Essential tremor is a common movement disorder that causes involuntary shaking, mainly during voluntary actions such as writing or holding objects. Recent research suggests that essential tremor is not caused by a single brain area, but by abnormal activity within a network that includes the cerebellum and motor areas of the brain. However, most non-invasive brain stimulation studies to date have targeted only one brain region and have shown inconsistent clinical benefits.
This randomized, double-blind, placebo-controlled clinical trial aims to evaluate the effects of a dual-site transcranial magnetic stimulation (rTMS) protocol targeting the supplementary motor area (SMA) and the cerebellum in patients with essential tremor that does not respond adequately to standard medications. The study is based on previous pilot data showing meaningful tremor reduction using combined stimulation of these two brain regions.
Participants will receive five sessions of rTMS, consisting of low-frequency stimulation over the SMA followed by high-frequency stimulation over the cerebellum. The main hypothesis is that this combined approach will lead to an immediate and sustained improvement in action tremor of the dominant upper limb, measured up to four weeks after treatment. Secondary outcomes include quality of life, safety, side effects, and changes in brain excitability associated with tremor improvement.
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.
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.
Parallel
Dual-site repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area and cerebellum
DeviceThis intervention consists of a sequential dual-site repetitive transcranial magnetic stimulation (rTMS) protocol targeting two interconnected nodes of the tremor network. Low-frequency stimulation (1 Hz) is first applied over the supplementary motor area at 110% of the resting motor threshold to modulate cortical motor drive, followed by high-frequency stimulation (10 Hz) over the cerebellar cortex at 90% of the resting motor threshold to modulate abnormal cerebellar output. Stimulation is delivered over five consecutive daily sessions using standardized anatomical localization and identical session duration across participants. Sham Intervention The sham intervention replicates the anatomical targeting, sequence, session duration, and acoustic characteristics of the active dual-site rTMS protocol without delivering an effective magnetic field. An inactive coil is positioned over the same supplementary motor area and cerebellar cortex
Transcranial Magnetic Stimulation Sham
DeviceThe sham intervention replicates the anatomical targeting, sequence, session duration, and acoustic characteristics of the active dual-site rTMS protocol without delivering an effective magnetic field. An inactive coil is positioned over the same supplementary motor area and cerebellar targets, while sound simulation is used to mimic active stimulation, ensuring maintenance of blinding and comparability with the active intervention.
Change in Action Tremor Severity of the Dominant Upper Limb
Assessed using items 5 and 6 of the Fahn-Tolosa-Marin Tremor Rating Scale, evaluated by a blinded examiner.
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