To compare the efficacy of lesional high-frequency rTMS, contralesional cTBS, and sham stimulation in improving motor and cognitive recovery in post-stroke patients undergoing physiotherapy.

Globally, stroke is the second leading cause of both death and disability. In 2020, the global prevalence of all stroke subtypes was 89.13 million cases, with acute ischemic stroke (AIS) comprising 76.47% of these, equating to 68.16 million cases . AIS presents a major global public health concern, given the wide range of disabilities it causes, including cognitive impairments. Survivors of stroke bear a significant burden due to the persistent disability they experience over time . Immediately following a stroke, motor impairments are accompanied by significant alterations in the affected primary motor cortex (M1) - detected by transcranial magnetic stimulation (TMS)- resulting in reduced cortical excitability. This can be evidenced by the absence of recordable motor evoked potentials (MEPs), diminished MEP amplitudes, and increased resting motor threshold (rMT). Additionally, stroke can alter brain connectivity, particularly in terms of functional connectivity, which has implications for recovery. Neuroplasticity plays a crucial role in recovery after stroke, allowing the brain to reorganize and compensate for lost functions. Physiotherapy is a cornerstone of post-stroke rehabilitation, particularly for upper limb recovery and cognitive improvement, with early intervention associated with better outcomes. Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the early stages post-stroke, enhancing motor and cognitive recovery, particularly when applied within two weeks of stroke onset. MEPs can be used to monitor changes in cortical excitability and have been linked to both cognitive and motor recovery. Combining rTMS with diffusion tensor imaging (DTI) allows for the assessment of both functional and structural brain changes, providing a deeper understanding of rTMS's therapeutic effects. DTI, through fractional anisotropy (FA), helps to evaluate white matter integrity, and studies have shown that increased FA correlates with motor recovery, making it a valuable tool in examining the structural changes induced by rTMS in stroke recovery. While high frequency rTMS targeting the ipsilesional motor cortex (M1) has demonstrated efficacy in enhancing motor recovery, contralesional continuous theta-burst stimulation (cTBS) has shown promising results offering an alternative by modulating interhemispheric inhibition. However, no studies have directly compared the efficacy of these two paradigms against each other and sham stimulation in subacute stroke recovery. This study seeks to address this gap by comparing the outcomes of lesional high frequency rTMS, contralesional cTBS, and sham stimulation in combination with physiotherapy.

Inclusion Criteria:

• First-ever ischemic stroke, confirmed by imaging.
• Stroke affecting the non-dominant hemisphere (cortical or subcortical) within the middle cerebral artery (MCA) territory.
• Acute to subacute stage of stroke (time since onset: 48 hours to 2 weeks).
• Ability to comply with the study protocol and interventions.

Exclusion Criteria:

• Hemorrhagic stroke or bilateral stroke.
• Severe cognitive impairment, defined as a Montreal Cognitive Assessment (MoCA) score < 10.
• Contraindications to TMS, such as: History of epilepsy, Metallic implants in the head, Other contraindications based on TMS safety guidelines.
• Comorbid conditions that limit participation in rehabilitation.
• Severe neglect or aphasia that would impede participation in therapy.

Both participants and investigators are blinded to the intervention type, with sham rTMS serving as the control for maintaining blinding integrity.