Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

Study Overview
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Brief Summary
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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.

Official Title
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Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response

Conditions
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Essential Tremor, Tremor

Intervention / Treatment
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* Other: Ethanol
* Drug: Propranolol


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Essential Tremor Group<br>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<br>* 50ml of 40% Ethanol<br>Drug: Propranolol<br>* Beta blocker<br>* Other names: Inderal LA;|
| No Intervention: Health Volunteer Group<br>Healthy Volunteers will receive no interventions. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Regions With fMRI Differences Between ET and Controls | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Essential Tremor, Magnetic Resonance Imaging, Therapy, Alcohol, Propranolol