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Over the last two decades, inhibitory control has featured prominently in accounts of how humans and other organisms regulate their behaviour and thought. Previous work on how the brain stops actions and thoughts, however, has emphasised distinct prefrontal regions supporting these functions, suggesting domain-specific mechanisms. Here we show that stopping actions and thoughts recruits common regions in the right dorsolateral and ventrolateral prefrontal cortex to suppress diverse content, via dynamic targeting. Within each region, classifiers trained to distinguish action-stopping from action-execution also identify when people are suppressing their thoughts (and vice versa). Effective connectivity analysis reveals that both prefrontal regions contribute to action and thought stopping by targeting the motor cortex or the hippocampus, depending on the goal, to suppress their task-specific activity. These findings support the existence of a domain-general system that underlies inhibitory control and establish Dynamic Targeting as a mechanism enabling this ability., The authors use fMRI to show that the ability to stop unwanted actions and thoughts arises from a common stopping mechanism that flexibly inhibits activity in diverse, content-specific brain areas.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. `We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales., AIL, JV and PAMM would like to thank Lena Dorfschmidt for co-organising OxBridge BrainHack 2019, where this work began. We also thank all volunteers and patients who provided data. This work was supported by grants from The Wellcome Trust Research Training Fellowship (grant no. 083660/Z/07/Z), Raymond and Beverly Sackler Studentship, and the Cambridge Commonwealth Trust [RA]; the UK Medical Research Council (U.1055.01.002.00001.01) [JDP]; The James S. McDonnell Foundation [JDP]; the Canadian Institute for Advanced Research (CIFAR; grant RCZB/072 RG93193) [to DKM and EAS]; The National Institute for Health Research (NIHR, UK), Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards [JDP and DKM]; The British Oxygen Professorship of the Royal College of Anaesthetists [DKM]; The Stephen Erskine Fellowship, Queens’ College, University of Cambridge [EAS]; The Evelyn Trust, Cambridge and the EoE CLAHRC fellowship [JA]; The Gates Cambridge Trust [AIL]; The Cambridge International Trust and the Howard Sidney Sussex Studentship [MMC]; The Oon Khye Beng Ch'Hia Tsio Studentship for Research in Preventive Medicine, Downing College, University of Cambridge [IP]; The Wellcome Trust (grant no. 210920/Z/18/Z) [PAMM]; The European Research Council Consolidator Grant CAREGIVING (615539) [MLK and SA]; The Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117) [MLK, SA and JV]; The Centre for Eudaimonia and Human Flourishing, funded by the Pettit and Carlsberg Foundations [MLK]; The Imperial College President’s Scholarship [LR]; The Alex Mosley Charitable Trust [RLCH]; The ketamine study was funded by the Bernard Wolfe Health Neuroscience Fund and the Wellcome Trust. The original LSD study received support from a Crowd Funding Campaign and the Beckley Foundation, as part of the Beckley-Imperial Research Programme. The research was also supported by the NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. Data used to obtain the human connectome were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funder: Alexander von Humboldt-Stiftung (Alexander von Humboldt Foundation); doi: https://doi.org/10.13039/100005156, Distinguishing animate from inanimate things is of great behavioural importance. Despite distinct brain and behavioural responses to animate and inanimate things, it remains unclear which object properties drive these responses. Here, we investigate the importance of five object dimensions related to animacy (“being alive”, “looking like an animal”, “having agency”, “having mobility”, and “being unpredictable”) in brain (fMRI, EEG) and behaviour (property and similarity judgements) of 19 participants. We used a stimulus set of 128 images, optimized by a genetic algorithm to disentangle these five dimensions. The five dimensions explained much variance in the similarity judgments. Each dimension explained significant variance in the brain representations (except, surprisingly, “being alive”), however, to a lesser extent than in behaviour. Different brain regions sensitive to animacy may represent distinct dimensions, either as accessible perceptual stepping stones toward detecting whether something is alive or because they are of behavioural importance in their own right.

Funder: Gates Cambridge Trust; doi: https://doi.org/10.13039/501100005370, Funder: Alex Mosley Charitable Trust, Funder: Spanish Ministry of Science and Innovation: BES-2017-080364, Funder: Spanish Research Project: PID2019-105772GB-I00 AEI FEDER EU Spanish Ministry of Science, Innovation and Universities State Research Agency European Regional Development Funds Human Brain Project Specific Grant Agreement: 945539 EU H2020 FET Flagship program and SGR Research Support Group support (ref. 2017 SGR 1545) Catalan Agency for Management of University and Research Grants (AGAUR), Funder: Stephen Erskine Fellowship, Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH), Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain's control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics.

Funder: Evelyn Trust; doi: https://doi.org/10.13039/501100004282, Funder: James S. McDonnell Foundation (McDonnell Foundation); doi: https://doi.org/10.13039/100000913, Funder: Canadian Institute for Advanced Research (L'Institut Canadien de Recherches Avancées), The human brain entertains rich spatiotemporal dynamics, which are drastically reconfigured when consciousness is lost due to anaesthesia or disorders of consciousness (DOC). Here, we sought to identify the neurobiological mechanisms that explain how transient pharmacological intervention and chronic neuroanatomical injury can lead to common reconfigurations of neural activity. We developed and systematically perturbed a neurobiologically realistic model of whole-brain haemodynamic signals. By incorporating PET data about the cortical distribution of GABA receptors, our computational model reveals a key role of spatially-specific local inhibition for reproducing the functional MRI activity observed during anaesthesia with the GABA-ergic agent propofol. Additionally, incorporating diffusion MRI data obtained from DOC patients reveals that the dynamics that characterise loss of consciousness can also emerge from randomised neuroanatomical connectivity. Our results generalise between anaesthesia and DOC datasets, demonstrating how increased inhibition and connectome perturbation represent distinct neurobiological paths towards the characteristic activity of the unconscious brain.

Brain activity is intrinsically organised into spatiotemporal patterns, but it is still not clear whether these intrinsic patterns are functional or epiphenomenal. Using a simultaneous fMRI-EEG implementation of a well-known bistable visual task, we showed that the latent transient states in the intrinsic EEG oscillations can predict upcoming involuntarily perceptual transitions. The critical state predicting a dominant perceptual transition was characterised by the phase coupling between the precuneus (PCU), a key node of the Default Mode Network (DMN), and the primary visual cortex (V1). The interaction between the lifetime of this state and the PCU- > V1 Granger-causal effect is correlated with the perceptual fluctuation rate. Our study suggests that the brain's endogenous dynamics are phenomenologically relevant, as they can elicit a diversion between potential visual processing pathways, while external stimuli remain the same. In this sense, the intrinsic DMN dynamics pre-empt the content of consciousness., Canadian Institute for Advanced Research The National Institute for Health Research, Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards The British Oxygen Professorship of the Royal College of Anaesthetists The China Scholarship Council and Cambridge Commonwealth, European & International Trust The Stephen Erskine Fellowship, Queens’ College, University of Cambridge Computing infrastructure at the WBIC High Performance Hub for Clinical Informatics was funded by Medical Research Council research infrastructure Award No. MR/M009041/1.

