Cortex In Autism Spectrum Disorder Research Articles

Specialization of anterior and posterior hippocampal functional connectivity differs in autism.

Structural and functional differences in the hippocampus have been related to the episodic memory and social impairments observed in autism spectrum disorder (ASD). In neurotypical individuals, hippocampal-cortical functional connectivity systematically varies between anterior and posterior hippocampus, with changes observed during typical development. It remains unknown whether this specialization of anterior-posterior hippocampal connectivity is disrupted in ASD, and whether age-related differences in this specialization exist in ASD. We examined connectivity of the anterior and posterior hippocampus in an ASD (N = 139) and non-autistic comparison group (N = 133) aged 5-21 using resting-state functional magnetic resonance imaging (MRI) data from the Healthy Brain Network (HBN). Consistent with previous results, we observed lower connectivity between the whole hippocampus and medial prefrontal cortex in ASD. Moreover, preferential connectivity of the posterior relative to the anterior hippocampus for memory-sensitive regions in posterior parietal cortex was reduced in ASD, demonstrating a weaker anterior-posterior specialization of hippocampal-cortical connectivity. Finally, connectivity between the posterior hippocampus and precuneus negatively correlated with age in the ASD group but remained stable in the comparison group, suggesting an altered developmental specialization. Together, these differences in hippocampal-cortical connectivity may help us understand the neurobiological basis of the memory and social impairments found in ASD.

Increased number of excitatory synapsis and decreased number of inhibitory synapsis in the prefrontal cortex in autism.

Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.

Atypical co-development of the thalamus and cortex in autism: Evidence from age-related white-gray contrast change.

Recent studies have shown that white-gray contrast (WGC) of either cortical or subcortical gray matter provides for accurate predictions of age in typically developing (TD) children, and that, at least for the cortex, it changes differently with age in subjects with autism spectrum disorder (ASD) compared to their TDpeers. Our previous study showed different patterns of contrast change between ASD and TD in sensorimotor and association cortices. While that study was confined to the cortex, we hypothesized that subcortical structures, particularly the thalamus, were involved in the observed cortical dichotomy between lower and higher processing. The current paper investigates that hypothesis using the WGC measures from the thalamus in addition to those from the cortex. We compared age-related WGC changes in the thalamus to those in the cortex. To capture the simultaneity of this change across the two structures, we devised a metric capturing the co-development of the thalamus and cortex (CoDevTC), proportional to the magnitude of cortical and thalamic age-related WGC change. We calculated this metric for each of the subjects in a large homogeneous sample taken from the Autism Brain Imaging Data Exchange (ABIDE) (N = 434). We used structural MRI data from the largest high-quality cross-sectional sample (NYU) as well as two other large high-quality sites, GU and OHSU, all three using Siemens 3T scanners. We observed that the co-development features in ASD and TD exhibit contrasting patterns; specifically, some higher-order thalamic nuclei, such as the lateral dorsal nucleus, exhibited reduction in codevelopment with most of the cortex in ASD compared to TD. Moreover, this difference in the CoDevTC pattern correlates with a number of behavioral measures across multiple cognitive and physiological domains. The results support previous notions of altered connectivity in autism, but add more specific evidence about the heterogeneity in thalamocortical development that elucidates the mechanisms underlying the clinical features of ASD.

Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain. We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR. Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens. These findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

Broad transcriptomic dysregulation occurs across the cerebral cortex in ASD

Neuropsychiatric disorders classically lack defining brain pathologies, but recent work has demonstrated dysregulation at the molecular level, characterized by transcriptomic and epigenetic alterations1–3. In autism spectrum disorder (ASD), this molecular pathology involves the upregulation of microglial, astrocyte and neural–immune genes, the downregulation of synaptic genes, and attenuation of gene-expression gradients in cortex1,2,4–6. However, whether these changes are limited to cortical association regions or are more widespread remains unknown. To address this issue, we performed RNA-sequencing analysis of 725 brain samples spanning 11 cortical areas from 112 post-mortem samples from individuals with ASD and neurotypical controls. We find widespread transcriptomic changes across the cortex in ASD, exhibiting an anterior-to-posterior gradient, with the greatest differences in primary visual cortex, coincident with an attenuation of the typical transcriptomic differences between cortical regions. Single-nucleus RNA-sequencing and methylation profiling demonstrate that this robust molecular signature reflects changes in cell-type-specific gene expression, particularly affecting excitatory neurons and glia. Both rare and common ASD-associated genetic variation converge within a downregulated co-expression module involving synaptic signalling, and common variation alone is enriched within a module of upregulated protein chaperone genes. These results highlight widespread molecular changes across the cerebral cortex in ASD, extending beyond association cortex to broadly involve primary sensory regions.

