Dual-Site Transcranial Magnetic Stimulation of the Supplementary Motor Area and Cerebellum for the Treatment of Essential Tremor.

This study is a randomized, double-blind, placebo-controlled, parallel-group phase II clinical trial designed to investigate the effects of dual-site repetitive transcranial magnetic stimulation (rTMS) in patients with medication-refractory essential tremor. The trial is conducted at the University of São Paulo.

Participants are randomized to receive either active or sham stimulation over five consecutive daily sessions. The active intervention consists of sequential stimulation of two interconnected nodes of the tremor network. Low-frequency rTMS (1 Hz, 110% of resting motor threshold) is first applied over the supplementary motor area in 24 trains with 3-second inter-train intervals, followed by high-frequency stimulation of the cerebellar cortex (10 Hz, 90% of resting motor threshold) delivered in 12 trains with 3-second inter-train intervals. The protocol is designed to modulate cortical motor drive and cerebellar output within the cerebello-thalamo-cortical circuit.

The stimulation parameters and dual-site approach were selected based on neurophysiological and neuroimaging evidence supporting a network-based model of essential tremor, as well as on pilot data demonstrating clinically meaningful tremor reduction following combined stimulation of the supplementary motor area and cerebellum.

Participants are evaluated at baseline, immediately after completion of the stimulation protocol, and during follow-up to assess clinical effects, safety, and neurophysiological changes associated with the intervention. This study aims to further characterize the therapeutic potential of network-targeted rTMS in essential tremor and to inform future neuromodulation strategies in this population.

Inclusion criteria

• Male or female participants, aged 18 to 80 years; women of childbearing potential must not be pregnant.
• Diagnosis of Essential Tremor with a score greater than 2 on items 5 or 6 of the Fahn-Tolosa-Marin Tremor Rating Scale despite optimized medical therapy.
• Medication-refractory tremor, defined as prior use of both first-line medications (propranolol and primidone) at maximally tolerated doses without adequate tremor control.
• Ability to provide written informed consent in accordance with institutional policies.
• Ability to comply with all study procedures and follow-up assessments as defined by the study protocol.

Exclusion criteria

• Unstable or untreated psychiatric disorders.
• Inability to provide informed consent.
• Uncontrolled medical conditions, including but not limited to uncontrolled diabetes mellitus, hypertension, symptomatic pulmonary disease, or symptomatic cardiac disease.
• Concomitant participation in another investigational drug or device study.
• Pregnancy or breastfeeding.
• Presence of an implanted deep brain stimulation (DBS) system.
• History of epilepsy not adequately controlled, defined as seizure-free for less than 5 years.
• Presence of a cardiac pacemaker.
• Presence of metallic implants in any part of the body that are contraindicated for rTMS.