Biology subjects

Holt, R. J.

Publications and source records attributed to Holt, R. J..

5 recordsLinked to original sources

bioRxiv2023

Characterizing Subcortical Structural Heterogeneity in Autism

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

neuroscience↗

bioRxiv2022

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

BACKGROUNDSensory atypicalities are particularly common in autism spectrum disorders (ASD). Nevertheless, our knowledge about the divergence of the underlying somatosensory region and its association with ASD phenotype features is limited. METHODSWe 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) during 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. RESULTSWe demonstrated that the S1 connectopy is organized along a dorsoventral axis, mapping onto the somatotopic organization of S1. We 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. CONCLUSIONSVariation of daily life adaptive skills appears to be reflected in the brains mesoscale neural circuitry, as shown by the S1 connectivity profile, which is also differentially modulated during rest and emotional processing.

neuroscience↗

bioRxiv2022

Autism is associated with inter-individual variations of gray and white matter morphology

BackgroundAlthough many studies have explored atypicalities in gray and white matter (GM, WM) morphology of autism, most of them rely on unimodal analyses that do not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish multimodal brain patterns that differentiate between autism and typically developing (TD) controls and explore associations between these brain patterns and clinical measures. MethodsWe studied 183 individuals with autism and 157 TD individuals (6-30 years) in a large deeply phenotyped autism dataset (EU-AIMS LEAP). Linked Independent Component Analysis was utilized to link all participants GM and WM images, and group comparisons of modality shared variances were examined. Subsequently, we performed a canonical correlation analysis to explore the aggregated effects between all multimodal GM-WM covariations and clinical profiles. ResultsOne multimodal pattern was significantly related to autism. This pattern was primarily associated with GM in bilateral insula, frontal, pre- and post-central, cingulate, and caudate areas, and co-occurred with altered WM features in the superior longitudinal fasciculus. The canonical analysis showed a significant multivariate correlation primarily between multimodal brain patterns that involved variation of corpus callosum, and symptoms of social affect in the autism group. ConclusionsOur findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism, and show that the complex clinical autism phenotype can be interpreted by multimodal brain patterns that are spread across the brain involving both cortical and subcortical areas.

neuroscience↗

bioRxiv2020

Gray matter covariations and core symptoms of autism. The EU-AIMS Longitudinal European Autism Project

BackgroundVoxel-based Morphometry (VBM) studies in Autism Spectrum Disorder (autism) have yielded diverging results. This might partly be attributed to structural alterations being associating with the combined influence of several regions rather than with a single region. Further, these structural covariation differences may relate to continuous measures of autism rather than with categorical case-control contrasts. The current study aimed to identify structural covariation alterations in autism, and assessed canonical correlations between brain covariation patterns and core autism symptoms. MethodsWe studied 347 individuals with autism and 252 typically developing individuals, aged between 6 and 30 years, who have been deeply phenotyped in the Longitudinal European Autism Project (LEAP). All participants VBM maps were decomposed into spatially independent components using Independent Component Analysis. A Generalized Linear Model (GLM) was used to examine case-control differences. Next, Canonical Correlation Analysis (CCA) was performed to separately explore the integrated effects between all the brain sources of gray matter variation and two sets of core autism symptoms. ResultsGLM analyses showed significant case-control differences for two independent components. The first component was primarily associated with decreased density of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and increased density of caudate nucleus in the autism group relative to typically developing individuals. The second component was related to decreased densities of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to typically developing individuals. The CCA results showed significant correlations between components that involved variation of thalamus, putamen, precentral gyrus, frontal, parietal, and occipital lobes, and the cerebellum, and repetitive, rigid and stereotyped behaviors and abnormal sensory behaviors in autism individuals. LimitationsOnly 55.9% of the participants with autism had complete questionnaire data on continuous parent-reported symptom measures. ConclusionsCovaried areas associated with autism diagnosis and/or symptoms are scattered across the whole brain and include the limbic system, basal ganglia, thalamus, cerebellum, precentral gyrus, and parts of the frontal, parietal, and occipital lobes. Some of these areas potentially subserve social-communicative behavior whereas others may underpin sensory processing and integration, and motor behavior.

neuroscience↗

bioRxiv2018

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sex-specific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.

neuroscience↗