Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

NCT ID: NCT02495883

Last Updated: 2020-12-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 56 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2017-04-30

Brief Summary

Essential Tremor (ET) is the most common tremor disorder, currently affecting an estimated 2.9 million Americans and leading to disability and decreased quality of life in 75% of cases. The pathophysiology of ET is poorly understood, with the source of the tremor remaining controversial since all studies show increased activity in the cerebellum (including mimicked tremor in controls), while animal models of ET using harmaline and a single human PET study implicate the inferior olivary nucleus in the brainstem.

There is evidence from the investigator's laboratory that the use of resting-state functional magnetic resonance imaging (rs-fMRI) is useful for characterizing the abnormal tremor neural network in ET compared with controls. The goal is to identify the source of the tremor, which is hypothesized to remain active during rest.

Current ET diagnostic criteria require the presence of postural and/or kinetic tremor, which are assumed to be different manifestations of the same tremor oscillator. This long-standing assumption may be incorrect based on several lines of evidence from the investigator's laboratory, and has major implications for understanding ET pathophysiology and treatment. The investigators will test the hypothesis that postural and kinetic tremors are generated through different neural mechanisms.

Treatment of ET focuses on pharmacological agents of various mechanisms and rarely deep brain stimulation of the Vim thalamus. Despite the assortment of agents used to treat ET, only ~50% of patients benefit from a particular agent. Furthermore, the mechanisms of action on tremor are not generally known. Understanding the mechanisms of action of various tremor-suppressing agents is critical for future drug development. In this proposal, the investigators plan to study the effects of ethanol (the most efficacious tremor-suppressant currently available) and propranolol (a non-specific β-adrenergic blocker with proven efficacy and unknown mechanism of action) on the tremor neural network.

Conditions

Essential Tremor; Tremor

Keywords

Essential Tremor; Magnetic Resonance Imaging; Therapy; Alcohol; Propranolol

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Essential Tremor Group

Patients will be randomized to start in one of two treatment arms: 1) 50ml of 40% ethanol or 2) Propranolol SR 60-120mg. In patients who receive ethanol first, they will return for a second visit when they will receive Propranolol, and vice versa. Ethanol will be administered to participants diagnosed with Essential Tremor during the study visit, whereas patients receiving Propranolol SR will be administered daily over an estimated period of two weeks prior to the fMRI visit.

Group Type: OTHER

Ethanol

Intervention Type: OTHER

50ml of 40% Ethanol

Propranolol

Intervention Type: DRUG

Beta blocker

Health Volunteer Group

Healthy Volunteers will receive no interventions.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Ethanol

50ml of 40% Ethanol

Intervention Type: OTHER

Propranolol

Beta blocker

Intervention Type: DRUG

Other Intervention Names

Propranolol SR; Inderal LA

Eligibility Criteria

Inclusion Criteria

• Diagnosed with ET by a Movement Disorder Neurologist.
• Tremors that improve with alcohol.
• Ability to abstain from drinking alcohol or caffeine for at least 2 days before both the screening and fMRI visits
• Over the age of 21.

Exclusion Criteria

• Significant non-ET related abnormal findings during neurological exam.
• Presence of a tremor at rest.
• Pregnant or nursing.
• Unable to safely undergo MRI based on completion of a safety questionnaire.
• History of dementia, brain tumor, stroke, head trauma or a vascular malformation based on history or MRI findings.
• Severe active medical condition, such as cardiovascular disease, that prevents subject from lying flat for up to 120 minutes.
• Unable or unwilling to provide informed consent.
• Claustrophobia (a fear of tight spaces) or other restrictions that prevent subject from undergoing an MRI in a confined space for up to 120 minutes.
• Unable to temporarily stop taking medications that may influence liver metabolism or brain function.
• Tremors so severe that subject cannot safely and effectively undergo MRI
• Past/current problems with alcohol abuse or dependence.
• Unwillingness to take alcohol (ethanol), which is a potentially intoxicating drug
• History of deep brain stimulation or thalamotomy surgery.
• Sinus bradycardia, bronchial asthma, or a known allergy to propranolol (Inderal).

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: lead

Responsible Party

Fatta B Nahab

Associate Professor of Neurosciences

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fatta B Nahab, MD

Role: PRINCIPAL_INVESTIGATOR

UCSD

Locations

University of California, San Diego

La Jolla, California, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1R01NS073683-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

131202

Identifier Type: -

Identifier Source: org_study_id