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 our laboratory that the use of resting-state functional magnetic resonance imaging (rs-fMRI) is useful for characterizing the aberrant tremor neural network in ET compared with controls, without the performance-related confounds associated with prior task-based methods. Using this data, we plan to use a more sensitive autocorrelation method to characterize whole-brain connectivity in patients and 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 our laboratory, and has major implications for understanding ET pathophysiology and treatment. First, patients can present with disproportionate amounts of one tremor subtype than the other. Second, treatments can disproportionately improve one subtype. Lastly, evidence from our lab using task-based fMRI methods suggests different connectivity patterns lead to the generation of each tremor subtype. We plan to test the hypothesis that postural and kinetic tremors are generated through different neural mechanisms. Treatment of ET focuses on pharmacological agents of various mechanisms (e.g. b-blockers, anticonvulsants, benzodiazepines) 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, we plan to study the effects of ethanol (the most efficacious tremor-suppressant currently available) and propranolol (a non-specific b- adrenergic blocker with proven efficacy and unknown mechanism of action) on the tremor neural network. The goals and methods in this proposal are critical to the further understanding of ET pathophysiology, phenotypic variability, and development of therapeutic strategies. While the proposed methods represent a shift from traditional neuroimaging methods, our preliminary work demonstrates our ability to carry out each component. Addressing these current barriers will lead to a better understanding of ET physiology, phenotypic variability and treatment mechanisms with the ultimate goal of reducing disability and improving quality of life.

Public Health Relevance

Essential tremor (ET) is the most common tremor disorder currently affecting ~ 2.9 million Americans of all ages; and is estimated to have a prevalence of 4.1 million by 2025. Of those affected; 75% experience significant morbidity in productivity; quality of life and activities of daily living. This proposal addresses this critical public health challenge using novel approaches to: 1) identify its neural correlates (aim 1); characterize the phenotypic spectrum of this disorder (aim 2); and elucidate the mechanisms of treatment with the goal of developing more targeted and effective therapies (aim 3).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS073683-04
Application #
8777004
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gwinn, Katrina
Project Start
2011-07-01
Project End
2016-03-31
Budget Start
2013-08-01
Budget End
2014-03-31
Support Year
Fiscal Year
2013
Total Cost
$293,689
Indirect Cost
$58,372
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Haubenberger, Dietrich; Nahab, Fatta B; Voller, Bernhard et al. (2014) Treatment of essential tremor with long-chain alcohols: still experimental or ready for prime time? Tremor Other Hyperkinet Mov (N Y) 4:
Nahab, Fatta B; Handforth, Adrian; Brown, Tyler et al. (2012) Octanoic acid suppresses harmaline-induced tremor in mouse model of essential tremor. Neurotherapeutics 9:635-8
Nahab, Fatta B; Wittevrongel, Loretta; Ippolito, Dominic et al. (2011) An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor. Neurotherapeutics 8:753-62
Haubenberger, Dietrich; Kalowitz, Daniel; Nahab, Fatta B et al. (2011) Validation of digital spiral analysis as outcome parameter for clinical trials in essential tremor. Mov Disord 26:2073-80