Can rTMS Enhance Somatosensory Recovery After Stroke?
Phase: NA
Conditions: Stroke
Sponsor: VA Office of Research and Development

 
Title:  Can rTMS Enhance Somatosensory Recovery After Stroke?   
NCT 02811913 
Date :  10/8/2020 
Last version of IRB-approved Research plan  - 2/12/2019 
 

Abbreviated protocol 
Specific Aims. There is a confluence of evidence that supports the proposed work. First, 
sensory recovery is a product of brain plasticity and can be achieved even in chronic stages 
after stroke as demonstrated by preliminary data and evidence from the literature. Second, 
rehabilitation therapies can be enhanced with rTMS. Both post-stroke rehabilitation and rTMS 
are well established methodologies in the investigators’ laboratories. Third, there is limited 
knowledge regarding the most effective type of rTMS (facilitatory or inhibitory) that would 
enhance recovery of somatosensation for individuals in chronic stages after stroke. Therefore, 
the main objective of this study is to test the feasibility and preliminary efficacy of a novel 
approach to treat sensory deficits after stroke with a combination of repetitive Transcranial 
Magnetic Stimulation (rTMS) and peripheral arm and hand sensory therapy. We propose to 
address the two study Aims by testing the following hypotheses. Aim 1: Test effect of rTMS of 
the contralesional S1 region on sensory function Hypothesis 1a.  Facilitatory rTMS of 
contralesional S1 produces a greater response versus sham rTMS, according to a measure of 
tactile discrimination. Hypothesis 1b. Facilitatory rTMS of contralesional S1 produces a greater 
response versus inhibitory rTMS in improving tactile discrimination. Aim 2: Characterize 
neurophysiological changes in response to rTMS of contralesional S1. Hypothesis 2:  Repetitive 
TMS of the contralesional S1 region leads to functional brain changes. 
Study design overview. We will enroll subjects who are at least 6 months from onset of the 
first ever stroke and who have residual sensory deficits. There will be 3 treatment sessions at 
least 7 days apart consisted of rTMS and sensory re-education therapies. Prior to the first 
intervention session, there will be a baseline data collection session. rTMS will target the 
contralesional (intact hemisphere) primary sensory region.  rTMS stimulation will be either 
facilitatory, i.e. temporary increasing brain activity, or inhibitory, i.e. temporary decreasing brain 
activity. rTMS will be administered in combination with peripheral sensory therapies. The order 
of the sessions will be randomly assigned. All evaluations will be performed by a therapist who 
will be blinded to the site or the type of rTMS.. 
rTMS intervention.  We will use a frameless stereotaxy system, Brainsight 2(Rogue Research, 
Inc., Montreal, QC) to perform image-guided TMS. The optimal stimulation site will be 
approximately 2 cm posterior to the hand motor area and to a hotspot for eliciting MEPs in first 
dorsal interossues (FDI) (Schneider 2010). 
A Magstim Super Rapid 2002 magnetic stimulator (MagStim Company Ltd., Wales, UK) will be 
used along with a flat 70 mm figure-of-eight magnetic air-cooled coil with a maximum magnetic 
field strength of 1.5 T (Tesla) and an average inductance of 15.5 H. The figure-of-eight coil 
produces a focal stimulation point in the middle of the junction between the two circular coil 
elements. We will use both inhibitory and facilitatory  rTMS stimulation protocols (Pleger  
2006,Huang  2005).  These protocols have been effectively used in achieving changes in 
somatosensation in healthy adults (Premji  2010,Ragert  2008). Facilitatory rTMS protocol will 
consist of 5Hz rTMS  at 90% resting MT; a total of 1250 pulses (Pleger  2006),  (Rossini  
1999,Rossini  1994).  Inhibitory rTMS protocol will consist of 1Hz rTMS for a total of 1200 
pulses. Sham intervention will be provided using a sham coil. The active coil is a flat 70 mm 
figure-of-eight magnetic air-cooled coil with a maximum magnetic field strength of 1.5 T (Tesla) 
and an average inductance of 15.5 H; the sham coil is identical in appearance to the active coil 
but has a maximum magnetic field of 0.2T and an average inductance of 2.8 H which is well 
below stimulus threshold while producing similar sensory and auditory effects. 

Peripheral Sensory stimulation  will consist of vibratory stimulation (5 minutes),  and 
functional neuromusclular electrical stimulation (5 minutes) of the affected arm and will be 
administered simultaneously after the rTMS treatments. 
Aim1 (testing Hypothesis 1a and 1b) Test effect of rTMS of the contralesional S1 region 
on sensory function  The primary outcome measures will be two point discrimination. It 
will be collected at 3 time points during the treatment session (once before and 2 times after the 
rTMS: immediately after and 1 hour after. Two-point discrimination will be measured with 
Disk-Criminator disks (Baltimore, MD) by determining subjects’ ability to distinguish if the touch 
consisted of one or two points.  
Aim 2 to test Hypothesis 2: Characterize neurophysiological changes in response to rTMS of 
contralesional S1..  The primary outcome measure to test Hypothesis 2 we will be SEP . It will 
be collected at 3 time points during the treatment session (once before and 2 times after the 
rTMS: immediately after and 1 hour after. Somatosensory evoked potentials (SEP). SEP will 
be induced by stimulation of the median nerves at the wrist with a square pulse of 0.2ms 
delivered at 3Hz  at an intensity of 2.5 times above sensory threshold but below pain threshold 
(Delberghe  1990). SEPs will be recorded with Ag-AgCl scalp electrodes placed on the scalp 
over S1 cortical region keeping impedance at 5kΩ (2 cm posterior to the C3 and C4 coordinate, 
International 10-20 system (Nuwer  1994)), referenced to a frontocentral Fz electrode and 
grounded with a clavicular electrode. Location of the scalp electrodes will be digitized with 
Brainsight system (Rogue, Montreal) for later coregistration with the TMS data. SEP will be 
acquired with a Neuroscan system (Compumedics, Charlotte, NC) at a sampling rate of 1kHz 
using a 10 DC gain and band filtered(low pass 40 Hz, high pass 0.1 Hz, notch at 60 Hz). SEP 
data will be collected in blocks of 500 epochs. The N20/P30 components will be identified based 
on their latency and polarity and their peak-to peak amplitude measured. N20 is a negative peak 
within a primary sensory receptive region at 20 ms following peripheral nerve stimulus (Allison  
1989,Lueders  1983).  We expect to find changes in the amplitude and possibly latency of 
N20/P25 SEP component (Premji  2010).  
Inclusion criteria 
• 
Medically stable and at least 6 months after first ever stroke 
• 
Cognition sufficiently intact to give valid informed consent to participate (Etchells  1999) 
• 
Ability to follow two stage commands 
• 
Impaired but not absent ability to feel touch, vibration, movement of affect arm 
• 
Sufficient endurance to participate in the study 
• 
Age > 18  
 
Exclusion Criteria 
• 
 
• 
More than one ischemic strokes or stroke affecting both sides 
• 
Significant neglect for those with left-sided deficits 
• 
Acute or progressive cardiac, renal, respiratory, neurological disorders or malignancy.  
• 
Any psychiatric diagnosis or active psychological condition 
• 
Presence of implanted medical devices such as cardiac pacemakers and defibrillators, 
intrathecal drug delivery pumps, or spinal cord, vagus nerve or similar stimulators, or 
cochlear implants 
• 
Presence of metallic hardware that would be in close contact with the TMS discharging coil 
such as intracranial implants, aneurysm clips, plates, electrodes 

• 
Past history of seizures or unexplained loss of consciousness 
• 
Family history of medication refractory epilepsy 
• 
History of substance abuse within the last 6 months 
• 
Chronic sleep deprivation, ongoing untreated sleep disorder 
• 
Concurrent ototoxic medication (aminoglycodides, cisplantine) 
• 
Pregnancy or pregnancy planning during the study period 
• 
Currently taking medications or substances that lower the threshold for onset of seizure: 
imipramine, amitriptyline, doxepine, nortriptyline, maprotiline, chlorpromazine, clozapine, 
foscarnet, ganciclovir, ritonavir, amphetamines, cocaine (MDMA, ecstasy), phencyclidine 
(PCP, angel’s dust), ketamine, gamma-hydroxybutyrate, alcohol, theophylline.   
• 
Individuals will be excluded if they recently stopped taking the following drugs within the past 
6 months: alcohol, barbiturates, benzodiazepines, meprobamate and chloral hydrate. 
• 
Inability to understand English 
• 
Unavailable to participate in the study 
 
Statistical Analysis Plan. The outcome measures for the aims are typical longitudinal data. 
Linear mixed models (LMM) will be fitted for the data. LMM is a generalization of the standard 
linear model, permitting the data to exhibit correlation and nonconstant variability.