Prof. T.W. Robbins

BackgroundThe nature of cognitive flexibility deficits in obsessive-compulsive disorder (OCD), which historically have been tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of unmedicated patients in the study sample illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.MethodsWe recruited 49 patients with OCD, 21 of whom were unmedicated, and 43 healthy control participants matched for age, IQ, and gender. Participants were tested on 2 tasks: a novel visuomotor deterministic reversal learning task with 3 reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a 2-choice visual probabilistic reversal learning task with …

One of the most complex human behaviours that defies singular explanatory models is suicidal behaviour, especially in the youth. A promising approach to make progress with this conundrum is to parse distinct subtypes of this behaviour. Utilizing 1,624 children with suicidal thoughts and behaviors (STBs) and 3,224 healthy controls from the ABCD Study, we clustered children with STB based on thirty-four cognitive and psychopathological measures which capture suicide-related risk-moderating traits. Environmental and genetic risk factors, as well as neuroanatomical characteristics of each subtype, were then compared with controls. We identified five distinct STB subtypes, each revealing unique neuroanatomy, environmental/genetic risks, and persistence patterns. Subtype 1 (Depressive, 9.6%) exhibited the most severe depressive symptoms. Subtype 2 (Externalizing, 20.1%) displayed anatomical and functional alterations in frontoparietal network and increased genetic risk for ADHD. Subtype 3 (Cognitive Deficit, 20.4%) demonstrated lower cognitive performance and widespread white-matter deficits. Subtype 4 (Mild Psychotic, 22.2%) presented higher prodromal psychotic symptoms, often unnoticed by parents. Subtype 5 (High Functioning, 27.6%) showed larger total brain volume, better cognition, and higher socio-economic status, contrasting subtypes 1-4. Only Subtypes 1 and 2 demonstrate persistent STB features at the 2-year follow-up. Our results suggested that youth suicidal behaviour may result from several distinct bio-behavioral pathways that are identifiable through co-occurring psychopathology, and provide insights into the …

2023-08-18 Assigned to SIRGARTAN HOLDINGS LTD reassignment SIRGARTAN HOLDINGS LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GARZYA, VICENZO, ROBBINS, Trevor, SIREAU, Nicolas Thierry, TANCOCK, Jon

Cognitive flexibility, the ability to adapt behavior in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Evidence suggests that flexibility, which can be operationalized using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behavior and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on cognitive flexibility and underlying RL mechanisms. Thirty-six male Lister-hooded rats were trained on the valence-probe visual discrimination (VPVD) task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning performance and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to VPVD choice data to extract RL parameters, including a novel model designed specifically for this task. 5-HT2AR antagonism impaired reversal learning during certain phases. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate at high and low doses. The low dose also increased exploration (beta) and increased stimulus and side stickiness (kappa). 5-HT2CR antagonism also increased beta, but …

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including substance use disorder and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesised to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%:20% basis, that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcbS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). Moreover, the exploitation-exploration parameter, beta, was increased (indicating greater exploitation of information) when this pathway was optogenetically stimulated after a spurious loss (i.e. an incorrect (20%) response at the 80% reinforrced location) compared to after a spurious win (i.e. a correct (20%) response at the 20% reinforced location). VTA -> NAcbS stimulation during other phases of the behavioural task was without effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or …

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive–compulsive disorder. However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning, using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition (‘stickiness’) or reinforcement learning rates following manipulations intended to increase or decrease serotonin function. More …

Compulsive behaviour, an apparently irrational perseveration in often maladaptive acts, is a potential transdiagnostic symptom of several neuropsychiatric disorders, including obsessive-compulsive disorder and addiction, and may reflect the severe manifestation of a dimensional trait termed compulsivity. In this Review, we examine the psychological basis of compulsions and compulsivity and their underlying neural circuitry using evidence from human neuroimaging and animal models. Several main elements of this circuitry are identified, focused on fronto-striatal systems implicated in goal-directed behaviour and habits. These systems include the orbitofrontal, prefrontal, anterior cingulate and insular cortices and their connections with the basal ganglia as well as sensoriomotor and parietal cortices and cerebellum. We also consider the implications for future classification of impulsive–compulsive disorders and …

BackgroundIndividuals with cocaine use disorder or gambling disorder demonstrate impairments in cognitive flexibility: the ability to adapt to changes in the environment. Flexibility is commonly assessed in a laboratory setting using probabilistic reversal learning, which involves reinforcement learning, the process by which feedback from the environment is used to adjust behavior.AimsIt is poorly understood whether impairments in flexibility differ between individuals with cocaine use and gambling disorders, and how this is instantiated by the brain. We applied computational modelling methods to gain a deeper mechanistic explanation of the latent processes underlying cognitive flexibility across two disorders of compulsivity.MethodWe present a re-analysis of probabilistic reversal data from individuals with either gambling disorder (n = 18) or cocaine use disorder (n = 20) and control participants (n = 18), using a …

BACKGROUNDIrritable bowel syndrome (IBS) interacts with psychopathology in a complex way, yet little is known about the underlying brain, biochemical and genetic mechanisms.METHODSTo clarify the phenotypic and genetic associations between IBS and brain health, we performed a comprehensive retrospective cohort study on a large population. Our study included 171,104 participants from the UK Biobank who underwent a thorough assessment of the IBS syndrome, with the majority also providing neuroimaging, behavioral, biochemical, and genetic information. Multistage linked analyses were conducted, including phenome-wide association analysis, polygenic risk score calculation, and two-sample Mendelian Randomization (MR) analysis.RESULTSThe phenome-wide association analysis showed that IBS is linked to brain health problems, including anxiety and depression, and poor cognitive …

Patients with obsessive compulsive disorder (OCD) randomised to sertraline, manualised cognitive behavioural therapy (CBT), or combination (sertraline+ CBT), underwent cognitive assessment. Cognitive testing was conducted at baseline and at week 16. The stop signal reaction time task (SSRT) was used to evaluate motor impulsivity and attentional flexibility was evaluated using the intra/extra-dimensional set shifting task. Paired-samples t-tests or nonparametric variants were used to compare baseline and posttreatment scores within each treatment group. Forty-five patients were tested at baseline (sertraline n= 14; CBT n= 14; sertraline+ CBT n= 17) and 23 patients at week 16 (sertraline n= 6; CBT n= 7; sertraline+ CBT n= 10). The mean dosage of sertraline was numerically higher in those taking sertraline as a monotherapy (166.67 mg) compared with those taking sertraline in combination with CBT (100 mg …

Background Compulsive checking, a common symptom of obsessive-compulsive disorder (OCD), has been difficult to capture experimentally. Therefore, determination of its neural basis remains challenging, despite some evidence suggesting it is linked to dysfunction of cingulo-striatal systems. This study introduces a novel experimental paradigm to measure excessive checking and its neurochemical correlates. Methods Thirty-one OCD and twenty-nine healthy volunteers performed a decision-making task requiring them to decide whether two perceptually similar visual representations were the same or different under a high uncertainty condition without feedback. Both groups underwent magnetic resonance spectroscopy scans at 7-Tesla on the same day. Correlations between out-of-scanner experimental measures of checking and the Glutamate/GABA ratio in the anterior cingulate cortex (ACC), supplementary motor area (SMA) and occipital cortex (OCC) were assessed. Their relationship with subjective ratings of doubt, anxiety and confidence was also investigated. Results OCD patients exhibited excessive and dysfunctional checking, which significantly correlated with changes in the Glutamate/GABA ratio within the ACC. No behavioral/neurochemical relationships were evident for either the SMA or OCC. Excessive checking observed in patients negatively correlated with their confidence levels and positively related to doubt, anxiety and compulsivity traits. Conclusions We conclude that experimental measures of excessive and dysfunctional checking in OCD, linked to increased doubt, anxiety and lack of confidence, are related to an …

Noradrenaline is a powerful modulator of cognitive processes, including action-decisions underlying saccadic control. Changes in saccadic eye movements are common across neurodegenerative diseases of ageing, including Parkinson’s disease. With growing interest in noradrenergic treatment potential for non-motor symptoms in Parkinson’s disease, the temporal precision of oculomotor function is advantageous to assess the effects of this modulation. Here we studied the effect of 40 mg atomoxetine, a noradrenaline reuptake inhibitor, in nineteen people with idiopathic Parkinson’s disease using a single dose, randomised double-blind crossover placebo-controlled design. Twenty-five healthy adult participants completed the assessments to provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity and accuracy of saccades, and resting pupil diameter, were measured. Increased pupil diameter on the drug confirmed its expected effect on the locus coeruleus ascending arousal system. Atomoxetine improved key aspects of saccade performance: prosaccade latencies were faster and the saccadic main sequence was normalised. These improvements were accompanied by increased antisaccade error rates on the drug. Together these findings suggest a shift in the speed-accuracy trade-off for visuo-motor decisions in response to noradrenergic treatment. Our results provide new evidence to substantiate a role for noradrenergic modulation of saccades, and based on known circuitry we advance the hypothesis that this reflects modulation at the level of the locus coeruleus–superior colliculus …

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were …

BackgroundA significant proportion of people with clozapine-treated schizophrenia develop ‘checking’ compulsions, a phenomenon yet to be understood.AimsTo use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive–compulsive symptoms (OCS).MethodUsing the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample.ResultsA total of 196 clozapine-treated individuals and 459 face-to-face assessments were …

Eugene Stern Paykel was born on 9 September 1934 in Auckland, New Zealand. His research work focused on affective disorders in which he made significant and far-reaching contributions to the study of both causes and treatments of depression, spanning the fields of epidemiology, community psychiatry, psychological therapy, and psychopharmacology. He was the sole editor of the influential ‘Handbook of Affective Disorders’(editions 1 and 2) which brought together these disparate areas of study as an early example of the biopsychosocial framework for understanding mental illness. Overall, he published approximately 400 papers, with over 32,000 citations, and authored, co-authored, or edited eight books. As a reflection of his research interest in psychopharmacology, he served as President of The British Association for Psychopharmacology (BAP) and The Collegium Internationale …

The present project is part of a larger project aimed at examining cognitive flexibility, other executive functions, and learning in healthy adults (Melani et al., 2022; Sam et al., 2022; Tong et al., 2021) in Singapore. The current pre-registration form primarily aims to examining specific hypotheses related to the association between socio-cognitive variables and career development/transitional behaviours and outcomes, which might not be described in the main studies (https://osf. io/ay9gr; https://osf. io/n352u; https://osf. io/6rc9h) in detail. Changes in the workplace over the past decades have spawned an increase in research investigating contemporary career types, which are characterized by increased self-directedness, flexibility, and the aim of subjective career success. Living in a dynamic and complex environment necessitates that all living organisms be flexible and adaptive to survive (Powell & Ragozzino, 2017). Humans are required to proactively equip themselves with the ability to shift their strategies and update their beliefs and actions in response to changing environmental demands (Diamond, 2006; Garcia-Garcia et al., 2010; Geurts et al., 2009; Herrmann et al., 2015). For instance, the increasing volatility in the 21st-century workforce, particularly during the unprecedented COVID-19 pandemic, has served as a timely reminder of the urgency of cultivating the flexibility to respond to unforeseen changes and uncertainties more adaptively in order to stay competitive in turbulent job markets. The view of a linear career path (whereby workers are only trained to perform and master one job) that dominated the mainstream workplace system …

BackgroundCocaine use disorder is associated with cognitive deficits that reflect dysfunctional processing across neural systems. Because there are currently no approved medications, treatment centers provide behavioral interventions that have only short-term efficacy. This suggests that behavioral interventions are not sufficient by themselves to lead to the maintenance of abstinence in patients with cocaine use disorder. Self-control, which includes the regulation of attention, is critical for dealing with many daily challenges that would benefit from medication interventions that can ameliorate cognitive neural disturbances.MethodsTo address this important clinical gap, we conducted a randomized, double-blind, placebo-controlled, crossover design study in patients with cocaine use disorder (n = 23) and healthy control participants (n = 28). We assessed the modulatory effects of acute atomoxetine (40 mg) on …

Trait differences in learning can be assessed in humans using Pavlovian-Instrumental Transfer (PIT; Quail et al., 2017; Perkes et al., 2022). PIT refers to the influence of previously learned pavlovian stimuli on instrumental action and is commonly used to assess the motivational influences of reward-related cues on behaviour. This study investigates how specific threat modulates PIT effects. Stress has previously been shown to influence PIT, however the impact of specific, relevant stress has not yet been investigated (Quail et al., 2017; Pool et al., 2016). To effectively evoke specific and relevant stress in participants, a fully immersive environment could help to facilitate real-world reward-seeking and habitual behaviours. Virtual reality has been found to be an immersive and effective method of evoking threat and is being increasingly utilised in learning research, for example in immersive fear conditioning (Quezada-Scholz et al., 2022). In participants with contamination fears, evoked contamination threat could affect habitual and goal-oriented pathways measured using PIT. This will allow an insight into which learning mechanisms are implicated in the development of compulsive, avoidance-based behaviour. Threat will be evoked in 96-120 participants using diverse immersive scenarios (for example a general threat scenario with spiders or a contamination-specific threat scenario with a contaminated environment) in individuals with high versus low contamination fears. Participants will then take part in a computer-based PIT task. Differences in stress levels will be measured through subjective reporting, via alpha amylase levels in participants …

BackgroundComorbidity is the rule rather than the exception for childhood and adolescent onset mental disorders, but we cannot predict its occurrence and do not know the neural mechanisms underlying comorbidity. We investigate if the effects of comorbid internalizing and externalizing disorders on anatomical differences represent a simple aggregate of the effects on each disorder and if these comorbidity-associated cortical surface differences relate to a distinct genetic underpinning.MethodsWe studied the cortical surface area (SA) and thickness (CT) of 11,878 preadolescents (9–10 years) from the Adolescent Brain and Cognitive Development Study. Linear mixed models were implemented in comparative and association analyses among internalizing (dysthymia, major depressive disorder, disruptive mood dysregulation disorder, agoraphobia, panic disorder, specific phobia, separation anxiety disorder …

Cognitive flexibility refers to the ability to adjust to changes in the environment and is essential for adaptive behavior. It can be investigated using laboratory tests such as probabilistic reversal learning (PRL). In individuals with both Cocaine Use Disorder (CUD) and Gambling Disorder (GD), overall impairments in PRL flexibility are observed. However, it is poorly understood whether this impairment depends on the same brain mechanisms in cocaine and gambling addictions. Reinforcement learning (RL) is the process by which rewarding or punishing feedback from the environment is used to adjust behavior, to maximise reward and minimise punishment. Using RL models, a deeper mechanistic explanation of the latent processes underlying cognitive flexibility can be gained. Here, we report results from a re-analysis of PRL data from control participants (n=18) and individuals with either GD (n=18) or CUD (n=20) using a hierarchical Bayesian RL approach. We observed significantly reduced ‘stimulus stickiness’ (i.e., stimulus-bound perseveration) in GD, which may reflect increased exploratory behavior that is insensitive to outcomes. RL parameters were unaffected in CUD. We relate the behavioral findings to their underlying neural substrates through an analysis of task-based fMRI data. We report differences in tracking reward and punishment expected values (EV) in individuals with GD compared to controls, with greater activity during reward EV tracking in the cingulate gyrus and amygdala. In CUD, we observed reduced responses to positive punishment prediction errors (PPE) and increased activity following negative PPEs in the superior …

在神经科学及临床研究中, 基于视频的动作识别方法日益成为神经疾病检测和预测的重要工具. 然而, 非人灵长类动物研究的动作识别目前仍依赖高强度的人工操作, 并且缺乏标准化的评估方法, 极大地影响研究效率及识别准确性. 因此, 该研究建立了在实验室环境下的两个非人灵长类动物基准数据集: MonkeyinLab (MiL) 数据集 (包括 13 类动作和姿态) 和 MiL2D 数据集 (包括 15 个 2D 骨骼特征点), 这两个标准数据集覆盖了食蟹猴的日常表型行为. 此外, 该研究还提出了一个基于深度学习的工具箱 MonkeyMonitorKit (MonKit), MonKit 采用 TSSA 网络识别猴子动作 (准确度 98.99%) 和 HRNet 网络识别猴子的骨骼特征点 (准确度 98.8%), 并结合动作姿势估计建立了精细动作的评估模型和行为分析方法, 可评估疾病状态下的低头行为 (抑郁症样表型), 刻板行为 (自闭症样表型) 等. 该研究利用 MonKit 工具箱量化比较了作为 Rett 综合征疾病模型的 MECP2 基因突变食蟹猴与野生型食蟹猴的日常行为分类和精细动作评估, 并与人工识别进行对比, 确认 …