Funder: Canadian Institute for Advanced Research (L'Institut Canadien de Recherches Avancées); doi: https://doi.org/10.13039/100007631, Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272, Funder: Evelyn Trust; doi: https://doi.org/10.13039/501100004282, Funder: Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards The British Oxygen Professorship of the Royal College of Anaesthetists the East of England Collaboration for Leadership in Applied Health Research and Care fellowship The L’Oreal-Unesco for Women in Science Excellence Research Fellowship The Stephen Erskine Fellowship, Queens’ College Cambridge Trust NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge Computing infrastructure at the Wolfson Brain Imaging Centre, Typical consciousness can be defined as an individual-specific stream of experiences. Modern consciousness research on dynamic functional connectivity uses clustering techniques to create common bases on which to compare different individuals. We propose an alternative approach by combining modern theories of consciousness and insights arising from phenomenology and dynamical systems theory. This approach enables a representation of an individual's connectivity dynamics in an intrinsically-defined, individual-specific landscape. Given the wealth of evidence relating functional connectivity to experiential states, we assume this landscape is a proxy measure of an individual's stream of consciousness. By investigating the properties of this landscape in individuals in different states of consciousness, we show that consciousness is associated with short term transitions that are less predictable, quicker, but, on average, more constant. We also show that temporally-specific connectivity states are less easily describable by network patterns that are distant in time, suggesting a richer space of possible states. We show that the cortex, cerebellum and subcortex all display consciousness-relevant dynamics and discuss the implication of our results in forming a point of contact between dynamical systems interpretations and phenomenology., The James S. McDonnell Foundation The Canada Excellence Research Chairs program The Canadian Institute for Advanced Research The British Oxygen Professorship of the Royal College of Anaesthetists The Evelyn Trust, Cambridge and the EoE CLAHRC The L’Oreal-Unesco for Women in Science Excellence Research Fellowship The Stephen Erskine Fellowship, Queens’ College, University of Cambridge Computing infrastructure at the Wolfson Brain Imaging Centre (WBIC-HPHI) the NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust Cambridge Trust

The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation.

Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ''Ideas'' Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): ERC-2012-StG_20111109 multsens, ERC-2012-StG_20111109 multsens, ERC-2012-StG_20111109 multsens, The brain adapts dynamically to the changing sensory statistics of its environment. Recent research has started to delineate the neural circuitries and representations that support this cross-sensory plasticity. Combining psychophysics and model-based representational fMRI and EEG we characterized how the adult human brain adapts to misaligned audiovisual signals. We show that audiovisual adaptation is associated with changes in regional BOLD-responses and fine-scale activity patterns in a widespread network from Heschl's gyrus to dorsolateral prefrontal cortices. Audiovisual recalibration relies on distinct spatial and decisional codes that are expressed with opposite gradients and time courses across the auditory processing hierarchy. Early activity patterns in auditory cortices encode sounds in a continuous space that flexibly adapts to misaligned visual inputs. Later activity patterns in frontoparietal cortices code decisional uncertainty consistent with these spatial transformations. Our findings suggest that regions within the auditory processing hierarchy multiplex spatial and decisional codes to adapt flexibly to the changing sensory statistics in the environment.

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

Funder: UCLH NIHR BRC, Low self-esteem is a risk factor for a range of psychiatric disorders. From a cognitive perspective a negative self-image can be maintained through aberrant learning about self-worth derived from social feedback. We previously showed that neural teaching signals that represent the difference between expected and actual social feedback (i.e., social prediction errors) drive fluctuations in self-worth. Here, we used model-based functional magnetic resonance imaging (fMRI) to characterize learning from social prediction errors in 61 participants drawn from a population-based sample (n = 2402) who were recruited on the basis of being in the bottom or top 10% of self-esteem scores. Participants performed a social evaluation task during fMRI scanning, which entailed predicting whether other people liked them as well as the repeated provision of reported feelings of self-worth. Computational modeling results showed that low self-esteem participants had persistent expectations that others would dislike them, and a reduced propensity to update these expectations in response to social prediction errors. Low self-esteem subjects also displayed an enhanced volatility in reported feelings of self-worth, and this was linked to an increased tendency for social prediction errors to determine momentary self-worth. Canonical correlation analysis revealed that individual differences in self-esteem related to several interconnected psychiatric symptoms organized around a single dimension of interpersonal vulnerability. Such interpersonal vulnerability was associated with an attenuated social value signal in ventromedial prefrontal cortex when making predictions about being liked, and enhanced dorsal prefrontal cortex activity upon receipt of social feedback. We suggest these computational signatures of low self-esteem and their associated neural underpinnings might represent vulnerability for development of psychiatric disorder.