Disrupted functional connectivity of the primary auditory cortex in autism

Autism Spectrum Disorder (ASD) has been found to influence hearing and sensory integration, while brain functional connectivity in ASD has been repeatedly shown to be atypical. However, functional connectivity of the auditory cortex in ASD has not been well studied. In the current study, we used resting-state functional magnetic resonance imaging data, provided by the Autism Brain Imaging Data Exchange (ABIDE), to examine functional connectivity of the primary auditory cortex in ASD. The study subjects included 68 individuals with ASD and 77 individuals without ASD. In the primary dataset, the ASD group showed lesser functional connectivity between the auditory cortex and four regions: the medial occipital cortex, primary motor cortex, insular cortex, and Wernicke's area. In the replication dataset (44 individuals with ASD and 39 individuals without ASD), reduced connectivity to the medial occipital cortex and primary motor cortex was replicated among these four regions, which have previously been shown to be influenced by ASD. Thus, the reduced functional connectivity to these indicated regions may partly explain deficient sensory integration associated with ASD.

Decreased number and increased activation state of astrocytes in gray and white matter of the prefrontal cortex in autism.

The cerebral cortex presents with alterations in the number of specific cell types in autism spectrum disorder (ASD). Astrocytes have many functions in the brain including a role in higher cognitive functions and in inflammatory brain processes. Therefore, an alteration in number, function, and/or activation state of astrocytes, could be present in ASD. We quantified astrocyte number in the gray and white matter of the prefrontal cortex-BA9, BA46, and BA47-in 15 ASD and 15 age- and sex-matched control cases. We labeled astrocytes with antibodies against the protein GFAP and S100β, markers of astrocytes. We found a significant decrease in the number of astrocytes in the gray and white matter of all prefrontal areas of interest with both markers. We also found an increased state of activation of GFAP+ astrocytes in all areas. A reduced number of astrocytes in the cerebral cortex in ASD could lead to impaired synaptic function and disrupted connectivity. An increased astrocyte activation may indicate a chronic mild inflammatory state of the cerebral cortex in ASD. Overall, we found that astrocytes are disrupted in ASD.

Disrupted functional connectivity between the nucleus accumbens and posterior cingulate cortex in autism spectrum disorder.

Dysfunctions in the basal ganglia have been repeatedly found in autism spectrum disorder (ASD). The nucleus accumbens (NAcc) is known for its central role in social functions and also in its abnormality in ASD. In this study, whole-brain functional connectivity of the NAcc was examined to isolate brain regions that are differently connected to the NAcc in autism, using resting-state functional MRI (rs-fMRI) data. In the initial dataset, 68 individuals with ASD (13.13 ± 2.41 years old) and 77 typically developing individuals (14.79 ± 3.57 years old) were compared. The precuneus cortex, lingual gyrus, thalamus, dorsal striatum, anterior cingulate cortex and posterior cingulate cortex showed weaker connectivity to the NAcc in the group with ASD. Among these regions, dysconnectivity of the posterior cingulate cortex (PCC) was replicated in the replication dataset, with 78 individuals with ASD and 105 without ASD. This study suggests that the dysconnectivity between the NAcc and PCC may account for social dysfunctions in ASD.

Small Nucleus Accumbens and Large Cerebral Ventricles in Infants and Toddlers Prior to Receiving Diagnoses of Autism Spectrum Disorder.