There has been little analysis of neurochemical correlates of compulsive behaviour to illuminate its underlying neural mechanisms. We use 7-Tesla proton magnetic resonance spectroscopy (1H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex (ACC) and supplementary motor area (SMA) of healthy volunteers and participants with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behaviour are related to glutamate levels, whereas a behavioural index of habitual control correlates with the glutamate:GABA ratio. Participants with OCD also show the latter relationship in the ACC while exhibiting elevated glutamate and lower GABA levels in that region. This study highlights SMA mechanisms of habitual control relevant to compulsive behaviour, common to the healthy sub …

The Pavlovian-Instrumental Transfer (PIT) procedure allows the impact of pavlovian cues on instrumental behaviour to be assessed in a cross-species manner. Individuals are trained to associate pavlovian cues with specific outcomes (eg CS1-O1, CS2-O2) before undergoing a separate phase of instrumental training in which actions are associated with the same outcomes (eg R1-O1, R2-O2). In a subsequent test session, the influence of the pavlovian cues on responding for the same and different outcomes is assessed in a non-reinforced transfer test. The effect of these cues can be specific or general. To date, the majority of procedures examining PIT in human populations have focused upon the use of positive reinforcers, ie responding for rewards. However, responding can also be potentially enhanced through the avoidance of aversive outcomes (negative reinforcement). The use of a virtual reality (VR) environment, will increase the immersive nature of the task. To date no other PIT study has been administered in VR. This study aims to determine the comparability of PIT effects produced by a positive and negative reinforcement using a between-subjects manipulation in which participants experience either an appetitive or an aversive version of the PIT procedure. It will investigate and compare the magnitude of general and specific PIT across these two task conditions, and will also use exploratory analyses to determine whether there are correlations between task performance and self-report measures of trait-stress, compulsivity, contamination fears and impulsivity.

Recent studies proposed a general psychopathology factor underlying common comorbidities among psychiatric disorders. However, its neurobiological mechanisms and generalizability remain elusive. In this study, we used a large longitudinal neuroimaging cohort from adolescence to young adulthood (IMAGEN) to define a neuropsychopathological (NP) factor across externalizing and internalizing symptoms using multitask connectomes. We demonstrate that this NP factor might represent a unified, genetically determined, delayed development of the prefrontal cortex that further leads to poor executive function. We also show this NP factor to be reproducible in multiple developmental periods, from preadolescence to early adulthood, and generalizable to the resting-state connectome and clinical samples (the ADHD-200 Sample and the STRATIFY & ESTRA Project). In conclusion, we identify a reproducible and …

Not everyone who uses drugs loses control over their intake, which is a hallmark of addiction. Although familial risk studies suggest significant addiction heritability, the genetic basis of vulnerability to drug addiction remains largely unknown. In the present study, we investigate the relationship between self-control, cocaine use, and the rs36024 single nucleotide polymorphism of the noradrenaline transporter gene (SLC6A2). We hypothesize that C-allele-carrying adults show impaired self-control, as measured by the stop-signal task and demonstrated previously in adolescents, and further exacerbated by chronic cocaine use. Patients with cocaine use disorder (CUD, n = 79) and healthy unrelated participants with no history of drug abuse (n = 54) completed the stop-signal task. All participants were genotyped for rs36024 allelic variants (CC/TT homozygotes, CT heterozygotes). We measured mean stop-signal …

BackgroundFindings of reward disturbances in unaffected relatives of patients with schizophrenia suggest reward disturbances as an endophenotype for schizophrenia. Twin studies, where 1 twin has been diagnosed with a schizophrenia spectrum disorder, can further explore this.MethodsWe used Danish registries to identify twin pairs with at least 1 twin having a schizophrenia spectrum disorder diagnosis and control twin pairs matched on age, sex, and zygosity. The analyses included data from 34 unaffected co-twins (16 females), 42 probands with schizophrenia spectrum disorder (17 females), and 83 control twins (42 females). Participants performed a modified incentive delay task during functional magnetic resonance imaging. Whole-brain group differences were analyzed by performing comparisons between co-twins and control twins. Correlations with cognitive flexibility were tested.ResultsCompared with …

Adolescence is a critical developmental with increased vulnerability to mental disorders. While the positive impact of physical exercise on adult mental health is well-established, dose-response relationships and the underlying neural and genetic mechanisms in adolescents remain elusive. Leveraging data from >11,000 pre-adolescents (9-10 years, ABCD Study) we examined associations between seven different measures of exercise dosage across 15 exercises and psychopathology, and the roles of brain function and structure and psychiatric genetic risks. Five specific exercises (basketball, baseball/softball, soccer, football, and skiing) were associated with better mental health while the beneficial effects varied with exercise types, dosage measures and dimensions of psychopathology. Interestingly, more exercise does not always translate to better mental health whilst earlier initiation was consistently advantageous. Communication between attention and default-mode brain networks mediated the beneficial effect of playing football. Crucially, exercise mitigates the detrimental effects of psychiatric genetic risks on mental health. We offer a nuanced understanding of exercise effects on adolescent mental health to promote personalized exercise-based interventions in youth.

Early-life stress (ELS) or adversity, particularly in the form of childhood neglect and abuse, is associated with poor mental and physical health outcomes in adulthood. However, whether these relationships are mediated by the consequences of ELS itself or by other exposures that frequently co-occur with ELS is unclear. To address this question, we carried out a longitudinal study in rats to isolate the effects of ELS on regional brain volumes and behavioral phenotypes relevant to anxiety and depression. We used the repeated maternal separation (RMS) model of chronic ELS, and conducted behavioral measurements throughout adulthood, including of probabilistic reversal learning (PRL), responding on a progressive ratio task, sucrose preference, novelty preference, novelty reactivity, and putative anxiety-like behavior on the elevated plus maze. Our behavioral assessment was combined with magnetic resonance …

Video-based action recognition is becoming a vital tool in clinical research and neuroscientific study for disorder detection and prediction. However, action recognition currently used in non-human primate (NHP) research relies heavily on intense manual labor and lacks standardized assessment. In this work, we established two standard benchmark datasets of NHPs in the laboratory: MonkeyinLab (MiL), which includes 13 categories of actions and postures, and MiL2D, which includes sequences of two-dimensional (2D) skeleton features. Furthermore, based on recent methodological advances in deep learning and skeleton visualization, we introduced the MonkeyMonitorKit (MonKit) toolbox for automatic action recognition, posture estimation, and identification of fine motor activity in monkeys. Using the datasets and MonKit, we evaluated the daily behaviors of wild-type cynomolgus monkeys within their home …

Background Cognitive flexibility (CF) enables individuals to readily shift from one concept or mode of practice/thoughts to another in response to changes in the environment and feedback, making CF vital to optimise success in obtaining goals. However, how CF relates to other executive functions (e.g., working memory, response inhibition), mental abilities (e.g., creativity, literacy, numeracy, intelligence, structure learning), and social factors (e.g., multilingualism, tolerance of uncertainty, perceived social support, social decision-making) is less well understood. The current study aims to (1) establish the construct validity of CF in relation to other executive function skills and intelligence, and (2) elucidate specific relationships between CF, structure learning, creativity, career decision making and planning, and other life skills. Methods This study will recruit up to 400 healthy Singaporean young adults (age 18–30) to complete a wide range of cognitive tasks and social questionnaires/tasks. The richness of the task/questionnaire battery and within-participant administration enables us to use computational modelling and structural equation modelling to examine connections between the latent constructs of interest. Significance and Impact The current study is the first systematic investigation into the construct validity of CF and its interrelationship with other important cognitive skills such as learning and creativity, within an Asian context. The study will further explore the concept of CF as a non-unitary construct, a novel theoretical proposition in the field. The inclusion of a structure learning paradigm is intended to inform future development of a novel …

Functional impairments in cognition are frequently thought to be a feature of individuals with depression or anxiety. However, documented impairments are both broad and inconsistent, with little known about when they emerge, whether they are causes or effects of affective symptoms, or whether specific cognitive systems are implicated. Here, we show, in the adolescent ABCD cohort (N = 11,876), that attention dysregulation is a robust factor underlying wide-ranging cognitive task impairments seen in adolescents with moderate to severe anxiety or low mood. We stratified individuals high in DSM-oriented depression or anxiety symptomology, and low in attention deficit hyperactivity disorder (ADHD), as well as vice versa – demonstrating that those high in depression or anxiety dimensions but low in ADHD symptoms not only exhibited normal task performance across several commonly studied cognitive …

ImportanceThe pathogenesis of obsessive-compulsive disorder (OCD) may involve altered dendritic morphology, but in vivo imaging of neurite morphology in OCD remains limited. Such changes must be interpreted functionally within the context of the multimodal neuroimaging approach to OCD.ObjectiveTo examine whether dendritic morphology is altered in patients with OCD compared with healthy controls (HCs) and whether such alterations are associated with other brain structural metrics in pathological networks.Design, Setting, and ParticipantsThis case-control study used cross-sectional data, including multimodal brain images and clinical symptom assessments, from 108 patients with OCD and 108 HCs from 2014 to 2017. Patients with OCD were recruited from Shanghai Mental Health Center, Shanghai, China, and HCs were recruited via advertisements. The OCD group comprised unmedicated adults …

Behavioral and cognitive flexibility allow adaptation to a changing environment. Most tasks used to investigate flexibility require switching reactively in response to deterministic task-response rules. In daily life, flexibility often involves a volitional decision to change behavior. This can be instigated by environmental signals, but these are frequently unreliable. We report results from a novel “change your mind” task, which assesses volitional switching under uncertainty without the need for rule-based learning. Participants completed a two-alternative choice task, and following spurious feedback, were presented with the same stimulus again. Subjects had the opportunity to repeat or change their response. Forty healthy participants completed the task while undergoing a functional magnetic resonance imaging scan. Participants predominantly repeated their choice but changed more when their first response was …

Methods: Two hundred and seventeen patients OCD outpatients (evaluated with DSM-5) were recruited. The OC symptom severity was assessed by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Socio-demographic characteristics were recorded together with family, illness and treatment history, comorbid psychiatric and medical conditions, suicidal symptoms and attempts, sleep patterns and metabolic status. Levels of vitamin B12, D, folic acid and homocysteine were measured by common chemical-clinical laboratory tests. The Kolmogorov-Smirnov test was used to determine normality of distribution of the variables. Comparisons for continuous variables were performed with the independentsample Student’s t-test. Comparisons for categorical variables were conducted by the use of χ2 test. The possible differences in Y-BOCS total-score and obsession/compulsion subscales between the subgroups were analyzed by the Mann-Whitney test.Results: Men showed a younger age at index evaluation and at onset, as well as a higher prevalence of lifetime and current sexual obsessional thoughts, with no significant gender differences. An earlier disease onset, a history of perinatal traumas and a chronic course were associated to more severe symptoms. The acute onset, when preceded by stressful life events was related to better clinical characteristics. Levels of vitamin B12 and folic acid were sufficient in most patients. The levels of folic acid showed a negative correlation with “resistance to obsessive thoughts”(r=-0.270, p= 0.019) and “resistance to compulsive behaviour”(r=-0.247, p= 0.031) item of Y-BOCS. Conclusions: There is a …

This article presents, in the form of an analytic narrative review, a complete picture of the state-of-the-art, challenges, and perspectives in the field of information and communication technology (ICT)-based neurocognitive interventions for older adults. The narrative particularly focuses on applications aimed at mild cognitive impairment and similar age-related cognitive deficits, which are analyzed in the context of the brain training controversy. Clarifying considerations are provided about the nature and present extent of the brain training debate, regarding the possible influence it has on the support received by research and development initiatives dealing with innovative computerized neurocognitive interventions. It is recommended that, because of the preliminary nature of most data currently available in this area, further research initiatives must be supported in the quest for better effectiveness of computer-based interventions intended for age-related cognitive impairment. The conclusion suggests that advanced ICT-based tools, such as virtual and augmented reality technologies, are the most fitting platforms for applying nonpharmacological computerized neurocognitive interventions.

Impulsive behaviour on the five-choice serial reaction time task (5CSRTT), a task measuring attention and impulsivity in rodents, is known to depend on dopamine (DA) neurotransmission in the mesolimbic DA pathway. Previous research in our lab reported that systemic administration of the D2/3 agonist quinpirole, which decreases DA release in the striatum, reduced premature responses in rats performing the 5CSRTT. It is unclear, however, whether this effect is mediated by the activation of inhibitory somatodendritic receptors in the ventral tegmental area (VTA), which in turn leads to a reduction in DA release in the nucleus accumbens, a major terminal region of the mesolimbic DA pathway. In the present study, we investigated this possibility by infusing quinpirole directly into the VTA of rats during performance on the 5CSRTT. We found that quinpirole, at the highest dose, significantly reduced the frequency of …

Adolescents exhibit remarkable heterogeneity in the structural architecture of brain development. However, due to the lack of large-scale longitudinal neuroimaging studies, existing research has largely focused on population averages and the neurobiological basis underlying individual heterogeneity remains poorly understood. Using structural magnetic resonance imaging from the IMAGEN cohort (n=1,543), we show that adolescents can be clustered into three groups defined by distinct developmental patterns of whole-brain gray matter volume (GMV). Genetic and epigenetic determinants of group clustering and long-term impacts of neurodevelopment in mid-to-late adulthood were investigated using data from the Adolescent Brain Cognitive Development (ABCD), IMAGEN and UK Biobank cohorts. Group 1, characterized by continuously decreasing GMV, showed generally the best neurocognitive performances during adolescence. Compared to Group 1, Group 2 exhibited a slower rate of GMV decrease and worsened neurocognitive development, which was associated with epigenetic changes and greater environmental burden. Further, Group 3 showed increasing GMV and delayed neurocognitive development during adolescence due to a genetic variation, while these disadvantages were attenuated in mid-to-late adulthood. In summary, our study revealed novel clusters of adolescent structural neurodevelopment and suggested that genetically-predicted delayed neurodevelopment has limited long-term effects on mental well-being and socio-economic outcomes later in life. Our results could inform future research on policy interventions …

Background A growing body of neuroimaging studies has reported common neural abnormalities among mental disorders in adults. However, it is unclear whether the distinct disorder-specific mechanisms operate during adolescence despite the overlap among disorders.Methods We studied a large cohort of more than 11 000 preadolescent (age 9–10 yr) children from the Adolescent Brain and Cognitive Development cohort. We adopted a regrouping approach to compare cortical thickness (CT) alterations and longitudinal changes between healthy controls (n = 4041) and externalizing (n = 1182), internalizing (n = 1959) and thought disorder (n = 347) groups. Genome-wide association study (GWAS) was performed on regional CT across 4468 unrelated European youth.Results Youth with externalizing or internalizing disorders exhibited increased regional CT compared with controls. Externalizing (p = 8 × 10−4 …

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive …

Original and unprocessed raw data is provided in support of the article" Action-Outcome Knowledge Dissociates From Behavior in Obsessive-Compulsive Disorder Following Contingency Degradation". The article was accepted for publication in 2018 in the journal" Biological Psychiatry: Cognitive Neuroscience and Neuroimaging". The data relate to the main findings of the study originating from the contingency degradation task described in the manuscript. Electronic supporting information is available from the publisher.

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19–49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that …

Background Obsessive–compulsive symptoms (OCS) are commonly associated with clozapine treatment but are frequently overlooked by clinicians despite their potential impact on patients' quality of life. In this study, we explored whether OCS severity impacted subjective wellbeing and general functioning, independently of depressive and psychotic symptoms. Methods We used anonymised electronic healthcare records from a large cohort of patients who were treated with clozapine and assessed annually for OCS, wellbeing, general functioning, and psychopathology using standardised scales as part of routine clinical practice. We used statistical mixed linear model techniques to evaluate the longitudinal influence of OCS severity on wellbeing and general functioning. Results A total of 184 patients were included, with 527 face-to-face assessments and 64.7% evaluated three or more times. Different linear …

RationaleUnconditioned tasks in rodents have been the mainstay of behavioural assessment for decades, but their validity and sensitivity to detect the behavioural consequences of early life stress (ELS) remains contentious and highly variable.ObjectivesIn the present study, we carried out a meta-analysis to investigate whether persistent behavioural effects, as assessed using unconditioned procedures in rats, are a reliable consequence of early repeated maternal separation, a commonly used procedure in rodents to study ELS.MethodsA literature search identified 100 studies involving maternally separated rats and the following unconditioned procedures: the elevated plus maze (EPM); open field test (OFT); sucrose preference test (SPT) and forced swim task (FST). Studies were included for analysis if the separation of offspring from the dam was at least 60 min every day during the pre-weaning period prior to …

How to retrieve latent neurobehavioural processes from complex neurobiological signals is an important yet unresolved challenge. Here, we develop a novel approach, orthogonal-Decoding multi-Cognitive Processes (DeCoP), to reveal underlying latent neurobehavioural processing and show that its performance is superior to traditional non-orthogonal decoding in terms of both false inference and robustness. Processing value and salience information are two fundamental but mutually confounded pathways of reward reinforcement essential for decision making. During reward/punishment anticipation, we applied DeCoP to decode brain-wide responses into spatially overlapping, yet functionally independent, evaluation and readiness processes, which are modulated differentially by meso‑limbic vs nigro-striatal dopamine systems. Using DeCoP, we further demonstrated that most brain regions only encoded …

Impaired working memory (WM) is a core neuropsychological dysfunction of schizophrenia, however complex interactions among the information storage, information processing and attentional aspects of WM tasks make it difficult to uncover the psychophysiological mechanisms of this deficit. Thirty-six first-episode and drug-naïve schizophrenia and 29 healthy controls (HCs) were enrolled in this study. Here, we modified a WM task to isolate components of WM storage and WM processing, while also varying the difficulty level (load) of the task to study regional differences in load-specific activation using mixed effects models, and its relationship to distributed gene expression. Comparing patients with HCs, we found both attentional deficits and WM deficits, with WM processing being more impaired than WM storage in patients. In patients, but not controls, a linear modulation of brain activation was observed mainly in …

Background The nature of cognitive flexibility deficits in obsessive–compulsive disorder (OCD), historically tested with probabilistic reversal learning tasks, remains elusive. Here, a novel deterministic reversal task and inclusion of an unmedicated patients illuminated the role of fixed versus uncertain rules/contingencies and of serotonergic medication. Additionally, our understanding of probabilistic reversal was enhanced through theoretical computational modeling of cognitive flexibility in OCD.Methods We recruited 49 patients with OCD, of whom 21 were unmedicated, and 43 healthy controls, matched for age, IQ, and gender. Participants were tested on two tasks: a novel visuo-motor deterministic reversal learning task with three reversals (feedback rewarding/punishing/neutral) measuring accuracy/perseveration and a two-choice visual probabilistic reversal learning task with uncertain feedback and a single reversal measuring win stay and lose shift. Bayesian computational modeling provided measures of learning rate, reinforcement sensitivity, and stimulus stickiness.Results Unmedicated OCD patients were impaired at the deterministic reversal task under punishment only at the first and third reversals, compared with both controls and medicated OCD patients, who had no deficit. Perseverative errors were correlated with OCD severity. On the probabilistic reversal task, unmedicated patients were only impaired at reversal, whereas medicated patients were impaired at both the learning and reversal stages. Computational modeling showed that the overall change was reduced feedback sensitivity in both OCD groups.Conclusions Both …

Preadolescence is a critical period characterized by dramatic morphological changes and accelerated cortico-subcortical development. Moreover, the coordinated development of cortical and subcortical regions underlies the emerging cognitive functions during this period. Deviations in this maturational coordination may underlie various psychiatric disorders that begin during preadolescence, but to date these deviations remain largely uncharted. We constructed a comprehensive whole-brain morphometric similarity network (MSN) from 17 neuroimaging modalities in a large preadolescence sample (N = 8908) from Adolescent Brain Cognitive Development (ABCD) study and investigated its association with 10 cognitive subscales and 27 psychiatric subscales or diagnoses. Based on the MSNs, each brain was clustered into five modules with distinct cytoarchitecture and evolutionary relevance. While …

Smoking of cigarettes among young adolescents is a pressing public health issue. However, the neural mechanisms underlying smoking initiation and sustenance during adolescence, especially the potential causal interactions between altered brain development and smoking behaviour, remain elusive. Here, using large longitudinal adolescence imaging genetic cohorts, we identify associations between left ventromedial prefrontal cortex (vmPFC) gray matter volume (GMV) and subsequent self-reported smoking initiation, and between right vmPFC GMV and the maintenance of smoking behaviour. Rule-breaking behaviour mediates the association between smaller left vmPFC GMV and smoking behaviour based on longitudinal cross-lagged analysis and Mendelian randomisation. In contrast, smoking behaviour associated longitudinal covariation of right vmPFC GMV and sensation seeking (especially hedonic …

BackgroundCompulsive behaviour is often triggered by Pavlovian cues. Assessing how Pavlovian cues drive instrumental behaviour in obsessive-compulsive disorder (OCD) is therefore crucial to understand how compulsions develop and are maintained. An aversive Pavlovian-to-Instrumental transfer (PIT) paradigm, particularly one involving avoidance/cancellation of negative outcomes, can enable such investigation and has not previously been studied in clinical-OCD. MethodsForty-one participants diagnosed with OCD (21 adults; 20 youths) and 44 controls (21 adults; 23 youths) completed an aversive PIT task. Participants had to cancel unpleasant noises by learning response-outcome (instrumental) and stimulus-outcome (Pavlovian) associations. We then assessed whether Pavlovian cues elicited specific instrumental avoidance responses (specific PIT) and induced general instrumental avoidance (general PIT). We investigated whether task learning and confidence indices influenced PIT strength differentially between groups. ResultsUrge to avoid unpleasant noises and preference for safe over unsafe stimuli influenced specific and general PIT respectively in OCD, while PIT in controls was more influenced by confidence in instrumental and Pavlovian learning. However, there was no overall group difference in PIT performance, although youths with OCD showed weaker specific PIT than youth controls. ConclusionsIn OCD, implicit motivational factors, but not learnt knowledge, contribute to the successful integration of aversive Pavlovian and instrumental cues. This implies that compulsive avoidance may be driven by these automatic …

Noradrenergic and cholinergic systems are among the most vulnerable brain systems in neuropsychiatric diseases of ageing, including Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, and progressive supranuclear palsy. As these systems fail, they contribute directly to many of the characteristic cognitive and psychiatric symptoms. However, their contribution to symptoms is not sufficiently understood, and pharmacological interventions targeting noradrenergic and cholinergic systems have met with mixed success. Part of the challenge is the complex neurobiology of these systems, operating across multiple timescales, and with non-linear changes across the adult lifespan and disease course. We address these challenges in a detailed review of the noradrenergic and cholinergic systems, outlining their roles in cognition and behaviour, and how they influence neuropsychiatric symptoms in disease …

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of “race models” of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested …

The influence of peers is particularly strong during adolescence, however, its impacts on the functional and structural organization of the developing brain, cognition and psychopathological symptoms still remain unknown. Here, we capitalized on data from 6,064 pre-adolescents (mean age= 11.93 years) from the Adolescent Brain Cognitive Development (ABCD) database, to determine associations between two distinct peer environments (proportion of prosocial or delinquent friends) and the structural and functional architecture of the brain, cognition, as well as behavioral and emotional dysregulation. A higher proportion of prosocial friends was associated with fewer behavioral problems and larger fronto-cingulo-insular regions characterized by a high density of serotonin receptors. In contrast, a higher proportion of delinquent friends was associated with increased behavioral and mental problems but lower neurocognitive performance and smaller posterior cingulate/precuneus, as well as decreased functional connectivity in default-mode and fronto-striato-limbic circuits characterized by high expression of dopamine receptors. Prosocial friends mediated the association between the volume of certain brain regions (eg, rACC) and prodromal psychosis/behavioral inhibition, while delinquent friends mediated the relationship between fronto-striato-limbic connectivity and behavioral problems. Prosocial friends also attenuated the development of internalizing problems whereas delinquent friends promoted externalizing symptoms. These results underscore the critical importance of a positive adolescent peer environment to promote mental health …

BackgroundInternalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety–impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear.AimsThe aim was to determine impulsivity-dependent subtypes in preadolescent internalising disorders that demonstrate distinct anxiety–impulsivity relationships, neurobiological, genetic, cognitive and clinical trajectory signatures.MethodWe applied a data-driven strategy to determine impulsivity-related subtypes in 2430 preadolescents with internalising disorders from the …

Striatal dopaminergic overactivity was hypothesized as the core pathophysiology of schizophrenia. However, understanding structural alterations in striatum of schizophrenia has been challenging, largely because spatial heterogeneity in striatum limited traditional group-mean based approach. Leveraging third-party functional maps of neurotransmitter and cognition behaviours, we developed a pattern-based representation feature score (ReFS) to investigate structural spatial pattern variation in schizophrenia. Structural ReFS of subcortical regions, particularly the striatum, were linked to schizophrenia diagnosis, symptom severity, and genetic susceptibility. Dopaminergic-ReFS of striatum was increased in schizophrenia patients and reliably reproduced across 13 datasets. The pattern-based ReFS effectively captured the shared genetic pathways underlying both schizophrenia and striatum. The results provide convergent, multimodal suggest the central role of striatal spatial patterns in schizophrenia psychopathologies and and open new avenues to develop individualized treatments for psychotic disorders

Major depressive disorder (MDD) is a stress-related condition hypothesized to involve aberrant reinforcement learning (RL) with positive and negative stimuli. The present study investigated whether repeated early maternal separation (REMS) stress, a procedure widely recognized to cause depression-like behaviour, affects how subjects learn from positive and negative feedback. The REMS procedure was implemented by separating male and female rats from their dam for 6 h each day from post-natal day 5–19. Control rat offspring were left undisturbed during this period. Rats were tested as adults for behavioral flexibility and feedback sensitivity on a probabilistic reversal learning task. A computational approach based on RL theory was used to derive latent behavioral variables related to reward learning and flexibility. To assess underlying brain substrates, a seed-based functional MRI connectivity analysis was …

Enhanced habit formation, greater automaticity and impaired goal/habit arbitration in obsessive-com-pulsive disorder (OCD) are key hypotheses from the goal/habit imbalance theory of compulsion which have not been directly investigated. This study tests these hypotheses using a combination of newly developed behavioral tasks. First, we trained both OCD patients and healthy controls, using a smartphone app, to perform chunked action sequences. This motor training was conducted daily for one month. Both groups displayed equivalent procedural learning and attainment of habitual perfor-mance (measured with an objective criterion of automaticity), despite greater subjective habitual tendencies in patients with OCD, self-reported via a recently developed questionnaire. Participants were subsequently tested on a re-evaluation task to assess choice between established automatic and novel goal-directed action sequences. This task showed that both groups were sensitive to re-evaluation based on monetary feedback. However, when re-evaluation was based on physical effort, OCD patients showed a pronounced preference for the previously trained habitual sequence, hypothetically due to its intrinsic value. This was particularly evident in patients with higher compulsive symptoms and habitual tendencies, who also engaged significantly more with the motor habit-training app and reported symptom relief at the end of the study. The tendency to attribute higher intrinsic value to familiar actions may be a potential mechanism leading to compulsions and an important addition to the goal/habit imbalance hypothesis in OCD. We also highlight the …

BackgroundCognitive flexibility refers to the capacity to shift between conceptual representations particularly in response to changes in instruction and feedback. It enables individuals to swiftly adapt to changes in their environment and has significant implications for learning. The present study focuses on investigating changes in cognitive flexibility following an intervention programme—Structure Learning training.MethodsParticipants are pseudo-randomised to either the Training or Control group, while matched on age, sex, intelligence and cognitive flexibility performance. In the Training group, participants undergo around 2 weeks of training (at least 13 sessions) on Structure Learning. In the Control group, participants do not have to undergo any training and are never exposed to the Structure Learning task. The effects of Structure Learning training are investigated at both the behavioural and neural level. We …

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive form of neurostimulation with potential for development as a self-administered intervention. It has shown promise as a safe and effective treatment for obsessive compulsive disorder (OCD) in a small number of studies. The two most favourable stimulation targets appear to be the left orbitofrontal cortex (L-OFC) and the supplementary motor area (SMA). We report the first study to test these targets head-to-head within a randomised sham-controlled trial. Our aim was to inform the design of future clinical research studies, by focussing on the acceptability and safety of the intervention, feasibility of recruitment, adherence to and tolerability of tDCS, and the size of any treatment-effect.MethodsFEATSOCS was a randomised, double-blind, sham-controlled, cross-over, multicentre study. Twenty adults with DSM-5-defined OCD were randomised to …

The ability to learn about other people is crucial for human social functioning. Dopamine has been proposed to regulate the precision of beliefs, but direct behavioural evidence of this is lacking. In this study, we investigate how a high dose of the D2/D3 dopamine receptor antagonist sulpiride impacts learning about other people’s prosocial attitudes in a repeated Trust game. Using a Bayesian model of belief updating, we show that in a sample of 76 male participants sulpiride increases the volatility of beliefs, which leads to higher precision weights on prediction errors. This effect is driven by participants with genetically conferred higher dopamine availability (Taq1a polymorphism) and remains even after controlling for working memory performance. Higher precision weights are reflected in higher reciprocal behaviour in the repeated Trust game but not in single-round Trust games. Our data provide evidence that the …

BackgroundThe non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans.MethodsHealthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating (‘learning rates …

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computerized neurocognitive assessment system administered using an adaptive touchscreen. CANTAB was constructed in the 1980s at the University of Cambridge. Based on extensive neuropsychological literature, it has facilitated translational research into cognition with clinical impact. The tests included were designed largely not to rely on language, to facilitate crossspecies research and to enable it to be used crossculturally (as it has been in more than 80 countries to date). The battery of tests has high-functioning and less complex versions to enable testing in both healthy and clinical populations (Robbins 1994; 1998).CANTAB has been used to assess neuropsychiatric disorders, such as major depressive disorder (MDD), schizophrenia, obsessive-compulsive disorder (OCD), and addiction; neurological disorders, such as …

Leslie Iversen was one of the most distinguished UK neuropharmacologists and neuroscientists. He led basic neuroscience research at Cambridge early in his career, in partnership with his wife Susan D. Iversen, directing the influential MRC Neurochemical Pharmacology Unit, which spawned a remarkable generation of outstanding neuroscientists. He subsequently made what was then an unusual transition to the industrial sector, to lead a major new research unit of Merck, Sharp and Dohme at Harlow, taking up the difficult challenge of discovering new compounds to transform psychiatry and neurology. Throughout his career he made seminal contributions to the study of the chemical neurotransmitters of the brain, and thereby to the mechanisms of action of drugs now commonly used in psychiatry such as the so-called anti-depressants and the anti-psychotics. His early work focused on the catecholamines …

RationaleAttention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown.ObjectivesWe applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes.MethodsRats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent …

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important both for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition (‘stickiness’) or reinforcement learning rates depending upon manipulations intended to increase or decrease serotonin function. More specifically, the rate at which expected value increased following reward and decreased following punishment (reward and punishment ‘learning rates’) was greatest after sub-chronic administration of the selective serotonin reuptake (SSRI) citalopram (5 mg/kg for 7 days followed by 10 mg/kg twice a day for 5 days) in rats. Conversely, humans given a single dose of an SSRI (20mg escitalopram), which can decrease post-synaptic serotonin signalling, and rats that received the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which destroys forebrain serotonergic neurons, exhibited decreased reward learning rates. A basic perseverative tendency (‘stickiness’), or choice repetition irrespective of the outcome produced …

Prosocial and moral behaviors have overlapping neural systems but whether they involve similar neurochemical systems is unclear. In the current pre-registered randomized placebo controlled trial on 180 adult male and female subjects we investigated effects of intranasal administration of two prosocial neuropeptides, oxytocin or vasopressin, on moral emotion ratings for situations involving accidental or intentional harm to others and in judgments of moral dilemmas where harm is inflicted for a greater good. Oxytocin, but not vasopressin, enhanced feelings of guilt and shame only for intentional harm and reduced endorsement of choices where direct intentional harm to others could achieve a greater good. Effects of oxytocin on guilt and shame were partially mediated by trait empathy. Overall, findings demonstrate for the first time that oxytocin, but not vasopressin, promotes unwillingness to deliberately harm others irrespective of the consequences. This may reflect stronger associations between oxytocin and empathy and vasopressin with aggression.

Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non …

Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits, including apathy. In healthy people, noradrenaline has been implicated in signalling the uncertainty of expectations about the environment. We proposed that noradrenergic deficits contribute to apathy by modulating the relative weighting of prior beliefs about action outcomes. We tested this hypothesis in the clinical context of Parkinson’s disease, given its associations with apathy and noradrenergic dysfunction. Participants with mild-to-moderate Parkinson’s disease (N = 17) completed a randomised double-blind, placebo-controlled, crossover study with 40 mg of the noradrenaline reuptake inhibitor atomoxetine. Prior weighting was inferred from psychophysical analysis of performance in an effort-based visuomotor task, and was confirmed as negatively correlated with apathy. Locus coeruleus integrity was assessed in vivo using magnetisation transfer imaging at ultra-high field 7T. The effect of atomoxetine depended on locus coeruleus integrity: participants with a more degenerate locus coeruleus showed a greater increase in prior weighting on atomoxetine versus placebo. The results indicate a contribution of the noradrenergic system to apathy and potential benefit from noradrenergic treatment of people with Parkinson’s disease, subject to stratification according to locus coeruleus integrity. More …

Background Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. Objectives This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. Methods Twenty‐five people with idiopathic PD, 14 people with probable PSP‐Richardson's syndrome, and 24 age‐matched healthy controls were recruited. Participants underwent clinical assessments and high‐resolution (0.08 mm3) 7 T‐magnetization‐transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the …

There has been relatively little analysis of possible neurochemical correlates of compulsive behavior to illuminate its underlying neural mechanisms. We utilised 7-Tesla proton magnetic resonance spectroscopy (1 H-MRS) to assess the balance of excitatory and inhibitory neurotransmission by measuring glutamate and GABA levels in anterior cingulate cortex and supplementary motor area (SMA) of healthy volunteers and patients with Obsessive-Compulsive Disorder (OCD). Within the SMA, trait and clinical measures of compulsive behavior were related to glutamate levels, whereas a behavioral index of habitual control correlated with the glutamate: GABA ratio. OCD patients additionally exhibited elevated glutamate levels and glutamate: GABA ratios in anterior cingulate cortex which also correlated with habitual control. This study highlights important underlying relationships between SMA mechanisms of habitual control relevant to compulsive behavior, common to the healthy sub-clinical and OCD populations. The results also demonstrate additional involvement of anterior cingulate in the balance between goal-directed and habitual responding in OCD.

As Cooper (1981) has recently pointed out, two main approaches have been taken in the analysis of the behavioural effects of drugs. The first of these, the rate-dependency principle, is based on an empirical generalisation by Dews and his colleagues (Dews & Wenger, 1977) about data obtained on drug effects using operant techniques. The second approach, emanating from Neal Miller (Miller, 1964), has assumed that many psychoactive drugs act upon motivational or reinforcement mechanisms and that the changes in behaviour produced by drugs result indirectly from this action. There has been some interaction between these two levels of explanation, because one of the main measures of change in motivational state is, of course, response rate. The two main manipulations employed in experiments on motivation are to vary the motivational status of an animal, for example, by food deprivation or injections of testosterone, or to vary the nature of the terminal reinforcing event, for example, food, access to a sexual partner, or postponement of shock.Response rate usually behaves in a predictable way in response to these manipulations, thus providing a consistent data base for comparing the effects of drugs. But most drugs do not have selective motivational effects. For example, d-amphetamine increases low rates of responding with many different reinforcers including intracranial stimulation, food, water, light, shock postponement, and shock presentation (see Robbins, 1981 for a review). One might then be tempted to argue that this drug generally enhances the effects of all reinforcers. But one problem with this account is the other side of the …

BackgroundEvidence suggests that reward processing and impulsivity contribute to the pathophysiology of addiction. However, the relationship between the two is currently not well characterised.MethodsAbstinent substance dependent (SD, n= 84) and healthy control (HC, n= 65) participants were recruited (REC number 11/H0707/9). Participants completed a battery of measures assessing trait impulsivity, choice impulsivity and response inhibition. Participants completed a monetary incentive delay task during an fMRI scan. An a-priori region of interest (ROI) approach was used during the following contrasts: reward anticipation> neutral anticipation (RA) and reward outcome> neutral outcome (RO) in the right inferior frontal gyrus (rIFG), bilateral orbitofrontal cortex (OFC) and bilateral caudate. We used regression analysis to investigate associations between reward and impulsivity.ResultsCompared with HC, SD …

HighlightsPaper summarizes the multidisciplinary discussion by authors of this Theme IssueTen directions were identified in international and multidisciplinary cooperation.There is a need in principles underlying biobehavioural taxonomies, not just statsMany continua to be accommodated: clinic-health, ontogenetic, sex, context etcNon-brain biomarkers, language biases, conceptual mix-ups, new math to be improved.This paper represents the outcome of a multidisciplinary discussion on what works, what does not, and what can be improved, in ongoing work on biobehavioral taxonomies and their biomarkers. The authors of this paper, representing a wide spectrum of biobehavioral disciplines (clinical, developmental, differential psychology, neurophysiology, endocrinology, psychiatry, neurochemistry, and neurosciences), have contributed more extensive opinions to the Theme Issue'Neurobiology of temperament …

ObjectiveChildren experiencing attention-deficit/hyperactivity disorder (ADHD) symptoms may retain symptoms into adulthood, but little is known about the underlying mechanism.MethodTo identify biomarkers of persistent ADHD symptom development, we carried out whole-brain analyses of neuroimaging data during the anticipation phase of the Monetary-Incentive-Delay (MID) task in 1,368 adolescents recruited by the IMAGEN Consortium at age 14 years, whose behavioral measurements were followed up longitudinally at age 16. In particular, we focused on comparing individuals with persistent high ADHD symptoms at both ages 14 and 16 years to unaffected control individuals, but also exploring which individuals demonstrating symptom remission (with high ADHD symptoms at age 14 but much reduced at age 16).ResultsWe identified reduced activations in the medial frontal cortex and the thalamus during …

Introduction Negative affective states contribute to the chronic-relapsing nature of addiction. Mesolimbic dopamine D3 receptors are well placed to modulate emotion and are dysregulated in substance dependence. Selective antagonists might restore dopaminergic hypofunction, thus representing a potential treatment target. We investigated the effects of selective D3 antagonist, GSK598809, on the neural response to negative emotional processing in substance dependent individuals and healthy controls. Methodology Functional MRI BOLD response was assessed during an evocative image task, 2 h following acute administration of GSK598809 (60 mg) or placebo in a multi-site, double-blind, pseudo-randomised, cross-over design. Abstinent drug dependent individuals (DD, n = 36) comprising alcohol-only (AO, n = 19) and cocaine-alcohol polydrug (PD, n = 17) groups, and matched controls (n = 32) were presented with aversive and neutral images in a block design (contrast of interest: aversive > neutral). Whole-brain mixed-effects and a priori ROI analyses tested for group and drug effects, with identical models exploring subgroup effects. Results No group differences in task-related BOLD signal were identified between DD and controls. However, subgroup analysis revealed greater amygdala/insular BOLD signal in PD compared with AO groups. Following drug administration, GSK598809 increased BOLD response across HC and DD groups in thalamus, caudate, putamen, and pallidum, and reduced BOLD response in insular and opercular cortices relative to placebo. Multivariate analyses in a priori ROIs revealed differential effects of …

BackgroundImpaired 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.MethodsWe 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.ResultsWe found that atomoxetine speeded Go response times in both control participants and those with CUD. Improvements in stopping …

The present pre-registration seeks to further elaborate on certain hypotheses and analyses related to tolerance of uncertainty (TOU) and perceived social support (PSS) that have been described, but without details, in the Tong et al.(2021; https://osf. io/6rc9h) and Melani et al.(2022; https://osf. io/ay9gr) pre-registrations. Both these projects include an investigation of how the relationship between structure learning and cognitive flexibility is independently moderated by TOU and PSS and includes self-report questionnaires and tasks to measure these variables (see the variable list furnished in the present pre-registration for the details of the questionnaires and tasks used to measure the TOU and PSS variables). Tolerance of uncertainty (TOU) is a cognitive tendency characterized by the willingness to engage in unconventional and novel ways of thinking and doing. The measures we use to assess tolerance of uncertainty include decision-making tasks such as Ambiguity Aversion and questionnaires such as the Need for Closure Scale and Multicultural Experiences Questionnaire (see attached variable list for the full list of measures). Ambiguity aversion is measured with the multiple price list paradigm (Holt & Laury, 2002) in which a participant makes nine binary choices between an ambiguous option and a risky option and choosing more ambiguous options indicates a higher tolerance of uncertainty. Need for closure is defined as a “desire for a firm answer to a question, any firm answer as compared to confusion and/or ambiguity”(Kruglanski, 2004, p. 6) and has been acknowledged by researchers to have conceptual overlap with tolerance of …

HighlightsEffects of acute tryptophan depletion (ATD) to reduce central 5-HT on emotions are reviewed.These jointly depend on both situational context and temperamental trait-related factors.ATD can have different qualitative effects on emotion in high trait empathy and psychopathy.Interplay of 5-HT with other neurochemical systems in social emotions is discussed.Accounting for temperament can enrich neurochemical studies of emotion and behaviour, with clear clinical relevance.This review highlights the utility of applying concepts of temperament and personality traits in healthy individuals to functional studies of serotonin (5-hydroxytryptamine, 5-HT), in an effort to better elucidate the complex roles of 5-HT, and ultimately advance our understanding of psychopathology. We highlight empirical demonstrations of multifaceted and trait-dependent emotional and behavioural effects of manipulating 5-HT in humans …

