A Novel Approach for Brain Stimulation in Severe Stroke

Study Overview
=================
Brief Summary
-----------------
The long-term goal of this project is to develop upper limb rehabilitation interventions that can be utilized for stroke survivors, specifically survivors with more severe limitations in use of their affected upper limb. This study will utilize a novel method of non-invasive brain stimulation in conjunction with upper limb training given for 12 visits over a period of 6 weeks. The study will include the following site visits: Eligibility Screening and Informed Consent Visit An MRI visit Two testing visits in which motor function of the upper limb and neurophysiology will be measured 12 intervention visits during which patients will receive upper limb training in conjunction with non-invasive brain stimulation Repeat testing of motor function of the upper limb and neurophysiology Repeat MRI testing A follow-up visit completed 3 months after the completion of interventions

Detailed Description
-----------------
In a pilot, randomized clinical trial, 24 stroke patients with moderate/severe impairments will receive non-invasive brain stimulation (repetitive Transcranial Magnetic Stimulation or rTMS) to one of two targets in the brain in conjunction with upper limb training for 2 days a week for 6 weeks. The primary outcome will be upper limb motor impairment, and secondary outcomes will be tests of functional abilities, proximal motor control, and patient-reported disability. Associated neural mechanisms will also be studied using neurophysiological and functional connectivity MRI techniques. Damage to ipsilesional corticospinal pathways will be indexed with diffusion tensor imaging (DTI).

Official Title
-----------------
A Novel Approach for Brain Stimulation in Severe Stroke

Conditions
-----------------
Stroke

Intervention / Treatment
-----------------
* Device: New rTMS Approach
* Device: Conventional rTMS Approach


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: chronic phase (≥6 months) after index stroke moderate or severely impaired (UEFM ≤42) have either extensive damage to ipsilesional pathways (MEP-), or, have one of the following: less than 10 degrees active wrist extension, less than 10 degrees active thumb extension/abduction, less than 10 degrees active extension in at least 2 additional digits (i.e. will not meet minimum CMIT criteria). medically stable Exclusion Criteria: cerebellar stroke brainstem stroke bilateral strokes affecting sensorimotor structures severe cognitive impairment substantially elevated tone/spasticity in wrist/hand (Modified Ashworth Scale >3) severe contracture participation in outpatient or Botox therapy within 2 months exclusion criteria for TMS and MRI (metal implant in head, H/O seizures, alcohol or substance abuse, intake of medications contraindicated with TMS, cardiac pacemaker or programmable implant).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In a pilot, randomized, assessor-blind clinical trial, an anticipated 24 patients will be assigned to either receive stimulation to a new brain target- contralesional dorsal premotor cortex (cPMd) located in the non-stroke hemisphere- or the conventional brain target- ipsilesional primary motor cortex (iM1) located in the stroke hemisphere. Stimulation will be delivered in conjunction with rehabilitation for 2 days a week for 6 weeks.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cPMD rTMS + Training<br>New Approach | Device: New rTMS Approach<br>* Participants in this arm will receive rTMS-based facilitation of the contralesional dorsal premotor cortex (cPMd) located in the non-stroke hemisphere before start of each session. High-frequency rTMS (5-Hz) will be delivered using 42 10-sec trains of 50 pulses each (total 2100 pulses) for a period of 24 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks, i.e., for a total of 12 sessions.<br>* Other names: cPMd rTMS + Training;|
| Active Comparator: iM1 rTMS + Training<br>Conventional Approach | Device: Conventional rTMS Approach<br>* Participants in this arm will receive rTMS-based facilitation of the ipsilesional primary motor cortex (iM1) before the start of each session. iM1 will be stimulated with high-frequency rTMS (5-Hz) using 42 10-sec trains of 50 pulses each (total 2100 pulses) for a period of 24 minutes. Immediately after the completion of rTMS, participants will undergo upper limb training for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks, i.e., for a total of 12 sessions.<br>* Other names: iM1 rTMS + Training;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Upper Extremity Fugyl-Meyer Score (UEFM) | Impairment will be measured using UEFM, one of the most widely used assessments in stroke. UEFM will serve as our primary outcome because it is sensitive to discerning the effects of rTMS/rehabilitation, and has excellent reliability (ICC= 0.97), consistency (Cronbach's α= 0.84) and validity. UEFM has a score ranging from 0-66 (0 meaning there is no movement of the paretic arm, and 66 meaning there is no functional limitation of the paretic arm.) | through study completion, on average 7 weeks | 
| Change in Inter-hemispheric Inhibition (IHI) | Inter-hemispheric connectivity will be characterized using IHI collected with TMS. | through study completion, on average 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Wolf Motor Function Test (WMFT) | Functional ability to use the paretic upper limb in a variety of tasks will be assessed using WMFT. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. Grip strength will also be recorded with WMFT. | through study completion, on average 6 weeks | 
| Change in Bimanual Grip Force Modulation Task | Measure the ability to produce and maintain differing levels of force using hand dynamometers. This measurement represents patient's ability to perform independent tasks with each hand. | through study completion, on average 7 weeks | 
| Change in Stroke Impact Scale (SIS-16) | Patient's perceived disability related to physical function will be indexed using the Stroke Impact Scale (SIS-16) which a subjective questionnaire asked to the subject pertaining of 16 questions. Each question is rated 1-5 and then the scores are totaled. Total scores can range from 16-80 (16 means that none of the functional tasks asked can be performed, a score of 80 means the subject has no issues at all performing any of the tasks asked). | through study completion, on average 7 weeks | 
| Change Resting State Functional Magnetic Resonance Imaging(rsfMRI) | Functional connectivity will complement IHI measurement as a secondary outcome because while IHI records neurophysiologic interactions between a contralesional and a weak ipsilesional region, functional connectivity defines global interactions across multiple regions. | through study completion, on average 7 weeks | 
| Change in ipsilateral MEPs (motor evoked potentials) | Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS. | through study completion, on average 7 weeks | 
| DTI | DTI enables the investigation of structural integrity and orientation of pathways in vivo through the estimation of magnitude and directionality of water diffusion. DTI metrics can help quantitate damage even when patients show no response to TMS due to extensive damage (MEP-). Ipsilesional and contralesional corticospinal tracts will be reconstructed using probabilistic tractography. FA, a unit-less measure of white matter integrity, will be calculated. | Baseline | 
| Change in SULCS | is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks. | through study completion, on average 7 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stroke, brain stimulation, TMS, Upper Limb, MRI, CVA, Rehabilitation