Patient-tailored Transcranial Direct Current Stimulation to Improve Stroke Rehabilitation

Not Applicable

Recruiting

• Conditions: Ischemic Stroke; Upper Extremity Hemiparesis
• Interventions: Device: Active Transcranial Direct Current Stimulation; Device: Sham stimulation

• Registration Number: NCT05355831
• Lead Sponsor: Christina Kruuse

Brief Summary

In a double-blinded sham-controlled study the effect of patient-tailored transcranial direct current stimulation during rehabilitation training will be examined.

Detailed Description

Approximately two thirds of stroke patients have reduced motor function which have a large impact on both activities of daily living and quality of life. Only 12-34% achieve full motor recovery.

There is a growing interest in using non-invasive brain stimulation (NIBS) techniques to supplement neurorehabilitation. NIBS can modulate cortical excitability and is a powerful tool for motor rehabilitation post-stroke. Application Transcranial Direct Current Stimulation (TDCS) is currently emerging as a tool used in neurorehabilitaiton. Prior studies have shown that TDCS-stimulation prior to physical training may significantly improve of motor function post-stroke. However, up to 50% of the participants recieving active TDCS show no response to stimulation.

A one-size-fits-all approach to TDCS in stroke rehabilitation may not be optimal and a more precise and individualized targeting is warranted to stimulate functionally relevant areas.

In this study TDCS will be personalized for stroke patients with upper-extremity paresis using individual functional and structural Magnetic Resonance Imaging (MRI) and an electric field modelling pipeline developed at Danish Research Centre for Magnetic Resonance (DRMCR). Based on these measures the electric current induced by TDCS will individually target the area with residual neural activity during movement. The effect of personalized TDCS will be assessed by clinical measures of motor improvement. Sub-studies furthermore assess if the functional reorganization of motor networks is affected by personalized TDCS by application of functional magnetic resonance (fMRI) and.

The study will have 3 phases:

1. Personalization: The stimulation profile of each patient will be individualized using structural MRI a pipeline for simulation based on MRI (SimNIBS) to make individual anatomical head models in order to estimate the best montage and current dosage. Further, task-based fMRI will be used to estimate residual motor activity location. The target current is set in the area displaying the highest residual motor activity in sensorimotor areas.

2. Intervention: Four weeks upper extremity training program of specialized supervised physiotherapeutic training 3 times per week. Each training session consists of 2x 20 minutes of training with concurrent personalized TDCS stimulation or montage of equipment but no stimulation (sham). Each bloc of 20 minutes training is separated by a small break of 5-10 minutes. Both patient, therapist and investigator will be blinded to the stimulation mode (activ TDCS or sham)

3. Follow-up: Immediately after the 4 weeks of intervention and 12 weeks after intervention has ended, follow-up with clinical examination and brain MRI will be done.

Ad baseline Transcranial Magnetic Stimulation (TMS) will be done as well to assess corticospinal integrity as well as estimation of intracortical inhibition.

Hypothesis:

The main hypothesis is that personalized ipsi-lesional anodal TDCS during specialized individualized arm-training will lead to significantly greater improvements in upper-extremity motor function compared to sham.

Substudy with healthy controls:

A cohort of 20 healthy age- and sex matched controls will be recruited for one session of MRI and TMS identical to the procedure of the patients at baseline as well as the same questionnaires (Protocol amendment approved by the local Ethics Committee the 10th October 2022).

These data will be analyzed in a substudy for normative comparison between the stroke patients and healthy age- and sex-matched controls.

Hypothesis - Healthy Controls:

Stroke patients will exhibit a higher laterality index measured by fMRI and a stronger degree of interhemispheric inhibition at baseline compared to healthy controls measued by task-related fMRI and by TMS iSP and SICI.

The degree of interhemispheric inhibition in stroke patients will normalize during recovery and be similar to normal controls at the last follow-up after 12 weeks.

Further, the degree of normalization of the interhemispheric inhibition in stroke patients will be proportional to degree of improvement of the upper-extremity measured by UE-FMA.

July 2024:

Due to challenging recruitment and at much lower recruitment rate than expected the trial design was changed from superiority to pilot- and feasibility trial. Therefore, the sample size was correspondingly adjusted to expected 24 with 12 participants in each of the two arms. Furthermore, outcome measures were re-prioritized to also contain feasibility outcome measures and primary outcome was changed to follow-up Fugl-Meyer Assessment score of upper-extremity (FMA-UE) adjusted for baseline in stead of change in FMA-UE from baseline to follow-up.

Study Timeline

• Study First Submitted: 2022-04-26
• Study First Submitted QC: 2022-04-26
• Study First Posted: 2022-05-02
• Study Start: 2022-08-28
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-10
• Last Update Posted: 2024-07-11
• Primary Completion: 2024-08
• Study Completion: 2024-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

1. Age >18 years
2. Ischemic stroke confirmed by clinical and imaging criteria
3. Hemiparesis including reduced upper-extremity function
4. Location of stroke either cortically involving middle cerebral artery or the anterior cerebral artery circulation or subcortical (involving thalamus, basal ganglia).
5. NIHSS score >2 and <8
6. Modified Rankin Scale (mRS) ≤ 3
7. Index of stroke within 4 weeks of inclusion
8. Signed informed consent

Patients -

Exclusion Criteria

1. >50% stenosis of extra- or intracranial artery as well as vascular malformations or aneurisms detected by brain CT-angiography.
2. Exclusively ischemic stroke in spine, pons, brainstem, medulla or cerebellum.
3. History of seizures, epilepsy, anxiety, dementia alcohol- or drug abuse.
4. Prior serious head injury or neurosurgery
5. Frequent severe headaches or migraine.
6. Pregnancy or breastfeeding
7. Current use of neuro-receptor/transmitter modulating medication, or medication interfering with seizure threshold (such as antiepileptic medication, some antidepressants, anxiety medication, antihistamines, stimulant drugs for attention deficit hyperactivity disorder).
8. Pacemaker, implantable cardiac device unit (ICD-unit), metal fragments or other materials implanted not compatible with MRI (see appendix B).
9. Claustrophobia
10. Prior adverse effect to TDCS or Transcranial Magnetic Stimulation.
11. Not able to provide informed consent.
12. Terminally ill or short life expectancy.

