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Robbins, T. W.

Publications and source records attributed to Robbins, T. W..

At least 19 recordsLinked to original sources
bioRxiv2026

Detrimental effects of atomoxetine on visual signal detection in rats: Comparison with ADHD psychomotor stimulant drugs

RationaleAttention-deficit/hyperactivity disorder (ADHD) is associated with executive dysfunction involving inattention and impulsivity, with evidence of disrupted functional expression of the dopamine and noradrenaline transporters. ObjectiveWe investigated the dose-dependent modulation of anti-ADHD drugs on selective and sustained visual attention in low-, mid-and high-attention phenotypes. Two mathematical approaches, signal detection theory and theory of visual attention were applied to further characterise the effects and mechanisms. MethodsRats were trained to detect and respond to the presence or absence of a visual target to obtain food reward on a signal detection task. After attentional performance stabilised, the indirect catecholamine agonist, d-amphetamine (0.1; 0.2; 0.4 mg/kg), the dopamine (DA) and noradrenaline (NA) reuptake inhibitor methylphenidate (0.3; 1; 3 mg/kg), and the NA reuptake inhibitor atomoxetine (0.1; 0.3; 1 mg/kg), were administered systemically. ResultsLow-dose d-amphetamine produced baseline-dependent effects on attention, improving target discrimination only in rats with lower attentive performance, whereas methylphenidate did not significantly improve attention but increased guessing. In contrast, low-dose atomoxetine selectively impaired attention in low-attentive subjects, whereas high-dose atomoxetine generally impaired discrimination performance. All three drugs had expected effects on motor response output. ConclusionsAs well as demonstrating baseline-dependent effects of amphetamine on visual attention, the findings for methylphenidate and atomoxetine suggest important, apparently opposing effects on visual signal detection performance produced via blockade of the DA and NA transporters. The deleterious effects of atomoxetine on performance were especially noteworthy in view of its use as a treatment in ADHD.

animal behavior and cognition↗
bioRxiv2026

Comparative effects of inactivation and dopamine receptor agents in the dorsolateral and dorsomedial striatum on performance of action sequences in rats

RationaleRecent research on habits and skills has produced a wave of new theories regarding the shift in control from medial to lateral regions of the dorsal striatum, and how these regions are implicated in the selected and executed of action sequences. ObjectivesTo examine the comparative effects of muscimol/baclofen inactivation and dopamine D1 and D2 receptor agents in the dorsomedial (DMS) and dorsolateral (DLS) striatum on the performance of skilled action sequences. MethodsInfusions were made in well-trained rats using the five-step nose poke task to isolate the effects on initiation, execution and termination components of skilled action sequences. ResultsDLS inactivation produced sequencing deficits like those observed with pre-training lesions, indicating that the DLS is critical for both the acquisition and performance of sequences. Behaviour was unchanged following DMS inactivation, consistent with models of DMS disengagement following training. Infusions of D1 and D2 antagonists did not alter behaviour, however the D2 receptor agonist quinpirole increased sequence errors at a low dose and reduced sequences at the high dose in the DLS. DLS manipulations impaired sequence initiation and termination as well as reward transitions, while the chunking ballistic response pattern was largely unaltered, indicating that between-but not within-sequence actions rely on the DLS. ConclusionsSkilled action sequencing, including chunk transitions was dependent on DLS and its modulation by D2 receptors, but not on DMS function. Using a novel sequencing task, these results support the dissociable and dopamine-dependent role of the dorsal striatum subregions in performing skilled motor actions.

neuroscience↗
bioRxiv2026

Plasma proteomics reveal heterogeneous subtypes of depression linked to inflammation and aging

The clinical heterogeneity of depression has defied biological classification, limiting personalized treatment. Previous neuroimaging- or symptom-based subtyping of depression failed to clarify the underlying pathoetiology, while plasma proteins which integrates signals from multiple organ systems, offers a promising way to define biologically grounded subtypes. Using plasma proteomics from 2,127 incident depression cases in a cohort of 53000 individuals, we identified three biologically distinct subtypes differing in inflammation, aging, and metabolic profiles. The most prevalent subtype ( inflammation/ageing) was characterized by aging-related inflammation, poorest prognosis with hippocampal atrophy and highest suicide risk, mediated by age-related amygdala atrophy; this subtype had highest anhedonia burden. A distinct inflammation/energy dysregulation group had metabolic pathway enrichment with high inflammation and lifestyle risk factors (smoking) but no ageing trend, predominantly physical/psychomotor symptoms and decreased thalamic volume. In contrast, the inflammation-resilient group had the lowest inflammatory proteomic loading, lowest depression severity, more resilient lifestyle and increased hippocampal volume. These proteomic signatures, detectable years before symptom onset, enable risk stratification and suggest subtype-specific targeted physical and lifestyle interventions.

neuroscience↗
bioRxiv2025

Dopamine Dynamics in the Nucleus Accumbens Reflect Confidence in Detecting the Occurrence and Non-Occurrence of Visual Signals in Perceptual Decision-Making

Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision - making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced either by degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.

neuroscience↗
bioRxiv2025

Brain Diffusion Transformer for Personalized Neuroscience and Psychiatry

Task-fMRI analyses typically focus on localized activation contrasts between stimuli, neglecting the brains dynamic hierarchy. We introduce Brain Diffusion Transformer (Brain-DiT), a deep generative model capturing recurrent processing underlying individualized neurocognitive state transitions via functional networks. Without prior assumptions, Brain-DiT identifies canonical cognitive regions in the brain and reveals replicable subgroups with distinct neural circuits in large cohorts, offering critical clinical insights overlooked by traditional methods: individuals exhibiting negative emotion bias, linked to language-related regions, had a 12-fold higher likelihood of major depression, and those with maladaptive inhibition strategies, associated with overactive medial frontal regions, showed a 9-fold increased risk of alcohol abuse. By bridging cognitive theory and psychiatric applications, Brain-DiT provides a unified analytical paradigm, paving the way for operational personalized medicine in psychiatry.

neuroscience↗
bioRxiv2024

Modelling determinants of region-specific dopamine dynamics in the striatum

Striatal dopamine (DA) release regulates reward-related learning and motivation and is believed to consist of a short-lived phasic and continuous tonic component. Here, we build a large-scale three-dimensional model of extracellular DA dynamics in dorsal (DS) and ventral striatum (VS). The model predicts rapid dynamics in DS with little-to-no basal DA, and slower dynamics in the VS enabling build-up of tonic DA levels. These regional differences do not reflect release-related phenomena but rather differential dopamine transporter (DAT) activity. Interestingly, our simulations posit DAT nanoclustering as a possible regulator of this activity. Receptor binding simulations show that D1 receptor occupancy follows extracellular DA concentration with milliseconds delay, while D2 receptors do not respond to brief pauses in firing but rather integrate DA signal over seconds. Summarized, our model distills recent experimental observations into a computational framework that challenge prevailing paradigms of striatal DA signalling.

neuroscience↗
bioRxiv2023

Comparative roles of caudate and putamen in the serial order of behavior: Effects of striatal glutamate receptor blockade on variable versus fixed spatial self-ordered sequencing in marmosets

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. 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 caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intra-striatal CNQX microinfusions, we demonstrate that caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited a greater impairment. We demonstrate that continuous perseverative errors in the variable array were caused by putamen infusions, likely due to interference with the putamens established role in monitoring motor feedback. Caudate infusions, on the other hand caused recurrent perseveration, with deficits possibly reflecting interference with the caudates established role in spatial working memory and goal-directed planning. In contrast to the variable array, whilst both caudate and putamen are needed for fixed array responding, combined effects were not additive, suggesting possible competing roles. Infusions in either region led to continuous perseveration when infused individually, but not when infused simultaneously. Caudate infusions did not cause recurrent perseveration in the fixed array; instead, this was caused by putamen infusions. The results overall are consistent with a role of caudate in planning and flexible responding, but putamen in more rigid habitual or automatic responding. Significance StatementThis investigation employing local intra-striatal infusions into caudate nucleus and/or putamen of the New World marmoset reveals important roles for these regions in variable and fixed spatial self-ordered sequencing. Here, we directly implicate subcortical output regions of the lateral prefrontal cortex in self-ordered sequencing behavior. The ability to self-order sequences, as well as more broadly to plan, organize information, and respond flexibly, is impaired in many neurological diseases and psychiatric disorders. By understanding the basic neural circuitry underlying these cognitive abilities, we may better understand how to rectify them in people with deficits across a plethora of disorders.

neuroscience↗
bioRxiv2023

Common roles for serotonin in rats and humans for computations underlying flexible decision-making

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, was likewise increased in rats after the 12-day SSRI regimen and decreased after single dose SSRI in humans and 5,7-DHT in rats. These common effects of serotonergic manipulations on rats and humans - identified via computational modelling - suggest an evolutionarily conserved role for serotonin in plasticity and behavioral flexibility and have clinical relevance transdiagnostically for neuropsychiatric disorders.

neuroscience↗
bioRxiv2021

Cortical dopamine reduces the impact of motivational biases governing automated behaviour

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) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n=35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomized, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

neuroscience↗
bioRxiv2021

Controlling one's world: identification of sub-regions of primate PFC underlying goal-directed behavior

