Habenula alterations in resting state functional connectivity among autistic individuals

Background The reward-based theoretical framework of autism suggests that altered reward circuitry contributes to core symptoms. Recent prior research has revealed autism-related structural alterations in the habenula, a small epithalamic structure associated with motivation and emotion; however, potential alterations in functional connectivity (FC) remain unexplored.

Anatomical and resting state functional magnetic resonance imaging (rs-fMRI) data were accessed for 1,479 participants (N=661 autism; agem: 16.68±8.23 years) in the Autism Brain Imaging Data Exchange (ABIDE). To investigate habenula alterations, we conducted a whole-brain resting state FC analysis using manually delineated subject-specific seeds, followed by regression analyses to explore age and brain-behavior interactions.

Across the entire sample, extensive habenula connectivity was observed within the midbrain dopaminergic reward system. Compared to neurotypical (NT) controls, autistic participants exhibited significantly increased habenular connectivity with the bilateral middle and superior temporal gyri. From childhood to early adulthood, autistic adolescents displayed an accelerated developmental habenula FC trajectory than NTs with the cingulate gyrus. Between groups, habenula hyperconnectivity was inversely associated with behavioral scores for social motivation and communication.

This study provides novel evidence of habenula connectivity alterations in autism, highlighting atypical FC with sensory processing regions. Further findings suggest that habenula circuitry develops differently among autistic adolescents, with links between habenula hyperconnectivity and social behaviors. Taken together, these results contribute to emerging evidence that the dopaminergic reward system may play a critical role in the pathophysiology of autism. Competing Interest Statement The authors have declared no competing interest. Footnotes Habenular Region of Interest section was updated to provide details on the manual delineation process, along with an updated Figure 1 showing this process; Authors Sangoi and Keller were added to the manuscript as they provided substantial contributions to the manual habenula delineation process; the Methods, Results and Discussion sections were revised to reflect the updated findings using the manually delineated regions of interest, including Tables 1, 2, 3, and 4, and Figures 2, 3, and 4; Methods were further revised to include additional details regarding the quality control process; Discussion was revised to include partial voluming effects as a limitation; Supplement was updated to include additional participant demographic details (Figures S1, S2, S3), a Model Selection section to provide transparency about our analytic approach, and a series of comparisons between the habenula connectivity maps observed in the current study with those that have been previously published in the literature (Figures S4, S5).