Showing papers by "Trevor W. Robbins published in 2021"

The role of noradrenaline in cognition and cognitive disorders.

Abstract: Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer's disease, Parkinson's disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.

The cognitive and perceptual correlates of ideological attitudes: a data-driven approach.

Abstract: Although human existence is enveloped by ideologies, remarkably little is understood about the relationships between ideological attitudes and psychological traits. Even less is known about how cognitive dispositions-individual differences in how information is perceived and processed- sculpt individuals' ideological worldviews, proclivities for extremist beliefs and resistance (or receptivity) to evidence. Using an unprecedented number of cognitive tasks (n = 37) and personality surveys (n = 22), along with data-driven analyses including drift-diffusion and Bayesian modelling, we uncovered the specific psychological signatures of political, nationalistic, religious and dogmatic beliefs. Cognitive and personality assessments consistently outperformed demographic predictors in accounting for individual differences in ideological preferences by 4 to 15-fold. Furthermore, data-driven analyses revealed that individuals' ideological attitudes mirrored their cognitive decision-making strategies. Conservatism and nationalism were related to greater caution in perceptual decision-making tasks and to reduced strategic information processing, while dogmatism was associated with slower evidence accumulation and impulsive tendencies. Religiosity was implicated in heightened agreeableness and risk perception. Extreme pro-group attitudes, including violence endorsement against outgroups, were linked to poorer working memory, slower perceptual strategies, and tendencies towards impulsivity and sensation-seeking-reflecting overlaps with the psychological profiles of conservatism and dogmatism. Cognitive and personality signatures were also generated for ideologies such as authoritarianism, system justification, social dominance orientation, patriotism and receptivity to evidence or alternative viewpoints; elucidating their underpinnings and highlighting avenues for future research. Together these findings suggest that ideological worldviews may be reflective of low-level perceptual and cognitive functions. This article is part of the theme issue 'The political brain: neurocognitive and computational mechanisms'.

Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease.

Abstract: Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model Twenty-six control subjects completed the same task without undergoing the drug manipulation In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson's disease Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches

Resolving heterogeneity in schizophrenia through a novel systems approach to brain structure: individualized structural covariance network analysis.

Abstract: Reliable mapping of system-level individual differences is a critical first step toward precision medicine for complex disorders such as schizophrenia. Disrupted structural covariance indicates a system-level brain maturational disruption in schizophrenia. However, most studies examine structural covariance at the group level. This prevents subject-level inferences. Here, we introduce a Network Template Perturbation approach to construct individual differential structural covariance network (IDSCN) using regional gray-matter volume. IDSCN quantifies how structural covariance between two nodes in a patient deviates from the normative covariance in healthy subjects. We analyzed T1 images from 1287 subjects, including 107 first-episode (drug-naive) patients and 71 controls in the discovery datasets and established robustness in 213 first-episode (drug-naive), 294 chronic, 99 clinical high-risk patients, and 494 controls from the replication datasets. Patients with schizophrenia were highly variable in their altered structural covariance edges; the number of altered edges was related to severity of hallucinations. Despite this variability, a subset of covariance edges, including the left hippocampus-bilateral putamen/globus pallidus edges, clustered patients into two distinct subgroups with opposing changes in covariance compared to controls, and significant differences in their anxiety and depression scores. These subgroup differences were stable across all seven datasets with meaningful genetic associations and functional annotation for the affected edges. We conclude that the underlying physiology of affective symptoms in schizophrenia involves the hippocampus and putamen/pallidum, predates disease onset, and is sufficiently consistent to resolve morphological heterogeneity throughout the illness course. The two schizophrenia subgroups identified thus have implications for the nosology and clinical treatment.

Cognitive Inflexibility in OCD and Related Disorders.

Abstract: Cognitive inflexibility is suggested by the hallmark symptoms of obsessive-compulsive disorder (OCD), namely the occurrence of repetitive thoughts and/or behaviours that persist despite being functionally impairing and egodystonic to the individual. As well as being implied by the top-level symptoms, cognitive inflexibility in OCD, and some related conditions, has also been objectively quantified in case–control studies using computerised cognitive tasks. This chapter begins by considering the objective measurement of different aspects of cognitive flexibility using neuropsychological paradigms, with a focus on neural and neurochemical substrates. It moves on to conduct a systematic review and meta-analysis of findings from a widely deployed flexibility task: the Intra-Dimensional/Extra-Dimensional Set-Shift Task (IDED). By pooling data from 11 studies (335 OCD patients and 311 controls), we show that Extra-Dimensional (ED) shift deficits are a robust and reproducible finding (effect size medium–large) in OCD across the literature, and that this deficit is not attributable to group differences in age or IQ. The OCD ED deficit is then discussed in terms of dysfunction of fronto-striatal pathways (as exemplified, for example, by functional connectivity data), and the putative role of different neurotransmitters. We consider evidence that impaired ED shifting constitutes a candidate vulnerability marker (or ‘endophenotype’) for OCD. The available literature is then surveyed as to ED findings in other obsessive-compulsive (OC) related disorders (e.g. hoarding, body-dysmorphic disorder, and trichotillomania), as well as in non-OC disorders (schizophrenia and anxiety symptoms in general). Lastly, we consider more recent, emerging developments in the quantification of compulsivity using cognitive tasks and questionnaires, as well as key directions for future research, including the need to refine compulsivity and its composite cognitive processes.

