iTBS Stimulation of the Bilateral IFG/IPL Alters the Oscillatory Pattern in ASD

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by impairments in social communication, reciprocity, and adaptive behavior. Converging neurobiological evidence suggests that these clinical features arise from aberrant connectivity and dysregulated neuronal oscillations across distributed brain networks. In particular, dysfunction within the mirror neuron regions, concentrated in the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL), has been implicated in deficits of imitation, empathy, and social cognition in ASD. Non-invasive neuromodulation using repetitive transcranial magnetic stimulation (rTMS) has shown modest behavioral benefits in ASD. However, most studies apply the conventional protocols targeting the dorsolateral prefrontal cortex. The effects of intermittent theta-burst stimulation (iTBS), a potent excitatory rTMS protocol targeting the mirror neuron regions, on the oscillatory dynamics in ASD remain largely unexplored.

To investigate whether iTBS targeting the bilateral IFG and IPL modulates EEG-derived oscillatory activity in adolescents with ASD and to explore the relationship between oscillatory changes and social reciprocity.

Six adolescents with Level I or II ASD (ages 13-18) underwent bilateral iTBS targeting the IFG and IPL using a figure-of-eight coil and standardized theta-burst parameters. Participants were randomized to receive either 18 active iTBS sessions or a waitlist-controlled crossover design (9 sham followed by 9 active sessions). Standard 21-channel EEG recordings were obtained during the first (EEG-1) and final (EEG-2) active stimulation sessions, including pre- and post-stimulation epochs. Power spectral analyses were conducted across frequency bands (delta through gamma). Behavioral outcomes were assessed using the Childhood Autism Rating Scale, Second Edition (CARS2), administered pre- and post-intervention.

All participants tolerated the intervention without adverse effects. Behavioral analysis demonstrated a significant reduction in CARS2 scores following iTBS and is reported in detail in our prior clinical outcomes manuscript, consistent with improved social reciprocity (p < 0.001). EEG analysis revealed an immediate post-stimulation increase in gamma-band power during EEG-1 in five of six participants, whereas lower-frequency bands exhibited variable responses. In contrast, EEG-2 showed no consistent post-stimulation gamma enhancement. Net comparisons between EEG-1 and EEG-2 demonstrated attenuation of the initial gamma response in the same five participants. At the group level, gamma percent change did not reach statistical significance at EEG-1 (p = 0.12) or EEG-2 (p = 0.66), and exploratory comparisons between the 9-active versus 18-active arms did not reach statistical significance. While ipsi-directional changes in gamma power and CARS2 scores were observed in four participants, correlation was not identified in this pilot sample.

Bilateral iTBS targeting the IFG and IPL induces a transient enhancement of gamma oscillations in adolescents with ASD that attenuates with repeated stimulation. This pattern is consistent with adaptive homeostatic plasticity (metaplasticity) within excitatory-inhibitory circuits, potentially mediated by GABAergic interneurons. These findings support the feasibility of EEG as an objective biomarker of neuromodulatory engagement in ASD and highlight the importance of network-level and oscillatory mechanisms in interpreting therapeutic responses. Larger, sham-controlled studies incorporating multimodal biomarkers are warranted to clarify clinical relevance and optimize personalized neuromodulation strategies.