Funder: Fondation pour la Recherche M��dicale (Foundation for Medical Research in France); doi: https://doi.org/10.13039/501100002915, Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism., Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.

Funder: Fundamental Research Funds for the Central Universities (Grant No.16CX06050A)., Funder: Medical Research Council (MRC) grant (MR/T004347/1), Funder: Alzheimer’s Research UK in partnership with Hidden Hearing (ARUK-PPG2016A-2); National Institute of Health Research (NIHR) Biomedical Research Centre (BRC), Funder: National Natural Science Foundation of P.R. China (Grant No.62072468) and the National Natural Science Foundation of Shandong Province (Grant No. ZR2018MF017)., Funder: Alzheimer’s Research UK in partnership with Hidden Hearing (ARUK-PPG2016A-2); National Institute of Health Research (NIHR) Biomedical Research Centre (BRC); Medical Research Council (MRC) grant (MR/T004347/1); Guangci Professorship Program of Ruijin Hospital (Shanghai Jiao Tong University), Funder: Alzheimer’s Research UK in partnership with Hidden Hearing (ARUK-PPG2016A-2); National Institute of Health Research (NIHR) Biomedical Research Centre (BRC); Wellcome Trust Fellowship (WT088441MA), Brain’s modular connectivity gives this organ resilience and adaptability. The ageing process alters the organised modularity of the brain and these changes are further accentuated by neurodegeneration, leading to disorganisation. To understand this further, we analysed modular variability—heterogeneity of modules—and modular dissociation—detachment from segregated connectivity—in two ageing cohorts and a mixed cohort of neurodegenerative diseases. Our results revealed that the brain follows a universal pattern of high modular variability in metacognitive brain regions: the association cortices. The brain in ageing moves towards a segregated modular structure despite presenting with increased modular heterogeneity—modules in older adults are not only segregated, but their shape and size are more variable than in young adults. In the presence of neurodegeneration, the brain maintains its segregated connectivity globally but not locally, and this is particularly visible in dementia with Lewy bodies and Parkinson’s disease dementia; overall, the modular brain shows patterns of differentiated pathology.

The human brain is characterized by highly dynamic patterns of functional connectivity. However, it is unknown whether this time-variant ‘connectome’ is related to the individual differences in the behavioural and cognitive traits described in the five-factor model of personality. To answer this question, inter-network time-variant connectivity was computed in n = 818 healthy people via a dynamical conditional correlation model. Next, network dynamicity was quantified throughout an ad-hoc measure (T-index) and the generalizability of the multi-variate associations between personality traits and network dynamicity was assessed using a train/test split approach. Conscientiousness, reflecting enhanced cognitive and emotional control, was the sole trait linked to stationary connectivity across several circuits such as the default mode and prefronto-parietal network. The stationarity in the ‘communication’ across large-scale networks offers a mechanistic description of the capacity of conscientious people to ‘protect’ non-immediate goals against interference over-time. This study informs future research aiming at developing more realistic models of the brain dynamics mediating personality differences.

Funder: National Institute for Health Research (NIHR), Hallucinations are a core feature of psychosis and common in Parkinson's. Their transient, unexpected nature suggests a change in dynamic brain states, but underlying causes are unknown. Here, we examine temporal dynamics and underlying structural connectivity in Parkinson's-hallucinations using a combination of functional and structural MRI, network control theory, neurotransmitter density and genetic analyses. We show that Parkinson's-hallucinators spent more time in a predominantly Segregated functional state with fewer between-state transitions. The transition from integrated-to-segregated state had lower energy cost in Parkinson's-hallucinators; and was therefore potentially preferable. The regional energy needed for this transition was correlated with regional neurotransmitter density and gene expression for serotoninergic, GABAergic, noradrenergic and cholinergic, but not dopaminergic, receptors. We show how the combination of neurochemistry and brain structure jointly shape functional brain dynamics leading to hallucinations and highlight potential therapeutic targets by linking these changes to neurotransmitter systems involved in early sensory and complex visual processing.

