Network Properties As Biomarkers for Non-Invasive Brain Stimulation (NIBS) After Stroke

Various studies have aimed to explore the potential of non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) to promote motor recovery after stroke. After promising results from early proof-of-concept studies, particularly for the stimulation of the primary motor cortex (M1), it has become evident that the translation from scientific to clinical application is challenging. Aiming to uncover alternative stimulation targets, the cortico-cerebellar network and cerebellar brain stimulation have gained an increasing interest in the field of neurorehabilitation. However, large inter-study and inter-subject variability in behavioural responses to tDCS indicated that a one-size-fits-all approach might not lead to sufficient effect sizes in clinical populations. As structural and functional brain imaging has significantly evolved to powerful tools to assess distinct neuronal networks, such as the cortico-cerebellar network, in individual stroke patients and to infer structure-function-behaviour-relationships, the question arises whether such information might serve as imaging biomarkers to inform about the treatment responsiveness to non-invasive brain stimulation.

The present study will evaluate the potential of cortico-cerebellar network properties in a group of chronic stroke patients and healthy participants to explain inter-subject variability in responsiveness to two brain stimulation approaches targeting the cortico-spinal and cortico-cerebellar network: 1) cortical M1 tDCS, 2) combined M1 and cerebellar tDCS. Participants will be examined clinically and by structural and functional MRI. Structural MRI will be used to primarily reconstruct cortico-spinal and cortico-cerebellar motor tracts. Tract-related diffusion-based parameters will be used to infer microstructural network integrity. Resting-state MRI will be acquired to assess functional network connectivity. The behavioural impact of the tDCS will be evaluated during a multi-session structured motor training paradigm over seven days.

Recruitment:

Early- or late chronic stroke patients who have a persistent upper extremity deficit.

Treatment/Intervention:

Three tDCS montages combined with 7 days of physiotherapy (45min per session) will be applied to chronic stroke patients in a double-blinded, parallel group design. The following montages will be tested: anodal ipsilesional M1-stimulation with 2mA, anodal ipsilesion M1-stimulation combined with anodal contralesional cerebellar stimulation with 2mA per anode and a sham stimulation. The stimulation will be applied for the first 20min of physiotherapy.

Evaluation/Measurement:

Prior to the intervention, patients will receive functional testing and a MRI scan. 7 days after physiotherapy, functional testing will be performed again. Functional tests include: NIH Stroke Scale (NIHSS), Fugl Meyer Assessment of the upper limb (FMA), Wolf Motor Function Test (WMFT), Jebsen Taylor Hand Function Test (JTT), Nine-Hole-Peg-Test (NHP), Mini-Mental-State Examination.

Analyses:

Statistics will be conducted to relate neuroimaging-based network properties of the cortico-spinal and cortico-cerebellar network to the treatment gains under tDCS combined with motor training (primary outcome). Importantly, group differences regarding the behavioural effects of the verum and sham condition will serve as secondary outcomes.

• Treatment effects for NIHSS on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and last training day (Day 7). [Time frame: Baseline - Day 7]
• Treatment effects for FMA on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and last training day (Day 7). [Time frame: Baseline - Day 7]
• Treatment effects for JTT on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and last training day (Day 7). [Time frame: Baseline - Day 7]
• Treatment effects for WMFT on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and last training day (Day 7). [Time frame: Baseline - Day 7]
• Treatment effects for NHP on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and last training day (Day 7). [Time frame: Baseline - Day 7]
• Treatment effects for NIHSS on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and 1 week after last training day (Day 14). [Time frame: Baseline - Day 14]
• Treatment effects for FMA on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and 1 week after last training day (Day 14). [Time frame: Baseline - Day 14]
• Treatment effects for WMFT on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and 1 week after last training day (Day 14). [Time frame: Baseline - Day 14]
• Treatment effects for JTT on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and 1 week after last training day (Day 14). [Time frame: Baseline - Day 14]
• Treatment effects for NHP on group level comparing M1 tDCS, M1-cerebellar tDCS and sham between baseline and 1 week after last training day (Day 14). [Time frame: Baseline - Day 14]