Diagnostic Classification for Human Autism and Obsessive-Compulsive Disorder Based on Machine Learning From a Primate Genetic Model.

Abstract: Objective:Psychiatric disorders commonly comprise comorbid symptoms, such as autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD)...

Substance Use Initiation, Particularly Alcohol, in Drug-Naive Adolescents: Possible Predictors and Consequences From a Large Cohort Naturalistic Study.

Abstract: Objective It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences. Method Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on >40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting. Results From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p .294), and uncharacteristically increased in the >40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008). Conclusion These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

The impact of COVID-19 social isolation on aspects of emotional and social cognition.

Abstract: The present study aimed to examine the impact of COVID-19 social isolation upon aspects of emotional and social cognitive function. We predicted that greater impairments in emotional and social cognition would be observed in people who experienced more disruption to their usual social connectivity during COVID-19 social isolation. Healthy volunteers (N = 92) without prior mental health problems completed assessments online in their own homes during the most stringent period of the first COVID-19 “lockdown” in the UK (March – May 2020). Measures included two questionnaires probing levels of social isolation, anxiety levels, as well as five neuropsychological tasks assessing emotional and social cognition. Reduced positive bias in emotion recognition was related to reduced contact with friends, household size and communication method during social isolation. In addition, reduced positive bias for attention to emotional faces was related to frequency of contact with friends during social isolation. Greater cooperative behaviour in an ultimatum game was associated with more frequent contact with both friends and family during social isolation. The present study provides important insights into the detrimental effects of subjective and objective social isolation upon affective cognitive processes.

Impulsive prepotent actions and tics in Tourette disorder underpinned by a common neural network.

Abstract: Tourette disorder (TD), which is characterized by motor and vocal tics, is not in general considered as a product of impulsivity, despite a frequent association with attention deficit hyperactivity disorder and impulse control disorders. It is unclear which type of impulsivity, if any, is intrinsically related to TD and specifically to the severity of tics. The waiting type of motor impulsivity, defined as the difficulty to withhold a specific action, shares some common features with tics. In a large group of adult TD patients compared to healthy controls, we assessed waiting motor impulsivity using a behavioral task, as well as structural and functional underpinnings of waiting impulsivity and tics using multi-modal neuroimaging protocol. We found that unmedicated TD patients showed increased waiting impulsivity compared to controls, which was independent of comorbid conditions, but correlated with the severity of tics. Tic severity did not account directly for waiting impulsivity, but this effect was mediated by connectivity between the right orbito-frontal cortex with caudate nucleus bilaterally. Waiting impulsivity in unmedicated patients with TD also correlated with a higher gray matter signal in deep limbic structures, as well as connectivity with cortical and with cerebellar regions on a functional level. Neither behavioral performance nor structural or functional correlates were related to a psychometric measure of impulsivity or impulsive behaviors in general. Overall, the results suggest that waiting impulsivity in TD was related to tic severity, to functional connectivity of orbito-frontal cortex with caudate nucleus and to structural changes within limbic areas.

Fronto-striatal circuits for cognitive flexibility in far from onset Huntington's disease: evidence from the Young Adult Study.

Abstract: Objectives Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington’s disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit. Methods In the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage. Results Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants. Conclusion We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

Serotonin depletion amplifies distinct human social emotions as a function of individual differences in personality

Abstract: Serotonin is involved in a wide range of mental capacities essential for navigating the social world, including emotion and impulse control. Much recent work on serotonin and social functioning has focused on decision-making. Here we investigated the influence of serotonin on human emotional reactions to social conflict. We used a novel computerised task that required mentally simulating social situations involving unjust harm and found that depleting the serotonin precursor tryptophan-in a double-blind randomised placebo-controlled design-enhanced emotional responses to the scenarios in a large sample of healthy volunteers (n = 73), and interacted with individual differences in trait personality to produce distinctive human emotions. Whereas guilt was preferentially elevated in highly empathic participants, annoyance was potentiated in those high in trait psychopathy, with medium to large effect sizes. Our findings show how individual differences in personality, when combined with fluctuations of serotonin, may produce diverse emotional phenotypes. This has implications for understanding vulnerability to psychopathology, determining who may be more sensitive to serotonin-modulating treatments, and casts new light on the functions of serotonin in emotional processing.

Opposing roles of the dorsolateral and dorsomedial striatum in the acquisition of skilled action sequencing

Abstract: The shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift co-operatively or competitively remains unclear. Cortical inputs have also been implicated in the shift towards automaticity, but it is unknown if they mirror their downstream striatal targets across this transition. We addressed these questions using a five-step heterogeneous action sequencing task in rats that is optimally performed by automated chains of actions. By optimising automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly the medial prefrontal cortex was not involved, however the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to a model of competitive opposition, where the dorsomedial striatum acts in a gating role to inhibit dorsolateral-striatum driven behavior.

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology.

Abstract: There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology. Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery. We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities. We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats.

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

Experimentally induced and real-world anxiety have no demonstrable effect on goal-directed behaviour.

Abstract: Research was funded by a Wellcome Trust Senior Investigator Award (TW Robbins 106431/Z/14/Z) and a Sir Henry Wellcome Postdoctoral Fellowship (CM Gillan 101521/Z/12/Z). CM Gillan is supported by a fellowship from MQ: transforming mental health (MQ16IP13). AB Bruhl was supported by a fellowship from the Swiss National Science Foundation (SNF PASMP3-145749). FH Hezemans is supported by a Cambridge Trust Vice-Chancellor’s Award and Fitzwilliam College scholarship and was previously supported by an Erasmus scholarship. G Savulich was funded by The Wallitt Foundation and Eton College, with support from the NIHR Cambridge Biomedical Research Centre (BRC) Mental Health theme.

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans.

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

Association of Environmental Uncertainty With Altered Decision-making and Learning Mechanisms in Youths With Obsessive-Compulsive Disorder.

Abstract: Importance Adults with obsessive-compulsive disorder (OCD) display perseverative behavior in stable environments but exhibit vacillating choice when payoffs are uncertain. These findings may be associated with intolerance of uncertainty and compulsive behaviors; however, little is known about the mechanisms underlying learning and decision-making in youths with OCD because research into this population has been limited. Objective To investigate cognitive mechanisms associated with decision-making in youths with OCD by using executive functioning tasks and computational modeling. Design, Setting, and Participants In this cross-sectional study, 50 youths with OCD (patients) and 53 healthy participants (controls) completed a probabilistic reversal learning (PRL) task between January 2014 and March 2020. A separate sample of 27 patients and 46 controls completed the Wisconsin Card Sorting Task (WCST) between January 2018 and November 2020. The study took place at the University of Cambridge in the UK. Main Outcomes and Measures Decision-making mechanisms were studied by fitting hierarchical bayesian reinforcement learning models to the 2 data sets and comparing model parameters between participant groups. Model parameters included reward and punishment learning rates (feedback sensitivity), reinforcement sensitivity and decision consistency (exploitation), and stickiness (perseveration). Associations of receipt of serotonergic medication with performance were assessed. Results In total, 50 patients (29 female patients [58%]; median age, 16.6 years [IQR, 15.3-18.0 years]) and 53 controls (30 female participants [57%]; median age, 16.4 years [IQR, 14.8-18.0 years]) completed the PRL task. A total of 27 patients (18 female patients [67%]; median age, 16.1 years [IQR, 15.2-17.2 years]) and 46 controls (28 female participants [61%]; median age, 17.2 [IQR, 16.3-17.6 years]) completed the WCST. During the reversal phase of the PRL task, patients made fewer correct responses (mean [SD] proportion: 0.83 [0.16] for controls and 0.61 [0.31] for patients; 95% CI, −1.31 to −0.64) and switched choices more often following false-negative feedback (mean [SD] proportion: 0.09 [0.16] for controls vs 0.27 [0.34] for patients; 95% CI, 0.60-1.26) and true-positive feedback (mean [SD] proportion: 0.93 [0.17] for controls vs 0.73 [0.34] for patients; 95% CI, −2.17 to −1.31). Computational modeling revealed that patients displayed enhanced reward learning rates (mean difference [MD], 0.21; 95% highest density interval [HDI], 0.04-0.38) but decreased punishment learning rates (MD, −0.29; 95% HDI, −0.39 to −0.18), reinforcement sensitivity (MD, −4.91; 95% HDI, −9.38 to −1.12), and stickiness (MD, −0.35; 95% HDI, −0.57 to −0.11) compared with controls. There were no group differences on standard WCST measures and computational model parameters. However, patients who received serotonergic medication showed slower response times (mean [SD], 1420.49 [279.71] milliseconds for controls, 1471.42 [212.81] milliseconds for patients who were unmedicated, and 1738.25 [349.23] milliseconds for patients who were medicated) (control vs medicated MD, −320.26 [95% CI, −547.00 to −88.68]) and increased unique errors (mean [SD] proportion: 0.001 [0.004] for controls, 0.002 [0.004] for patients who were unmedicated, and 0.008 [0.01] for patients who were medicated) (control vs medicated MD, −0.007 [95% CI, −3.14 to −0.36]) on the WCST. Conclusions and Relevance The results of this cross-sectional study indicated that youths with OCD showed atypical probabilistic reversal learning but were generally unimpaired on the deterministic WCST, although unexpected results were observed for patients receiving serotonergic medication. These findings have implications for reframing the understanding of early-onset OCD as a disorder in which decision-making is associated with uncertainty in the environment, a potential target for therapeutic treatment. These results provide continuity with findings in adults with OCD.

