Transcutaneous vagus nerve stimulation (tVNS) in stroke: the evidence, challenges and future directions.

Stroke is one of the leading causes of death and disability globally. A significant proportion of stroke survivors are left with long term neurological deficits that have a detrimental effect on personal wellbeing and wider socioeconomic impacts. As such, there is an unmet need for novel therapies that improve neurological recovery after stroke. Invasive vagus nerve stimulation (VNS) paired with rehabilitation has been shown to improve upper limb motor function in chronic stroke. However, invasive VNS requires a surgical procedure and therefore may not be suitable for all stroke patients. Non-invasive, transcutaneous VNS (tVNS) via auricular vagus nerve stimulation in the ear (taVNS) and cervical vagus nerve stimulation in the neck (tcVNS) have been shown to activate similar vagal nerve projections in the central nervous system to invasive VNS. A number of pre-clinical studies indicate that tVNS delivered in acute middle cerebral artery occlusion reduces infarct size through anti-inflammatory effects, reduced excitotoxicity and increased blood-brain barrier integrity. Longer term effects of tVNS in stroke that may mediate neuroplasticity include microglial polarisation, angiogenesis and neurogenesis. Pilot clinical trials of taVNS indicate that taVNS paired with rehabilitation may improve upper limb motor and sensory function in patients with chronic stroke. In this review, we summarise and critically appraise the current pre-clinical and clinical evidence, outline the major ongoing clinical trials and detail the challenges and future directions regarding tVNS in acute and chronic stroke.