Back to resultsA Novel Approach for Brain Stimulation in Severe Stroke
Primary Purpose
Stroke
Status
Completed
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
New rTMS Approach
Conventional rTMS Approach
Sponsored by
About this trial
This is an interventional treatment trial for Stroke focused on measuring stroke, brain stimulation, TMS, Upper Limb, MRI, CVA, Rehabilitation
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).
Sites / Locations
- Lerner Research Institute; Cleveland Clinic Foundation
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
cPMD rTMS + Training
iM1 rTMS + Training
Arm Description
New Approach
Conventional Approach
Outcomes
Primary Outcome Measures
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.)
Change in Inter-hemispheric Inhibition (IHI)
Inter-hemispheric connectivity will be characterized using IHI collected with TMS.
Secondary Outcome Measures
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.
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.
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).
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.
Change in ipsilateral MEPs (motor evoked potentials)
Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.
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.
Change in SULCS
is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks.
Full Information
NCT ID
NCT03868410
First Posted
September 24, 2018
Last Updated
October 10, 2023
Sponsor
The Cleveland Clinic
Collaborators
American Heart Association
1. Study Identification
Unique Protocol Identification Number
NCT03868410
Brief Title
A Novel Approach for Brain Stimulation in Severe Stroke
Official Title
A Novel Approach for Brain Stimulation in Severe Stroke
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
April 1, 2019 (Actual)
Primary Completion Date
April 21, 2023 (Actual)
Study Completion Date
July 13, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Cleveland Clinic
Collaborators
American Heart Association
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
No
5. 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
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke
Keywords
stroke, brain stimulation, TMS, Upper Limb, MRI, CVA, Rehabilitation
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
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
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.
Allocation
Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
cPMD rTMS + Training
Arm Type
Active Comparator
Arm Description
New Approach
Arm Title
iM1 rTMS + Training
Arm Type
Active Comparator
Arm Description
Conventional Approach
Intervention Type
Device
Intervention Name(s)
New rTMS Approach
Other Intervention Name(s)
cPMd rTMS + Training
Intervention Description
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.
Intervention Type
Device
Intervention Name(s)
Conventional rTMS Approach
Other Intervention Name(s)
iM1 rTMS + Training
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Upper Extremity Fugyl-Meyer Score (UEFM)
Description
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.)
Time Frame
through study completion, on average 7 weeks
Title
Change in Inter-hemispheric Inhibition (IHI)
Description
Inter-hemispheric connectivity will be characterized using IHI collected with TMS.
Time Frame
through study completion, on average 7 weeks
Secondary Outcome Measure Information:
Title
Change in Wolf Motor Function Test (WMFT)
Description
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.
Time Frame
through study completion, on average 6 weeks
Title
Change in Bimanual Grip Force Modulation Task
Description
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.
Time Frame
through study completion, on average 7 weeks
Title
Change in Stroke Impact Scale (SIS-16)
Description
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).
Time Frame
through study completion, on average 7 weeks
Title
Change Resting State Functional Magnetic Resonance Imaging(rsfMRI)
Description
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.
Time Frame
through study completion, on average 7 weeks
Title
Change in ipsilateral MEPs (motor evoked potentials)
Description
Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.
Time Frame
through study completion, on average 7 weeks
Title
DTI
Description
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.
Time Frame
Baseline
Title
Change in SULCS
Description
is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks.
Time Frame
through study completion, on average 7 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ela Plow, PhD
Organizational Affiliation
Lerner Research Institute; Cleveland Clinic Foundation
Official's Role
Principal Investigator
Facility Information:
Facility Name
Lerner Research Institute; Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
26484700
Citation
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.
Results Reference
background
PubMed Identifier
29563050
Citation
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.
Results Reference
background
PubMed Identifier
24951091
Citation
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.
Results Reference
background
PubMed Identifier
28402865
Citation
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.
Results Reference
result
PubMed Identifier
35051941
Citation
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.
Results Reference
derived
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A Novel Approach for Brain Stimulation in Severe Stroke
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