Theta-burst direct electrical stimulation remodels human brain networks

Patterned brain stimulation is a powerful therapeutic approach for treating a wide range of brain disorders. In particular, theta-burst stimulation (TBS), characterized by rhythmic bursts of 3-8 Hz mirroring endogenous brain rhythms, is delivered by transcranial magnetic stimulation to improve cognitive functions and relieve symptoms of depression. However, the mechanism by which TBS alters underlying neural activity remains poorly understood. In 10 pre-surgical epilepsy participants undergoing intracranial monitoring, we investigated the neural effects of TBS. Employing intracranial EEG (iEEG) during direct electrical stimulation across 29 stimulation cortical locations, we observed that individual bursts of electrical TBS consistently evoked strong neural responses spanning broad cortical regions. These responses exhibited dynamic changes over the course of stimulation presentations including either increasing or decreasing voltage responses, suggestive of short-term plasticity in the amplitude of the local field potential voltage response. Notably, stronger stimulation augmented the mean amplitude and distribution of TBS responses , leading to greater proportion of recording sites demonstrating short-term plasticity. TBS responses were stimulation site-specific and propagated according to the underlying functional brain architecture, as stronger responses were observed in regions with strong baseline effective (cortico-cortical evoked potentials) and functional (low frequency phase locking) connectivity. Further, our findings enabled the predictions of locations where both TBS responses and change in these responses (e.g. short-term plasticity) were observed. Future work may focus on using pre-treatment connectivity alongside other biophysical factors to personalize stimulation parameters, thereby optimizing induction of neuroplasticity within disease-relevant brain networks. ### Competing Interest Statement The authors have declared no competing interest.