A Novel Approach for Brain Stimulation in Severe Stroke

Sponsor

The Cleveland Clinic (Other)

Overall Status

Recruiting

CT.gov ID

NCT03868410

Collaborator

American Heart Association (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Stroke	Device: New rTMS Approach Device: Conventional rTMS Approach	Early Phase 1

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Outcomes Assessor)

Masking Description:

Subjects will be told they will receive brain stimulation, but will be given no indication as to which target will be stimulated. Investigators analyzing functional outcome data, neurophysiology data and MRI data will receive coded data that conceals the identity of the subject.

Primary Purpose:

Treatment

Official Title:

A Novel Approach for Brain Stimulation in Severe Stroke

Actual Study Start Date :

Apr 1, 2019

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: cPMD rTMS + Training New Approach	Device: New rTMS Approach 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. Other Names: cPMd rTMS + Training
Active Comparator: iM1 rTMS + Training Conventional Approach	Device: Conventional rTMS Approach 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. Other Names: iM1 rTMS + Training

Arm

Intervention/Treatment

Active Comparator: cPMD rTMS + Training

New Approach

Device: New rTMS Approach

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.

Other Names:

cPMd rTMS + Training

Active Comparator: iM1 rTMS + Training

Conventional Approach

Device: Conventional rTMS Approach

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.

Other Names:

iM1 rTMS + Training

Outcome Measures

Primary Outcome Measures

Change in Upper Extremity Fugyl-Meyer Score (UEFM) [through study completion, on average 7 weeks]
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.)
Change in Inter-hemispheric Inhibition (IHI) [through study completion, on average 7 weeks]
Inter-hemispheric connectivity will be characterized using IHI collected with TMS.

Secondary Outcome Measures

Change in Wolf Motor Function Test (WMFT) [through study completion, on average 6 weeks]
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.
Change in Bimanual Grip Force Modulation Task [through study completion, on average 7 weeks]
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.
Change in Stroke Impact Scale (SIS-16) [through study completion, on average 7 weeks]
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).
Change Resting State Functional Magnetic Resonance Imaging(rsfMRI) [through study completion, on average 7 weeks]
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.
Change in ipsilateral MEPs (motor evoked potentials) [through study completion, on average 7 weeks]
Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.
DTI [Baseline]
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.
Change in SULCS [through study completion, on average 7 weeks]
is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).