Trevor W. Robbins

Multiscale Computation in Psychoradiology for Developmental Psychiatric Disorders: A Conceptual Framework

Developmental psychiatric disorders like ADHD and ASD remain difficult to characterize and treat, mainly due to significant clinical heterogeneity and a lack of objective biomarkers. Conventional neuroimaging often fails to distinguish etiology from correlation and lacks the insights for actionable molecular targets, as most rely on cross-sectional correlations. Here, we present a conceptual framework for multiscale computation that proceeds from longitudinal imaging-marker discovery to cross-scale mechanistic hypothesis generation and molecular imaging-assisted evaluation of interventions. Emotional dysregulation as a transdiagnostic dimension and related research in ASD and ADHD as illustrative cases are used to demonstrate the application of this framework. We first demonstrate how longitudinal trajectory algorithms can identify predictive imaging biomarkers, using developmental deviations in the inferior frontal gyrus and insula associated with emotional dysregulation and related symptoms as illustrative examples. We then describe multiscale fusion models (mFusion) that integrate multi-omics data, including genetics, transcriptomics, and PET, to link neuroimaging markers to candidate molecular pathways, illustrated by findings implicating pathways related to excitatory–inhibitory balance and GABAergic signalling in ADHD and ASD. Finally, we highlight the integration of magnetic resonance spectroscopy (MRS) into clinical trials for intervention-based evaluation, using changes in insular GABA associated with clinical improvement in ASD as an example. Together, these approaches provide a conceptual framework for progressing from imaging-marker discovery toward mechanistic and therapeutic translation.

Over Fifteen Years of Confusion: How the Big Five Inventory Mismeasures Openness

Assesses the flawed openness measurement in the Big Five Inventory, indicating potential biases in personality assessments.

Set-shifting and task-switching make differential contributions to divergent thinking in adolescence

BACKGROUND: Cognitive flexibility, as the capacity to adaptively shift between mental sets, comprises multiple subprocesses, including set-shifting and task-switching, and goes through changes in capacity throughout development. Divergent thinking, a core aspect of human creativity, also goes through substantial development during adolescence, a period marked by rapid refinement of executive functions. Despite their developmental interdependence, the distinct contributions of cognitive flexibility subcomponents to divergent thinking during adolescence remain insufficiently understood. METHODS: We examined cognitive flexibility and divergent thinking in a large sample of adolescents (N = 344). Participants completed established cognitive flexibility measures (e.g., Wisconsin Card Sorting Task; Task-Set Switching), additional cognitive tasks (i.e., working memory, inhibitory control and abstract reasoning) and the Alternate Uses Task to assess fluency and originality in divergent thinking. RESULTS: Findings provide novel evidence that cognitive flexibility subprocesses differentially contribute to divergent thinking. Specifically, set-shifting, as indexed by Wisconsin Card Sorting Task performance, was a positive predictor of both fluency (i.e., number of ideas generated) and originality (i.e., creative quality of those ideas). In contrast, task-switching performance predicted lower originality, suggesting that rapid, cue-driven shifts may impede the deeper idea exploration required for producing novel responses. This dissociation suggest that cognitive flexibility is not a unitary construct; rather, its distinct components exert separable and, at times, opposing influences on divergent thinking. CONCLUSIONS: These results underscore the importance of distinguishing cognitive flexibility subprocesses when understanding the cognitive mechanisms underlying creativity. The findings carry educational implications, suggesting that fostering strategic, self-guided flexibility, while tempering overly rapid shifting, may support adolescents' capacity to generate original solutions to complex problems.

From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus

Uncovers how neurogenesis-driven microglial remodeling links chronic pain and depression, suggesting new treatment pathways.

Midbrain hypoactivation and mesocortical hypoconnectivity in inhibitory control learning in autism

Repetitive behaviour, resulting from impaired inhibitory control and error monitoring, represents a core manifestation of autism, with a poorly understood neural basis. Our primary hypothesis was that a striatum-midbrain framework could provide a theoretical basis for understanding neural changes underlying response inhibition in autism. This conceptual approach considered two critical neurobehavioural factors: (a) inhibition as a dynamic process requiring trial-and-error learning, and (b) efficient error learning relying on the striatum receiving dopaminergic signals from the midbrain-a framework analogous to an 'actor-critic' architecture. Eighteen adults with a diagnosis of autism spectrum disorder and 21 age-matched healthy controls performed a stop-signal task adjusted for functional MRI (fMRI). To dissect domain-dependent correlates of neural inhibition, we measured brain activation and connectivity as a function of task phases in the dorsal striatum and dopaminergic midbrain nuclei. Repetitive behaviour severity was assessed using the observer-reported Repetitive Behaviours Scale-Revised. A striking hypoactivation in the midbrain during failed inhibition events was observed in relation with the severity of repetitive behaviours. We also identified, in the autism group, reduced functional connectivity between the midbrain-striatum hubs and regions involved in cognitive control (prefrontal cortex) and error monitoring (bilateral insula), during response preparation periods. Finally, although both groups achieved similar final performance levels, neurodivergent subjects learned slower and displayed delayed striatal engagement when behavioural adjustment was required. These results reveal a novel autism profile characterized by midbrain hypoactivation mediating repetitive behaviour manifestations and reduced long-range mesocortical hypoconnectivity during inhibitory response preparation phases. Accordingly, we suggest that individuals with autism exhibit midbrain-dependent reduced motivational arousal, limiting their ability to develop proactive strategies for trial-and-error learning and regulate out-of-context behaviours. By highlighting the key role of dopaminergic midbrain structures and related long-range pathways, we challenge the view autism as solely a cortical dysfunction condition and provide evidence for promising targets for neurobiologically-driven interventions based on dopaminergic mechanisms.

Validation of the CILD-Q for measuring contextual linguistic diversity in Singapore

Exploratory factor analyses reveal updated factors of linguistic diversity in a multilingual setting, suggesting improvements in CILD-Q applicability.

Longitudinal Associations of Structural and Functional Brain Connectivity With Dimensions of Psychopathology in Adolescence

BACKGROUND: Adolescence is a critical period of neurodevelopment marked by ongoing maturation of structural and functional brain connectivity. Simultaneously, this period is associated with an increase in mental health problems, spanning from subclinical symptoms to diagnosable disorders. METHODS: This study investigated longitudinal associations between psychopathology dimensions and voxelwise brain measures related to connectivity across 3 time points (ages 14, 19, and 23) in more than 1500 participants using the IMAGEN dataset. White matter (WM) microstructure was indexed using diffusion metrics quantified along the WM skeleton (N = 1736), while functional connectivity was captured as voxelwise degree centrality (DC) derived from resting-state functional imaging (N = 1510). RESULTS: Development of WM microstructure was selectively linked to externalizing (but not internalizing) symptoms. Here, higher externalizing symptoms were associated with widespread reductions in fractional anisotropy (FA) across the WM skeleton as well as accelerated decreases in FA in the corticospinal tract over time. In contrast, functional DC was developmentally associated with general, rather than specific, psychopathology in frontal and temporal regions. An increase in total difficulties over time was associated with developmental decrease in DC in bilateral superior frontal gyri. In addition, a positive association between total difficulties and DC in left inferior temporal gyrus was observed in younger, but not older, adolescents or young adults. CONCLUSIONS: These findings highlight the dynamic interplay between brain connectivity development and psychopathology in adolescence, with potential implications for identifying neural markers of risk and resilience during sensitive windows of development.

Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

Neural and Behavioral Evidence From Reinforcement Learning Converge in Support of Relaxed Beliefs Under LSD

Reinforcement learning findings demonstrate increased sensitivity to surprise under psychedelics, indicating changes in belief confidence.

Pathological Networking of Gray Matter Dendritic Density With Classic Brain Morphometries in Ocd

Case-control study reveals dendritic alterations in OCD patients via multimodal neuroimaging, suggesting a connectopathy framework.

Cracking the Valence Code: Patterned Facial Kinematics and Neural Signatures of Emotional Expressions in Mice

AI reveals valence dimensions in emotional expressions of mice, suggesting novel insights into neural signatures.

Pharmacological and pupillary evidence for the noradrenergic contribution to reinforcement learning in Parkinson’s disease

Noradrenaline plays an integral role in learning by optimising behavioural strategies and facilitating choice execution. Testing the noradrenergic framework of learning in the context of human diseases offers a test bed for current normative neuroscience theories and may also indicate therapeutic potential. Parkinson's disease is often considered as a model of dopamine deficits, including dopamine's role in reinforcement learning. However, noradrenergic function is also severely impaired by Parkinson's disease, contributing to cognitive deficits. Using a single dose of the noradrenaline reuptake inhibitor atomoxetine in people with Parkinson's disease (in a randomised double-blind placebo-controlled crossover design), we show improvements in learning compared to placebo. Computational cognitive modelling confirmed a substantial shift in the decision noise parameter, indicative of more exploitative choices. This response pattern closely resembled that of age-matched controls and simulations of optimal response strategies. Pupillometry revealed increased baseline pupil diameter under atomoxetine, which correlated with behavioural improvements, and a heightened phasic pupillary response to feedback. Our findings confirm the noradrenergic contribution to reinforcement learning, and in doing so they challenge the simple interpretation of tonic-phasic locus coeruleus firing patterns based on pupillometry. Noradrenergic modulation is a potential treatment strategy for cognitive symptoms in Parkinson's disease and related disorders.

Overlooked for three decades: A systematic examination of a problematic item in the 10-item Big Five Inventory

Systematic examination reveals a flawed item in the Big Five Inventory, suggesting the need for adoption of a revised question for better validity and reliability.

Single-dose (10 mg) psilocybin reduces symptoms in adults with obsessive-compulsive disorder: A pharmacological challenge study

In this study, which was limited by a small sample size and the absence of randomisation, a 10 mg dose of oral psilocybin was found to be well-tolerated and potentially efficacious in patients with OCD. Psilocybin produced a rapid-onset, moderate to large effect on compulsive symptoms, which lasted up to one week after dosing. Future randomised placebo-controlled clinical trials investigating a longer course of multiple weekly doses of 10 mg psilocybin are indicated in OCD and in other obsessive-compulsive and related disorders characterised by compulsions.

Circuit-targeted neuromodulation shows promise as a transdiagnostic treatment for impulsivity across psychiatric conditions.

Does not support clinical adoption of neuromodulation for impulsivity; leaves open its transdiagnostic promise pending randomized trials.

Framework for Brain-Derived Dimensions of Psychopathology

Importance: Psychiatric diagnoses are not defined by neurobiological measures hindering the development of therapies targeting mechanisms underlying mental illness. Research confined to diagnostic boundaries yields heterogeneous biological results, whereas transdiagnostic studies often investigate individual symptoms in isolation. Objective: To develop a framework that groups clinical symptoms compatible with ICD-10 and DSM-5 according to their covariation and shared brain mechanisms. Design, Setting, and Participants: This diagnostic study was conducted in 2 samples, the population-based Reinforcement-Related Behaviour in Normal Brain Function and Psychopathology (IMAGEN) cohort (longitudinal assessments at 14, 19, and 23 years; study duration from March 2010 to the present) and the cross-diagnostic Brain Network Based Stratification of Mental Illness (STRATIFY)/Earlier Detection and Stratification of Eating Disorders and Comorbid Mental Illnesses (ESTRA) samples (study duration from October 2016 to September 2023). The samples are from 8 clinical research hospitals in Germany, the UK, France, and Ireland. For the population-based IMAGEN study, 794 of 1253 23-year-old participants had complete assessments including complete clinical assessments and neuroimaging data across all time points. For the cross-diagnostic STRATIFY/ESTRA samples, 209 of 485 participants aged 18 to 26 years had complete clinical and neuroimaging data. The sample included healthy control individuals and patients with alcohol use disorder, major depressive disorder, anorexia nervosa, and bulimia nervosa. Exposures: Sparse generalized canonical correlation analysis was used to integrate diverse data from clinical symptoms and 7 brain imaging modalities. Main Outcomes and Measures: The prediction of symptom features was the main outcome. The model was developed in the training set from the IMAGEN Study at age 23 years (70%), then applied in the remaining holdout test sample (30%), the independent STRATIFY/ESTRA patient sample, and longitudinally in the IMAGEN set. Results: In total, 1003 participants were included (425 male and 578 female; mean [SD] age, 22.1 [1.5] years). The reassembly of existing ICD-10 and DSM-5 symptoms revealed 6 cross-diagnostic psychopathology scores. They were consistently associated with multimodal neuroimaging components: excitability and impulsivity (training set: r, 0.26; 95% CI, 0.18-0.33; test set: r, 0.22; 95% CI, 0.10-0.35; STRATIFY/ESTRA set: r, 0.19; 95% CI, 0.07-0.31), depressive mood and distress (training: r, 0.30; 95% CI, 0.20-0.38; test: r, 0.22; 95% CI, 0.09-0.35; STRATIFY/ESTRA: r, 0.19; 95% CI, 0.04-0.33), emotional and behavioral dysregulation (training: r, 0.40; 95% CI, 0.31-0.48; test: r, 0.17; 95% CI, 0.14-0.36; STRATIFY/ESTRA: r, 0.19; 95% CI, 0.06-0.30), stress pathology (training: r, 0.32; 95% CI, 0.19-0.43; test: r, 0.14; 95% CI, 0.05-0.23; STRATIFY/ESTRA: r, 0.12; 95% CI, 0.01-0.22), eating pathology (training: r, 0.34; 95% CI, 0.25-0.42; test: r, 0.26; 95% CI, 0.15-0.37; STRATIFY/ESTRA: r, 0.15; 95% CI, 0.12-0.34), and social fear and avoidance symptoms (training: r, 0.31; 95% CI, 0.25-0.42; test: r, 0.18; 95% CI, 0.15-0.35; STRATIFY/ESTRA: r, 0.12; 95% CI, 0.12-0.33). Conclusion and Relevance: In this study, the identification of symptom groups of mental illness robustly defined by precisely characterized brain mechanisms enabled the characterization of dimensions of psychopathology based on quantifiable neurobiological measures.

