A Novel Approach for Brain Stimulation in Severe Stroke

NCT03868410 | Completed Early Phase 1 Results FDA Device

• 1 other identifier: 18-861
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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

Conditions

Stroke

Keywords

stroke; brain stimulation; TMS; Upper Limb; MRI; CVA; Rehabilitation

Outcome Measures

Primary Outcomes (2)

• Change in Upper Extremity Fugyl-Meyer Score (UEFM)

  Change between Baseline and Post-Test (average 6 weeks) is reported for the 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.)

  Change between Baseline and Post-Test (average 6 weeks)

• Change in Inter-hemispheric Inhibition (IHI)

  Inter-hemispheric connectivity (IHI) will be collected with transcranial magnetic stimulation (TMS) and is assessed using ipsilateral silent period (ISP) method. TMS is delivered to the contralesional motor hotspot at supra-maximal intensity (100% maximum stimulator output) while participants maintain sub-maximal contraction (50% maximum volitional contraction) of the ipsilateral paretic extensor digitorum communis muscle for 40 trials. Ipsilateral TMS produces transient suppression of on-going EMG activity, called ISP. ISP is analyzed using an algorithm that compares psotstimulus average rectified EMG to mean consecutive difference (MCD) of background EMG. A threshold of MCD x1.77 below mean background EMG is used to define ISP onset and offset. ISP duration is then calculated as a difference between onset and offset of the ISP.

  Change between Baseline and Post-Test (average 6 weeks)

Secondary Outcomes (9)

• Change in Wolf Motor Function Test (WMFT) Functional Ability

  Change between Baseline and Post-Test (average 6 weeks)

• Change in Wolf Motor Function Test (WMFT) Rate Paretic Limb

  Change between Baseline and Post-Test (average 6 weeks)

• Change in Wolf Motor Function Test (WMFT) Rate Non-paretic Limb

  Change between Baseline and Post-Test (average 6 weeks)

• Change in Wolf Motor Function Test (WMFT) Rate Paretic Limb Normalized to the Non-paretic Limb

  Change between Baseline and Post-Test (average 6 weeks)

• Change in Stroke Impact Scale (SIS-16)

  Change between Baseline and Post-Test (average 6 weeks)

Study Arms (2)

Contralesional dorsal premotor cortex (cPMD) rTMS + Training

ACTIVE COMPARATOR

New Approach

Device: New Repetitive Magnetic Stimulation (rTMS) Approach

Ipsilesional Primary Motor Cortex (iM1) rTMS + Training

ACTIVE COMPARATOR

Conventional Approach

Device: Conventional Repetitive Magnetic Stimulation (rTMS) Approach

Interventions

New Repetitive Magnetic Stimulation (rTMS) Approach DEVICE

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.

Also known as: Contralesional dorsal premotor cortex (cPMD) rTMS + Training

Contralesional dorsal premotor cortex (cPMD) rTMS + Training

Conventional Repetitive Magnetic Stimulation (rTMS) Approach DEVICE

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.

Also known as: Ipsilesional Primary Motor Cortex (iM1) rTMS + Training

Ipsilesional Primary Motor Cortex (iM1) rTMS + Training

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 Constraint-Induced Movement Therapy \[CIMT\] criteria).
• medically stable

You may not qualify if:

• 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

Sponsors & Collaborators

• The Cleveland Clinic: lead
• American Heart Association: collaborator

Study Sites (1)

Lerner Research Institute; Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Related Publications (5)

• 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.

  PMID: 26484700 BACKGROUND

• 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.

  PMID: 29563050 BACKGROUND

• 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.

  PMID: 24951091 BACKGROUND

• 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.

  PMID: 28402865 RESULT

• 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.

  PMID: 35051941 DERIVED

MeSH Terms

Conditions

Stroke

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Results Point of Contact

• Title: Dr. Ela Plow
• Organization: Cleveland Clinic

plowe2@ccf.org

216-445-6728

Study Officials

• Ela Plow, PhD

  Lerner Research Institute; Cleveland Clinic Foundation

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Staff

Model Details: 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.

Study Record Dates

• First Submitted: September 24, 2018
• First Posted: March 11, 2019
• Study Start: April 1, 2019
• Primary Completion: April 21, 2023
• Study Completion: July 13, 2023
• Last Updated: June 5, 2025
• Results First Posted: June 5, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)