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

Official title

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

Overview

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.

Detailed description

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.

Interventions

• Device Dual-site repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area and cerebellum
  This 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 deli
• Device Transcranial Magnetic Stimulation Sham
  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 targets, while sound simulation is used to mimic active stimulation, ensuring maintenance of blinding and comparability with the active intervention.

Primary outcome measures

• Change in Action Tremor Severity of the Dominant Upper Limb [Time frame: baseline (pre-stimulation), at the end of the stimulation protocol, 4 weeks after the last session]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Brazil · 1 center

• Sao Paulo University — São Paulo

Identifiers

NCT: NCT07344194 · 81190724.8.0000.0068

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