Functional Imaging of Tremor Circuits and Mechanisms of Treatment Response
Condition: Essential Tremor; Tremor
MeSH terms: Tremor; Essential Tremor
Intervention: Ethanol; Propranolol
Intervention description: 50ml of 40% Ethanol; Beta blocker
Intervention MeSH terms: Ethanol; Propranolol
Phase: Phase 4
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 56.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Essential Tremor; Magnetic Resonance Imaging; Therapy; Alcohol; Propranolol

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.
    

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).