Essential Tremor, Tremor
Conditions
Keywords
Essential Tremor, Magnetic Resonance Imaging, Therapy, Alcohol, Propranolol
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.
Interventions
OTHEREthanol
50ml of 40% Ethanol
DRUGPropranolol
Beta blocker
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
Yes
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regions With fMRI Differences Between ET and Controls | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Essential Tremor Group 50ml of 40% ethanol will be administered to participants diagnosed with Essential Tremor.
Propranolol SR 60-120mg will be administered daily to participants over an estimated period of two weeks.
Ethanol: 50ml of 40% Ethanol
Propranolol: Beta blocker | 31 |
| Health Volunteer Group Healthy Volunteers | 24 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Excessive head motion | 1 | 0 |
Baseline characteristics
| Characteristic | Health Volunteer Group | Essential Tremor Group | Total |
|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 11.5 | 63.5 years STANDARD_DEVIATION 15.4 | 62.2 years STANDARD_DEVIATION 13.7 |
| Montreal Cognitive Assessment | 28.1 units on a scale STANDARD_DEVIATION 1.6 | 27.9 units on a scale STANDARD_DEVIATION 1.7 | 28.0 units on a scale STANDARD_DEVIATION 1.7 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 8 Participants | 17 Participants | 25 Participants |
| Tremor Research Group Essential Tremor Rating Scale (TETRAS) | NA units on a scale | 37.8 units on a scale STANDARD_DEVIATION 19 | 37.8 units on a scale STANDARD_DEVIATION 19 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 24 |
| other Total, other adverse events | 0 / 31 | 0 / 24 |
| serious Total, serious adverse events | 0 / 31 | 0 / 24 |
Outcome results
Primary
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.
Time frame: At visit 1 or 2 based on randomization table.
Population: The methodology of this trial utilizes functional MRI measures. In order to understand the significance of a group's unique brain responses, the data between the two groups (Essential Tremor vs. Healthy Controls) are statistically compared to derive regions that are unique. The output of the analyses show regions that are unique to ET.~NOTE: Data structure cannot be provided separately for each group based on the experiment paradigm and analysis methods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Subjects | Regions With fMRI Differences Between ET and Controls | Right Cerebellum | 139 Number of Activated Voxels |
| All Subjects | Regions With fMRI Differences Between ET and Controls | Left Putamen | 93 Number of Activated Voxels |
| All Subjects | Regions With fMRI Differences Between ET and Controls | Right Posterior Cingulate/Thalamus | 85 Number of Activated Voxels |
| All Subjects | Regions With fMRI Differences Between ET and Controls | Right Sensorimotor Cortex | 74 Number of Activated Voxels |