Multiscale Mechanisms that Underlie Intermittent Theta-burst Stimulation in Post-stroke Motor Recovery: From...

Although intermittent theta-burst stimulation (iTBS) has emerged as a promising time-efficient and non-invasive neuromodulatory strategy in post-stroke motor rehabilitation, its clinical efficacy remains variable across patients and studies. In this review, we propose a multiscale framework for understanding how iTBS may support post-stroke motor recovery while emphasizing the current limits of translational evidence. At the microscopic and mesoscopic levels, preclinical studies suggest that iTBS contributes to early post-stroke repair by modulating ferroptosis, endoplasmic reticulum stress-related apoptosis, pyroptosis, neuroimmune responses involving astrocytes, white matter integrity, neurovascular remodeling, and neurotrophic signaling. These mechanisms are acknowledged to provide a biological substrate for post-stroke plasticity. At the clinical neurophysiological and neuroimaging levels, the available human studies indicate that iTBS modulates corticospinal excitability, cortical oscillatory dynamics, interhemispheric interactions, and large-scale motor-network organization. We herein further discuss the determinants of treatment variability, including stroke stage, lesion location, corticospinal tract integrity, baseline impairment severity, stimulation target, dosage parameters, co-interventions, genetic polymorphisms, and endogenous brain state. Current evidence remains limited due to small-sample size, heterogeneous protocols, incomplete safety and dose reporting, and temporal and geographic concentrations of the available studies. We posit that investigators in their future studies prioritize standardized reporting, multicenter and internationally diverse trials, biomarker-guided stratification, individualized electric-field modeling, and closed-loop stimulation strategies. Overall, iTBS remains a promising but protocol-sensitive and patient-dependent intervention, and this review provides a hypothesis-generating framework for future mechanistic and clinical studies in post-stroke motor rehabilitation.