Stroke
Conditions
Keywords
Stroke, upper limb impairment, HD-tDCS
Brief summary
Stroke is the leading cause of serious, long-term disability. The emergence of abnormal muscle synergies following a stroke presents a major limitation to the recovery of independent function. Despite the development of many interventions for movement recovery post-stroke, rehabilitation treatments are minimally effective to the muscle synergy impairment. Previous studies have found that muscle synergy impairment is associated with the damage to the corticospinal tract and the maladaptive recruitment of the contralesional cortico-reticulospinal tract. The investigators hypothesize that facilitating the damaged cortico-spinal tract (via primary motor cortex) and/or inhibiting the contralesional cortico-reticulospinal tract (via dorsal premotor cortex) will reduce muscle synergy impairment. In this pilot project, the investigators propose to run a proof-of-concept pilot trial to evaluate the effect of the targeted high-definition transcranial direct current stimulation (HD-tDCS) on mitigating muscle synergy impairment.
Detailed description
This randomized, double-blinded, sham-controlled cross-over study will include three stimulation conditions: 1) anodal stimulation over the ipsilesional primary motor cortex, 2) cathodal one over the contralesional premotor cortex, 3) sham stimulation in chronic hemiparetic stroke patients. Stroke participants (\> 3 months after stroke) with moderate to severe motor impairments (Fugl-Meyer Motor Assessment - Upper Extremity score between 10-40, in absence of clinically defined sensory deficits) and an ischemic unilateral subcortical lesion will receive each type of stimulation for 20 minutes. Their brain activity and behavior data will be collected for the outcome measures. The patient time commitment in this study is approximately 7 weeks where subjects have 3 x 1-day intervention and measurements, with 2 weeks washout period in between. The total number of potential enrolled subjects in this pilot study is 12.
Interventions
DEVICETranscranial direct current stimulation (high-definition)
Three conditions (2 mA, 20 mins): 1. anodal stimulation over the ipsilesional primary motor cortex 2. cathodal one over the contralesional premotor cortex 3. Sham
Sponsors
Oklahoma Shared Clinical and Translational Resources
University of Oklahoma
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
This sham-controlled cross-over study design will include three visits: 1) anodal stimulation targeting ipsilesional primary motor cortex, 2) cathodal one at the contralesional premotor cortex, 3) a sham stimulation visit. The sequence of the stimulations will be randomized and double-blinded. After each intervention, there will be at least 2 weeks wash-out period before participants receive the next intervention and assessments.
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Ischemic unilateral stroke lesion (confirmed by the most recent clinical or radiological reports) at least 3 months prior to participation in this project. * Paresis confined to one side, with moderate to severe motor impairment of the upper limb (Fugl-Meyer upper extremity scores of 10-40) * Capacity to provide informed consent
Exclusion criteria
* Muscle tone abnormalities and motor or sensory impairment in the unimpaired limb * Severe wasting or contracture or significant sensory deficits in the paretic upper limb * Severe cognitive or affective dysfunction that prevents normal communication and understanding of consent or instruction * Severe concurrent medical problems (e.g. cardiorespiratory impairment) * Using a pacemaker * Metal implants in the head * Known adverse reaction to TMS and tDCS * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fugl-Meyer Upper Extremity Assessment Part A | The FM-UE assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intenvention) and recorded for each treatment group (anodal, cathodal, and sham). . | The Fugl-Meyer Upper Extremity (FM-UE) subset is a component of the Fugl-Meyer Assessment (FM) assessing motor impairment in individuals with stroke or other arm impairments. The (FM-UE) subset focuses on evaluating motor impairment and recovery using movements assessing strength, coordination, sensation, and range of motion of the upper extremity. Each item in the FM-UE subset is scored on a scale from 0-2. These are added together, with higher scores indicating better motor function. The FM-UE subset has 33 items for a maximum possible (highest functioning) score of 66. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Onset Latency of Transcranial Magnetic Stimulation (TMS)-Evoke Motor-evoked Potentials (MEP) | The latency of TMS-evoke MEP assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intevention) and recorded for each treatment group (anodal, cathodal, and sham). | This is a neurophysiological measure that determines the use of ipsilesional corticospinal tract. The paired-pulse TMS was applied at the respective hotspot for the elbow flexor muscle at the paretic arm over the ipsilesional primary motor cortex. The center of the coil was positioned tangentially to the skull. The patient was considered MEP+ if MEPs of any amplitude are observed at a consistent latency on at least 5 out 10 trials. After determining the status of MEP, at least eight more pulses were applied. We calculated average latency across all positive trials to determine the latency of MEP. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Brain Symmetry Index | The BSI assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intevention) and recorded for each treatment group (anodal, cathodal, and sham). | This is a neurophysiological measure used to quantify the symmetry or asymmetry between the left and right hemispheres of the brain. It was calculated using EEG data from a 3-minute resting state EEG recording. The scale of the index is from -1 to 1, where zero is considered perfect symmetry between hemispheres and values close to -1 and 1 indicate asymmetry. |
Countries
United States
Participant flow
Recruitment details
Our primary patient resource is from OU Physician Neurology Clinic and Allied Health Clinical Network. We also seek referrals from clinicians in the Oklahoma City areas and recruit stroke survivors residing in these two areas who wish to participate in the study. The recruitment method include doctor referrals and direct contact (if study doctor's patients) via the study doctor. Recruitment period: 1/18/2022-5/12/2023
Pre-assignment details
Stroke participants will be examined by the study doctor to verify their admissibility to the study based on the inclusion criteria. Participants will then undergo the upper extremity portion of the Fugl-Meyer Motor Assessment, and a structured interview pertaining to the inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Sham, Anodal, Cathodal Treatment order 1: Sham, Anodal, Cathodal
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 1 |
| Anodal, Cathodal, Sham Treatment order 2: Anodal, Cathodal, Sham
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 4 |
| Cathodal, Sham, Anodal Treatment order 3: Cathodal, Sham, Anodal
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 1 |
| Sham, Cathodal, Anodal Treatment order 4: Sham, Cathodal, Anodal
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 4 |
| Cathodal, Anodal, Sham Treatment order 5: Cathodal, Anodal, Sham
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 2 |
| Anodal, Sham, Cathodal Treatment order 6: Anodal, Sham, Cathodal
Transcranial direct current stimulation (high-definition): Three conditions (2 mA, 20 mins):
1. anodal stimulation over the ipsilesional primary motor cortex
2. cathodal one over the contralesional premotor cortex
3. Sham | 1 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 2 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Sham, Anodal, Cathodal | Total | Anodal, Sham, Cathodal | Cathodal, Anodal, Sham | Sham, Cathodal, Anodal | Cathodal, Sham, Anodal | Anodal, Cathodal, Sham |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 0 | 61 years STANDARD_DEVIATION 12.88 | 67 years STANDARD_DEVIATION 0 | 64.5 years STANDARD_DEVIATION 10.6 | 62.4 years STANDARD_DEVIATION 12.95 | 81 years STANDARD_DEVIATION 0 | 51.75 years STANDARD_DEVIATION 13.18 |
| Brain symmetry index | -0.091 Index STANDARD_DEVIATION 0 | -0.015 Index STANDARD_DEVIATION 0.173 | -0.439 Index STANDARD_DEVIATION 0 | 0.061 Index STANDARD_DEVIATION 0.009 | 0.093 Index STANDARD_DEVIATION 0.149 | -0.091 Index STANDARD_DEVIATION 0 | 0.007 Index STANDARD_DEVIATION 0.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 12 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Onset Latency of Transcranial magnetic stimulation (TMS)-evoke motor-evoked potentials (MEP) | 23.82 ms STANDARD_DEVIATION 0 | 52.03 ms STANDARD_DEVIATION 16.83 | 60.82 ms STANDARD_DEVIATION 0 | 62.66 ms STANDARD_DEVIATION 14.86 | 48.50 ms STANDARD_DEVIATION 9.81 | 74.48 ms STANDARD_DEVIATION 0 | 49.49 ms STANDARD_DEVIATION 20.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 12 Participants | 1 Participants | 2 Participants | 4 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 1 participants | 13 participants | 1 participants | 2 participants | 4 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 10 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Subset of Fugl-Meyer Upper Extremity assessment which is mainly related to the muscle synergy | 25 units on a scale STANDARD_DEVIATION 0 | 18.15 units on a scale STANDARD_DEVIATION 9.47 | 7 units on a scale STANDARD_DEVIATION 0 | 12.5 units on a scale STANDARD_DEVIATION 2.12 | 17.75 units on a scale STANDARD_DEVIATION 6.9 | 8 units on a scale STANDARD_DEVIATION 0 | 25 units on a scale STANDARD_DEVIATION 11.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Fugl-Meyer Upper Extremity Assessment Part A
The Fugl-Meyer Upper Extremity (FM-UE) subset is a component of the Fugl-Meyer Assessment (FM) assessing motor impairment in individuals with stroke or other arm impairments. The (FM-UE) subset focuses on evaluating motor impairment and recovery using movements assessing strength, coordination, sensation, and range of motion of the upper extremity. Each item in the FM-UE subset is scored on a scale from 0-2. These are added together, with higher scores indicating better motor function. The FM-UE subset has 33 items for a maximum possible (highest functioning) score of 66.
Time frame: The FM-UE assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intenvention) and recorded for each treatment group (anodal, cathodal, and sham). .
Population: Eight subjects completed the study were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anodal Stimulation | Fugl-Meyer Upper Extremity Assessment Part A | 4.13 score on a scale | Standard Deviation 4.29 |
| Cathodal Stimulation | Fugl-Meyer Upper Extremity Assessment Part A | 5.38 score on a scale | Standard Deviation 3.58 |
| Sham | Fugl-Meyer Upper Extremity Assessment Part A | 0.88 score on a scale | Standard Deviation 0.99 |
Comparison: We will report first anode compared to sham and then cathode compared to shamp-value: <0.000195% CI: [2.4, 8.4]Generalized Estimating Equations
Secondary
Change in Onset Latency of Transcranial Magnetic Stimulation (TMS)-Evoke Motor-evoked Potentials (MEP)
This is a neurophysiological measure that determines the use of ipsilesional corticospinal tract. The paired-pulse TMS was applied at the respective hotspot for the elbow flexor muscle at the paretic arm over the ipsilesional primary motor cortex. The center of the coil was positioned tangentially to the skull. The patient was considered MEP+ if MEPs of any amplitude are observed at a consistent latency on at least 5 out 10 trials. After determining the status of MEP, at least eight more pulses were applied. We calculated average latency across all positive trials to determine the latency of MEP.
Time frame: The latency of TMS-evoke MEP assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intevention) and recorded for each treatment group (anodal, cathodal, and sham).
Population: Eight subjects completed the study were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anodal Stimulation | Change in Onset Latency of Transcranial Magnetic Stimulation (TMS)-Evoke Motor-evoked Potentials (MEP) | -24.21 ms | Standard Deviation 9.55 |
| Cathodal Stimulation | Change in Onset Latency of Transcranial Magnetic Stimulation (TMS)-Evoke Motor-evoked Potentials (MEP) | -22.20 ms | Standard Deviation 10.1 |
| Sham | Change in Onset Latency of Transcranial Magnetic Stimulation (TMS)-Evoke Motor-evoked Potentials (MEP) | 1.16 ms | Standard Deviation 2.52 |
Comparison: We compared anode to sham We compared cathode to sham We compared the change over time of anode to sham We compared the change over time of cathode to shalp-value: 0.00295% CI: [-32.2, -16.2]Regression, Cox
Other Pre-specified
Change in Brain Symmetry Index
This is a neurophysiological measure used to quantify the symmetry or asymmetry between the left and right hemispheres of the brain. It was calculated using EEG data from a 3-minute resting state EEG recording. The scale of the index is from -1 to 1, where zero is considered perfect symmetry between hemispheres and values close to -1 and 1 indicate asymmetry.
Time frame: The BSI assessment is completed before and immediately after (within 30 min range) the intervention. The mean difference is then calculated (Post-Pre intevention) and recorded for each treatment group (anodal, cathodal, and sham).
Population: 1 missing data for anodal and sham stimulation caused by a device failure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anodal Stimulation | Change in Brain Symmetry Index | 0.078 score on a scale | Standard Deviation 0.077 |
| Cathodal Stimulation | Change in Brain Symmetry Index | -0.068 score on a scale | Standard Deviation 0.22 |
| Sham | Change in Brain Symmetry Index | -0.125 score on a scale | Standard Deviation 0.213 |
Comparison: e compare anode to sham We compare cathode to shamp-value: 0.000195% CI: [0, 0.1]Regression, Linear