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA., Jade Jackson et al. use fMRI concurrent with transcranial magnetic stimulation (TMS) in an attention task to evaluate whether the right dorsolateral prefrontal cortex (dlPFC) is involved in facilitation of relevant information, or suppression of irrelevant information. Their results suggest that the dlPFC is causally involved in processing relevant information in an attention task and highlight the utility of a dual fMRI-TMS approach.

Funder: Fundamental Research Funds for the Central Universities (2020FZZX001-05, 2019FZJD005) and Zhejiang Lab (2019KE0AD01), Convergent evidence has suggested a significant effect of antipsychotic exposure on brain structure and function in patients with schizophrenia, yet the characteristics of favorable treatment outcome remains largely unknown. In this work, we aimed to examine how large-scale brain networks are modulated by antipsychotic treatment, and whether the longitudinal changes could track the improvements of psychopathologic scores. Thirty-four patients with first-episode drug-naïve schizophrenia and 28 matched healthy controls were recruited at baseline from Shanghai Mental Health Center. After 8 weeks of antipsychotic treatment, 24 patients were re-scanned. Through a systematical dynamic functional connectivity (dFC) analysis, we investigated the schizophrenia-related intrinsic alterations of dFC at baseline, followed by a longitudinal study to examine the influence of antipsychotic treatment on these abnormalities by comparing patients at baseline and follow-up. A structural connectivity (SC) association analysis was further carried out to investigate longitudinal anatomical changes that underpin the alterations of dFC. We found a significant symptomatic improvement-related increase in the occurrence of a dFC state characterized by stronger inter-network integration. Furthermore, symptom reduction was correlated with increased FC variability in a unique connectomic signature, particularly in the connections within the default mode network and between the auditory, cognitive control, and cerebellar network to other networks. Additionally, we observed that the SC between the superior frontal gyrus and medial prefrontal cortex was decreased after treatment, suggesting a relaxation of normal constraints on dFC. Taken together, these findings provide new evidence to extend the dysconnectivity hypothesis in schizophrenia from static to dynamic brain network. Moreover, our identified neuroimaging markers tied to the neurobiology of schizophrenia could be used as potential indicators in predicting the treatment outcome of antipsychotics.

Traditional models of future alcohol use in adolescents have used variable-centered approaches, predicting alcohol use from a set of variables across entire samples or populations. Following the proposition that predictive factors may vary in adolescents as a function of family history, we used a two-pronged approach by first defining clusters of familial risk, followed by prediction analyses within each cluster. Thus, for the first time in adolescents, we tested whether adolescents with a family history of drug abuse exhibit a set of predictors different from adolescents without a family history. We apply this approach to a genetic risk score and individual differences in personality, cognition, behavior (risk-taking and discounting) substance use behavior at age 14, life events, and functional brain imaging, to predict scores on the alcohol use disorders identification test (AUDIT) at age 14 and 16 in a sample of adolescents (N = 1659 at baseline, N = 1327 at follow-up) from the IMAGEN cohort, a longitudinal community-based cohort of adolescents. In the absence of familial risk (n = 616), individual differences in baseline drinking, personality measures (extraversion, negative thinking), discounting behaviors, life events, and ventral striatal activation during reward anticipation were significantly associated with future AUDIT scores, while the overall model explained 22% of the variance in future AUDIT. In the presence of familial risk (n = 711), drinking behavior at age 14, personality measures (extraversion, impulsivity), behavioral risk-taking, and life events were significantly associated with future AUDIT scores, explaining 20.1% of the overall variance. Results suggest that individual differences in personality, cognition, life events, brain function, and drinking behavior contribute differentially to the prediction of future alcohol misuse. This approach may inform more individualized preventive interventions.

Understanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14–24 y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Human visual cortex contains discrete areas that respond selectively to specific object categories such as faces, bodies, and places. A long-standing question is whether these areas are shaped by genetic or environmental factors. To address this question, here we analyzed functional MRI data from an unprecedented number (n = 424) of monozygotic (MZ) and dizygotic (DZ) twins. Category-selective maps were more identical in MZ than DZ twins. Within each category-selective area, distinct subregions showed significant genetic influence. Structural MRI analysis revealed that the ‘genetic voxels’ were predominantly located in regions with higher cortical curvature (gyral crowns in face areas and sulcal fundi in place areas). Moreover, we found that cortex was thicker and more myelinated in genetic voxels of face areas, while it was thinner and less myelinated in genetic voxels of place areas. This double dissociation suggests a differential development of face and place areas in cerebral cortex.

Patterns of functional interactions across distributed brain regions are suggested to provide a scaffold for the conscious processing of information, with marked topological alterations observed in loss of consciousness. However, establishing a firm link between macro-scale brain network organisation and conscious cognition requires direct investigations into neuropsychologically-relevant architectural modifications across systematic reductions in consciousness. Here we assessed both global and regional disturbances to brain graphs in a group of healthy participants across baseline resting state fMRI as well as two distinct levels of propofol-induced sedation. We found a persistent modular architecture, yet significant reorganisation of brain hubs that formed parts of a wider rich-club collective. Furthermore, the reduction in the strength of rich-club connectivity was significantly associated with the participants' performance in a semantic judgment task, indicating the importance of this higher-order topological feature for conscious cognition. These results highlight a remarkable interplay between global and regional properties of brain functional interactions in supporting conscious cognition that is relevant to our understanding of clinical disorders of consciousness., Scientific Reports, 10 (1), ISSN:2045-2322

Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide.

Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain’s default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice., How do diversity (entropy) and integration of activity across brain regions interact to support consciousness? Here the authors show that anaesthetised individuals and patients with disorders of consciousness exhibit overlapping reductions in both diversity and integration in the brain’s default mode network.

The brain is possibly the most complex system known to mankind, and its complexity has been called upon to explain the emergence of consciousness. However, complexity has been defined in many ways by multiple different fields: here, we investigate measures of algorithmic and process complexity in both the temporal and topological domains, testing them on functional MRI BOLD signal data obtained from individuals undergoing various levels of sedation with the anaesthetic agent propofol, replicating our results in two separate datasets. We demonstrate that the various measures are differently able to discriminate between levels of sedation, with temporal measures showing higher sensitivity. Further, we show that all measures are strongly related to a single underlying construct explaining most of the variance, as assessed by Principal Component Analysis, which we interpret as a measure of “overall complexity” of our data. This overall complexity was also able to discriminate between levels of sedation and serum concentrations of propofol, supporting the hypothesis that consciousness is related to complexity - independent of how the latter is measured.

Funder: This work was supported by British Academy postdoctoral fellowship and a Marie Curie fellowship (753441) to A.A., a Cambridge University international scholarship and IDB merit scholarship award to H.A., and Medical Research Council programme grant (SUAG/010 RG91365) to R.N.H., Inferring neural mechanisms from functional magnetic resonance imaging (fMRI) is challenging because the fMRI signal integrates over millions of neurons. One approach is to compare computational models that map neural activity to fMRI responses, to see which best predicts fMRI data. We use this approach to compare four possible neural mechanisms of fMRI adaptation to repeated stimuli (scaling, sharpening, repulsive shifting and attractive shifting), acting across three domains (global, local and remote). Six features of fMRI repetition effects are identified, both univariate and multivariate, from two independent fMRI experiments. After searching over parameter values, only the local scaling model can simultaneously fit all data features from both experiments. Thus fMRI stimulus repetition effects are best captured by down-scaling neuronal tuning curves in proportion to the difference between the stimulus and neuronal preference. These results emphasise the importance of formal modelling for bridging neuronal and fMRI levels of investigation.

Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain’s default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice.

