Altered Hippocampal-Cortical Gray-Matter Structural Covariance in Males with Autism Spectrum Disorder

Background: Inter-regional covariation of brain structural volumetry has been suggested to reflect systemic neurodevelopmental architectural processes. In individuals with autism spectrum disorder (ASD), several pathophysiological brain structural abnormalities have been reported to be involved across various regions. In particular, aberrant morphometry of the hippocampus, despite mixed results, may be implicated in specific memory patterns in ASD. How brain systems structurally covary with the hippocampus in ASD remains unclear. 

Objectives: We investigated the patterns of hippocampal morphometry relating to various structural indices across cortical regions in ASD and typically developing (TD) individuals. We hypothesized that to the extent that aberrant hippocampal structure captures systemic neurodevelopmental disorders in ASD, positive associations should be observed across various cortical areas. By contrast, in TD, hippocampal structure should be less associated with the morphometry of other cortical regions.

Methods: Structural MRI imaging data (3 Tesla system) of 117 males with ASD (aged 14.6 ± 4.4 years) and 108 TD males (aged 15.0 ± 5.9 years), with age ranging from 7 to 30 years were acquired. Surface-based morphometry analysis was implemented using Freesurfer ver. 5.2.0, which parcellated gray matter into cortical areas (based on the Desikan-Kiliany atlas) and hippocampus for each participant. Partial correlations, controlling for age, intelligence and intracranial volume, were undertaken to assess the significance and differences in volumetric covariance between the bilateral hippocampus and the ipsilateral cortical regions, respectively, among ASD and TD males. All the correlation results were corrected for multiple comparisons using False-Discovery Rate (q < 0.05).

Results: In the TD group, the volume of the right hippocampus was positively correlated with that of all the major right-hemispheric cortical regions, including frontal, temporal, parietal, occipital, and cingulate cortices; and there were less extensively positive associations between the volume of left hippocampus and the left hemispheric frontal, parietal, occipital, and cingulate cortices. In the ASD group, right hippocampal volume was positively correlated with the volume of the right lingual gyrus, middle temporal gyrus, pars opercularis, parahippocampus, and posterior cingulate cortex; the left hippocampal volume was only structurally covaried with the medial orbital frontal gyrus.  

Conclusions: In general, hippocampal-cortical structural correlations were more widespread and positive in the TD group, while this covaried relationship was reduced in the ASD group. Our findings point to a systemic pattern of neuropathological gray matter development across various brain regions in individuals with ASD that is distinct from more homogeneously inter-regional morphometric co-variations in TD individuals. The functional significance of aberrant hippocampal-cortical structural correlations in ASD warrants further investigation.