Background: Transcranial direct current stimulation (tDCS) has been gaining increasing interest as a potential therapeutic tool to improve upper extremity (UE) rehabilitation outcomes following stroke. Within the concept of interhemispheric inhibition (IHI), most tDCS studies have applied anodal ipsilesional and/or cathodal contralesional primary motor cortex (M1) tDCS to rebalance IHI and enhance motor recovery. However, compelling evidence suggests that an excitation/inhibition model is oversimplified, and the role of both hemispheres in the encoding of information during motor learning should be acknowledged. Moreover, multiple lines of evidence have demonstrated the potential relevance of contralesional premotor cortex (PMC) for recovery after M1 injury.

Objective: We are aiming to investigate and compare the effects of two tDCS montages at different cortical sites (Dual-M1 vs. a-tDCS over contralesional PMC) by measuring the clinical outcomes of the most affected UE in patients with chronic subcortical stroke.

Methods: 35 participants will be randomly assigned to 1 of 3 groups (Group A received dual- M1 tDCS, Group B received a-tDCS over contralesional PMC, and Group C received sham stimulation). tDCS will be applied using intensity of 2 mA for 20 min. (5 times/week) for 2 consecutive weeks. Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) and Action Research Arm Test (ARAT) will be used to quantify the UE functional motor ability. Box and Block Test (BBT) will be used for gross manual dexterity and Nine Hole Peg Test (NHPT) will be used to measure fine hand dexterity. All measurements will be taken pre-treatment (T0) and post-treatment (T1) immediately after the 10th session, then 4 weeks after the end of stimulation period (T2) to assess the long-term effects.

Expected results: This study would verify whether enhancing the motor cortical hyperexcitability in the contralesional hemisphere has a beneficial on recovery of the paretic hand, or regaining the balance of transcallosal inhibitory circuits between the motor areas in both hemispheres has more positive effects on the motor outcomes . This study would also provide a predictive approach to enable realistic rehabilitation goal-setting by identifying the proper tDCS montage for patients with stroke depending on their impairment level.

This experimental study will be conducted in a sham-controlled, single-blinded randomized controlled design. The subjects will be recruited - by convenience sampling - from the outpatient population of different governmental hospitals in Eastern Province of Saudi Arabia. Neurologists, Physiatrists and Physical therapists will be contacted to recruit potential subjects and IRB-approved letter will be sent to them. The subjects will be screened to determine whether a potential participant is eligible to be enrolled in the study or not. Only the principal investigator (PI) will conduct the screening procedures, which include reviewing medical record, in-person interview and administration of Mini-Mental State Examination. All screening activities will take 15-20 min., and they will be performed in a private screening room. Enrollment will occur after verifying the eligibility and obtaining the signed written consent form. Participants will be enrolled in the study only if they met all the inclusion criteria, which are:

1. Male or Female participants aged ≥ 18
2. First ever, unilateral, ischemic, subcortical stroke in the territories supplied by the Middle Cerebral Artery (MCA) verified by brain imaging, at chronic stage (≥ 6 months).
3. Upper Extremity impairment verified by Fugl-Meyer Assessment-Upper Extremity (FMA-UE).
4. Mini Mental State Examination Score ≥ 24.

All the participants were receiving conventional physical therapy and occupational therapy sessions (1-2 times/week).

The Exclusion Criteria included the following:

1. History of epileptic seizures.
2. Pre-stroke motor impairment(s) affecting UE.
3. Presence of UE contractures or deformities.
4. Botulinum toxin to UE muscles in the last 6 months.
5. Presence of damaged skin on the scalp that would interfere with tDCS stimulation.
6. Individuals with metallic implant in the brain or medical devices (i.e., cardiac pacemaker, deep brain stimulator, cochlear implants).
7. Use of CNS-affecting drugs.
8. Additional neurological or psychiatric problem.
9. Pregnancy.

After enrollment, all participants will be scheduled to receive 10 sessions over two consecutive weeks (5 sessions/week). Each participant will be seen initially (1st visit) for about 90 min. to conduct all baseline measurements (T0), which will include clinical examinations using different standardized tests for upper limb function, and to conduct the experiment. The follow up sessions (8 sessions) will last for around 30 min. (10 min. for preparation and employing the electrodes + 20 min. for the stimulation). The 10th session will last for about 90 min. to carry out the measurement tests (T1) and to conduct the last stimulation session. The final visit will be scheduled to be 4 weeks after the 10th session to evaluate the long-term effects using the same measurement tests (T2).

All the participants will be blinded to the type of stimulation they received. The PI will take all the baseline measurements (T0), post-stimulation measurements immediately after the 10th session (T1), and long-term effects 4 weeks after the end of the stimulation period (T2). The PI will carry out all tDCS sessions as well.

All the participants will be randomly assigned, using opaque envelopes, to one of three groups:

• Group A (n=11) receive dual-tDCS
• Group B (n=13) receive a-tDCS over PMC in the contralesional hemisphere, and
• Group C (n=11) receive sham stimulation.

This study protocol has been approved by the IRB from the research ethics committee in Imam Abdulrahman Bin Faisal University.

Inclusion Criteria:

1. First ever, unilateral, ischemic, subcortical stroke in the territories supplied by the Middle Cerebral Artery (MCA) verified by brain imaging, at chronic stage (≥ 6 months).
2. Upper Extremity impairment verified by Fugl-Meyer Assessment-Upper Extremity (FMA-UE)
3. Mini Mental State Examination Score ≥ 24

Exclusion Criteria:

1. History of epileptic seizures.
2. Pre-stroke motor impairment(s) affecting UE.
3. Presence of UE contractures or deformities.
4. Botulinum toxin to UE muscles in the last 6 months.
5. Presence of damaged skin on the scalp that would interfere with tDCS stimulation.
6. Individuals with metallic implant in the brain or medical devices (i.e., cardiac pacemaker, deep brain stimulator, cochlear implants).
7. Use of CNS-affecting drugs.
8. Additional neurological or psychiatric problem.
9. Pregnancy.