Early interventions for autism spectrum disorder (ASD) are increasingly available, while only 42-50% of ASD children are diagnosed before 3 years old (YO). To identify neuroimaging biomarkers for early ASD diagnosis, we evaluated surface- and voxel-based brain morphometry in participants under 3YO who were later diagnosed with ASD. Magnetic resonance imaging data were retrospectively obtained from patients later diagnosed with ASD at Boston Children's Hospital. The ASD participants with comorbidities such as congenital disorder, epilepsy, and global developmental delay/intellectual disability were excluded from statistical analyses. Eighty-five structural brain magnetic resonance imaging images were collected from 81 participants under 3YO and compared with 45 images from 45 gender- and age-matched nonautistic controls (non-ASD). Using an Infant FreeSurfer pipeline, 236 regionally distributed measurements were extracted from each scan. By t-tests and linear mixed models, the smaller nucleus accumbens and larger bilateral lateral, third, and fourth ventricles were identified in the ASD group. Vertex-wise t-statistical maps showed decreased thickness in the caudal anterior cingulate cortex and increased thickness in the right medial orbitofrontal cortex in ASD. The smaller bilateral accumbens nuclei and larger cerebral ventricles were independent of age, gender, or gestational age at birth, suggesting that there are MRI-based biomarkers in prospective ASD patients before they receive the diagnosis and that the volume of the nucleus accumbens and cerebral ventricles can be key MRI-based early biomarkers to predict the emergence of ASD.

Neuronal and glial cell number is altered in a cortical layer-specific manner in autism.

The cerebral cortex affected with autism spectrum disorder presents changes in the number of neurons and glia cells, possibly leading to a dysregulation of brain circuits and affecting behavior. However, little is known about cell number alteration in specific layers of the cortex in autism spectrum disorder. We found an increase in the number of neurons and a decrease in the number of astrocytes in specific layers of the prefrontal cortex in postmortem human brains from autism spectrum disorder cases. We hypothesize that this may be due to a failure in neural stem cells to shift differentiation from neurons to glial cells during prenatal brain development. These data provide key anatomical findings that contribute to the bases of autism spectrum disorder pathogenesis.

Genome-wide, integrative analysis of circular RNA dysregulation and the corresponding circular RNA-microRNA-mRNA regulatory axes in autism.

Circular RNAs (circRNAs), a class of long noncoding RNAs, are known to be enriched in mammalian neural tissues. Although a wide range of dysregulation of gene expression in autism spectrum disorder (ASD) have been reported, the role of circRNAs in ASD remains largely unknown. Here, we performed genome-wide circRNA expression profiling in postmortem brains from individuals with ASD and controls and identified 60 circRNAs and three coregulated modules that were perturbed in ASD. By integrating circRNA, microRNA, and mRNA dysregulation data derived from the same cortex samples, we identified 8170 ASD-associated circRNA-microRNA-mRNA interactions. Putative targets of the axes were enriched for ASD risk genes and genes encoding inhibitory postsynaptic density (PSD) proteins, but not for genes implicated in monogenetic forms of other brain disorders or genes encoding excitatory PSD proteins. This reflects the previous observation that ASD-derived organoids show overproduction of inhibitory neurons. We further confirmed that some ASD risk genes (NLGN1, STAG1, HSD11B1, VIP, and UBA6) were regulated by an up-regulated circRNA (circARID1A) via sponging a down-regulated microRNA (miR-204-3p) in human neuronal cells. Particularly, alteration of NLGN1 expression is known to affect the dynamic processes of memory consolidation and strengthening. To the best of our knowledge, this is the first systems-level view of circRNA regulatory networks in ASD cortex samples. We provided a rich set of ASD-associated circRNA candidates and the corresponding circRNA-microRNA-mRNA axes, particularly those involving ASD risk genes. Our findings thus support a role for circRNA dysregulation and the corresponding circRNA-microRNA-mRNA axes in ASD pathophysiology.

M57 THE IMPACT OF COPY NUMBER VARIANTS ON BRAIN MORPHOMETRY

Autism spectrum disorders (ASD) have been associated with atypical cortical gray and subcortical white matter development. Neurodevelopmental theories postulate that a relation between cortical maturation and structural brain connectivity may exist. We therefore investigated the development of gyrification and white matter connectivity and their relationship in individuals with ASD and their typically developing peers.T1- and diffusion-weighted images were acquired from a representative sample of 30 children and adolescents with ASD (aged 8–18 years), and 29 typically developing children matched for age, sex, hand preference, and socioeconomic status. The FreeSurfer suite was used to calculate cortical volume, surface area, and gyrification index. Measures of structural connectivity were estimated using probabilistic tractography and tract-based spatial statistics (TBSS).Left prefrontal and parietal cortex showed a relative, age-dependent decrease in gyrification index in children and adolescents with ASD compared to typically developing controls. This result was replicated in an age-and IQ-matched sample provided by the Autism Brain Imaging Data Exchange (ABIDE) initiative. Furthermore, tractography and TBSS showed a complementary pattern in which left prefrontal gyrification was negatively related to radial diffusivity in the forceps minor in participants with ASD.The present study builds on earlier findings of abnormal gyrification and structural connectivity in the prefrontal cortex in ASD. It provides a more comprehensive neurodevelopmental characterization of ASD, involving interdependent changes in microstructural white and cortical gray matter. The findings of related abnormal patterns of gyrification and white matter connectivity support the notion of the intertwined development of 2 major morphometric domains in ASD.

Sensory-to-Cognitive Systems Integration Is Associated With Clinical Severity in Autism Spectrum Disorder

Impaired multisensory integration in autism spectrum disorder (ASD) may arise from functional dysconnectivity among brain systems. Our study examines the functional connectivity integration between primary modal sensory regions and heteromodal processing cortex in ASD, and whether abnormalities in network integration relate to clinical severity. We studied a sample of 55 high-functioning ASD and 64 healthy control (HC) male children and adolescents (total n= 119, age range 7-18 years). Stepwise functional connectivity analysis (SFC) was applied to resting state functional magnetic resonance images (rsfMRI) to characterize the connectivity paths that link primary sensory cortices to higher-order brain cognitive functional circuits and to relate alterations in functional connectivity integration with three clinical scales: Social Communication Questionnaire, Social Responsiveness Scale, and Vineland Adaptive Behavior Scales. HC displayed typical functional connectivity transitions from primary sensory systems to association areas, but the ASD group showed altered patterns of multimodal sensory integration to heteromodal systems. Specifically, compared to the HC group, the ASD group showed the following: (1) hyperconnectivity in the visual cortex at initial link step distances; (2) hyperconnectivity between sensory unimodal regions and regions of the default mode network; and (3) hypoconnectivity between sensory unimodal regions and areas of the fronto-parietal and attentional networks. These patterns of hyper- and hypoconnectivity were associated with increased clinical severity in ASD. Networkwise reorganization in high-functioning ASD individuals affects strategic regions of unimodal-to-heteromodal cortical integration predicting clinical severity. In addition, SFC analysis appears to be a promising approach for studying the neural pathophysiology of multisensory integration deficits in ASD.

Diffusion tensor imaging in neurodevelopmental disorders

Autism spectrum disorders (ASD) have been associated with atypical cortical gray and subcortical white matter development. Neurodevelopmental theories postulate that a relation between cortical maturation and structural brain connectivity may exist. We therefore investigated the development of gyrification and white matter connectivity and their relationship in individuals with ASD and their typically developing peers.T1- and diffusion-weighted images were acquired from a representative sample of 30 children and adolescents with ASD (aged 8–18 years), and 29 typically developing children matched for age, sex, hand preference, and socioeconomic status. The FreeSurfer suite was used to calculate cortical volume, surface area, and gyrification index. Measures of structural connectivity were estimated using probabilistic tractography and tract-based spatial statistics (TBSS).Left prefrontal and parietal cortex showed a relative, age-dependent decrease in gyrification index in children and adolescents with ASD compared to typically developing controls. This result was replicated in an age-and IQ-matched sample provided by the Autism Brain Imaging Data Exchange (ABIDE) initiative. Furthermore, tractography and TBSS showed a complementary pattern in which left prefrontal gyrification was negatively related to radial diffusivity in the forceps minor in participants with ASD.The present study builds on earlier findings of abnormal gyrification and structural connectivity in the prefrontal cortex in ASD. It provides a more comprehensive neurodevelopmental characterization of ASD, involving interdependent changes in microstructural white and cortical gray matter. The findings of related abnormal patterns of gyrification and white matter connectivity support the notion of the intertwined development of 2 major morphometric domains in ASD.

Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons

Autism spectrum disorder (ASD) is highly heritable but genetically heterogeneous. The affected neural circuits and cell types remain unclear and may vary at different developmental stages. By analyzing multiple sets of human single cell transcriptome profiles, we found that ASD candidates showed relatively enriched gene expression in neurons, especially in inhibitory neurons. ASD candidates were also more likely to be the hubs of the co-expression gene module that is highly expressed in inhibitory neurons, a feature not detected for excitatory neurons. In addition, we found that upregulated genes in multiple ASD cortex samples were enriched with genes highly expressed in inhibitory neurons, suggesting a potential increase of inhibitory neurons and an imbalance in the ratio between excitatory and inhibitory neurons in ASD brains. Furthermore, the downstream targets of several ASD candidates, such as CHD8, EHMT1 and SATB2, also displayed enriched expression in inhibitory neurons. Taken together, our analyses of single cell transcriptomic data suggest that inhibitory neurons may be a major neuron subtype affected by the disruption of ASD gene networks, providing single cell functional evidence to support the excitatory/inhibitory (E/I) imbalance hypothesis.

Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism.

Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.

Network component analysis reveals developmental trajectories of structural connectivity and specific alterations in autism spectrum disorder.

The structural organization of the brain can be characterized as a hierarchical ensemble of segregated modules linked by densely interconnected hub regions that facilitate distributed functional interactions. Disturbances to this network may be an important marker of abnormal development. Recently, several neurodevelopmental disorders, including autism spectrum disorder (ASD), have been framed as disorders of connectivity but the full nature and timing of these disturbances remain unclear. In this study, we use non-negative matrix factorization, a data-driven, multivariate approach, to model the structural network architecture of the brain as a set of superposed subnetworks, or network components. In an openly available dataset of 196 subjects scanned between 5 and 85 years we identify a set of robust and reliable subnetworks that develop in tandem with age and reflect both anatomically local and long-range, network hub connections. In a second experiment, we compare network components in a cohort of 51 high-functioning ASD adolescents to a group of age-matched controls. We identify a specific subnetwork representing an increase in local connection strength in the cingulate cortex in ASD (t = 3.44, P < 0.001). This work highlights possible long-term implications of alterations to the developmental trajectories of specific cortical subnetworks. Hum Brain Mapp 38:4169-4184, 2017. © 2017 Wiley Periodicals, Inc.

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

Children with ASD show links between aberrant sound processing, social symptoms, and atypical auditory interhemispheric and thalamocortical functional connectivity

Autism spectrum disorder (ASD) is a complex and prevalent neurodevelopmental disorder characterized by social and communicative deficits, as well as repetitive behaviors and atypical sensitivity to sensory stimulation. Alterations in network connectivity are widely recognized, but their interplay with social and sensory symptoms remains largely unclear. Here, functional magnetic resonance imaging and diagnostic and behavioral assessments were used in a cohort of children and adolescents with ASD (n=40) and matched typically developing (TD, n=38) controls to examine the relation between auditory processing, interhemispheric and thalamocortical network connectivity, and social-behavioral symptom severity. We found that atypical processing of sounds was related to social, cognitive, and communicative impairments. Additionally, severity of sensory processing deficits and lower verbal IQ were related to reduced interhemispheric connectivity of auditory cortices in ASD. Increased connectivity between the thalamus and auditory cortex in ASD, however, was associated with reduced cognitive and behavioral symptomatology, suggesting that thalamocortical overconnectivity might reflect a compensatory mechanism in ASD. These findings provide novel evidence for links between auditory sensory deficits and impairments in social interaction and communication.

Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism.

Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.