Overview

# Brief Summary (English Version) Tardive Dyskinesia (TD) is a hyperkinetic movement disorder induced by long-term use of dopamine receptor blockers and related drugs. Characterized by involuntary spasms or choreiform movements involving the tongue, lower face, jaw, and limbs (persisting for at least several weeks), TD causes irreversible neurological damage that persists even after discontinuing the causative drugs, significantly impairing patients' functional outcomes [14].

Epidemiologically, TD has an annual incidence of 4-8% and a prevalence ranging from 8.5% to 75.3% across populations. A 2021 survey of long-term hospitalized patients with chronic schizophrenia in Beijing and Hebei Province (China) reported a TD incidence of 41.4% [56], while a 2017 meta-analysis of 41 global antipsychotic studies (2000-2015, involving 11,493 patients) found an average TD prevalence of 25.3% [7]. However, TD treatments remain limited: pharmacological options (e.g., VMAT2 inhibitors, clonazepam, antioxidants, amantadine) lack specificity and show modest efficacy, while non-pharmacological approaches (e.g., botulinum toxin injection, repetitive Transcranial Magnetic Stimulation [rTMS], transcranial direct current stimulation, deep brain stimulation of the globus pallidus) serve only as supplementary therapies-typically reserved for pharmacoresistant cases. Research on combined pharmacologic-nonpharmacologic therapy for TD is scarce, representing a key future research direction [8].

rTMS is a non-invasive neuromodulation technique: time-varying currents in a coil generate magnetic fields that penetrate the scalp and skull to act on brain neurons, inducing depolarization, neural network activation, neurotransmitter release, metabolic changes, and gene expression, thereby producing physiological effects [9]. In recent years, rTMS has gained attention for treating movement disorders (e.g., Parkinson's disease, motor neuron disease, dystonia, essential tremor, Huntington's disease) due to its non-invasiveness, high safety, and repeatability. Studies have reported that rTMS can significantly improve motor symptoms in TD patients [10, 11]; however, existing research is limited by small sample sizes, conventional treatment parameters, large inter-individual variability, and unclear long-term efficacy.

rTMS efficacy in TD is strongly influenced by parameters including stimulation targets, localization methods, sequences, and cycles. Previously reported targets (Primary Motor Cortex [M1], Dorsolateral Prefrontal Cortex [DLPFC]) [10, 11] have shown suboptimal outcomes. Recent studies on Huntington's chorea, tic disorders, and levodopa-induced dyskinesia indicate that rTMS targeting the preSupplementary Motor Area (pre-SMA)-a brain region critical for motor planning, task switching, acquisition of new motor skills, and motor inhibition-effectively alleviates hyperkinetic symptoms. Additionally, Gordon et al. (2023) identified the Somatosensory-Cognitive-Action Network (SCAN), which regulates overall motor planning, control, and coordination and has demonstrated roles in managing movement disorders [14]. Thus, pre-SMA and SCAN represent promising novel targets for TD treatment. For localization, optical navigation (using personalized MRI) is the most accurate and yields the best therapeutic effects, compared to manual localization or positioning caps [15]. Regarding stimulation sequences, 1Hz and 20Hz rTMS have shown efficacy but with short-lived effects. Continuous theta-Burst Stimulation (cTBS)-a specialized rTMS mode that delivers rapid pulse trains mimicking endogenous theta-wave bursts-provides higher therapeutic doses in less time, enabling more durable efficacy and effectively reducing motor cortex excitability [16, 17]. Given that excessive motor cortex excitability contributes to TD's involuntary hyperkinesia [17], cTBS is expected to improve TD motor symptoms as a novel adjuvant therapy.

Therefore, this study aims to investigate the effect of cTBS (under precise localization) on improving motor symptoms in patients with TD.

Eligibility

Inclusion Criteria:

• (1) Age between 18 and 65 years; (2) Patients whose diagnosis is consistent with the tardive dyskinesia (TD) diagnostic criteria defined by the Schooler-Kane criteria, with a disease duration of at least 3 months before screening, and a history of treatment with dopamine receptor antagonists for at least 3 months (a minimum of 1 month for patients aged ≥ 60 years); other diseases that may cause involuntary movements are excluded

Exclusion Criteria:(1) Diagnosed with movement disorders other than tardive dyskinesia (TD); (2) A history of focal brain injury or severe leukoencephalopathy (Fazekas grade 3 or higher) identified on previous head MRI/CT; (3) A personal history of epilepsy, unexplained loss of consciousness, or current use of anticonvulsant medications for seizure management; (4) Presence of metallic medical devices in the body (e.g., cardiac pacemakers, cochlear implants), other metallic foreign bodies, or any electronic devices implanted in the body; or having other contraindications to repetitive Transcranial Magnetic Stimulation (rTMS); (5) Presence of contraindications to MRI scanning, such as having metallic implants in the body or claustrophobia

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