A Novel Approach for Brain Stimulation in Severe Stroke

Status

Completed

Phases

Early Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03868410

Enrollment

Registered

2019-03-11

Start date

2019-04-01

Completion date

2023-07-13

Last updated

2025-06-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Stroke

Keywords

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

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).

Interventions

DEVICENew Repetitive Magnetic Stimulation (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.

DEVICEConventional Repetitive Magnetic Stimulation (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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

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.

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.

Eligibility

Sex/Gender

ALL

Age

18 Years to 90 Years

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 Constraint-Induced Movement Therapy \[CIMT\] 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 *

Design outcomes

Primary

Measure	Time frame	Description
Change in Upper Extremity Fugyl-Meyer Score (UEFM)	Change between Baseline and Post-Test (average 6 weeks)	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 in Inter-hemispheric Inhibition (IHI)	Change between Baseline and Post-Test (average 6 weeks)	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.

Secondary

Measure	Time frame	Description
Change in Wolf Motor Function Test (WMFT) Rate Non-paretic Limb	Change between Baseline and Post-Test (average 6 weeks)	Change in Rate of the Non-paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Non-paretic limb \[WMFT Rate (NP)\]. The higher the rate the quicker they were able to complete the task.
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 the normalized Rate of the Paretic limb to the Non-paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Paretic limb normalized to the Non-paretic limb \[WMFT Rate (P/NP)\]. The higher the rate the quicker they were able to complete the task.
Change in Stroke Impact Scale (SIS-16)	Change between Baseline and Post-Test (average 6 weeks)	Change in total score between Baseline and Post-Test (average 6 weeks) is reported for the Stoke Impact Scale (SIS-16) for each group. 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 on scale from 1 to 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 in Wolf Motor Function Test (WMFT) Functional Ability	Change between Baseline and Post-Test (average 6 weeks)	Change in Functional Ability (FA) from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Functional ability (FA) to use the paretic upper limb in a variety of tasks will be assessed using WMFT. FA is scored on a scale from 0-5 with 0 not attempting the task at all and 5 being completely normal movement compared to non paretic limb. 15 items of WMFT are given a FA for the Paretic limb and then the score is averaged to give an overall FA for each participant.
Change in Ipsilateral MEPs (Motor Evoked Potentials)	Change between Baseline and Post-Test (average 6 weeks)	Output of uncrossed pathways will be studied as ipsilateral MEPs elicited in the paretic-muscle with TMS.
Diffusion Tensor Imaging (DTI)	Baseline	Diffusion Tensor Imaging (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 Transcranial Magnetic Stimulation (TMS) due to extensive damage (MEP-). Ipsilesional and contralesional corticospinal tracts will be reconstructed using probabilistic tractography. Fractional Anisotropy (FA), a unit-less measure of white matter integrity, will be calculated.
Change in SULCS	Change between Baseline and Post-Test (average 6 weeks)	Change in total score between Baseline and Post-Test (average 6 weeks) is reported for the Stroke Upper Limb Capacity Scale (SULCS). SULCS is a stroke-specific assessment instrument that evaluates functional capacity of the upper limb based on the execution of 10 tasks. Score ranges from 0-10 where 0 is the lowest level of function in which the participant cannot perform any of the tasks as instructed and 10 is the highest level of function in which all 10 tasks are completed as instructed.
Change Resting State Functional Magnetic Resonance Imaging(rsfMRI)	Change between Baseline and Post-Test (average 6 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 Wolf Motor Function Test (WMFT) Rate Paretic Limb	Change between Baseline and Post-Test (average 6 weeks)	Change in Rate of the Paretic limb from Baseline to Post-Test (average 6 weeks) is reported for the Wolf Motor Function Test. Time to complete each task will be noted and converted to rate (60/Performance Time (sec)), optimized for measurement in moderately/severely-impaired patients. The rate will be calculated for the Paretic limb \[WMFT Rate (P)\]. The higher the rate the quicker they were able to complete the task.

Countries

United States

Participant flow

Participants by arm

Arm	Count
cPMD Repetitive Transcranial Magnetic Stimulation (rTMS) + Training New Approach 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.	8
iM1 Repetitive Transcranial Magnetic Stimulation (rTMS) + Training Conventional Approach 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.	8
Total	16

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Physician Decision	0	1

Baseline characteristics

Characteristic	cPMD Repetitive Transcranial Magnetic Stimulation (rTMS) + Training	Total	iM1 Repetitive Transcranial Magnetic Stimulation (rTMS) + Training
Active wrist extension no	3 Participants	7 Participants	4 Participants
Active wrist extension yes	5 Participants	9 Participants	4 Participants
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	4 Participants	7 Participants	3 Participants
Age, Categorical Between 18 and 65 years	4 Participants	9 Participants	5 Participants
Age, Continuous	63.1 years STANDARD_DEVIATION 13.7	64.2 years STANDARD_DEVIATION 11.7	65.3 years STANDARD_DEVIATION 10.1
Dominant Paresis no	3 Participants	5 Participants	2 Participants
Dominant Paresis yes	5 Participants	11 Participants	6 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	8 Participants	16 Participants	8 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	3 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	7 Participants	13 Participants	6 Participants
Region of Enrollment United States	8 participants	16 participants	8 participants
Resting Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential (MEP) no	6 Participants	12 Participants	6 Participants
Resting Transcranial Magnetic Stimulation (TMS) Motor Evoked Potential (MEP) yes	2 Participants	4 Participants	2 Participants
Sex: Female, Male Female	5 Participants	11 Participants	6 Participants
Sex: Female, Male Male	3 Participants	5 Participants	2 Participants
Stroke Type hemorrhagic	2 Participants	3 Participants	1 Participants
Stroke Type ischemic	6 Participants	13 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8
other Total, other adverse events	2 / 8	2 / 8
serious Total, serious adverse events	0 / 8	0 / 8

Outcome results

Primary

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.