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. Methods: Anatomical and resting state functional magnetic resonance imaging (rs-fMRI) data were accessed for 1,584 participants (N=705 autism; mean age: 16.26 plus-or-minus sign 8.15 years) in the Autism Brain Imaging Data Exchange (ABIDE). To investigate habenula alterations, we conducted a whole-brain resting state FC analysis, followed by regression analyses to explore age and brain-behavior interactions. Results: 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 right middle temporal gyrus and bilateral superior temporal gyri. From childhood to early adulthood, habenula FC increased in autistic adolescents, and inversely decreased in NTs, with the left culmen and left parahippocampus. Between groups, habenula hyperconnectivity was inversely associated with behavioral scores for social motivation, executive functioning, and daily living skills, but not social communication. Conclusions: This study provides novel evidence of habenula connectivity alterations in autism, highlighting atypical FC with the auditory cortex. Further findings suggest that habenula circuitry develops differently among autistic adolescents, with links between habenula hyperconnectivity and motivation and adaptive behaviors. Taken together, these results contribute to emerging evidence that the dopaminergic reward system may play a critical role in the pathophysiology of autism.