Funder: Oon Khye Beng Ch’Hia Tsio Studentship for Research in Preventive Medicine, administered via Downing College, Funder: L’Oréal-Unesco for Women in Science Excellence Research Fellowship, Funder: Canadian Institute for Advanced research (CIFAR), Funder: Cambridge Biomedical Research Centre NIHR Senior Investigator Awards, Funder: Stephen Erskine Fellowship at Queens’ College, Cambridge, The brain is possibly the most complex system known to mankind, and its complexity has been called upon to explain the emergence of consciousness. However, complexity has been defined in many ways by multiple different fields: here, we investigate measures of algorithmic and process complexity in both the temporal and topological domains, testing them on functional MRI BOLD signal data obtained from individuals undergoing various levels of sedation with the anaesthetic agent propofol, replicating our results in two separate datasets. We demonstrate that the various measures are differently able to discriminate between levels of sedation, with temporal measures showing higher sensitivity. Further, we show that all measures are strongly related to a single underlying construct explaining most of the variance, as assessed by Principal Component Analysis, which we interpret as a measure of “overall complexity” of our data. This overall complexity was also able to discriminate between levels of sedation and serum concentrations of propofol, supporting the hypothesis that consciousness is related to complexity - independent of how the latter is measured.

Funder: American Foundation for Suicide Prevention (AFSP); doi: https://doi.org/10.13039/100001455, Funder: Brain and Behavior Research Foundation (Brain & Behavior Research Foundation); doi: https://doi.org/10.13039/100000874, Funder: MQ Brighter Futures Award MQBFC/2, International Bipolar Foundation, For the Love of Travis Foundation, Women's Health Research at Yale, John and Hope Furth Endowment, Funder: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH), Funder: Brain and Behavior Research Foundation (Brain & Behavior Research Foundation), Funder: Robert E. Leet and Clara Guthrie Patterson Trust (Robert E. Leet & Clara Guthrie Patterson Trust); doi: https://doi.org/10.13039/100000938, Funder: U.S. Department of Veterans Affairs (Department of Veterans Affairs); doi: https://doi.org/10.13039/100000738, Identifying brain alterations that contribute to suicidal thoughts and behaviors (STBs) are important to develop more targeted and effective strategies to prevent suicide. In the last decade, and especially in the last 5 years, there has been exponential growth in the number of neuroimaging studies reporting structural and functional brain circuitry correlates of STBs. Within this narrative review, we conducted a comprehensive review of neuroimaging studies of STBs published to date and summarize the progress achieved on elucidating neurobiological substrates of STBs, with a focus on converging findings across studies. We review neuroimaging evidence across differing mental disorders for structural, functional, and molecular alterations in association with STBs, which converges particularly in regions of brain systems that subserve emotion and impulse regulation including the ventral prefrontal cortex (VPFC) and dorsal PFC (DPFC), insula and their mesial temporal, striatal and posterior connection sites, as well as in the connections between these brain areas. The reviewed literature suggests that impairments in medial and lateral VPFC regions and their connections may be important in the excessive negative and blunted positive internal states that can stimulate suicidal ideation, and that impairments in a DPFC and inferior frontal gyrus (IFG) system may be important in suicide attempt behaviors. A combination of VPFC and DPFC system disturbances may lead to very high risk circumstances in which suicidal ideation is converted to lethal actions via decreased top-down inhibition of behavior and/or maladaptive, inflexible decision-making and planning. The dorsal anterior cingulate cortex and insula may play important roles in switching between these VPFC and DPFC systems, which may contribute to the transition from suicide thoughts to behaviors. Future neuroimaging research of larger sample sizes, including global efforts, longitudinal designs, and careful consideration of developmental stages, and sex and gender, will facilitate more effectively targeted preventions and interventions to reduce loss of life to suicide.

Funder: Centre for Integrative Neuroscience and Neurodynamics, University of Reading, Funder: ARC Discovery Project (DP170101840) ARC Discovery Project (DP12102835), Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA.