rTMS Therapy for Primary Orthostatic Tremor

NCT ID: NCT02441985

Last Updated: 2025-04-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-31
• Study Completion Date: 2019-01-08

Brief Summary

Primary orthostatic tremor(POT) is a rare progressive functionally disabling tremor disorder. The characteristic features of POT are symptoms of unsteadiness in legs reported by patients when they are standing and improvement of symptoms upon walking and sitting. Due to the limited success of other treatment options there is a clear merit in continuing efforts to explore and investigate novel treatment modalities. Transcranial magnetic stimulation (TMS) is a well-established physiological tool to understand brain function. When repetitious TMS pulses are delivered to a specific target at predefined stimulation parameters, it is referred to as rTMS therapy.The investigators propose a novel approach to investigate the clinical and physiological effects of low frequency rTMS therapy in POT. The overarching hypothesis of this study is that low frequency rTMS therapy delivered to the cerebellum will modulate the cerebellar excitability and result in clinical improvements.In order to determine the physiological effects related to rTMS, the tremor physiology will also be recorded with surface electromyography (EMG). The investigator will also record the changes in cerebellum excitability in response to rTMS using cerebello-cortical inhibition (CBI), a well-established TMS parameter.

Detailed Description

POT tremors recorded on surface electromyography (EMG) reveal distinct high frequency bursts of 13-18 Hz tremors in the leg muscles. POT was first described in 1984 at the University of Florida. Since then several clinical descriptions have been published however despite this knowledge for thirty years, treatment opportunities for POT have remained poor. Several medications have been tried, but the results have been disappointing. Thalamic deep brain stimulation (DBS) surgery, which is an invasive therapy approved by the FDA for treatment of essential tremor, was recently investigated in POT but the early results have only been partially successful. In clinical descriptions, POT has been observed to be associated with clinical features of cerebellar dysfunction such as dysmetria and gait ataxia. Positron emission tomography (PET) imaging has shown an increased activation of bilateral cerebellum related either to a mismatch between the peripheral afferent and the cerebellar efferent traffic or to a primary disorder of the cerebellum. MRI study has confirmed a cerebellar atrophy in POT and finally transcranial magnetic stimulation (TMS), has shown POT can be reset by stimulation of the cerebellum. The primary goal of this study is to test the efficacy of low frequency rTMS therapy in POT. The first aim of the study is to determine the clinical impact of 1-Hz rTMS therapy in POT when delivered to the cerebellum. This impact will be evaluated by the clinical scoring of leg tremors in standing posture, and the functional assessment of gait mobility. The second aim of this study is to determine the physiological effects of 1-Hz rTMS therapy in POT when delivered to the cerebellum. The investigator will determine the effects on the amplitude and frequency of tremors recorded with surface EMG. They will also determine the effects on the cerebello-cortical inhibition measured with TMS. Comparisons will be drawn between before rTMS therapy, immediately or +5 minutes after and 60+ minutes after assessments to determine the time course of effects. In this application, subjects with POT will be enrolled based on clinical history, physical exam and a 13-18 Hz tremor recorded on the surface EMG in accordance with the Consensus Statement of the Movement Disorder Society. Data will be presented as mean (SD) unless otherwise indicated. For each of the outcome variables, the statistical analyst will conduct a mixed model analysis using time and stimulation arm as repeated factors adjusted for baseline values, and subjects as the random factor.

Conditions

Primary Orthostatic Tremor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Real rTMS Stimulation

rTMS will be delivered over each cerebellar hemisphere, using a 70mm figure-of-eight coil connected to a Magstim RapidStim2 machine while positioned 3 cm lateral to the inion on the line joining the inion and the external auditory meatus. 900 pulses will be delivered consecutively to each side with a frequency of 1 Hz and at an intensity of 90% of the resting motor threshold (RMT) for a total duration of 15 min for each cerebellar hemisphere. The RMT will be defined as the lowest stimulation intensity required to evoke a 50 μV potential in a target muscle. The inion will be taken as the boundary between the posterior cerebellum and the occipital cortex. Therefore the area stimulated will be caudal to the inion to stimulate the posterior cerebellum.

Group Type: EXPERIMENTAL

Magstim RapidStim2

Intervention Type: DEVICE

Application of repetitious transcranial magnetic stimulation (TMS) pulses using Magstim RapidStim2 to a specific brain target at predefined stimulation parameters.

Fullerton Advanced Balance (FAB) Scale

Intervention Type: OTHER

All participants will receive a clinical assessment of balance ability and fall risk.

Timed "Up & Go" Test (TUG) test

Intervention Type: OTHER

All participants will receive a clinical assessment of basic mobility skills by using the TUG test.

10m walk test

Intervention Type: OTHER

All participants will receive a clinical assessment of walking speed by using the walk test.

Tremor electrophysiology

Intervention Type: OTHER

All participant tremors will by analyzed using an EMG system

Cerebellar-brain Inhibition (CBI)

Intervention Type: OTHER

All participants will have a measure of the cerebellar-brain inhibition (CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.

Sham rTMS Stimulation

Patients randomized to receive sham treatment will undergo the same procedure for identifying stimulus location used in patients receiving real rTMS. Simulated rTMS will be administered using sham Magstim RapidStim2 Placebo which produces discharge noise and vibration similar to the real coil without stimulating the cerebral cortex. However, in addition to obvious coil discharge noise, rTMS also causes electrical stimulation of the scalp. The investigator will simulate this experience by attaching surface electrodes underneath the sham coil and in contact with the scalp. The investigator will use an electromyography to administer electrical shocks to the scalp simultaneous to each simulated rTMS train.

Group Type: SHAM_COMPARATOR

Sham Magstim RapidStim2

Intervention Type: DEVICE

Same procedure as real rTMS without stimulating the cerebral cortex.

Fullerton Advanced Balance (FAB) Scale

Intervention Type: OTHER

All participants will receive a clinical assessment of balance ability and fall risk.

Timed "Up & Go" Test (TUG) test

Intervention Type: OTHER

All participants will receive a clinical assessment of basic mobility skills by using the TUG test.

10m walk test

Intervention Type: OTHER

All participants will receive a clinical assessment of walking speed by using the walk test.

Tremor electrophysiology

Intervention Type: OTHER

All participant tremors will by analyzed using an EMG system

Cerebellar-brain Inhibition (CBI)

Intervention Type: OTHER

All participants will have a measure of the cerebellar-brain inhibition (CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.

Interventions

Magstim RapidStim2

Application of repetitious transcranial magnetic stimulation (TMS) pulses using Magstim RapidStim2 to a specific brain target at predefined stimulation parameters.

Intervention Type: DEVICE

Sham Magstim RapidStim2

Same procedure as real rTMS without stimulating the cerebral cortex.

Intervention Type: DEVICE

Fullerton Advanced Balance (FAB) Scale

All participants will receive a clinical assessment of balance ability and fall risk.

Intervention Type: OTHER

Timed "Up & Go" Test (TUG) test

All participants will receive a clinical assessment of basic mobility skills by using the TUG test.

Intervention Type: OTHER

10m walk test

All participants will receive a clinical assessment of walking speed by using the walk test.

Intervention Type: OTHER

Tremor electrophysiology

All participant tremors will by analyzed using an EMG system

Intervention Type: OTHER

Cerebellar-brain Inhibition (CBI)

All participants will have a measure of the cerebellar-brain inhibition (CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Potential participants will be diagnosed with Primary orthostatic tremor (POT) and be recruited through IRB approved database maintained by the Movement Disorders Center

Exclusion Criteria

• Pregnancy
• Active seizure disorder
• Significant cognitive impairment
• Presence of a metallic body such as pacemaker, implants, prosthesis,artificial limb or joint, shunt, metal rods and hearing aid

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Organization for Rare Disorders

OTHER

Sponsor Role: collaborator

Neuronetics

OTHER

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Aparna Wagle-Shukla, M.D.

Role: PRINCIPAL_INVESTIGATOR

Center for Movement Disorders and Neurorestoration

Locations

Center for Movement Disorders and Neurorestoration

Gainesville, Florida, United States

Countries

United States

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Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

IRB201500347

Identifier Type: -

Identifier Source: org_study_id