rTMS Therapy for Primary Orthostatic Tremor

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.

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.

rTMS will be delivered over each cerebellar hemisphere, using a 70mm figure-of-eight coil connected to a Magstim RapidStim2 machine while positioned 3 cm lateral to the inion on the line joining the inion and the external auditory meatus. 900 pulses will be delivered consecutively to each side with a frequency of 1 Hz and at an intensity of 90% of the resting motor threshold (RMT) for a total duration of 15 min for each cerebellar hemisphere. The RMT will be defined as the lowest stimulation intensity required to evoke a 50 μV potential in a target muscle. The inion will be taken as the boundary between the posterior cerebellum and the occipital cortex. Therefore the area stimulated will be caudal to the inion to stimulate the posterior cerebellum.

Patients randomized to receive sham treatment will undergo the same procedure for identifying stimulus location used in patients receiving real rTMS. Simulated rTMS will be administered using sham Magstim RapidStim2 Placebo which produces discharge noise and vibration similar to the real coil without stimulating the cerebral cortex. However, in addition to obvious coil discharge noise, rTMS also causes electrical stimulation of the scalp. The investigator will simulate this experience by attaching surface electrodes underneath the sham coil and in contact with the scalp. The investigator will use an electromyography to administer electrical shocks to the scalp simultaneous to each simulated rTMS train.

Application of repetitious transcranial magnetic stimulation (TMS) pulses using Magstim RapidStim2 to a specific brain target at predefined stimulation parameters.

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.

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.

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.

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 cover the distance. For the outcome assessment the test will be videotaped and scored by a blind rater.

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.

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.

Inclusion Criteria: Potential participants will be diagnosed with Primary orthostatic tremor (POT) and be recruited through IRB approved database maintained by the Movement Disorders Center Exclusion Criteria: Pregnancy Active seizure disorder Significant cognitive impairment Presence of a metallic body such as pacemaker, implants, prosthesis,artificial limb or joint, shunt, metal rods and hearing aid

Wagle Shukla A, Vaillancourt DE. Treatment and physiology in Parkinson's disease and dystonia: using transcranial magnetic stimulation to uncover the mechanisms of action. Curr Neurol Neurosci Rep. 2014 Jun;14(6):449. doi: 10.1007/s11910-014-0449-5.

Udupa K, Chen R. Motor cortical plasticity in Parkinson's disease. Front Neurol. 2013 Sep 4;4:128. doi: 10.3389/fneur.2013.00128.

Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol. 1995 Jun;37(6):703-13. doi: 10.1002/ana.410370603.

Stacy MA, Elble RJ, Ondo WG, Wu SC, Hulihan J; TRS study group. Assessment of interrater and intrarater reliability of the Fahn-Tolosa-Marin Tremor Rating Scale in essential tremor. Mov Disord. 2007 Apr 30;22(6):833-8. doi: 10.1002/mds.21412.

Mathias S, Nayak US, Isaacs B. Balance in elderly patients: the "get-up and go" test. Arch Phys Med Rehabil. 1986 Jun;67(6):387-9.

Ugawa Y, Terao Y, Hanajima R, Sakai K, Furubayashi T, Machii K, Kanazawa I. Magnetic stimulation over the cerebellum in patients with ataxia. Electroencephalogr Clin Neurophysiol. 1997 Sep;104(5):453-8. doi: 10.1016/s0168-5597(97)00051-8.

Roth BJ, Saypol JM, Hallett M, Cohen LG. A theoretical calculation of the electric field induced in the cortex during magnetic stimulation. Electroencephalogr Clin Neurophysiol. 1991 Feb;81(1):47-56. doi: 10.1016/0168-5597(91)90103-5.

Amassian VE, Cracco RQ, Maccabee PJ, Cracco JB. Cerebello-frontal cortical projections in humans studied with the magnetic coil. Electroencephalogr Clin Neurophysiol. 1992 Aug;85(4):265-72. doi: 10.1016/0168-5597(92)90115-r.

Cohen LG, Roth BJ, Nilsson J, Dang N, Panizza M, Bandinelli S, Friauf W, Hallett M. Effects of coil design on delivery of focal magnetic stimulation. Technical considerations. Electroencephalogr Clin Neurophysiol. 1990 Apr;75(4):350-7. doi: 10.1016/0013-4694(90)90113-x.

Werhahn KJ, Taylor J, Ridding M, Meyer BU, Rothwell JC. Effect of transcranial magnetic stimulation over the cerebellum on the excitability of human motor cortex. Electroencephalogr Clin Neurophysiol. 1996 Feb;101(1):58-66. doi: 10.1016/0013-4694(95)00213-8.

Hashimoto M, Ohtsuka K. Transcranial magnetic stimulation over the posterior cerebellum during visually guided saccades in man. Brain. 1995 Oct;118 ( Pt 5):1185-93. doi: 10.1093/brain/118.5.1185.

Deuschl G, Lucking CH, Quintern J. [Orthostatic tremor: clinical aspects, pathophysiology and therapy]. EEG EMG Z Elektroenzephalogr Elektromyogr Verwandte Geb. 1987 Mar;18(1):13-9. German.

Heilman KM. Orthostatic tremor. Arch Neurol. 1984 Aug;41(8):880-1. doi: 10.1001/archneur.1984.04050190086020.

Espay AJ, Duker AP, Chen R, Okun MS, Barrett ET, Devoto J, Zeilman P, Gartner M, Burton N, Miranda HA, Mandybur GT, Zesiewicz TA, Foote KD, Revilla FJ. Deep brain stimulation of the ventral intermediate nucleus of the thalamus in medically refractory orthostatic tremor: preliminary observations. Mov Disord. 2008 Dec 15;23(16):2357-62. doi: 10.1002/mds.22271.

Guridi J, Rodriguez-Oroz MC, Arbizu J, Alegre M, Prieto E, Landecho I, Manrique M, Artieda J, Obeso JA. Successful thalamic deep brain stimulation for orthostatic tremor. Mov Disord. 2008 Oct 15;23(13):1808-11. doi: 10.1002/mds.22001.

Benito-Leon J, Rodriguez J. Orthostatic tremor with cerebellar ataxia. J Neurol. 1998 Dec;245(12):815. doi: 10.1007/s004150050294. No abstract available.

Setta F, Jacquy J, Hildebrand J, Manto MU. Orthostatic tremor associated with cerebellar ataxia. J Neurol. 1998 May;245(5):299-302. doi: 10.1007/s004150050222. No abstract available.

Wills AJ, Thompson PD, Findley LJ, Brooks DJ. A positron emission tomography study of primary orthostatic tremor. Neurology. 1996 Mar;46(3):747-52. doi: 10.1212/wnl.46.3.747.

Manto MU, Setta F, Legros B, Jacquy J, Godaux E. Resetting of orthostatic tremor associated with cerebellar cortical atrophy by transcranial magnetic stimulation. Arch Neurol. 1999 Dec;56(12):1497-500. doi: 10.1001/archneur.56.12.1497.

Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord. 1998;13 Suppl 3:2-23. doi: 10.1002/mds.870131303.