White matter alterations linked to social cognitive improvements following theta burst stimulation of the right inferior frontal gyrus in autism

Objectives Intermittent theta burst stimulation (iTBS) over the right inferior frontal gyrus (RIFG) has been shown to improve social cognitive function in autistic individuals. However, whether this intervention modulates underlying brain structure remains unknown. This study aimed to investigate the impact of iTBS over the RIFG on white matter macro- and micro-structure in intellectually able autistic children and young adults. Materials and methods In this 8-week double-blind, parallel, sham-controlled trial, autistic participants (aged 8–30 years) were randomized to receive twice-weekly neuro-navigated iTBS targeting the RIFG or sham stimulation using a sham coil applied over the same target. The social cognitive performance was measured with the Frith-Happé Animations Test. Diffusion MRI and behavioral assessments were acquired at baseline, week 8 (immediately after intervention), and week 12 (four-week follow-up). After quality control, data from 26 participants in the active group and 23 in the sham group were included in the final longitudinal whole-brain fixel-based analysis (FBA). Results No significant treatment-by-time interaction emerged: changes in the composite fiber-density-and-cross-section (FDC) metric did not differ between groups at either week 8 or week 12. Within the active group, however, a significant negative association was found between the change in FDC in the rostral body of the corpus callosum and the improvement in social cognitive performance from baseline to week 12. Conclusions An 8-week course of neuro-navigated RIFG iTBS did not produce significant group-level white matter macro/microstructural changes compared to sham stimulation in our autistic cohort. Nevertheless, the finding that individual improvements in social cognition correlated with specific white matter alterations in the active group suggests a potential link between treatment-induced benefits and neural plasticity. Future studies should investigate whether different TBS parameters could induce more pronounced or detectable structural changes on MRI in autistic individuals and further explore the intricate mechanisms underlying observed brain-behavior relationships.