Lesions Associated With Autism Symptoms Map to a Cerebellar Brain Network in Tuberous Sclerosis Complex

ABSTRACT Objective Autism spectrum disorder (ASD) affects 1 in 36 individuals in the United States and is characterized by impaired social communication and restrictive/repetitive behaviors. Individuals with tuberous sclerosis complex (TSC) have a high incidence of ASD (40%) and exhibit congenital brain lesions (tubers), offering a unique lesion‐based model to investigate the neural circuits underlying ASD symptoms. We tested whether tuber connectivity is associated with specific ASD symptom profiles in TSC patients. Methods Brain tuber locations were analyzed in 115 children with TSC from the TSC Autism Centers of Excellence Research Network. Lesion network mapping was performed using normative resting‐state functional magnetic resonance imaging data from 1000 typically developing 9‐year‐olds to identify brain networks functionally connected to tuber locations. Multivariable linear regression analyses assessed associations between these networks and specific domain subscores on the Autism Diagnostic Observation Schedule (ADOS). Results Greater severity of social affect symptoms was associated with tubers connected to bilateral deep cerebellar nuclei, particularly the right side, localizing to Crus V despite no cerebellar tubers being included in this analysis. No significant associations were found for total ADOS scores or repetitive/restrictive behavior subscores. These effects were independent of age, sex, lesion burden, epilepsy severity, and language ability. Interpretation Social affect impairments in TSC patients with ASD are associated with to functional connectivity between tubers and cerebellar crus V. This symptom‐specific neuroanatomical association supports the concept that different ASD features map to distinct brain circuits and highlights the role of cortico‐cerebellar pathways in early social development.