Healthy controls - Inclusion criteria:

1. Age between >18 years (matched to patients)
2. Sex and age matched to patients
3. Able bodied
4. Have the ability to comply with all requirements of the study protocol, as determined by the investigator
5. No history of stroke or dementia
6. Eligible for MRI and TMS

Healthy controls - Exclusion Criteria:

1. History of neurologic disease
2. History of cerebral haemorrhage or brain damage
3. Pregnancy
4. Pacemaker or other implanted electronic devices
5. Claustrophobia
6. Psychiatric disorder
7. Epilepsy or close relatives suffering from epilepsy
8. Migraine
9. Any contraindication to MRI or TMS

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Transcranial Direct Current Stimulation	Active Transcranial Direct Current Stimulation	Anodal TDCS 1mV for 2x 20 minutes.
Sham stimulation	Sham stimulation	2x 20 minutes of sham stimulation (30 sec ramp up, followed by current of 0 for 18.5 minutes followed by 30 sec ramp down).

Primary Outcome Measures

Name	Time	Method
Pilot outcome	From baseline to four months	Difference in Upper-extremity Fugl-Meyer Assessment (UE-FMA) score at end of treatment. Range 0-66.

Secondary Outcome Measures

Name	Time	Method
Change in upper-extremity function	From baseline to four months	Difference in change in Action Reach Arm Test (ARAT) score. Range 0-57. High scores mean a better outcome.
Stroke severity	From baseline to four months	Difference in change in National Health Institutes Stroke Scale (NIHSS). Range 0-42. High scores mean a better outcome.
Gait speed	From baseline to four months	Difference in change in 10 Meter Walk Test (10MWT) in minutes:sec.
WHO-5 Well-Beeing Index	From baseline to four months	Difference in change in WHO-5 score. Score range 0-100. Higher score means better quality of life.
fMRI - Interhemispheric inhibition	From baseline to four months	Change in activation pattern measured by blood-oxygen-level dependent (BOLD) during both single and bimanual task.
fMRI - Laterality Index	From baseline to four months	Change in activation pattern for hemispheric dominance measured by the ratio of active fMRI voxels in each hemisphere.
MRI - Infarct lesion load	From baseline to four months	Difference in change in size of infarct lesion meaured by structural MRI.
MRI - Cerebral bloodflow	From baseline to four months	Change in cerebral blood flow measured with arterial spin labeling (ASL) during rest
Stroke disability	From baseline to four months	Difference in change in Modified Rankin Scale (mRS). Range 0-6. Lower scores mean a better outcome.
Physical Activity	From baseline to four months	Difference in change in Physical Activity Scale 2.0 (PAS2). The answers will be translated into a Metabolic Equivalent of Task (MET)-score. The higher MET-score the higher level of activity.
Symbol Digit Modalities Test	From baseline to four months	Difference in change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome.
Health-related quality of life	From baseline to four months	Difference in change in EQ-5D-5L score. Range 1 to 20, a high score means low health-related quality of life. Includes a 0-100 visual analogue scale for overall percieved quality of life.
Upper-extremity motor outcome	From baseline to four months	Follow-up Upper-extremity Fugl-Meyer Assessment (UE-FMA) score adjusted for baseline. Range 0-66
Feasibility: Compliance to interventions	During intervention	Proportion of TDCS-intervention sessions attended out of the 12 planned sessions
Feasibilitiy: Compliance to home-exercises	During intervention	Extent to which the participant has completed the planned home exercises ('fully', 'most', 'about 50%', 'below 50%', or 'not done')
ADL performance	From baseline to four months	Difference in change in Bartel's 20-item Index (BI-20). Range 0-100. Higher scores mean better outcome.
Montreal Cognitive Assessment	From baseline to four months	Difference in change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.
Becks Depression Inventory (BDI)	From baseline to four months	Difference in change in BDI-II score. Score range 0-63. Higher score means increased risk of depression.
Fatigue Severity Scale (FSS)	From baseline to four months	Difference in change in FSS score. Score range 0-7. Higher score means increased fatigue severity.
Biomarker of inflammation and exercise	From baseline to four months	Difference in change in serum level Cathepsin-B (unit mikro gram/L)
fMRI - Effective connectivity	From baseline to four months	Change in activation patterns measured with blood-oxygen-level dependent (BOLD) during both single and bimanual task.
Feasibility: Patient feed-back	Follow-up1	The patients are asked if they would recommend TDCS to a peer patient (Yes/No)
MRI - Corticospinal integrity	From baseline to four months	Change in corticospinal integrity measured by diffusion MRI.
Feasibility: TDCS sensations	During intervention	Proportion of participants experiencing sensations of TDCS (itching, pain, burning, vertigo, headache, fatigue, nausea, and/or other)

Trial Locations

Locations (3)

Copenhagen University Department of Nutrition and Exercise; 🇩🇰 Copenhagen, Denmark

Department of Neurology, Herlev Gentofte Hospital; 🇩🇰 Herlev, Denmark

Danish Research Centre for Magnetic Resonance; 🇩🇰 Hvidovre, Denmark