A Novel Brain Stimulation for Bimanual Motor Function and Control in Chronic Stroke

The long-term goal of this project is to develop and test upper Iimb rehabilitation interventions that can improve bimanual motor function, or the ability to use both arms and hands together, for stroke survivors with moderate to severe impairment.

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
• Baseline testing (4 visits total): 1 visit each for MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• Repeat baseline testing (4 visits total) of MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• 12 intervention visits during which patients will receive upper limb therapy in conjunction with non-invasive brain stimulation
• Repeat testing (4 visits total) of MRI, upper limb and bimanual motor function test, bimanual motor control, and neurophysiology related to control of the upper limbs
• A follow-up visit 1 month after the completion of interventions

Study Overview

• Status: Recruiting
• Conditions: Stroke
• Intervention / Treatment: Device: Novel rTMS Approach; Device: Sham rTMS Approach

Detailed Description

In a pilot randomized controlled clinical trial, 18 stroke survivors more than 6 months after stroke onset, and have upper limb impairment will be enrolled. Participants will be randomized to receive a form of non-invasive brain stimulation called repetitive transcranial magnetic stimulation or rTMS or sham rTMS. Real or sham rTMS will be delivered over an area in the brain called the higher motor cortices within the stroke-unaffected hemisphere, cHMC for short. This area (cHMC) is important for using both arms and hands together, or bimanual motor function. Real or sham cHMC rTMS will be given prior to upper limb therapy twice a week for 6 weeks in the lab. The investigators will measure bimanual motor function and control twice at the beginning, once after the 6-week treatment and once at 1-month after treatment. The investigators will also test possible mechanisms related to the treatment using brain functional MRI and TMS twice at the beginning and once after 6-week treatment.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Kyle J. O'Laughlin, MS; Phone Number: 216-445-6728; Email: olaughk@ccf.org
• Study Contact Backup: Name: Xin Li, MD, PhD; Phone Number: 216-445-6728; Email: LIX10@ccf.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Recruiting
      • Lerner Research Institute, Cleveland Clinic Foundation
      • Contact: Xin Li, MD, PhD; Phone Number: 216-445-6728; Email: LIX10@ccf.org
      • Contact: Morgan Widina, BS; Phone Number: 866-449-1394; Email: widinam@ccf.org

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18-90 yrs
• ≥6 months since first clinical stroke
• Impairment of the paretic hand, indicated by a score of <= 11 out of 14 on the hand section of UEFM
• Sufficient range of motion in the wrist and fingers for functional task practice: have at least 10 degrees active wrist extension, 10 degrees active thumb abduction/extension, and 10 degrees active extension in at least 2 additional digits
• Sufficient active shoulder and elbow movement to volitionally position the paretic hand in the workspace for table-top task practice

Exclusion Criteria:

• Brainstem or cerebellar stroke
• Bilateral strokes or multiple strokes affecting sensorimotor structures
• Cognitive impairment (Mini-Mental State Examination <24)
• Severe impairment of the paretic hand that limits functional task practice (UEFM hand score < 4 out of 14)
• Severe spasticity (Modified Ashworth Scale >3) or upper limb contracture
• Occupational therapy or upper limb Botox completed ≤ 2 months prior
• Contraindications to TMS or MRI (e.g. metal implant in head, seizure history, cardiac pacemaker)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cHMC rTMS + Upper Limb Training Training; Real Repetitive Transcranial Magnetic Stimulation given to facilitate the Contralesional Higher Motor Cortices+ Upper Limb Training	Device: Novel rTMS Approach; Participants in this arm will receive rTMS-based facilitation of the contralesional higher motor cortices located in the non-stroke hemisphere before the start of each rehabilitation session. High-frequency rTMS (5Hz) will be delivered using 42 10 second trains of 50 pulses each (total 2100 pulses) for a period of 22 minutes. Immediately after the completion of rTMS, participants will undergo therapist-guided upper limb therapy for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks for a total of 12 sessions.
Sham Comparator: Sham rTMS + Upper Limb Training Training; Sham Repetitive Transcranial Magnetic Stimulation over Contralesional Higher Motor Cortices+ Upper Limb Training	Device: Sham rTMS Approach; Participants in this arm will receive sham rTMS given over the contralesional higher motor cortices located in the non-stroke hemisphere before the start of each rehabilitation session. Immediately after the completion of sham rTMS, participants will undergo therapist-guided upper limb therapy for a total of one hour. Participants will receive these interventions 2 days a week for 6 weeks for a total of 12 sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Bimanual Assessment Measure (BAM)	Measure of the functional ability to perform 11 bimanual tasks scoring the spontaneous role of the affected hand, timing, and quality of movement.	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks) and after end of 1 month of follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks) and after end of 1 month of follow-up.
Change in ABILHAND	ABILHAND assesses the participant's perception of bimanual ability by rating the difficulty of performing 23 bimanual activities without assistance on a 3 point ordinal scale (impossible, difficult, easy) This test has excellent reliability (ICC = 0.85-0.91).	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks) and after end of 1 month of follow-up.
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.)	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks) and after end of 1 month of follow-up.
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.	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks) and after end of 1 month of follow-up.
Change Resting State Functional Magnetic Resonance Imaging(rsfMRI)	Functional connectivity will assess the connectivity between cHMC and iM1 using temporal correlation of blood oxygneation level-dependent (BOLD) signal given as z-scores.	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks)
Change in excitability of cortical and corticospinal physiology (TMS)	Transcranial magnetic stimulation will be used to test crossed and uncrossed output from both hemispheres and will be measured as motor evoked potentials(MEPS) of the Extensor Digitorum Communis (EDC).	Baseline (0 weeks and 2 weeks), after intervention(up to 7 weeks)

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: American Heart Association
• Investigators: Principal Investigator: Ela Plow, PhD, The Cleveland Clinic

Publications and helpful links

General Publications

• Haaland KY, Mutha PK, Rinehart JK, Daniels M, Cushnyr B, Adair JC. Relationship between arm usage and instrumental activities of daily living after unilateral stroke. Arch Phys Med Rehabil. 2012 Nov;93(11):1957-62. doi: 10.1016/j.apmr.2012.05.011. Epub 2012 May 24.
• 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.
• Liao WW, Whitall J, Wittenberg GF, Barton JE, McCombe Waller S. Not all brain regions are created equal for improving bimanual coordination in individuals with chronic stroke. Clin Neurophysiol. 2019 Aug;130(8):1218-1230. doi: 10.1016/j.clinph.2019.04.711. Epub 2019 May 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2022
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 16, 2022
• First Posted (Actual): May 19, 2022

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 27, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: MRI; stroke; rehabilitation; neuromodulation; 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: 22-074

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
• product manufactured in and exported from the U.S.: No