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Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder.

ABSTRACT: The amygdala is a complex structure with distinct subregions and dissociable functional networks. The laterobasal subregion of the amygdala is hypothesized to mediate the presentation and severity of autism symptoms, although very little data are available regarding amygdala dysfunction at the subregional level. In this study, we investigated the relationship between abnormal amygdalar intrinsic connectivity, autism symptom severity, and anxiety and depressive symptoms. We collected resting state fMRI data on 31 high functioning adolescents and adults with autism spectrum disorder and 38 typically developing (TD) controls aged 14-45. Twenty-five participants with ASD and 28 TD participants were included in the final analyses. ASD participants were administered the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule. Adult participants were administered the Beck Depression Inventory II and the Beck Anxiety Inventory. Functional connectivity analyses were conducted from three amygdalar subregions: centromedial (CM), laterobasal (LB) and superficial (SF). In addition, correlations with the behavioral measures were tested in the adult participants. In general, the ASD group showed significantly decreased connectivity from the LB subregion and increased connectivity from the CM and SF subregions compared to the TD group. We found evidence that social symptoms are primarily associated with under-connectivity from the LB subregion whereas over-connectivity and under-connectivity from the CM, SF and LB subregions are related to co-morbid depression and anxiety in ASD, in brain regions that were distinct from those associated with social dysfunction, and in different patterns than were observed in mildly symptomatic TD participants. Our findings provide new evidence for functional subregional differences in amygdala pathophysiology in ASD. Autism Res 2016, 9: 760-772. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

SUBMITTER: Kleinhans NM

PROVIDER: S-EPMC4909596 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder.

Kleinhans Natalia M NM Reiter Maya A MA Neuhaus Emily E Pauley Greg G Martin Nathalie N Dager Stephen S Estes Annette A

Autism research : official journal of the International Society for Autism Research 20151215 7

The amygdala is a complex structure with distinct subregions and dissociable functional networks. The laterobasal subregion of the amygdala is hypothesized to mediate the presentation and severity of autism symptoms, although very little data are available regarding amygdala dysfunction at the subregional level. In this study, we investigated the relationship between abnormal amygdalar intrinsic connectivity, autism symptom severity, and anxiety and depressive symptoms. We collected resting stat ...[more]

PMID: 26666502

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Project description:Background: Analyses of resting-state functional magnetic resonance imaging (rs-fMRI) have been performed to investigate pathophysiological changes in the brains of patients with autism spectrum disorder (ASD) relative to typically developing controls (CTLs). However, the results of these previous studies, which have reported mixed patterns of hypo- and hyperconnectivity, are controversial, likely due to the small sample sizes and limited age range of included participants. Methods: To overcome this issue, we analyzed multisite neuroimaging data from a large sample (n = 626) of male participants aged between 5 and 29 years (mean age = 13 years). The rs-fMRI data were preprocessed using SPM12 and DPARSF software, and signal changes in 90 brain regions were extracted. Multiple linear regression was used to exclude the effect of site differences in connectivity data. Subcortical-cortical connectivity was computed using connectivities in the hippocampus, amygdala, caudate nucleus, putamen, pallidum, and thalamus. Eighty-eight connectivities in each structure were compared between patients with ASD and CTLs using multiple linear regression with group, age, and age × group interactions, head movement parameters, and overall connectivity as variables. Results: After correcting for multiple comparisons, patients in the ASD group exhibited significant increases in connectivity between the thalamus and 19 cortical regions distributed throughout the fronto-parietal lobes, including the temporo-parietal junction and posterior cingulate cortices. In addition, there were significant decreases in connectivity between the amygdala and six cortical regions. The mean effect size of hyperconnectivity (0.25) was greater than that for hypoconnectivity (0.08). No other subcortical structures showed significant group differences. A group-by-age interaction was observed for connectivity between the thalamus and motor-somatosensory areas. Conclusions: These results demonstrate that pathophysiological changes associated with ASD are more likely related to thalamocortical hyperconnectivity than to amygdala-cortical hypoconnectivity. Future studies should examine full sets of clinical and behavioral symptoms in combination with functional connectivity to explore possible biomarkers for ASD.

Project description:BACKGROUND:Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS:Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20?years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS:Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS:We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS:Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.

Dataset Information

Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder.

Publications

Subregional differences in intrinsic amygdala hyperconnectivity and hypoconnectivity in autism spectrum disorder.

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