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Background and objectivesIntermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson’s disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity.MethodsA total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS.DiscussionThe findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.