Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

December 1, 2020 updated by: Fatta B Nahab, University of California, San Diego

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

56

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • La Jolla, California, United States, 92037
        • University of California, San Diego

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: OTHER
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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.
Other: Ethanol
50ml of 40% Ethanol
Drug: Propranolol
Beta blocker
Other Names:
  • Inderal LA
  • Propranolol SR
No Intervention: Health Volunteer Group
Healthy Volunteers will receive no interventions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Regions With fMRI Differences Between ET and Controls
Time Frame: At visit 1 or 2 based on randomization table.
Regions that were differentially activated in ET as measured by number of statistically significant voxels (cluster size). This represents the number of activated voxels seen in the ET group that were not present in the Healthy Control group.
At visit 1 or 2 based on randomization table.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Diego

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Fatta B Nahab, MD, UCSD

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2013

Primary Completion (Actual)

April 1, 2017

Study Completion (Actual)

April 1, 2017

Study Registration Dates

First Submitted

September 26, 2013

First Submitted That Met QC Criteria

July 8, 2015

First Posted (Estimate)

July 13, 2015

Study Record Updates

Last Update Posted (Actual)

December 2, 2020

Last Update Submitted That Met QC Criteria

December 1, 2020

Last Verified

December 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 131202
  • 1R01NS073683-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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