A Novel Approach for Brain Stimulation in Severe Stroke

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

Study Overview

• Status: Completed
• Conditions: Stroke
• Intervention / Treatment: Device: New rTMS Approach; Device: Conventional rTMS Approach

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 Type: Interventional
• Enrollment (Actual): 23
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Lerner Research Institute; Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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

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

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Ela Plow, PhD, Lerner Research Institute; Cleveland Clinic Foundation

Publications and helpful links

General Publications

• Cunningham DA, Varnerin N, Machado A, Bonnett C, Janini D, Roelle S, Potter-Baker K, Sankarasubramanian V, Wang X, Yue G, Plow EB. Stimulation targeting higher motor areas in stroke rehabilitation: A proof-of-concept, randomized, double-blinded placebo-controlled study of effectiveness and underlying mechanisms. Restor Neurol Neurosci. 2015;33(6):911-26. doi: 10.3233/RNN-150574.
• Potter-Baker KA, Lin YL, Machado AG, Conforto AB, Cunningham DA, Sankarasubramanian V, Sakaie K, Plow EB. Variability of motor evoked potentials in stroke explained by corticospinal pathway integrity. Brain Stimul. 2018 Jul-Aug;11(4):929-931. doi: 10.1016/j.brs.2018.03.004. Epub 2018 Mar 9. No abstract available.
• Plow EB, Cunningham DA, Varnerin N, Machado A. Rethinking stimulation of the brain in stroke rehabilitation: why higher motor areas might be better alternatives for patients with greater impairments. Neuroscientist. 2015 Jun;21(3):225-40. doi: 10.1177/1073858414537381. Epub 2014 Jun 20.
• Sankarasubramanian V, Machado AG, Conforto AB, Potter-Baker KA, Cunningham DA, Varnerin NM, Wang X, Sakaie K, Plow EB. Inhibition versus facilitation of contralesional motor cortices in stroke: Deriving a model to tailor brain stimulation. Clin Neurophysiol. 2017 Jun;128(6):892-902. doi: 10.1016/j.clinph.2017.03.030. Epub 2017 Mar 21.
• Li X, Lin YL, Cunningham DA, Wolf SL, Sakaie K, Conforto AB, Machado AG, Mohan A, O'Laughlin K, Wang X, Widina M, Plow EB. Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial. Cerebrovasc Dis. 2022;51(5):557-564. doi: 10.1159/000521514. Epub 2022 Jan 20.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Actual): April 21, 2023
• Study Completion (Actual): July 13, 2023

Study Registration Dates

• First Submitted: September 24, 2018
• First Submitted That Met QC Criteria: March 6, 2019
• First Posted (Actual): March 11, 2019

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: MRI; Rehabilitation; stroke; TMS; brain stimulation; CVA; Upper Limb
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke
• Other Study ID Numbers: 18-861

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes