patients with OCD and their relatives exhibited significantly reduced connectivity between neural nodes, including frontal cortical, middle occipital cortical, and cerebellar regions, during the stop signal task.ConclusionsThese findings indicate that hypoconnectivity between anterior and posterior cortical regions during inhibitory control represents a candidate vulnerability marker for OCD. Such vulnerability markers, if found to generalize, may be valuable to shed light on etiological processes contributing not only to OCD but also obsessive-compulsive–related disorders more widely.

Background Mental disorders are typically defined as distinct diagnostic entities, but similar patterns of clinical and cognitive impairments are frequently found across diagnostic groups. We investigated whether these transdiagnostic deficits result from common neural substrates across disorders or various illness-specific mechanisms, or a combination of both. Methods Functional magnetic resonance imaging data were collected from clinically stable patients with major depressive disorder (n = 53), bipolar disorder (n = 78), or schizophrenia (n = 100) and matched healthy control subjects (n = 109) using a single scanner. Group comparisons were conducted to identify transdiagnostic and illness-specific features, and possible confounding effects of medication were considered. A multivariate approach with cross-validation was used to associate dysconnectivity features with shared cognitive deficits. Results Transdiagnostic dysconnectivities were identified within somatomotor (Cohen’s d = 0.50–0.58) and salience (Cohen’s d = 0.52–0.58) networks and between subcortical-limbic (Cohen’s d = 0.55–0.69) and subcortical-dorsal attention (Cohen’s d = 0.56–0.61) networks. The executive control network was found to be illness-specifically disconnected from the prefrontal-limbic-pallidal circuit in major depressive disorder (Cohen’s d = 0.57–0.58), prefronto-striato-parietal circuit in bipolar disorder (Cohen’s d = 0.48–0.53), and default mode network in schizophrenia (Cohen’s d = 0.47–0.56). Working memory deficits were associated with a linear combination of 11 transdiagnostic and 5 illness-specific dysconnectivities (r = .322, p = 9.7 × 10−4, n = 340). The associations of the identified dysconnectivities with medication dosage were nonsignificant. Conclusions Disconnectivity in the somatomotor network was a common transdiagnostic profile, while there were illness-specific patterns in different parts of the prefrontal cortex for different disorders. These findings suggest that prominent psychiatric disorders share common impairments, possibly linked to perception and motor output, as well as unique dysconnectivity profiles that hypothetically mediate the more distinctive features of the disorder-specific psychopathology.

Habits are a powerful route to efficiency; the ability to constantly shift between goal-directed and habitual strategies, as well as integrate them into behavioral output, is key to optimal performance in everyday life. When such ability is impaired, it may lead to loss of control and to compulsive behavior. Habits have successfully been induced and investigated in rats using methods such as overtraining stimulus-response associations and outcome devaluation, respectively. However, such methods have ineffectively measured habits in humans because (1) human habits usually involve more complex sequences of actions than in rats and (2) of pragmatic impediments posed by the extensive time (weeks or even months), it may take for routine habits to develop. We present here a novel behavioral paradigm-a mobile-phone app methodology-for inducing and measuring habits in humans during their everyday schedule and environment. It assumes that practice is key to achieve automaticity and proficiency and that the use of a hierarchical sequence of actions is the best strategy for capturing the cognitive mechanisms involved in habit formation (including "chunking") and consolidation. The task is a gamified self-instructed and self-paced app on a mobile phone that enables subjects to learn and practice two sequences of finger movements, composed of chords and single presses. It involves a step-wise learning procedure in which subjects begin responding to a visual and auditory cued sequence by generating responses on the screen using four fingers. Such cues progressively disappear throughout 1 month of training, enabling the subject ultimately to master the motor skill involved. We present preliminary data for the acquisition of motor sequence learning in 29 healthy individuals, each trained over a month period. We demonstrate an asymptotic improvement in performance, as well as its automatic nature. We also report how people integrate the task into their daily routine, the development of motor precision throughout training, and the effect of intermittent reinforcement and reward extinction in habit preservation. The findings help to validate this "real world" app for measuring human habits.

Neuroimaging research has highlighted maladaptive thalamo-cortico-striatal interactions in obsessive-compulsive disorder as well as a more general deficit in prefrontal functioning linked with compromised executive functioning. More specifically, dysfunction in the ventromedial prefrontal cortex, a central hub in coordinating flexible behaviour, is thought to be central to obsessive-compulsive disorder symptomatology. We sought to determine the intrinsic alterations of the ventromedial prefrontal cortex in obsessive-compulsive disorder employing resting-state functional connectivity magnetic resonance imaging analyses with a ventromedial prefrontal cortex seed region of interest. A total of 38 obsessive-compulsive disorder patients and 33 matched controls were included in our analyses. We found widespread ventromedial prefrontal cortex hyperconnectivity during rest in patients with obsessive-compulsive disorder, displaying increased connectivity with its own surrounding region in addition to hyperconnectivity with several areas along the thalamo-cortico-striatal loop: thalamus, caudate and frontal gyrus. Obsessive-compulsive disorder patients also exhibited increased functional connectivity from the ventromedial prefrontal cortex to temporal and occipital lobes, cerebellum and the motor cortex, reflecting ventromedial prefrontal cortex hyperconnectivity in large-scale brain networks. Furthermore, hyperconnectivity of the ventromedial prefrontal cortex and caudate correlated with obsessive-compulsive disorder symptomatology. Additionally, we used three key thalamo-cortico-striatal regions that were hyperconnected with our ventromedial prefrontal cortex seed as supplementary seed regions, revealing hypoconnectivity along the orbito- and lateral prefrontal cortex-striatal pathway. Taken together, these results confirm a central role of a hyperconnected ventromedial prefrontal cortex in obsessive-compulsive disorder, with a special role for maladaptive crosstalk with the caudate, and indications for hypoconnectivity along the lateral and orbito pathways.

Graphical abstract Network based statistics (NBS) analyses detected a graph sub-network comprising 153 edges between 59 nodes of the connectome where the ADD group demonstrated significantly less connectivity compared with the CON group. These differences in connectivity were mostly intra-hemispheric (55%), the majority (38%) being in the right hemisphere. The anatomical distribution of these connectivity differences between the two groups involved frontal (insula, inferior frontal gyrus, orbitofrontal cortex), limbic-associated (anterior cingulate gyrus, thalamus), and striatal (accumbens, caudate, pallidum) regions. The connectivity differences reported in this ADD sample indicate alterations between cognitive, striatal and limbic-associated regions during reward anticipation that persist into extended abstinence., Highlights • Analytical methods can capture key features of whole brain networks in addiction. • We compared reward network connectivity in addiction (ADD) and control (CON) groups. • The ADD group showed disruptions in global network connectivity. • Global network measures may be more sensitive than traditional voxel-wise analyses., The prevalent spatial distribution of abnormalities reported in cognitive fMRI studies in addiction suggests there are extensive disruptions across whole brain networks. Studies using resting state have reported disruptions in network connectivity in addiction, but these studies have not revealed characteristics of network functioning during critical psychological processes that are disrupted in addiction populations. Analytic methods that can capture key features of whole brain networks during psychological processes may be more sensitive in revealing additional and widespread neural disturbances in addiction, that are the provisions for relapse risk, and targets for medication development. The current study compared a substance addiction (ADD; n = 83) group in extended abstinence with a control (CON; n = 68) group on functional MRI (voxel-wise activation) and global network (connectivity) measures related to reward anticipation on a monetary incentive delay task. In the absence of group differences on MID performance, the ADD group showed reduced activation predominantly across temporal and visual regions, but not across the striatum. The ADD group also showed disruptions in global network connectivity (lower clustering coefficient and higher characteristic path length), and significantly less connectivity across a sub-network comprising frontal, temporal, limbic and striatal nodes. These results show that an addiction group in extended abstinence exhibit localised disruptions in brain activation, but more extensive disturbances in functional connectivity across whole brain networks. We propose that measures of global network functioning may be more sensitive in highlighting latent and more widespread neural disruptions during critical psychological processes in addiction and other psychiatric disorders.

To-date it has been difficult to ascertain the exact cognitive profile of childhood OCD as studies report variable results. Adult OCD research lately utilises the endophenotype approach; studying cognitive traits that are present in both patients and their unaffected first-degree relatives, and are thought to lie closer to the genotype than the full-blown disorder. By observing whether candidate endopenotypes of adult OCD are present in child patients, we can determine whether the two subtypes show cognitive overlap. We conducted a systematic review of the paediatric OCD literature focussing on proposed neurocognitive endophenotypes of OCD: cognitive flexibility, response inhibition, memory, planning, decision-making, action monitoring, and reversal learning. We found that paediatric patients present robust increases in brain error related negativity associated with abnormal action monitoring, impaired decision-making under uncertainty, planning, and visual working memory, but there is less evidence for deficits in other cognitive domains. This implies that children with OCD show some cognitive similarities with adult patients, but other dysfunctions may only manifest later in the disorder trajectory.

Habits may develop when meaningful action patterns are frequently repeated in a stable environment. We measured the differing tendencies of people to form habits in a population sample of n = 533 using the Creature of Habit Scale (COHS). We confirmed the high reliability of the two latent factors measured by the COHS, automaticity and routines. Whilst automatic behaviours are triggered by context and do not serve a particular purpose or goal, routines often have purpose, and because they have been performed so often in a given context, they become automatic only after their action sequence has been activated. We found that both types of habitual behaviours are influenced by the frequency of their occurrence and they are differentially influenced by personality traits. Compulsive personality is associated with an increase in both aspects of habitual tendency, whereas impulsivity is linked with increased automaticity, but reduced routine behaviours. Our findings provide further evidence that the COHS is a useful tool for understanding habitual tendencies in the general population and may inform the development of therapeutic strategies that capitalise on functional habits and help to treat dysfunctional ones.

OBJECTIVE: To identify the white matter correlates of apathy and impulsivity in the major syndromes associated with frontotemporal lobar degeneration, using diffusion-weighted imaging and data from the PiPPIN (Pick's Disease and Progressive Supranuclear Palsy: Prevalence and Incidence) study. We included behavioral and language variants of frontotemporal dementia, corticobasal syndrome, and progressive supranuclear palsy. METHODS: Seventy patients and 30 controls underwent diffusion tensor imaging at 3-tesla after detailed assessment of apathy and impulsivity. We used tract-based spatial statistics of fractional anisotropy and mean diffusivity, correlating with 8 orthogonal dimensions of apathy and impulsivity derived from a principal component analysis of neuropsychological, behavioral, and questionnaire measures. RESULTS: Three components were associated with significant white matter tract abnormalities. Carer-rated change in everyday skills, self-care, and motivation correlated with widespread changes in dorsal frontoparietal and corticospinal tracts, while carer observations of impulsive-apathetic and challenging behaviors revealed disruption in ventral frontotemporal tracts. Objective neuropsychological tests of cognitive control, reflection impulsivity, and reward responsiveness were associated with focal changes in the right frontal lobe and presupplementary motor area. These changes were observed across clinical diagnostic groups, and were not restricted to the disorders for which diagnostic criteria include apathy and impulsivity. CONCLUSION: The current study provides evidence of distinct structural network changes in white matter associated with different neurobehavioral components of apathy and impulsivity across the diverse spectrum of syndromes and pathologies associated with frontotemporal lobar degeneration.

Background Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. Methods Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. Results Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. Conclusions These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes., Highlights • Positive allosteric mGluR4 modulation increases motor impulsivity and impairs aspects of visual attention. • Positive allosteric mGluR4 modulation decreases choice impulsivity as well as indices of motor function. • Blocking D2 receptors selectively attenuates the effect of positive allosteric mGluR4 modulation on motor impulsivity.

BACKGROUND: A recent hypothesis has suggested that core deficits in goal-directed behavior in obsessive-compulsive disorder (OCD) are caused by impaired frontostriatal function. We tested this hypothesis in OCD patients and control subjects by relating measures of goal-directed planning and cognitive flexibility to underlying resting-state functional connectivity. METHODS: Multiecho resting-state acquisition, combined with micromovement correction by blood oxygen level-dependent sensitive independent component analysis, was used to obtain in vivo measures of functional connectivity in 44 OCD patients and 43 healthy comparison subjects. We measured cognitive flexibility (attentional set-shifting) and goal-directed performance (planning of sequential response sequences) by means of well-validated, standardized behavioral cognitive paradigms. Functional connectivity strength of striatal seed regions was related to cognitive flexibility and goal-directed performance. To gain insights into fundamental network alterations, graph theoretical models of brain networks were derived. RESULTS: Reduced functional connectivity between the caudate and the ventrolateral prefrontal cortex was selectively associated with reduced cognitive flexibility. In contrast, goal-directed performance was selectively related to reduced functional connectivity between the putamen and the dorsolateral prefrontal cortex in OCD patients, as well as to symptom severity. Whole-brain data-driven graph theoretical analysis disclosed that striatal regions constitute a cohesive module of the community structure of the functional connectome in OCD patients as nodes within the basal ganglia and cerebellum were more strongly connected to one another than in healthy control subjects. CONCLUSIONS: These data extend major neuropsychological models of OCD by providing a direct link between intrinsically abnormal functional connectivity within dissociable frontostriatal circuits and those cognitive processes underlying OCD symptoms.

Background Rats reared in social isolation exhibit various cognitive and behavioural abnormalities in adulthood. However, impulsivity following this treatment still remains unclear, especially in response to medications used in attention deficit hyperactivity disorder, such as amphetamine. Methods Using an isolation-rearing (IR) manipulation, the present study examined the effects of IR on impulsive action and impulsive choice when also treated with doses of d-amphetamine, by employing the five-choice serial reaction time task (5-CSRTT) and a temporal discounting of reward task (TDRT), respectively. Results IR rats showed similar acquisition of the 5-CSRTT. Amphetamine increased premature responding in both groups; however, IR rats showed less responding overall. For the TDRT, IR rats revealed a greater preference for the large but delayed reward during task acquisition (i.e. were less impulsive) with a higher rate of nose poking during the delay, and exhibited a compressed dose-response function (i.e. reduced dose sensitivity) for amphetamine. Discussion Impulsive action and impulsive choice were reduced in IR rats under certain conditions, and a blunted response to d-amphetamine was found on these measures. These reductions in impulsivity contrast with locomotor hyperactivity normally shown in IR rats and the findings have implications for the utility of IR as a model of psychopathology. Electronic supplementary material The online version of this article (doi:10.1007/s00213-017-4579-8) contains supplementary material, which is available to authorized users.

Contains fulltext : 175149.pdf (Publisher’s version ) (Open Access) Rationale: Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as cocaine. Objectives: We examined the potentially beneficial effects of the noradrenaline reuptake inhibitor atomoxetine in improving cognitive control during two tasks that used cocaine- and non-cocaine-related stimuli. Methods: A double-blind, placebo-controlled, and cross-over psycho-pharmacological design was employed. A single oral dose of atomoxetine (40 mg) was administered to 28 cocaine-dependent individuals (CDIs) and 28 healthy controls. All participants performed a pictorial attentional bias task involving both cocaine- and non-cocaine-related pictures as well as a verbal go/no-go task composed of cocaine- and food-related words. Results: As expected, CDIs showed attentional bias to cocaine-related cues whilst controls did not. More importantly, however, atomoxetine, relative to placebo, significantly attenuated attentional bias in CDIs (F26 = 6.73, P = 0.01). During the go/no-go task, there was a treatment x trial x group interaction, although this finding only showed a trend towards statistical significance (F26 = 3.38, P = 0.07). Conclusions: Our findings suggest that atomoxetine reduces attentional bias to drug-related cues in CDIs. This may result from atomoxetine’s modulation of the balance between tonic/phasic activity in the locus coeruleus and the possibly parallel enhancement of noradrenergic neurotransmission within the prefrontal cortex. Studying how cognitive enhancers such as atomoxetine influence key neurocognitive indices in cocaine addiction may help to develop reliable biomarkers for patient stratification in future clinical trials. 9 p.

Rationale: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. Objective: In this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. Methods: We studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg; a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. Results: There were no significant group, drug or interaction effects in number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial ƞ2=0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial ƞ2=0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial ƞ2=0.26, 1-β error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. Conclusions Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

A large proportion of schizophrenia patients treated with second generation antipsychotics will develop Obsessive Compulsive Disorder (OCD). However, there are few studies about the impact of this comorbidity and who is at higher risk. In this study of clozapine-treated patients, we aimed to determine the impact on outcome of clozapine-induced OCD, as well as the clinical and sociodemographic risk factors related to OCD-onset in clozapine patients. We had strict and novel inclusion criteria to minimise mis-identification of cases. The Obsessive-Compulsive Inventory-Revised (OCI-R) was used to divide 231 clozapine-treated patients into extreme cases of OCD (OCI ≥ 24 or checking subscale ≥6) versus non-OCD (OCI

Much evidence suggests that reversal learning is mediated by cortico-striatal circuitries with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, but potential differential roles of lateral (lOFC) and medial (mOFC) portions in visual reversal learning have yet to be determined. We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). Inactivating mOFC and lOFC produced opposite effects; lOFC impairing, and mOFC improving, performance in the early, perseverative phase specifically. Additionally, mOFC inactivation enhanced negative feedback sensitivity, while lOFC inactivation diminished feedback sensitivity in general. mOFC and lOFC inactivation also affected novel visual discrimination learning differently; lOFC inactivation paradoxically improved learning, and mOFC inactivation had no effect. We also observed dissociable roles of the OFC and the IL/PrL. Whereas the OFC inactivation affected only perseveration, IL/PrL inactivation improved learning overall. BLA inactivation did not affect perseveration, but improved the late phase of reversal learning. These results support opponent roles of the rodent mOFC and lOFC in deterministic visual reversal learning.

Obsessive-compulsive disorder is a severe and disabling psychiatric disorder that presents several challenges for neuroscience. Recent advances in its genetic and developmental causation, as well as its neuropsychological basis, are reviewed. Hypotheses concerning an imbalance between goal-directed and habitual behavior together with neural correlates in cortico-striatal circuitry are evaluated and contrasted with metacognitive theories. Treatments for obsessive-compulsive disorder (OCD) tend to be of mixed efficacy but include psychological, pharmacological, and surgical approaches, the underlying mechanisms of which are still under debate. Overall, the prospects for new animal models and an integrated understanding of the pathophysiology of OCD are considered in the context of dimensional psychiatry.

Detecting causal relationships between actions and their outcomes is fundamental to guiding goal-directed behaviour. The ventromedial prefrontal cortex (vmPFC) has been extensively implicated in computing these environmental contingencies, via animal lesion models and human neuroimaging. However, whether the vmPFC is critical for contingency learning, and whether it can occur without subjective awareness of those contingencies, has not been established. To address this, we measured response adaption to contingency and subjective awareness of action-outcome relationships in individuals with vmPFC lesions and healthy elderly subjects. We showed that in both vmPFC damage and ageing, successful behavioural adaptation to variations in action-outcome contingencies was maintained, but subjective awareness of these contingencies was reduced. These results highlight two contexts where performance and awareness have been dissociated, and show that learning response-outcome contingencies to guide behaviour can occur without subjective awareness. Preserved responding in the vmPFC group suggests that this region is not critical for computing action-outcome contingencies to guide behaviour. In contrast, our findings highlight a critical role for the vmPFC in supporting awareness, or metacognitive ability, during learning. We further advance the hypothesis that responding to changing environmental contingencies, whilst simultaneously maintaining conscious awareness of those statistical regularities, is a form of dual-tasking that is impaired in ageing due to reduced prefrontal function., Highlights • In both vmPFC lesions and ageing, intact responding to variations in action-outcome contingencies was maintained. • In contrast, vmPFC damage and ageing impaired subjective awareness of action-outcome contingencies. • vmPFC is not critical for contingency learning. • vmPFC has a critical role in supporting awareness (metacognition) during learning. • Impaired causal awareness in ageing may result from dual-tasking costs.

OBJECTIVE: To determine the influence of apathy, impulsivity, and behavioral change on survival in patients with frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome. METHODS: We assessed 124 patients from the epidemiologic PiPPIN (Pick's Disease and Progressive Supranuclear Palsy, Prevalence and Incidence) study. Patients underwent detailed baseline cognitive and behavioral assessment focusing on apathy, impulsivity, and behavioral change. Logistic regression identified predictors of death within 2.5 years from assessment, including age, sex, diagnosis, cognition, and 8 neurobehavioral profiles derived from a principal component analysis of neuropsychological and behavioral measures. RESULTS: An apathetic neurobehavioral profile predicted death (Wald statistic = 8.119, p = 0.004, Exp(B) = 2.912, confidence interval = >1 [1.396-6.075]) and was elevated in all patient groups. This profile represented apathy, weighted strongly to carer reports from the Apathy Evaluation Scale, Neuropsychiatric Inventory, and Cambridge Behavioral Inventory. Age at assessment, sex, and global cognitive impairment were not significant predictors. Differences in mortality risk across diagnostic groups were accounted for by their neuropsychiatric and behavioral features. CONCLUSIONS: The relationship between apathy and survival highlights the need to develop more effective and targeted measurement tools to improve its recognition and facilitate treatment. The prognostic importance of apathy suggests that neurobehavioral features might be useful to predict survival and stratify patients for interventional trials. Effective symptomatic interventions targeting the neurobiology of apathy might ultimately also improve prognosis.

Parkinson’s disease has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson’s disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission. Here, we study global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks. Thirty-three patients with idiopathic Parkinson’s disease were studied three times in a double-blinded, placebo-controlled counter-balanced crossover design, following placebo, 40 mg oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30 mg oral citalopram (selective serotonin reuptake inhibitor). Neuropsychological assessments were performed outside the scanner. Seventy-six controls were scanned without medication to provide normative data for comparison to the patient cohort. Graph theoretical analysis of task-free brain connectivity, with a random 500-node parcellation, was used to measure the effect of disease in placebo-treated state (versus unmedicated controls) and pharmacological intervention (drug versus placebo). Relative to controls, patients on placebo had executive impairments (reduced fluency and inhibitory control), which was reflected in dysfunctional network dynamics in terms of reduced clustering coefficient, hub degree and hub centrality. In patients, atomoxetine improved fluency in proportion to plasma concentration (P = 0.006, r2 = 0.24), and improved response inhibition in proportion to increased hub Eigen centrality (P = 0.044, r2 = 0.14). Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering (P = 0.01, r2 = 0.22), modularity (P = 0.043, r2 = 0.14) and path length (P = 0.006, r2 = 0.25) increased in patients with milder forms of Parkinson’s disease, but decreased in patients with more advanced disease (Unified Parkinson’s Disease Rating Scale motor subscale part III > 30). This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. We propose that hub connectivity contributes to cognitive performance in Parkinson’s disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function., Targeting the deficits in serotonergic and noradrenergic transmission can restore cognitive function in Parkinson’s disease. Borchert et al. use resting-state imaging to show that changes in hub connectivity on atomoxetine correlate with improved response inhibition while the potential therapeutic effect of citalopram depends on severity of disease., Graphical Abstract Graphical Abstract

International audience; BackgroundObsessive-compulsive disorder (OCD) is common in clozapine-treated patients although the actual prevalence, phenomenology and risk factors remain unclear. The aim of the present study was to address the three aforementioned questions.MethodsThe electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined.ResultsOCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p = 0.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean = 5.1; SD = 3.6) correlated with length of clozapine treatment (r = 0.21; p = 0.026), and obsessing factor (mean = 4.8; SD = 3.6) correlated with psychosis severity (r = 0.59; p = 0.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plasma levels, after correcting for psychosis severity.ConclusionsScreening for OCD in clozapine patients, and probably in those treated with structurally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.

Negative life events (NLE) contribute to anxiety and depression disorders, but their relationship with brain functioning in adolescence has rarely been studied. We hypothesized that neural response to social threat would relate to NLE in the frontal–limbic emotional regions. Participants (N = 685) were drawn from the Imagen database of 14-year-old community adolescents recruited in schools. They underwent functional MRI while viewing angry and neutral faces, as a probe to neural response to social threat. Lifetime NLEs were assessed using the ‘distress’, ‘family’ and ‘accident’ subscales from a life event dimensional questionnaire. Relationships between NLE subscale scores and neural response were investigated. Links of NLE subscales scores with anxiety or depression outcomes at the age of 16 years were also investigated. Lifetime ‘distress’ positively correlated with ventral-lateral orbitofrontal and temporal cortex activations during angry face processing. ‘Distress’ scores correlated with the probabilities of meeting criteria for Generalized Anxiety Disorder or Major Depressive Disorder at the age of 16 years. Lifetime ‘family’ and ‘accident’ scores did not relate with neural response or follow-up conditions, however. Thus, different types of NLEs differentially predicted neural responses to threat during adolescence, and differentially predicted a de novo internalizing condition 2 years later. The deleterious effect of self-referential NLEs is suggested.

The significance of investigating effects of deprivation of social experience in rodents is reviewed in the context of the review by Robbins et al. (1996) in the Journal of Psychopharmacology (10: 39-47). The early development of the paradigm by which rats were reared post-weaning in social isolation is described and compared with other early experience manipulations. The specification of the neural and behavioural phenotype of the isolate is brought up-to-date, focusing on changes in motivation and cognitive function, as well as on contrasting changes in the dopamine and serotonin systems, and in cortical (including hippocampal) structure and function. The relevance of the isolate for animal models of psychiatric disorders such as attention deficit hyperactivity disorder and schizophrenia is reviewed, and it is considered that the paradigm best exemplifies a manipulation that can be applied to test effects of certain forms of social adversity during adolescence on brain development and behaviour.

This paper critically reviews the unidimensional construct of General Arousal as utilised by models of temperament in differential psychology for example, to underlie 'Extraversion'. Evidence suggests that specialization within monoamine neurotransmitter systems contrasts with the attribution of a "general arousal" of the Ascending Reticular Activating System. Experimental findings show specialized roles of noradrenaline, dopamine, and serotonin systems in hypothetically mediating three complementary forms of arousal that are similar to three functional blocks described in classical models of behaviour within kinesiology, clinical neuropsychology, psychophysiology and temperament research. In spite of functional diversity of monoamine receptors, we suggest that their functionality can be classified using three universal aspects of actions related to expansion, to selection-integration and to maintenance of chosen behavioural alternatives. Monoamine systems also differentially regulate analytic vs. routine aspects of activities at cortical and striatal neural levels. A convergence between main temperament models in terms of traits related to described functional aspects of behavioural arousal also supports the idea of differentiation between these aspects analysed here in a functional perspective.

Two learning mechanisms contribute to decision-making: goal-directed actions and the "habit" system, by which action-outcome and stimulus-response associations are formed, respectively. Rodent lesion studies and human neuroimaging have implicated both the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC) in the neural basis of contingency learning, a critical component of goal-directed actions, though some published findings are conflicting. We sought to reconcile the existing literature by comparing the effects of excitotoxic lesions of the perigenual anterior cingulate cortex (pgACC), a region of the mPFC, and OFC on contingency learning in the marmoset monkey using a touchscreen-based paradigm, in which the contingent relationship between one of a pair of actions and its outcome was degraded selectively. Both the pgACC and OFC lesion groups were insensitive to the contingency degradation, whereas the control group demonstrated selectively higher performance of the nondegraded action when compared with the degraded action. These findings suggest the pgACC and OFC are both necessary for normal contingency learning and therefore goal-directed behavior.

Moral emotions are thought to influence moral behaviour by providing a driving force to do good and to avoid doing bad. In this study we examined moral emotions; specifically, guilt, shame, annoyance and feeling “bad” from two different perspectives in a moral scenario; the agent and the victim whilst manipulating the intentionality of the harm; intentional and unintentional. Two hundred participants completed a moral emotions task, which utilised cartoons to depict everyday moral scenarios. As expected, we found that self-blaming emotions such as shame and guilt were much more frequent when taking on the perspective of the agent whilst annoyance was more frequent from the victim perspective. Feeling bad, however, was not agency-specific. Notably, when the harm was intentional, we observed significantly greater shame ratings from the perspective of the agent compared to when the harm was unintentional. In addition, we also found clear gender differences and further observed correlations between moral emotions and personality variables such as psychoticism and neuroticism., MRC - Medical Research Council (MR/J011894/1)

Summary Neuroscience research in non-human primates (NHPs) has delivered fundamental knowledge about human brain function as well as some valuable therapies that have improved the lives of human patients with a variety of brain disorders. Research using NHPs, although it is facing serious challenges, continues to complement studies in human volunteers and patients, and will continue to be needed as the burdens of mental health problems and neurodegenerative diseases increase. At the same time, research into the 3Rs is helping to ameliorate the harms experienced by NHPs in experimental procedures, allowing the effective combination of optimal welfare conditions for the NHPs and high quality research., Mitchell et al. outline the benefits of non-human primate research for medicine and argue that the general public in the UK has been misled about the degree to which animals are harmed during research.