Alpha rhythm subharmonics underlie responsiveness to theta burst stimulation via calcium metaplasticity

Abstract Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique to modulate brain activity, often used in treating Major Depressive Disorder (MDD) by targeting fronto-limbic circuitry. Despite its clinical utility, optimizing rTMS protocols remains challenging due to the complex and variable effects of stimulation parameter changes on synaptic plasticity. Oscillatory brain activity, measurable via Electroencephalography (EEG), serves as a biomarker for functional circuits and treatment response. To better understand the impact of rTMS on brain oscillations and connectivity, we used computational modeling of corticothalamic circuits to explore the mechanisms of stimulus-induced plasticity. We integrated calcium-dependent plasticity (CaDP) with Bienenstock-Cooper-Munro (BCM) metaplasticity formulations in a neural population model of resting-state EEG. By varying protocol parameters, we simulated iTBS effects on spectral power, synaptic efficacy, and calcium concentrations. Our findings highlight a resonance between theta stimulation and individual resting-state alpha rhythms, enhancing incoming excitatory long-term depression (LTD) and inhibitory long-term potentiation (LTP), leading to corticothalamic feed-forward inhibition (FFI). Induced effects were encapsulated by a weakening of corticothalamic loops and enhancement of intrathalamic loops. This work offers a novel paradigm for individualizing iTBS treatments, provides insights into the neurophysiological basis of clinical responsiveness, and offers a framework with which to derive tailored protocols. Competing Interest Statement The authors have declared no competing interest. Footnotes Minor typos and equation term corrections