Lifespan investigation of brain volumetric changes associated with substance use disorders

Substance use disorder (SUD) stands as a critical public health concern, contributing to substantial morbidity, mortality and societal costs. The effects of SUD on structural brain changes have been well documented. However, the neural mechanisms underlying SUD and the spatial-temporal volumetric changes associated with SUD remained underexplored. In this investigation, neuroimaging, behavioral and genomic data across four large population cohorts jointly covering the full lifespan were harmonized, and whole-brain volumetric trajectories between substance use disorders (SUDs) and healthy controls (HCs) were compared, revealing the potential neurobiological mechanisms and the genomic basis underlying SUD. Results highlighted three distinct life stages critical for the development of SUD: 1) adolescence to early adulthood (before 25y), where SUD is suspected to be the consequence of prefrontal-subcortical imbalance during neurodevelopment; 2) early-to-mid adulthood (25y - 45y), where SUD was strongly associated with compulsivity-related brain volumetric changes; 3) mid-to-late adulthood (after 45y), where SUD-related brain structural changes could be explained by neurotoxicity. Results were externally validated both via longitudinal analysis of these population cohorts and in independent cross-sectional samples. In summary, our study demonstrated the lifespan whole-brain volumetric changes associated with SUD, revealed potential neurobehavioral mechanisms for the development of SUD, and suggested critical time window for effective prevention and treatment of SUD.

Developing brain asymmetry shapes cognitive and psychiatric outcomes in adolescence

Cerebral asymmetry, fundamental to various cognitive functions, is often disrupted in neuropsychiatric disorders. While brain growth has been extensively studied, the maturation of brain asymmetry in children and the factors influencing it in adolescence remain poorly understood. We analyze longitudinal data from 11,270 children aged 10-14 years in the Adolescent Brain Cognitive Development (ABCD) study. Our analysis maps the developmental trajectory of structural brain asymmetry. We identify significant age-related, modality-specific development patterns. These patterns link to crystallized intelligence and mental health problems, but with weak correlations. Genetically, structural asymmetry relates to synaptic processes and neuron projections, likely through asymmetric synaptic pruning. At the microstructural level, corpus callosum integrity emerged as a key factor modulating the developing asymmetry. Environmentally, favorable perinatal conditions were associated with prolonged corpus callosum development, which affected future asymmetry patterns and cognitive outcomes. These findings underscore the dynamic yet predictable interactions between brain asymmetry, its structural determinants, and cognitive and psychiatric outcomes during a pivotal developmental stage. Our results provide empirical support for the adaptive plasticity theory in cerebral asymmetry and offer insights into both cognitive maturation and potential risk for early-onset mental health problems.

Neural, cognitive and psychopathological signatures of a prosocial or delinquent peer environment during early adolescence

Adolescence is a critical period for brain development, yet the impact of peer environments on brain structure, cognition, and psychopathology remains poorly understood. Here, we capitalized on data from 7806 adolescents (age = 12.02 ± 0.67) from the Adolescent Brain Cognitive Development (ABCD) study, 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-cingulate and striatal regions. In contrast, a higher proportion of delinquent friends was linked to increased behavioral problems, lower neurocognitive performance, and decreased functional connectivity in the default-mode and fronto-striato-limbic circuits, which spatially overlapped with external dopamine density maps. Moreover, the associations between prosocial friends and behaviors were mediated by brain volumes (e.g., pallidum), while the associations between delinquent friends and behaviors were primarily mediated by fronto-striato-limbic connectivity. Prosocial friends also attenuated the development of internalizing problems, whereas delinquent friends promoted externalizing symptoms. These findings underscore the profound influence of peer environments on adolescent brain development and mental health, highlighting the need for early interventions to promote resilience and healthy neuro-maturation.

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

Experimental study demonstrates that nucleus accumbens dopamine dynamics encode choice confidence under visual uncertainty in rats, highlighting dopamine's key role in adaptive decision-making.