Clinical Trial: rTMS Therapy for Primary Orthostatic Tremor

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: rTMS Therapy for Primary Orthostatic Tremor: A Novel Treatment Approach

Brief Summary: Primary orthostatic tremor(POT) is a rare progressive functionally disabling tremor disorder. The characteristic features of POT are symptoms of unsteadiness in legs reported by patients when they are standing and improvement of symptoms upon walking and sitting. Due to the limited success of other treatment options there is a clear merit in continuing efforts to explore and investigate novel treatment modalities. Transcranial magnetic stimulation (TMS) is a well-established physiological tool to understand brain function. When repetitious TMS pulses are delivered to a specific target at predefined stimulation parameters, it is referred to as rTMS therapy.The investigators propose a novel approach to investigate the clinical and physiological effects of low frequency rTMS therapy in POT. The overarching hypothesis of this study is that low frequency rTMS therapy delivered to the cerebellum will modulate the cerebellar excitability and result in clinical improvements.In order to determine the physiological effects related to rTMS, the tremor physiology will also be recorded with surface electromyography (EMG). The investigator will also record the changes in cerebellum excitability in response to rTMS using cerebello-cortical inhibition (CBI), a well-established TMS parameter.

Detailed Summary: POT tremors recorded on surface electromyography (EMG) reveal distinct high frequency bursts of 13-18 Hz tremors in the leg muscles. POT was first described in 1984 at the University of Florida. Since then several clinical descriptions have been published however despite this knowledge for thirty years, treatment opportunities for POT have remained poor. Several medications have been tried, but the results have been disappointing. Thalamic deep brain stimulation (DBS) surgery, which is an invasive therapy approved by the FDA for treatment of essential tremor, was recently investigated in POT but the early results have only been partially successful. In clinical descriptions, POT has been observed to be associated with clinical features of cerebellar dysfunction such as dysmetria and gait ataxia. Positron emission tomography (PET) imaging has shown an increased activation of bilateral cerebellum related either to a mismatch between the peripheral afferent and the cerebellar efferent traffic or to a primary disorder of the cerebellum. MRI study has confirmed a cerebellar atrophy in POT and finally transcranial magnetic stimulation (TMS), has shown POT can be reset by stimulation of the cerebellum. The primary goal of this study is to test the efficacy of low frequency rTMS therapy in POT. The first aim of the study is to determine the clinical impact of 1-Hz rTMS therapy in POT when delivered to the cerebellum. This impact will be evaluated by the clinical scoring of leg tremors in standing posture, and the functional assessment of gait mobility. The second aim of this study is to determine the physiological effects of 1-Hz rTMS therapy in POT when delivered to the cerebellum. The investigator will determine the effects on the amplitude and frequency of tremors recorded with surface EMG. They will also determine the effects on the cerebello-cortical inhibition measured with TMS. Comparisons will be drawn between before rTMS therapy, immediately or +5 minutes after and
Sponsor: University of Florida

Current Primary Outcome:

  • Fahn-Tolosa-Marin Tremor Rating Scale (TRS) [ Time Frame: Day 1 ]
    Part A assesses examiner-reported tremor location/severity (amplitude), Part B assesses examiner-reported ability to perform specific motor tasks/functions (writing, drawing, and pouring with dominant and non-dominant hand), and Part C assesses patient-reported functional disability resulting from the tremor (speaking, eating, drinking, hygiene, dressing, writing, working, and social activities).All tremor items will be rated based on a scale of 0=none to 4=severe. Finally, the TRS includes one separate item dealing with global assessment of tremor-related disability, rated both by patient and examiner on a 5-point scale. For outcome analysis, total tremor score and leg tremor score (derived from leg motor item on the scale) will be recorded. For the outcome assessment the test will be videotaped and scored by a blind rater.
  • Timed "Up & Go" Test (TUG) test [ Time Frame: Day 1 ]
    The TUG is a mobility test that is used to measure the basic mobility skills and gait speed of people who have neurological conditions. It includes a sit-to-stand component as well as walking 3 m, turning, and returning to the chair. People perform these tasks using regular footwear and customary walking aids. The measured outcome is the time in seconds to complete the entire sequence. For the outcome assessment the test will be videotaped and scored by a blind rater.
  • 10m walk test [ Time Frame: Day 1 ]
    In this test, subjects are instructed to walk 10m distance and timed. The speed of walking is determined as the distance covered (10m) divided by the amount of time needed to

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Tremor electrophysiology [ Time Frame: Day 1 ]
      POT tremors will be recorded on the surface EMG for amplitude and power spectral frequency analysis. The investigator will use Bagnoli EMG system and Trigno wireless EMG system to record the surface EMG signals arising from muscles and the accelerometer findings respectively.Tremor amplitude and frequencies will be calculated with the surface EMG using Bagnoli system and accelerometry recorded using Trigno system.
    • TMS measure [ Time Frame: Baseline to 60 Minutes ]
      Cerebellar inhibition (CBI) will be recorded which is a well-established TMS measure. A paired pulse protocol will be used with right cerebellar stimulation as the conditioning stimulus, (cerebellar conditioning stimulus or CCS) and left motor cortex stimulation (M1) as the test stimulus (TS). The investigator will determine the 'TS 0.5mV' which will indicate a stimulator setting (determined to the nearest 1% of the maximum stimulator output) that produces a peak-to-peak MEP amplitude of ≥0.5mV in at least five out of 10 trials. Interstimulus intervals (ISI) of 3 to 8 milliseconds at increment of 1 millisecond will be tested. Each run will consist of 10 trials of each of the paired stimuli (CCS-TS) and 10 trials of TS alone delivered in random order. Inhibition trial will be expressed as a ratio of mean conditioned to mean unconditioned MEP amplitude for each subject.


    Original Secondary Outcome: Same as current

    Information By: University of Florida

    Dates:
    Date Received: May 8, 2015
    Date Started: August 2015
    Date Completion: May 2017
    Last Updated: December 2, 2016
    Last Verified: December 2016