Probing the Neurodynamic Mechanisms of Cognitive Flexibility in Depressed Individuals with Autism Spectrum Disorder

Introduction: Autism spectrum disorder (ASD) is characterized by deficits in social behavior and executive function (EF), particularly in cognitive flexibility. Whether transcranial magnetic stimulation (TMS) can improve cognitive outcomes in patients with ASD remains an open question. We examined the acute effects of prefrontal TMS on cortical excitability and fluid cognition in individuals with ASD who underwent TMS for refractory major depression. Methods: We analyzed data from an open-label pilot study involving nine participants with ASD and treatment-resistant depression who received 30 sessions of accelerated theta burst stimulation of the dorsolateral prefrontal cortex, either unilaterally or bilaterally. Electroencephalography data were collected at baseline and 1, 4, and 12-weeks posttreatment and analyzed using a mixed-effects linear model to assess changes in regional cortical excitability using three models of spectral parametrization. Fluid cognition was measured using the National Institutes of Health Toolbox Cognitive Battery. Results: Prefrontal TMS led to a decrease in prefrontal cortical excitability and an increase in right temporoparietal excitability, as measured using spectral exponent analysis. This was associated with a significant improvement in the NIH Toolbox Fluid Cognition Composite score and the Dimensional Change Card Sort subtest from baseline to 12 weeks posttreatment (t = 3.79, p = 0.005, n = 9). Improvement in depressive symptomatology was significant (HDRS-17, F (3, 21) = 28.49, p < 0.001) and there was a significant correlation between cognitive improvement at week 4 and improvement in depression at week 12 (r = 0.71, p = 0.05). Conclusion: These findings link reduced prefrontal excitability in patients with ASD and improvements in cognitive flexibility. The degree to which these mechanisms can be generalized to ASD populations without Major Depressive Disorder remains a compelling question for future research.