Noradrenergic deficits contribute to apathy in Parkinson’s disease through the precision of expected outcomes

Abstract: AO_SCPLOWBSTRACTC_SCPLOWApathy is a debilitating feature of many diseases, including Parkinsons disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinsons disease (N=17) completed a 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 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 Parkinsons disease, subject to stratification according to locus coeruleus integrity.

Neural network involving medial orbitofrontal cortex and dorsal periaqueductal gray regulation in human alcohol abuse.

Abstract: Prompted by recent evidence of neural circuitry in rodent models, functional magnetic resonance imaging and functional connectivity analyses were conducted for a large adolescent population at two ages, together with alcohol abuse measures, to characterize a neural network that may underlie the onset of alcoholism A network centered on the medial orbitofrontal cortex (mOFC), as well as including the dorsal periaqueductal gray (dPAG), central nucleus of the amygdala, and nucleus accumbens, was identified, consistent with the rodent models, with evidence of both inhibitory and excitatory coregulation by the mOFC over the dPAG Furthermore, significant relationships were detected between raised baseline excitatory coregulation in this network and impulsivity measures, supporting a role for negative urgency in alcohol dependence

Flexible versus Fixed Spatial Self-Ordered Response Sequencing: Effects of Inactivation and Neurochemical Modulation of Ventrolateral Prefrontal Cortex.

Abstract: Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, though not significantly impairing accuracy overall, and the latter significantly impairing accuracy but not error perseveration. A second cohort of marmosets were directly compared on performance of fixed versus variable spatial arrays. Inactivation of vlPFC again impaired self-ordered sequencing, but only with varying, and not fixed spatial arrays, the latter leading to the consistent use of fewer, preferred sequences. These findings add to evidence that vlPFC is implicated in goal-directed behavior that requires higher-order response heuristics that can be applied flexibly over different (variable), as compared with fixed stimulus exemplars. They also show that dopaminergic and serotonergic chemomodulation has distinctive effects on such performance. SIGNIFICANCE STATEMENT This investigation employing local intracerebral infusions to inactivate the lateral prefrontal cortex (PFC) of the New World marmoset reveals the important role of this region in self-ordered response sequencing in variable but not fixed spatial arrays. These novel findings emphasize the higher order functions of this region, contributing to cognitive flexibility and planning of goal directed behavior. The investigation also reports for the first time somewhat contrasting neuromodulatory deficits produced by infusions of dopamine (DA) D2 and 5-HT2A receptor (R) antagonists into the same region, of possible significance for understanding cognitive deficits produced by anti-psychotic drugs.

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD

Abstract: Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding.

Set-shifting-related basal ganglia deformation as a novel familial marker of obsessive–compulsive disorder

Abstract: 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 propensity toward habitual response patterns and deficits in goal-directed planning.

Impaired learning from negative feedback in stimulant use disorder: Dopaminergic modulation

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

The Habitual Tendencies Questionnaire: A tool for psychometric individual differences research

Abstract: Habits are automatic responses to learned stimuli or contextual cues that are insensitive to goals. Although habits may allow for automated behaviours that increase efficiency in our daily lives, an over-reliance on habits has been suggested to contribute to disorders such as obsessive-compulsive disorder (OCD). There are currently few established measures of individual differences in habitual tendencies. To fill this gap, the present study generated and validated a novel 11-item scale, the Habitual Tendencies Questionnaire (HTQ), to measure individual differences in habitual tendencies in the general population. In Study 1, factor analysis revealed three underlying subcomponents of the HTQ: Compulsivity, Preference for Regularity, and Aversion to Novelty, with Compulsivity showing the strongest association with subclinical OCD symptomatology. Study 2 validated the HTQ and replicated the findings of Study 1 in a larger sample, and explored relationships with other personality traits. The results emphasise the importance of measuring individual variation in habitual thinking styles, illustrating that different facets of habitual tendencies may contribute to diverse behavioural and clinical outcomes. The present investigation provides a new, reliable way of measuring habitual tendencies and has important implications for future explorations into the nature of individual differences from a dimensional perspective to psychiatry.