Habenula Alterations in Resting-State Functional Connectivity Among Autistic Individuals

The reward-based theoretical framework of autism suggests that altered reward circuitry contributes to core symptoms. Recent 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 data were accessed for 1479 participants (autism n = 661; mean age = 16.68 ± 8.23 years) in the ABIDE (Autism Brain Imaging Data Exchange). To investigate habenula alterations, we conducted a whole-brain resting-state FC analysis using manually delineated participant-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 with neurotypical (NT) control participants, 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 with the cingulate gyrus compared with NT participants. 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.