Patient-tailored Transcranial Direct Current Stimulation to Improve Stroke Rehabilitation (PRACTISE)

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

Study Overview

• Status: Recruiting
• Conditions: Ischemic Stroke; Upper Extremity Hemiparesis
• Intervention / Treatment: Device: Active Transcranial Direct Current Stimulation; Device: Sham stimulation

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christina Krusse, MD, Prof; Phone Number: +4538681233; Email: christina.kruuse@regionh.dk
• Study Contact Backup: Name: Mia Kolmos, MD; Phone Number: +4538681375; Email: mia.kolmos@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2200
    • Recruiting
    • Copenhagen University Department of Nutrition and Exercise
    • Contact: Anke Karabanov, MSc, PhD; Phone Number: +4535328039; Email: anke@nexs.ku.dk
    • Sub-Investigator: Anke Karabanov, MSc, PhD
  • Herlev, Denmark, 2730
    • Recruiting
    • Department of Neurology, Herlev Gentofte Hospital
    • Contact: Mia Kolmos, MD; Phone Number: +4538681375; Email: mia.kolmos@regionh.dk
    • Contact: Christina Kruuse, MD, Prof; Phone Number: +4538681233
    • Principal Investigator: Christina Kruuse, MD, Prof
    • Sub-Investigator: Mia Kolmos, MD
  • Hvidovre, Denmark, 2650
    • Recruiting
    • Danish Research Centre for Magnetic Resonance
    • Contact: Hartwig R Siebner, MD, Prof; Phone Number: +4538626541; Email: hartwig.roman.siebner@regionh.dk
    • Contact: Axel Thielscher, MSc, Prof; Phone Number: +4538623326; Email: axelt@drcmr.dk
    • Sub-Investigator: Hartwig R Siebner, MD, Prof
    • Sub-Investigator: Axel Thielscher, MSc, Prof
    • Sub-Investigator: Marie Louise Liu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Patients - 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Transcranial Direct Current Stimulation; Anodal TDCS 1mV for 2x 20 minutes.	Device: Active Transcranial Direct Current Stimulation; See arm/group description
Sham Comparator: 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).	Device: Sham stimulation; See arm/group description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper-extremity motor outcome	Difference in change in Upper-extremity Fugl-Meyer Assessment (UE-FMA) score. Range 0-66.	From baseline to four months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper-extremity function	Difference in change in Action Reach Arm Test (ARAT) score. Range 0-57. High scores mean a better outcome.	From baseline to four months
Stroke severity	Difference in change in National Health Institutes Stroke Scale (NIHSS). Range 0-42. High scores mean a better outcome.	From baseline to four months
Stroke disability	Difference in change in Modified Rankin Scale (mRS). Range 0-6. Lower scores mean a better outcome.	From baseline to four months
ADL performance	Difference in change in Bartel's 20-item Index (BI-20). Range 0-100. Higher scores mean better outcome.	From baseline to four months
Gait speed	Difference in change in 10 Meter Walk Test (10MWT) in minutes:sec.	From baseline to four months
Physical Activity	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.	From baseline to four months
Montreal Cognitive Assessment	Difference in change in Montreal Cognitive Assessment (MoCA) score. Score range 0-30. Higher scores mean a better outcome.	From baseline to four months
Symbol Digit Modalities Test	Difference in change in Symbol Digit Modalities Test (SDMT) score. Score range 0-110. Higher scores mean a better outcome.	From baseline to four months
Health-related quality of life	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.	From baseline to four months
Becks Depression Inventory (BDI)	Difference in change in BDI-II score. Score range 0-63. Higher score means increased risk of depression.	From baseline to four months
Fatigue Severity Scale (FSS)	Difference in change in FSS score. Score range 0-7. Higher score means increased fatigue severity.	From baseline to four months
WHO-5 Well-Beeing Index	Difference in change in WHO-5 score. Score range 0-100. Higher score means better quality of life.	From baseline to four months
Biomarker of inflammation and exercise	Difference in change in serum level Cathepsin-B (unit mikro gram/L)	From baseline to four months
MRI - Cerebral bloodflow	Change in cerebral blood flow measured with arterial spin labeling (ASL) during rest	From baseline to four months
fMRI - Effective connectivity	Change in activation patterns measured with blood-oxygen-level dependent (BOLD) during both single and bimanual task.	From baseline to four months
fMRI - Interhemispheric inhibition	Change in activation pattern measured by blood-oxygen-level dependent (BOLD) during both single and bimanual task.	From baseline to four months
fMRI - Laterality Index	Change in activation pattern for hemispheric dominance measured by the ratio of active fMRI voxels in each hemisphere.	From baseline to four months
MRI - Corticospinal integrity	Change in corticospinal integrity measured by diffusion MRI.	From baseline to four months
MRI - Infarct lesion load	Difference in change in size of infarct lesion meaured by structural MRI.	From baseline to four months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain Derived Neutrotrophic Factor (BDNF) genetic polymorphism	Determination of BDNF genetic variant - either Val66Met variant or wildtype.	Baseline
Feasibility of intervention	Completion of intervention in the active vs. control group	From baseline to four months
TMS - motor evoked potential	Determination of existence of a MEP-response by TMS as an indicator of cortico-spinal tract integrity. Prognostic marker of motor recovery.	Baseline
TMS - Ipsilateral silent period (iSP)	Determination of degree of interhemispheric inhibition unaffected vs. affected hemisphere	Baseline
TMS - Short latency intracortical inhibition (SICI)	Determination of degree of interhemispheric inhibition unaffected vs. affected hemisphere	Baseline
TMS - cortico-motor conduction time (CMCT)	Determination of conduction time from stimulation of cortical neurons to response measured in a peripheral muscle (FDI)	Baseline

Collaborators and Investigators

• Sponsor: Christina Kruuse
• Collaborators: University of Copenhagen; The Novo Nordic Foundation; Lundbeck Foundation; Danish Research Centre for Magnetic Resonance
• Investigators: Principal Investigator: Christina Kruuse, MD, Prof, Herlev Gentofte Hospital, Department of Neurology

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: April 26, 2022
• First Submitted That Met QC Criteria: April 26, 2022
• First Posted (Actual): May 2, 2022

Study Record Updates

• Last Update Posted (Estimate): December 15, 2022
• Last Update Submitted That Met QC Criteria: December 13, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: transcranial direct current stimulation; Functional Magnetic Resonance Imaging; non-invasive brain stimulation; functional connectivity; effective connectivity; Fugl-Meyer Assessment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Stroke; Ischemic Stroke; Paresis
• Other Study ID Numbers: H-20036199

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD can be accessed upon reasonable request and after evaluation from the investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No