Abstract

This study examines habenula resting-state functional connectivity (rsFC) using functional magnetic resonance imaging (fMRI) data among participants with Autism Spectrum Disorder (ASD). The results highlight significant atypical hyperconnectivity in the habenula, particularly with the primary and associative auditory cortices, which play a role in multimodal sensory integration. These findings provide new insights into the potential underlying mechanisms of ASD, linking alterations in reward-based circuitry to deficits in speech and sensory processing. The habenula is suggested to be a critical hub for emotional and motivational processing that underlies adaptive behavior deficits in ASD.

Methods

The participant sample included 587 individuals with ASD and 728 neurotypical (NT) controls from the ABIDE I and II datasets. Phenotypic measures assessed the severity of daily living skills, executive functioning, and social motivation. Resting-state fMRI data were preprocessed using fMRIPrep and MRIQC, and the habenula region of interest (ROI) was manually defined using the MNI 152-subject averaged T1 template brain. Voxelwise time series were extracted for the left and right habenula. rsFC analyses were conducted to identify group-level and age-related alterations in habenula connectivity. Thresholded rsFC maps were generated and decoded using Nilearn and Neurosynth. Z-scored beta coefficients from significant clusters were analyzed using linear regression to examine age-related differences and associations with behavioral symptoms.

Results

Group-level connectivity analyses revealed that group-averaged results showed habenula rsFC with key regions of the dopaminergic reward system, consistent with prior research. Group-difference results (ASD > NT) identified increased habenula connectivity in ASD with the primary and associative auditory cortices. Atypical hyperconnectivity was significantly associated with differences in daily living skills, executive function, and social motivation. Age-related analyses indicated variability in habenula connectivity during adolescence in regions associated with decision-making and adaptive control.

Conclusions

These findings highlight the critical role of the habenula in ASD-related neural mechanisms, suggesting its contribution to alterations in reward-based circuitry and adaptive behavior deficits. The results emphasize the habenula as a central hub for emotional and motivational processing, providing insights into the mechanisms underlying deficits in speech and sensory integration in ASD​