Clinical trial NCT05355831: Patient-tailored Transcranial Direct Current Stimulation to Improve Stroke Rehabilitation
Official title: Patient-tailored Transcranial Direct Current Stimulation to Improve Stroke Rehabilitation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Ischemic Stroke
Upper Extremity Hemiparesis
Keywords: non-invasive brain stimulation
transcranial direct current stimulation
effective connectivity
functional connectivity
Fugl-Meyer Assessment
Functional Magnetic Resonance Imaging
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
Collaborators: name: Danish Research Centre for Magnetic Resonance
name: The Novo Nordic Foundation
name: University of Copenhagen
name: Lundbeck Foundation
First posted: 2022-05-02
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Intervention pilot- and feasibility trial
Primary purpose: SUPPORTIVE_CARE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Pilot outcome
timeFrame: From baseline to four months
Secondary outcomes:
measure: Change in upper-extremity function
timeFrame: From baseline to four months
measure: Stroke severity
timeFrame: From baseline to four months
measure: Stroke disability
timeFrame: From baseline to four months
measure: ADL performance
timeFrame: From baseline to four months
measure: Gait speed
timeFrame: From baseline to four months
measure: Physical Activity
timeFrame: From baseline to four months
measure: Montreal Cognitive Assessment
timeFrame: From baseline to four months
measure: Symbol Digit Modalities Test
timeFrame: From baseline to four months
measure: Health-related quality of life
timeFrame: From baseline to four months
measure: Becks Depression Inventory (BDI)
timeFrame: From baseline to four months
measure: Fatigue Severity Scale (FSS)
timeFrame: From baseline to four months
measure: WHO-5 Well-Beeing Index
timeFrame: From baseline to four months
measure: Biomarker of inflammation and exercise
timeFrame: From baseline to four months
measure: MRI - Cerebral bloodflow
timeFrame: From baseline to four months
measure: fMRI - Effective connectivity
timeFrame: From baseline to four months
measure: fMRI - Interhemispheric inhibition
timeFrame: From baseline to four months
measure: fMRI - Laterality Index
timeFrame: From baseline to four months
measure: MRI - Corticospinal integrity
timeFrame: From baseline to four months
measure: MRI - Infarct lesion load
timeFrame: From baseline to four months
measure: Upper-extremity motor outcome
timeFrame: From baseline to four months
measure: Feasibility: TDCS sensations
timeFrame: During intervention
measure: Feasibility: Compliance to interventions
timeFrame: During intervention
measure: Feasibilitiy: Compliance to home-exercises
timeFrame: During intervention
measure: Feasibility: Patient feed-back
timeFrame: Follow-up1
Other outcomes:
measure: Brain Derived Neutrotrophic Factor (BDNF) genetic polymorphism
timeFrame: Baseline
measure: Feasibility of intervention
timeFrame: From baseline to four months
measure: TMS - motor evoked potential
timeFrame: Baseline
measure: TMS - Ipsilateral silent period (iSP)
timeFrame: Baseline
measure: TMS - Short latency intracortical inhibition (SICI)
timeFrame: Baseline
measure: TMS - cortico-motor conduction time (CMCT)
timeFrame: Baseline
Locations:
city: Copenhagen
country: Denmark
facility: Copenhagen University Department of Nutrition and Exercise
city: Herlev
country: Denmark
facility: Department of Neurology, Herlev Gentofte Hospital
city: Hvidovre
country: Denmark
facility: Danish Research Centre for Magnetic Resonance
Study officials:
affiliation: Herlev Gentofte Hospital, Department of Neurology
name: Christina Kruuse, MD, Prof
role: PRINCIPAL_INVESTIGATOR
References: