Abstract
Dysfunction of corticostriatal circuitry is related to the emergence of self-injurious behavior (SIB) in autism spectrum disorder (ASD). Despite mounting interest in circuit-based interventions for severe, refractory SIB, the lack of causal evidence linking modulation of corticostriatal networks to changes in SIB has limited the advancement of effective, targeted therapies. In this study, we demonstrate that electrical stimulation of the nucleus accumbens (NAcc) mitigates SIB and induces structural changes along corticostriatal circuits in a mouse model relevant for ASD and children with severe SIB undergoing NAcc-targeted deep brain stimulation. In BTBR T(+) Itpr3(tf)/J mice, NAcc stimulation selectively reduced injurious self-grooming-a behavioral metric of SIB-and led to morphological changes in corticostriatal networks. In children with severe SIB, electric stimulation at a locus of optimal therapeutic response within the NAcc engaged widespread sensorimotor, limbic, and striatal networks and induced longitudinal structural changes in fronto-limbic-striatal brain regions. These findings highlight the role of the fronto-limbic-striatal network in SIB regulation and support corticostriatal neuromodulation as a mechanistic therapy for these extreme behaviors.