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

neuroscience↗
bioRxiv2020

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans

The 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 largely unexplored. Here we examined how LSD affects probabilistic reversal learning in healthy humans. Healthy volunteers received intravenous LSD (75g in 10 mL saline) or placebo (10mL saline) in a within-subjects design and completed a probabilistic reversal learning 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 were fitted to the behavioural data to assess how LSD affected the updating ("learning rates") and deployment ("reinforcement sensitivity") of value representations during choice, as well as "stimulus stickiness", which assays choice repetition irrespective of reinforcement history. Conventional measures assessing sensitivity to immediate feedback ("win-stay" and "lose-shift" probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploratory behaviour, while reinforcement sensitivity was unaffected. Increased reinforcement learning rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD. Significance statementThe psychedelic ("mind-manifesting") drug LSD holds promise for the treatment of some psychiatric disorders. Theories have postulated its therapeutic potential centres on enhancing learning and flexible thinking. Here we provide substantiating empirical evidence by examining the computations underlying behaviour as healthy volunteers learned through trial and error under LSD. Viewing choice as based on representations of an actions value, LSD increased the speed at which value was updated following feedback, which was more pronounced following reward than punishment. Behaviour was also more exploratory under LSD, irrespective of the outcome of actions. These results indicate that LSD impacted a fundamental belief-updating process inherent in the brain which can be leveraged to revise maladaptive associations characteristic of a range of mental disorders.

neuroscience↗
bioRxiv2020

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

Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions 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 emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively. Upon depleting the serotonin precursor tryptophan - in a double-blind randomised placebo-controlled design - healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

neuroscience↗
bioRxiv2020

Effect of tryptophan depletion on conditioned threat memory expression: role of intolerance of uncertainty

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

neuroscience↗
bioRxiv2019

Cross-species machine learning improves diagnostic classification of human psychiatric disorders

Psychiatric disorders often exhibit shared (co-morbid) symptoms, raising controversies over accurate diagnosis and the overlap of their neural underpinnings. Because the complexity of data generated by clinical studies poses a formidable challenge, we have pursued a reductionist framework using brain imaging data of a transgenic primate model of autism spectrum disorder (ASD). Here we report an interpretable cross-species machine learning approach which extracts transgene-related core regions in the monkey brain to construct the classifier for diagnostic classification in humans. The cross-species classifier based on core regions, mainly distributed in frontal and temporal cortex, identified from the transgenic primate model, achieved an accuracy of 82.14% in one clinical ASD cohort obtained from Autism Brain Imaging Data Exchange (ABIDE-I), significantly higher than the human-based classifier (61.31%, p < 0.001), which was validated in another independent ASD cohort obtained from ABIDE-II. Such monkey-based classifier generalized to achieve a better classification in obsessive-compulsive disorder (OCD) cohorts, and enabled parsing of differential connections to right ventrolateral prefrontal cortex being attributable to distinct traits in patients with ASD and OCD. These findings underscore the importance of investigating biologically homogeneous samples, particularly in the absence of real-world data adequate for deconstructing heterogeneity inherited in the clinical cohorts.\n\nOne Sentence SummaryFeatures learned from transgenic monkeys enable improved diagnosis of autism-related disorders and dissection of their underlying circuits.

neuroscience↗
bioRxiv2019

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

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.

neuroscience↗
bioRxiv2019

Dynamic brain network changes reflect neuroplasticity: molecular and cognitive evidence

Resting-state functional brain networks demonstrate dynamic changes on the scale of seconds. However, their genetic mechanisms and profound cognitive relevance remain less explored. We identified 459 Bonferroni-corrected genes, by associating temporal variability of regional functional connectivity patterns with Allen Brain gene expression profiles across the whole brain. These genes are partially verified in developing human brain gene expression in the BrainSpan Atlas, and are found to be involved in the enrichment of short- and long-term plasticity processes. The former process depends on synaptic plasticity, involving ion transmembrane transport, action potential propagation, and modulation. The latter process depends on structural plasticity, including axonal genesis, development, and guidance. Results from a longitudinal cognitive training study further revealed that baseline variability of the hippocampal network predicted cognitive ability changes after three months of training. Our genetic association results suggest that the short-term plasticity processes may account for the rapid changes of regional functional connectivity, while the underlying long-term plasticity processes explain why temporal variability can predict long-term learning outcomes. To our knowledge, this is the first demonstration that measuring the dynamic brain network can lead to a non-invasive quantification of neuroplasticity in humans.

neuroscience↗
bioRxiv2019

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

Compulsivity is associated with failures in goal-directed control, an important cognitive faculty that protects against developing habits. But might this effect be explained by co-occurring anxiety? Previous studies have found goal-directed deficits in other anxiety disorders, and to some extent when healthy individuals are stressed, suggesting this is plausible. We carried out a causal test of this hypothesis in two experiments (between-subject N=88; within-subject N=50) that used the inhalation of hypercapnic gas (7.5% CO2) to induce an acute state of anxiety in healthy volunteers. In both experiments, we successfully induced anxiety, assessed physiologically and psychologically, but this did not affect goal-directed performance. In a third experiment (N=1413), we used a correlational design to test if real-life anxiety-provoking events (panic attacks, stressful events) impair goal-directed control. While small effects were observed, none survived controlling for individual differences in compulsivity. These data suggest that anxiety has no meaningful impact on goal-directed control.

animal behavior and cognition↗