Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Smartphone keyboard dynamics predict affect in suicidal ideation.

While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (ß = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.

Principal and independent genomic components of brain structure and function.

The highly polygenic and pleiotropic nature of behavioural traits, psychiatric disorders and structural and functional brain phenotypes complicate mechanistic interpretation of related genome-wide association study (GWAS) signals, thereby obscuring underlying causal biological processes. We propose genomic principal and independent component analysis (PCA, ICA) to decompose a large set of univariate GWAS statistics of multimodal brain traits into more interpretable latent genomic components. Here we introduce and evaluate this novel methods various analytic parameters and reproducibility across independent samples. Two UK Biobank GWAS summary statistic releases of 2240 imaging-derived phenotypes (IDPs) were retrieved. Genome-wide beta-values and their corresponding standard-error scaled z-values were decomposed using genomic PCA/ICA. We evaluated variance explained at multiple dimensions up to 200. We tested the inter-sample reproducibility of output of dimensions 5, 10, 25 and 50. Reproducibility statistics of the respective univariate GWAS served as benchmarks. Reproducibility of 10-dimensional PCs and ICs showed the best trade-off between model complexity and robustness and variance explained (PCs: |rz - max| = 0.33, |rraw - max| = 0.30; ICs: |rz - max| = 0.23, |rraw - max| = 0.19). Genomic PC and IC reproducibility improved substantially relative to mean univariate GWAS reproducibility up to dimension 10. Genomic components clustered along neuroimaging modalities. Our results indicate that genomic PCA and ICA decompose genetic effects on IDPs from GWAS statistics with high reproducibility by taking advantage of the inherent pleiotropic patterns. These findings encourage further applications of genomic PCA and ICA as fully data-driven methods to effectively reduce the dimensionality, enhance the signal to noise ratio and improve interpretability of high-dimensional multitrait genome-wide analyses.

Gray matter covariations in autism: out-of-sample replication using the ENIGMA autism cohort.

BACKGROUND: Autism spectrum disorder (henceforth autism) is a complex neurodevelopmental condition associated with differences in gray matter (GM) volume covariations, as reported in our previous study of the Longitudinal European Autism Project (LEAP) data. To make progress on the identification of potential neural markers and to validate the robustness of our previous findings, we aimed to replicate our results using data from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) autism working group. METHODS: We studied 781 autistic and 927 non-autistic individuals (6-30 years, IQ ≥ 50), across 37 sites. Voxel-based morphometry was used to quantify GM volume as before. Subsequently, we used spatial maps of the two autism-related independent components (ICs) previously identified in the LEAP sample as templates for regression analyses to separately estimate the ENIGMA-participant loadings to each of these two ICs. Between-group differences in participants' loadings on each component were examined, and we additionally investigated the relation between participant loadings and autistic behaviors within the autism group. RESULTS: The two components of interest, previously identified in the LEAP dataset, showed significant between-group differences upon regressions into the ENIGMA cohort. The associated brain patterns were consistent with those found in the initial identification study. The first IC was primarily associated with increased volumes of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and caudate in the autism group relative to the control group (ß = 0.129, p = 0.013). The second IC was related to increased volumes of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to non-autistic individuals (ß = 0.116, p = 0.024). However, when accounting for the site-by-group interaction effect, no significant main effect of the group can be identified (p > 0.590). We did not find significant univariate association between the brain measures and behavior in autism (p > 0.085). LIMITATIONS: The distributions of age, IQ, and sex between LEAP and ENIGMA are statistically different from each other. Owing to limited access to the behavioral data of the autism group, we were unable to further our understanding of the neural basis of behavioral dimensions of the sample. CONCLUSIONS: The current study is unable to fully replicate the autism-related brain patterns from LEAP in the ENIGMA cohort. The diverse group effects across ENIGMA sites demonstrate the challenges of generalizing the average findings of the GM covariation patterns to a large-scale cohort integrated retrospectively from multiple studies. Further analyses need to be conducted to gain additional insights into the generalizability of these two GM covariation patterns.

Digital behavioural signatures reveal trans-diagnostic clusters of Schizophrenia and Alzheimer's disease patients.

The current neuropsychiatric nosological categories underlie pragmatic treatment choice, regulation and clinical research but does not encompass biological rationale. However, subgroups of patients suffering from schizophrenia or Alzheimer's disease have more in common than the neuropsychiatric nature of their condition, such as the expression of social dysfunction. The PRISM project presents here initial quantitative biological insights allowing the first steps toward a novel trans-diagnostic classification of psychiatric and neurological symptomatology intended to reinvigorate drug discovery in this area. In this study, we applied spectral clustering on digital behavioural endpoints derived from passive smartphone monitoring data in a subgroup of Schizophrenia and Alzheimer's disease patients, as well as age matched healthy controls, as part of the PRISM clinical study. This analysis provided an objective social functioning characterization with three differential clusters that transcended initial diagnostic classification and was shown to be linked to quantitative neurobiological parameters assessed. This emerging quantitative framework will both offer new ways to classify individuals in biologically homogenous clusters irrespective of their initial diagnosis, and also offer insights into the pathophysiological mechanisms underlying these clusters.

Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder.

BACKGROUND: Autism is a heterogeneous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in intrinsic (i.e., gray matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs. METHODS: Here, we examined intrinsic global and local wiring costs in the brain of 359 individuals with autism and 279 healthy control participants ages 6 to 30 years from the EU-AIMS LEAP (Longitudinal European Autism Project). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray matter. Vertexwise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings. RESULTS: Group differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes that had been previously implicated in the etiology of autism at genetic and transcriptomic levels. CONCLUSIONS: Based on intrinsic gray matter connectivity, the current study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches.

Smartphone keyboard dynamics predict affect in suicidal ideation.

While digital phenotyping provides opportunities for unobtrusive, real-time mental health assessments, the integration of its modalities is not trivial due to high dimensionalities and discrepancies in sampling frequencies. We provide an integrated pipeline that solves these issues by transforming all modalities to the same time unit, applying temporal independent component analysis (ICA) to high-dimensional modalities, and fusing the modalities with linear mixed-effects models. We applied our approach to integrate high-quality, daily self-report data with BiAffect keyboard dynamics derived from a clinical suicidality sample of mental health outpatients. Applying the ICA to the self-report data (104 participants, 5712 days of data) revealed components related to well-being, anhedonia, and irritability and social dysfunction. Mixed-effects models (55 participants, 1794 days) showed that less phone movement while typing was associated with more anhedonia (ß = -0.12, p = 0.00030). We consider this method to be widely applicable to dense, longitudinal digital phenotyping data.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder - study protocol for a randomized clinical trial.

BACKGROUND: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated. METHODS: This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. DISCUSSION: This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05347199. April 12, 2022.

The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings.

BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings. METHODS: We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings. RESULTS: In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes. LIMITATIONS: Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting. CONCLUSION: Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.

Linking functional and structural brain organisation with behaviour in autism: a multimodal EU-AIMS Longitudinal European Autism Project (LEAP) study.

Neuroimaging analyses of brain structure and function in autism have typically been conducted in isolation, missing the sensitivity gains of linking data across modalities. Here we focus on the integration of structural and functional organisational properties of brain regions. We aim to identify novel brain-organisation phenotypes of autism. We utilised multimodal MRI (T1-, diffusion-weighted and resting state functional), behavioural and clinical data from the EU AIMS Longitudinal European Autism Project (LEAP) from autistic (n = 206) and non-autistic (n = 196) participants. Of these, 97 had data from 2 timepoints resulting in a total scan number of 466. Grey matter density maps, probabilistic tractography connectivity matrices and connectopic maps were extracted from respective MRI modalities and were then integrated with Linked Independent Component Analysis. Linear mixed-effects models were used to evaluate the relationship between components and group while accounting for covariates and non-independence of participants with longitudinal data. Additional models were run to investigate associations with dimensional measures of behaviour. We identified one component that differed significantly between groups (coefficient = 0.33, padj = 0.02). This was driven (99%) by variance of the right fusiform gyrus connectopic map 2. While there were multiple nominal (uncorrected p < 0.05) associations with behavioural measures, none were significant following multiple comparison correction. Our analysis considered the relative contributions of both structural and functional brain phenotypes simultaneously, finding that functional phenotypes drive associations with autism. These findings expanded on previous unimodal studies by revealing the topographic organisation of functional connectivity patterns specific to autism and warrant further investigation.

Regional, circuit and network heterogeneity of brain abnormalities in psychiatric disorders.

The substantial individual heterogeneity that characterizes people with mental illness is often ignored by classical case-control research, which relies on group mean comparisons. Here we present a comprehensive, multiscale characterization of the heterogeneity of gray matter volume (GMV) differences in 1,294 cases diagnosed with one of six conditions (attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, depression, obsessive-compulsive disorder and schizophrenia) and 1,465 matched controls. Normative models indicated that person-specific deviations from population expectations for regional GMV were highly heterogeneous, affecting the same area in <7% of people with the same diagnosis. However, these deviations were embedded within common functional circuits and networks in up to 56% of cases. The salience-ventral attention system was implicated transdiagnostically, with other systems selectively involved in depression, bipolar disorder, schizophrenia and attention-deficit/hyperactivity disorder. Phenotypic differences between cases assigned the same diagnosis may thus arise from the heterogeneous localization of specific regional deviations, whereas phenotypic similarities may be attributable to the dysfunction of common functional circuits and networks.

Fine-grained topographic organization within somatosensory cortex during resting-state and emotional face-matching task and its association with ASD traits.

Sensory atypicalities are particularly common in autism spectrum disorders (ASD). Nevertheless, our knowledge about the divergent functioning of the underlying somatosensory region and its association with ASD phenotype features is limited. We applied a data-driven approach to map the fine-grained variations in functional connectivity of the primary somatosensory cortex (S1) to the rest of the brain in 240 autistic and 164 neurotypical individuals from the EU-AIMS LEAP dataset, aged between 7 and 30. We estimated the S1 connection topography ('connectopy') at rest and during the emotional face-matching (Hariri) task, an established measure of emotion reactivity, and accessed its association with a set of clinical and behavioral variables. We first demonstrated that the S1 connectopy is organized along a dorsoventral axis, mapping onto the S1 somatotopic organization. We then found that its spatial characteristics were linked to the individuals' adaptive functioning skills, as measured by the Vineland Adaptive Behavior Scales, across the whole sample. Higher functional differentiation characterized the S1 connectopies of individuals with higher daily life adaptive skills. Notably, we detected significant differences between rest and the Hariri task in the S1 connectopies, as well as their projection maps onto the rest of the brain suggesting a task-modulating effect on S1 due to emotion processing. All in all, variation of adaptive skills appears to be reflected in the brain's mesoscale neural circuitry, as shown by the S1 connectivity profile, which is also differentially modulated during rest and emotional processing.

Brain structure and function link to variation in biobehavioral dimensions across the psychopathological continuum.

In line with the Research Domain Criteria (RDoC) , we set out to investigate the brain basis of psychopathology within a transdiagnostic, dimensional framework. We performed an integrative structural-functional linked independent component analysis to study the relationship between brain measures and a broad set of biobehavioral measures in a sample (n = 295) with both mentally healthy participants and patients with diverse non-psychotic psychiatric disorders (i.e. mood, anxiety, addiction, and neurodevelopmental disorders). To get a more complete understanding of the underlying brain mechanisms, we used gray and white matter measures for brain structure and both resting-state and stress scans for brain function. The results emphasize the importance of the executive control network (ECN) during the functional scans for the understanding of transdiagnostic symptom dimensions. The connectivity between the ECN and the frontoparietal network in the aftermath of stress was correlated with symptom dimensions across both the cognitive and negative valence domains, and also with various other health-related biological and behavioral measures. Finally, we identified a multimodal component that was specifically associated with the diagnosis of autism spectrum disorder (ASD). The involvement of the default mode network, precentral gyrus, and thalamus across the different modalities of this component may reflect the broad functional domains that may be affected in ASD, like theory of mind, motor problems, and sensitivity to sensory stimuli, respectively. Taken together, the findings from our extensive, exploratory analyses emphasize the importance of a dimensional and more integrative approach for getting a better understanding of the brain basis of psychopathology.

Unpacking the functional heterogeneity of the Emotional Face Matching Task: a normative modelling approach.

Functional neuroimaging has contributed substantially to understanding brain function but is dominated by group analyses that index only a fraction of the variation in these data. It is increasingly clear that parsing the underlying heterogeneity is crucial to understand individual differences and the impact of different task manipulations. We estimate large-scale (N=7728) normative models of task-evoked activation during the Emotional Face Matching Task, which enables us to bind heterogeneous datasets to a common reference and dissect heterogeneity underlying group-level analyses. We apply this model to a heterogenous patient cohort, to map individual differences between patients with one or more mental health diagnoses relative to the reference cohort and determine multivariate associations with transdiagnostic symptom domains. For the face>shapes contrast, patients have a higher frequency of extreme deviations which are spatially heterogeneous. In contrast, normative models for faces>baseline have greater predictive value for individuals' transdiagnostic functioning.

Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism.

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Connectome-wide Mega-analysis Reveals Robust Patterns of Atypical Functional Connectivity in Autism.

BACKGROUND: Neuroimaging studies of functional connectivity (FC) in autism have been hampered by small sample sizes and inconsistent findings with regard to whether connectivity is increased or decreased in individuals with autism, whether these alterations affect focal systems or reflect a brain-wide pattern, and whether these are age and/or sex dependent. METHODS: The study included resting-state functional magnetic resonance imaging and clinical data from the EU-AIMS LEAP (European Autism Interventions Longitudinal European Autism Project) and the ABIDE (Autism Brain Imaging Data Exchange) 1 and 2 initiatives of 1824 (796 with autism) participants with an age range of 5-58 years. Between-group differences in FC were assessed, and associations between FC and clinical symptom ratings were investigated through canonical correlation analysis. RESULTS: Autism was associated with a brainwide pattern of hypo- and hyperconnectivity. Hypoconnectivity predominantly affected sensory and higher-order attentional networks and correlated with social impairments, restrictive and repetitive behavior, and sensory processing. Hyperconnectivity was observed primarily between the default mode network and the rest of the brain and between cortical and subcortical systems. This pattern was strongly associated with social impairments and sensory processing. Interactions between diagnosis and age or sex were not statistically significant. CONCLUSIONS: The FC alterations observed, which primarily involve hypoconnectivity of primary sensory and attention networks and hyperconnectivity of the default mode network and subcortex with the rest of the brain, do not appear to be age or sex dependent and correlate with clinical dimensions of social difficulties, restrictive and repetitive behaviors, and alterations in sensory processing. These findings suggest that the observed connectivity alterations are stable, trait-like features of autism that are related to the main symptom domains of the condition.

Evidence for embracing normative modeling.

In this work, we expand the normative model repository introduced in Rutherford et al., 2022a to include normative models charting lifespan trajectories of structural surface area and brain functional connectivity, measured using two unique resting-state network atlases (Yeo-17 and Smith-10), and an updated online platform for transferring these models to new data sources. We showcase the value of these models with a head-to-head comparison between the features output by normative modeling and raw data features in several benchmarking tasks: mass univariate group difference testing (schizophrenia versus control), classification (schizophrenia versus control), and regression (predicting general cognitive ability). Across all benchmarks, we show the advantage of using normative modeling features, with the strongest statistically significant results demonstrated in the group difference testing and classification tasks. We intend for these accessible resources to facilitate the wider adoption of normative modeling across the neuroimaging community.

Excitatory/inhibitory imbalance in autism: the role of glutamate and GABA gene-sets in symptoms and cortical brain structure.

The excitatory/inhibitory (E/I) imbalance hypothesis posits that imbalance between excitatory (glutamatergic) and inhibitory (GABAergic) mechanisms underlies the behavioral characteristics of autism. However, how E/I imbalance arises and how it may differ across autism symptomatology and brain regions is not well understood. We used innovative analysis methods-combining competitive gene-set analysis and gene-expression profiles in relation to cortical thickness (CT) to investigate relationships between genetic variance, brain structure and autism symptomatology of participants from the AIMS-2-TRIALS LEAP cohort (autism = 359, male/female = 258/101; neurotypical control participants = 279, male/female = 178/101) aged 6-30 years. Using competitive gene-set analyses, we investigated whether aggregated genetic variation in glutamate and GABA gene-sets could be associated with behavioral measures of autism symptoms and brain structural variation. Further, using the same gene-sets, we corelated expression profiles throughout the cortex with differences in CT between autistic and neurotypical control participants, as well as in separate sensory subgroups. The glutamate gene-set was associated with all autism symptom severity scores on the Autism Diagnostic Observation Schedule-2 (ADOS-2) and the Autism Diagnostic Interview-Revised (ADI-R) within the autistic group. In adolescents and adults, brain regions with greater gene-expression of glutamate and GABA genes showed greater differences in CT between autistic and neurotypical control participants although in opposing directions. Additionally, the gene expression profiles were associated with CT profiles in separate sensory subgroups. Our results suggest complex relationships between E/I related genetics and autism symptom profiles as well as brain structure alterations, where there may be differential roles for glutamate and GABA.

Dissociating the functional roles of arcuate fasciculus subtracts in speech production.

Recent tractography and microdissection studies have shown that the left arcuate fasciculus (AF)-a fiber tract thought to be crucial for speech production-consists of a minimum of 2 subtracts directly connecting the temporal and frontal cortex. These subtracts link the posterior superior temporal gyrus (STG) and middle temporal gyrus (MTG) to the inferior frontal gyrus. Although they have been hypothesized to mediate different functions in speech production, direct evidence for this hypothesis is lacking. To functionally segregate the 2 AF segments, we combined functional magnetic resonance imaging with diffusion-weighted imaging and probabilistic tractography using 2 prototypical speech production tasks, namely spoken pseudoword repetition (tapping sublexical phonological mapping) and verb generation (tapping lexical-semantic mapping). We observed that the repetition of spoken pseudowords is mediated by the subtract of STG, while generating an appropriate verb to a spoken noun is mediated by the subtract of MTG. Our findings provide strong evidence for a functional dissociation between the AF subtracts, namely a sublexical phonological mapping by the STG subtract and a lexical-semantic mapping by the MTG subtract. Our results contribute to the unraveling of a century-old controversy concerning the functional role in speech production of a major fiber tract involved in language.

Amplitudes of resting-state functional networks - investigation into their correlates and biophysical properties.

Resting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former.