Transcranial Stimulation for Essential Tremor

The main purpose of this study is to see if transcranial magnetic stimulation (TMS) can be used to help study brain function in healthy people and in those with neurological diseases like essential tremor. This portion of the study is being done to establish the optimal methods for stimulating the brain to measure its responses.

Study Overview

• Status: Terminated
• Conditions: Essential Tremor
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation; Device: Sham Transcranial Magnetic Stimulation

Detailed Description

Essential tremor (ET) is a movement disorder characterized by tremor of both hands, and often head and voice, affecting approximately 4.8-6.7 million individuals over the age of 40 in the United States alone. Hand tremor can limit basic activities of daily living like feeding, drinking, writing and dressing. While medications can be effective for tremor, they are often poorly tolerated due to their sedative or neuronal activity depressant properties. Surgical options such as deep brain stimulation of the ventral intermedius thalamus (Vim DBS) can be highly effective but its invasive nature limits its popularity. Noninvasive brain stimulation has demonstrated the ability to reduce tremor but precisely where to target brain stimulation to achieve the best results is currently unknown.

Repetitive transcranial magnetic stimulation (rTMS) enables noninvasive, selective and sustained modulation of specific neural networks, and can lead to clinical benefits in debilitating neurologic and psychiatric disorders, including medication-resistant depression, paresis following stroke or traumatic brain injury, Parkinson's disease, or dementia. There is also recent evidence that rTMS of the cerebellum can relieve hand tremor due to essential tremor. TMS uses electromagnetic induction to generate controlled currents in targeted brain structures that can be identified and defined using MRI-based neuronavigation. TMS is safe if appropriate guidelines are adhered to. To date, the impact of rTMS on ET has not been sufficiently established, but pilot studies offer promising results.

The investigators are testing whether MRI-guided neuronavigated cerebellar paired pulse TMS demonstrates abnormal physiologic measures in ET subjects compared to controls and whether there is reduction of tremor via cerebellar rTMS in patients with ET. The investigators plan to collect imaging, functional and neurophysiological assessments before and after the rTMS to identify the mechanistic underpinnings of rTMS-induced changes in tremor and cerebello-cortical inhibition.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for ET subjects:

1. Outpatients with essential tremor as diagnosed and confirmed by movement disorder specialist
2. Women of child-bearing potential must provide a negative pregnancy test at entry into the study
3. Stable doses of all medications for at least 14 days prior to study entry and for the duration of the study,
4. At least a 1cm amplitude tremor as judged by the screener using a ruler

Inclusion Criteria for Healthy Volunteers:

1. Healthy subjects without tremor and without significant neurologic disease suggestive of cerebellar ataxia or other neurodegenerative diseases
2. Ages 18-80

Exclusion Criteria:

1. Any unstable illness or concomitant medical condition that, in the investigator's opinion, precludes participation in this study, including disorders that may affect gait or balance (i.e., stroke, arthritis, etc).
2. Pregnancy or lactation.
3. Concurrent participation in another clinical study.
4. Dementia or other psychiatric illness that prevents the patient from giving informed consent (Montreal Cognitive Assessment Score score less than or equal to 21).
5. Legal incapacity or limited legal capacity.
6. Tremor derived from any cause other than essential tremor (Parkinson's disease, drug-induced, anxiety-induced) in the clinical assessment at screening
7. Currently taking lithium or amiodarone or any other drug judged to be contributing to tremor as judged by the investigator (may be a cause of tremor)

8. No medication is an absolute exclusion from TMS. Medications will be reviewed by the responsible MD and a decision about inclusion will be made based on the following:

   • The patient's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination with other Central Nervous System active drugs.
   • The published TMS guidelines review of medications to be considered with TMS
9. History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform) EEG, or family history of treatment resistant epilepsy with the exception of a single seizure of benign etiology (e.g. febrile seizures) in the judgement of the investigator

10. TMS and MRI-Specific exclusion criteria including:

    • Known metal in the head (such as a surgical aneurysm clip) or a history of prior neurosurgical procedures.
    • Ferromagnetic bioimplants activated by any electronic, mechanical or magnetic means, such as cochlear implants, pacemakers, medication pumps, vagal stimulators, deep brain stimulators, neurostimulators, biostimulators, or ventriculo-peritoneal shunts.
    • Subjects who have or might have bullet fragments or other shrapnel (veterans or workers exposed to metal in their work environment).
    • Subjects with metallic paint (e.g. color contact lenses, tattoos, metallic eyeliner)
    • Subjects expressing significant claustrophobia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Cerebellar rTMS; Cerebellar rTMS will be carried out in ET subjects using a MagPro stimulator with a double cone coil at 1Hz (1 pulse every second) for 3 minutes on the left and 3 minutes on the right, at the cerebellar location indicated by resting state functional connectivity MRI analysis. Subjects with ET will undergo 5 consecutive daily sessions of cerebellar rTMS at either the connectivity map generated target or sham rTMS and then crossover to the other target after 2 weeks. Subjects will be blinded to the treatment order assignment. The intensity of the stimulation will be determined as 90% of the resting motor threshold, to be determined at the beginning of the first visit.	Device: Transcranial Magnetic Stimulation; Transcranial Magnetic Stimulation or TMS is a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. This magnetic field can pass through the head safely and painlessly. TMS can be used to change activity in the brain.; Other Names: TMS
Sham Comparator: Sham Cerebellar rTMS; In sham rTMS, the same parameters and procedures as Treatment Procedures 4-8 will be used, except that the coil will be angled 90 degrees from the scalp, resting on one wing of the coil.	Device: Sham Transcranial Magnetic Stimulation; Sham Transcranial Magnetic Stimulation or sham TMS is like active TMS, a noninvasive procedure (meaning it does not enter the body) that is used to stimulate a part of the brain using a magnetic field. TMS can be used to change activity in the brain but in this intervention, the coil will be angled 90 degrees from the scalp, resting on one wing of the coil, and therefore will not be delivering active TMS.; Other Names: Sham TMS
No Intervention: Healthy control pilot; This pilot phase is done to assess feasibility of obtaining MRI and cerebellocortical inhibition measures in healthy control subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tremor Reduction	tremor rating scale with questions regarding impact of tremor on activities of daily living and an physician-rated assessment of degree of tremor in hands, head, voice, and while drawing and writing	One week after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebellocortical Inhibition	Ratio of conditioned to unconditioned motor evoked potentials	One week after intervention

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): November 28, 2016
• Study Completion (Actual): November 28, 2016

Study Registration Dates

• First Submitted: January 6, 2017
• First Submitted That Met QC Criteria: January 17, 2017
• First Posted (Estimate): January 19, 2017

Study Record Updates

• Last Update Posted (Actual): December 19, 2017
• Last Update Submitted That Met QC Criteria: December 15, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Tremor; Essential Tremor
• Other Study ID Numbers: 2015P000011