Effects of chronic oxytocin administration on white matter microstructure in autistic adults: a pharmaco-neuroimaging DTI study

Intranasal oxytocin is increasingly recognized as a promising therapeutic candidate for addressing social and stress-regulatory difficulties in individuals with autism spectrum disorder. A growing body of research has demonstrated that oxytocin modulates socio-emotional behavior and influences functional activity within amygdala-centered neural circuits. However, it remains largely unknown whether repeated administration regimens can induce durable neuroplastic changes at the level of white matter microstructure, and to what extent such changes may relate to clinically meaningful behavioral outcomes.

In a double-blind, randomized, placebo-controlled trial (EudraCT 2014-000586-45), we investigated the effects of a four-week intranasal oxytocin administration regimen (24 IU daily) on white matter organization in a sample of 27 young adult men with autism. Diffusion tensor imaging (DTI) data were acquired at baseline (T0), immediately following the intervention (T1), and at follow-up intervals of four weeks (T2) and one year (T3). Using tractography analyses, we specifically examined segment-wise fractional anisotropy (FA) within key amygdala-centered white matter tracts implicated, including the bilateral uncinate fasciculus (UF), connecting the amygdala and anterior temporal regions with the orbitofrontal cortex; the inferior longitudinal fasciculus (ILF), linking occipital visual regions to the anterior temporal lobe; and the inferior fronto-occipital fasciculus (IFOF), connecting occipital and posterior temporal regions with the prefrontal cortex.

Oxytocin administration resulted in spatially selective and tract-specific alterations in white matter microstructure. Specifically, bilateral increases in FA were observed in the uncinate fasciculus, suggesting enhanced integrity of fronto-limbic pathways connecting the amygdala with the orbitofrontal cortex. In contrast, the ILF and IFOF exhibited a hemispherically lateralized pattern, characterized by FA increases predominantly in right-hemispheric segments alongside relative reductions in homologous left-sided segments. Notably, these microstructural changes emerged immediately following the four-week administration period and remained stable at both follow-up assessments, indicating sustained neuroplastic adaptations.

Importantly, structural changes were associated with clinically relevant behavioral improvements, indicating that increases in FA within anterior segments of the bilateral UF and right IFOF were significantly associated with enhanced social responsiveness, as measured by the Social Responsiveness Scale (SRS-A), and with reduced avoidant attachment, as indexed by the State Adult Attachment Measure (SAAM). These findings suggest that structural remodeling within amygdala-centered pathways may represent a neurobiological mechanism underlying oxytocin’s beneficial effects on socio-emotional functioning.

Taken together, the present findings provide novel evidence that repeated intranasal oxytocin administration can induce enduring microstructural reorganization in white matter tracts central to socio-emotional processing in adult men with autism, although the modest and exclusively male sample warrants caution in generalizing these results and highlights the need for replication in larger and more diverse cohorts, including women and younger populations.

More broadly, these results underscore the utility of advanced neuroimaging markers in capturing treatment-induced neuroplasticity and contribute to a more mechanistic understanding of oxytocin’s therapeutic potential across neuropsychiatric conditions characterized by social difficulties.

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