rTMS Therapy for Primary Orthostatic Tremor
Condition: Primary Orthostatic Tremor
MeSH terms: Tremor
Study type: Interventional

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 description: 
      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 60+ minutes after assessments to determine the time course of effects. In
      this application, subjects with POT will be enrolled based on clinical history, physical exam
      and a 13-18 Hz tremor recorded on the surface EMG in accordance with the Consensus Statement
      of the Movement Disorder Society. Data will be presented as mean (SD) unless otherwise
      indicated. For each of the outcome variables, the statistical analyst will conduct a mixed
      model analysis using time and stimulation arm as repeated factors adjusted for baseline
      values, and subjects as the random factor.
    

Intervention name(s): Magstim RapidStim2; Sham Magstim RapidStim2; Fahn-Tolosa-Marin Tremor Rating Scale (TRS); Timed "Up & Go" Test (TUG) test; 10m walk test; Tremor electrophysiology; Cerebellar-brain Inhibition (CBI)
Intervention type(s): Device; Device; Other; Other; Other; Other; Other
Intervention description(s): Application of repetitious transcranial magnetic stimulation (TMS) pulses using Magstim RapidStim2 to a specific brain target at predefined stimulation parameters.; Same procedure as real rTMS without stimulating the cerebral cortex.; All participants will receive a clinical assessment of tremor severity by using the TRS test.; All participants will receive a clinical assessment of basic mobility skills by using the TUG test.; All participants will receive a clinical assessment of walking speed by using the walk test.; All participant tremors will by analyzed using an EMG system; All participants will have a measure of the cerebellar-brain inhibition(CBI) which will be conducted by using a TMS device determining the ability of the coil to activate the cerebellum.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Primary orthostatic tremor