Combined taVNS and tDCS in Subacute Stroke Patients

Ischemic stroke, the most prevalent neurological disorder, is treated with medication and thrombectomy but with limited success, especially in chronic stages where traditional rehabilitation is the primary option. Stroke often leads to post-stroke autonomic imbalance, deteriorating functional outcomes and increasing recurrence risk. Emerging non-pharmacological treatments like Transcutaneous Auricular Vagus Nerve Stimulation (VNS) and Focused Transcranial Direct Current Stimulation (tDCS) offer new possibilities. VNS targets post-stroke tissue injury and promotes healing and neurogenesis, while tDCS aims to enhance motor learning by rebalancing brain activity. Both therapies seek to improve outcomes in both acute and chronic stroke stages.

Ischemic stroke is the most common neurological disease. The main treatment options include medication and endovascular thrombectomy. The benefits of treatments at acute stage are significant but far from satisfactory. There is no effective treatment for improvement at chronic stage, except traditional rehabilitation. In addition, stroke may induce post-stroke autonomic imbalance, further leading to worse post-stroke functional outcomes and the risk of recurrent stroke.

Except for pharmacological therapy against the risk of stroke, non-pharmacological neuromodulation may be proposed as another therapeutic options. Transcutaneous auricular vagus nerve stimulation (VNS) and focused transcranial direct current stimulation (tDCS) may be two of the options. The function of VNS is to modulate post-stroke tissue injury and promote angiogenesis/neurogenesis through non-pharmacological pathway. VNS may increase the parasympathetic activity for balancing the hyper-sympathetic state in the acute stage and enhancing neural plasticity in the chronic stage. On the other hand, the purpose of tDCS is to make substantial motor learning improvements, which may be through the re-balance both excitatory and inhibitory activation between hemispheres after stroke.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years old
* Subacute ischemic stroke patients within 7-30 days after stroke symptoms is stabilized
* Stroke will be documented by DWI-MRI
* Lesion locations at least involve supratentorial area
* Patients have unilateral weakness documented with manual muscle testing scales less than 4
* Stable vital signs and stable neurological signs
* Able to receive regular rehabilitation programs, and 8) modified Rankin Scales (mRS) less than 5.

Exclusion Criteria:

* A National Institute of Health Stroke Scale (NIHSS) score \> 25 at study entry
* The presence of hemineglect
* Moderate-to-severe pain in any limb
* Unstable clinical condition
* Recurrent strokes or brainstem strokes
* Marked arrhythmia or cardiovascular complications
* Bradycardia (HR≤50 bpm) or low blood pressure (SBP≤100 mmHg or DBP≤60mmHg) at admission
* Patients with radiographic evidence or suspicion of chronic conditions that may predispose them to intracranial hemorrhage including brain arteriovenous malformations, cerebral cavernous malformations, cerebral telangiectasia, multiple previous intracerebral hemorrhages (amyloid angiopathy)
* Pre-existing coagulopathy, consist of platelet count of ≤100, INR≥ 3, PTT≥ 90
* Patients suspected of having infective endocarditis and ischemic stroke related to septic emboli
* Signs or symptoms of acute myocardial infarction, including EKG findings
* Concomitant experimental therapy
* Suspected cerebral vasculitis based on medical history and CTA/Magnetic Resonance Angiogram (MRA)
* Suspected cranial dural arteriovenous fistula, and evidence of dissection in the intracranial cerebral arteries
* Cerebral venous thrombosis and significant mass effect with midline shift
* History of left atrial myxoma
* Presence of contraindication for VNS (TENS) and tDCS: (A) Intracranial space occupied lesion, (B) Presence of a pacemaker, (C) History of brain neurosurgery, (D) Active CNS or systemic infection, (E) Presence of a metallic foreign body implant, (F) Skin abnormalities, (G) History of alcohol/drug abuse, (H) Epilepsy/History of epilepsy at family (I) Hyperacusis, (J) Cognitive/Consciousness disturbance, (K) Pregnancy or nursing females, (L) Use of neuropsycoactive drugs, (M) Psychiatric/ Neurologic disease
* Not suitable for equipping ECG recorders: (A) Chronic disease, and allergic to polyester, (B) Acute and severe patients