Background The HD Young Adult Study provided deep phenotyping of the earliest cohort of adult HD mutation carriers to date. We previously reported elevated levels of neurofilament light protein, suggestive of early neurodegenerative change. Putaminal volumes were also significantly reduced in HD mutation carriers. However, there was no evidence of any motor, cognitive or neuropsychiatric impairment approximately 24 years before expected disease onset.Aims We aim to follow up this valuable cohort to quantify longitudinal changes in imaging and biofluid markers and document premanifest emergence of motor, cognitive and neuropsychiatric changes.Methods We will undertake two follow up visits on our cohort of 64 young adult premanifest HD mutation carriers (preHD) and 67 matched controls at 5 and 6.5 years post baseline. In addition to the clinical, cognitive, neuropsychiatric, imaging and biofluid …

Background Computational research had determined that adults with obsessive–compulsive disorder (OCD) display heightened action updating in response to noise in the environment and neglect metacognitive information (such as confidence) when making decisions. These features are proposed to underlie patients’ compulsions despite the knowledge they are irrational. Nonetheless, it is unclear whether this extends to adolescents with OCD as research in this population is lacking. Thus, this study aimed to investigate the interplay between action and confidence in adolescents with OCD. Methods Twenty‐seven adolescents with OCD and 46 controls completed a predictive‐inference task, designed to probe how subjects’ actions and confidence ratings fluctuate in response to unexpected outcomes. We investigated how subjects update actions in response to prediction errors (indexing mismatches between …

BackgroundObsessive-compulsive disorder (OCD) is characterized by both internalizing (anxiety) and externalizing (compulsivity) symptoms. Currently, little is known about their interrelationships and their relative contributions to disease heterogeneity. Our goal is to resolve affective and cognitive symptom heterogeneity related to internalized and externalized symptom dimensions by determining subtypes of children with OCD symptoms, and to identify any corresponding neural differences.MethodsA total of 1269 children with OCD symptoms screened using the Child Behavior Checklist Obsessive-Compulsive Symptom scale and 3987 matched control subjects were obtained from the Adolescent Brain Cognitive Development (ABCD) Study. Consensus hierarchical clustering was used to cluster children with OCD symptoms into distinct subtypes. Ten neurocognitive task scores and 20 Child Behavior Checklist …

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i …

The symptoms of obsessive–compulsive disorder (OCD) are suggestive of cognitive rigidity, and previous work identified impaired flexible responding on set-shifting tasks in such patients. The basal ganglia are central to habit learning and are thought to be abnormal in OCD, contributing to inflexible, rigid habitual patterns of behaviour. Here, we demonstrate that increased cognitive inflexibility, indexed by poor performance on the set-shifting task, correlated with putamen morphology, and that patients and their asymptomatic relatives had common curvature abnormalities within this same structure. The association between the structure of the putamen and the extradimensional errors was found to be significantly familial in OCD proband–relative pairs. The data implicate changes in basal ganglia structure linked to cognitive inflexibility as a familial marker of OCD. This may reflect a predisposing heightened …

Evidence suggests that alcohol dependence (AD) is associated with microstructural deficits in white matter, but the relationship with lifetime alcohol exposure and the impact of polydrug dependence is not well understood. Using diffusion tensor magnetic resonance (MR) imaging, we examined white matter microstructure in relation to alcohol and polydrug dependence using data from the Imperial College Cambridge Manchester (ICCAM) platform study. Tract‐based spatial statistics were used to examine fractional anisotropy (FA) in a cohort of abstinent AD participants, most of whom had a lifetime history of dependence to nicotine. A further subgroup also had a lifetime history of dependence to cocaine and/or opiates. Individuals with AD had lower FA throughout the corpus callosum, and negative associations with alcohol and nicotine exposure were found. A group‐by‐age interaction effect was found showing …

Social distancing measures to combat the spread of the severe acute respiratory syndromecoronavirus 2 (SARS-CoV2) infections are likely to have unintended consequences on mental health and emotional wellbeing. Social isolation, loneliness and uncertainty are key risk factors for developing mental health problems and pose a significant concern for the long-term consequences of social distancing (Vatansever, Wang, & Sahakian, 2020). Nevertheless, this pandemic has illuminated the struggle of many people with mental health disorders, who live socially disconnected and isolated lives every day, long before the emergence of coronavirus 2019 (COVID-19) and societal ‘lockdown’.Social integration has been found to be robustly linked to social cognitive ability; the mental operations needed to perceive, interpret and process information for adaptive social interactions (Green, Horan, & Lee, 2019). Without the …

Only some individuals using drugs recreationally eventually become addicted, and persist in drug seeking and taking despite adverse consequences. The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. We report that in drug naïve rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.One sentence summaryDistinct neurobehavioral correlates of impulsivity and behavioral inflexibility together predispose to compulsive cocaine seeking in rats.

The ability to flexibly adjust beliefs about other people is crucial for human social functioning. Dopamine has been proposed to regulate the precision of beliefs, but direct behavioural evidence of this is lacking. We investigated how a relatively high dose of the selective D2/D3 dopamine receptor antagonist sulpiride impacts learning about other people’s prosocial attitudes in a repeated trust game. Using a Bayesian model of belief updating, we show that sulpiride increased the volatility of beliefs, which led to higher precision-weights on prediction errors. This effect was entirely driven by participants with genetically conferring higher dopamine availability (Taq1a polymorphism). Higher precision weights were reflected in higher reciprocal behaviour in the repeated trust game but not in single-round trust games. This finding suggests that antipsychotic medication might acutely reduce rigidity of pathological beliefs.

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 …

This chapter concerns the behavioural effects of amphetamine, not only because this drug and related compounds produce the most pronounced rate-dependent effects, but also because their neuropharmacological modes of action upon the catecholamine neurotransmitters, dopamine and noradrenaline, are relatively specific and well understood. The effect of the drug depends on the control rate of responding. The chapter reviews some of our recent work on response switching with amphetamine and other drugs which attempts to characterise it systematically and provides some behavioural explanation of this effect. The behavioural competition hypothesis assumes that there are interactions between different responses and that the effect of amphetamine depends to a marked extent on the overall pattern of behaviour. Responding under d-amphetamine clearly becomes independent of the effects of …

Early-life stress (ELS) or adversity, particularly in the form of childhood neglect and abuse, is associated with poor mental and physical health outcomes in adulthood. However, whether these relationships are mediated by the consequences of ELS itself or by other exposures that frequently co-occur with ELS is unclear. To address this question, we carried out a longitudinal study in rats to isolate the effects of ELS on regional brain volumes and behavioral phenotypes relevant to anxiety and depression. We used the repeated maternal separation (RMS) model of chronic ELS, and conducted behavioral measurements throughout adulthood, including of probabilistic reversal learning (PRL), responding on a progressive ratio task, sucrose preference, novelty preference, novelty reactivity, and putative anxiety-like behavior on the elevated plus maze. Our behavioral assessment was combined with magnetic resonance imaging (MRI) for quantitation of regional brain volumes at three time points: immediately following RMS, young adulthood without further stress, and late adulthood with further stress. We found that RMS caused long-lasting, sexually dimorphic biased responding to negatively-valenced stimuli on the PRL task. RMS also slowed response time on the PRL task, but without this directly impacting task performance. RMS animals were also uniquely sensitive to a second stressor, which further slowed and biased their responding on the PRL task. MRI at the time of the adult stress revealed a larger amygdala volume in RMS animals compared with controls. These behavioral and neurobiological effects persisted well into adulthood despite a …

Despite decades of research in the field of substance withdrawal, molecular biomarkers and related mechanistic study have generally been lacking. In addition to known neurotransmitters, circulating miRNAs are found in small vesicles known as exosomes within blood that have diagnostic potential and are known to contribute to psychiatric disorders. The aim of this work was to characterize the changes in neurotransmitter and exosomal miRNA profiles during heroin and methamphetamine withdrawal using a cross-sectional study design, and to determine their associations to psychiatric comorbidities in a large group of patients with substance use disorders (SUDs). Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal miRNAs were identified as being associated with the severity of anxiety and depression, as well as the concentrations of neurotransmitters GABA …