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Sahakian, B. J.

Publications and source records attributed to Sahakian, B. J..

11 recordsLinked to original sources
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↗
bioRxiv2024

Genetic-Dependent Brain Signatures of Resilience: Interactions among Childhood Abuse, Genetic Risks and Brain Function

Resilience to emotional disorders is critical for adolescent mental health, especially following childhood abuse. Yet, brain signatures of resilience remain undetermined due to the differential susceptibility of the brains emotion processing system to environmental stresses. Analyzing brains responses to angry faces in a longitudinally large-scale adolescent cohort (IMAGEN), we identified two functional networks related to the orbitofrontal and occipital regions as candidate brain signatures of resilience. In girls, but not boys, higher activation in the orbitofrontal-related network was associated with fewer emotional symptoms following childhood abuse, but only when the polygenic burden for depression was high. This finding defined a genetic-dependent brain (GDB) signature of resilience. Notably, this GDB signature predicted subsequent emotional disorders in late adolescence, extending into early adulthood and generalizable to another independent prospective cohort (ABCD). Our findings underscore the genetic modulation of resilience-brain connections, laying the foundation for enhancing adolescent mental health through resilience promotion.

neuroscience↗
bioRxiv2024

Neural correlates of device-based sleep characteristics in adolescents

Understanding the brain mechanisms underlying objective sleep patterns in adolescents and their implications for psychophysiological development is a complex challenge. Here, we applied sparse canonical correlation (sCCA) analysis on 3300 adolescents from Adolescent Brain Cognitive Development (ABCD) study, integrating extensive device-based sleep characteristics and multimodal imaging data. We revealed two sleep-brain dimensions: one characterized by later being asleep and shorter duration, linked to decreased subcortical-cortical network functional connectivities; the other showed higher heart rate and shorter light sleep duration, associated with lower brain volumes and decreased functional connectivities. Hierarchical clustering based on brain dimension associated with sleep characteristics revealed three biotypes of adolescents, marked by unique sleep profiles: biotype 1 exhibited delayed and shorter sleep, coupled with higher heart rate during sleep; biotype 3 with earlier and longer sleep, accompanied by lower heart rate; and biotype 2 with intermediate pattern. This biotypic differences also extended to cognition, academic attainment, brain structure and function in a gradient order. Longitudinal analysis demonstrated consistent biotypic differences from ages 9 to14, highlighting enduring cognitive and academic advantages in biotype3. The linked sleep-brain dimensions and the associated biotypes were well replicated in a longitudinal sample of 1271 individuals. Collectively, our novel findings delineate a linkage between objective sleep characteristics and developing brain in adolescents, underscoring their significance in cognitive development and academic attainment, which could serve as references for individuals with sleep difficulties and offer insights for optimizing sleep routines to enhance better cognitive development and school achievement.

neuroscience↗
bioRxiv2023

Oxytocin, but not vasopressin, decreases willingness to harm others by promoting moral emotions of guilt and shame

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

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↗
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

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↗
bioRxiv2017

Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder

RationalePatients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function.\n\nObjectiveIn this study we investigate potential dopaminergic dysfunction during reward processing in the context of OCD.\n\nMethodsWe studied OCD patients (n=18) and controls (n=18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of: a dopamine receptor agonist, pramipexole 0.5mg; a dopamine receptor antagonist, amisulpride 400mg, and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest.\n\nResultsThere were no significant group, drug or interaction effects in number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p=0.089, partial 2=0.1). In the imaging results, there was a significant interaction of group by drug (p=0.013, partial 2=0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p=0.014, partial 2=0.26, 1-{beta} error probability=0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD.\n\nConclusionsOur data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

neuroscience↗