This post is about VNS after stroke and how VNS helps with recovery. VNS is short for vagus nerve stimulation, a form of bioelectric neuromodulation, a nuanced treatment for brain disorders. It’s been around for decades, but recent discoveries mean it no longer requires invasive surgery. We’ve been using the noninvasive form of VNS at Ormond Neuroscience for a few years now. It’s safe and gentle. Reassuringly, the patient controls the intensity of the stimulation.
What is a Stroke?
An ischaemic stroke occurs when a blood vessel supplying the brain becomes blocked or severely narrowed, typically by a blood clot or atherosclerotic plaque, preventing brain tissue from receiving the oxygen and nutrients it needs to survive. Ischaemia (lack of blood supply) causes an infarct, an area of damaged brain tissue.
Bleeding occurs in a small percentage (about 13%) of strokes. We distinguish between ischaemic and haemorrhagic strokes. In haemorrhagic strokes, a blood vessel ruptures, causing bleeding into or around the brain. Although the mechanisms differ from ischaemic stroke, secondary injury processes — including inflammation, oedema, metabolic dysfunction, and impaired perfusion in surrounding tissue — contribute substantially to tissue damage.
What is the ischaemic penumbra — and why it matters
When a cerebral artery is blocked, the brain region supplied by that blood vessel, the infarct, forms two zones: a central core of irreversibly injured tissue and a surrounding ring of threatened but potentially salvageable tissue called the ischaemic penumbra. Cells within the penumbra are functionally impaired because blood flow is critically reduced, but they remain structurally viable for a limited period of time. Without intervention, ongoing metabolic stress and secondary injury processes may cause this tissue to progress to irreversible infarction.
You can see an ischaemic infarct in the image below. The penumbra is the green patch on the right of the image, the red represents the core.
How VNS after Stroke helps to shrink the Penumbra
I want to highlight recent findings that suggest that VNS hope to shrink the penumbra of a stroke. let’s unpack what this means.
VNS reduces Inflammation
VNS diminishes inflammation by activating the cholinergic anti-inflammatory pathway, lowering harmful cytokine signalling and reducing immune-mediated collateral damage to peri-infarct (penumbral) tissue. (Tang et al., 2022, Jelinek et al., 2023).
VNS after Stroke reduces Spreading Depolarisations
Experimental studies suggest that VNS may reduce the frequency and propagation of spreading depolarisations — pathological waves of near-complete neuronal and glial depolarisation that propagate through metabolically vulnerable cortex after stroke and other acute brain injuries. These depolarisations are believed to contribute to progressive penumbral injury (Lindemann et al., 2020, Jelinek et al., 2023).
VNS protects Blood–Brain Barrier (BBB) and Microvessels
During a stroke, lack of oxygen and glucose impairs the integrity of BBB endothelial cells. This leads to vasogenic oedema and the leakage of blood-derived products into the brain, and secondary injury to the “penumbra” tissue. Experimental models suggest that VNS may help preserve blood–brain barrier integrity and microvascular function, potentially limiting oedema formation and secondary injury within peri-infarct tissue (Jiang et al., 2014).
VNS promotes pro-repair Biology
VNS stimulates pro-repair biological processes. It also upregulates BDNF (brain-derived neurotrophic hormone) signalling, which in turn enhances neuroplasticity. Furthermore, VNS increases VEGF (vascular endothelial growth factor) expression, promoting angiogenesis, the creation of new blood vessels. Additionally, VNS shifts microglia into an M2 state in which inflammation is resolved, rather than initiated, supporting recovery. These biological effects may contribute to tissue preservation, neuroplasticity, and post-stroke recovery (Zhang, et al., 2022, Zhao et al., 2022).
Why penumbra shrinkage predicts outcome
The expansion of the infarct into the penumbra is driven by ongoing energy failure, inflammation, oxidative stress and spreading depolarizations. If these damaging processes are limited, more penumbral tissue survives and the resulting infarct is smaller. Across animal models and clinical imaging studies, smaller infarct volumes correlate with better motor and cognitive recovery — so reducing stroke’s penumbra translates into meaningful functional benefits. Specifically, animal research has repeatedly shown that VNS after stroke reduces the size of the penumbra, enhancing recovery (Ay et al., 2009, Ma et al., 2019).
Human application of VNS after Stroke
Early human data are promising: invasive VNS has been shown to be feasible and safe in acute settings, and randomized trials pairing VNS with rehabilitation in chronic stroke have demonstrated enhanced motor recovery (for example, Dawson, et al., 2021, Francisco et al., 2023). The scientific literature on non invasive VNS is much smaller because it is a newer technique but initial findings suggest similar benefits from transcutaneous auricular VNS, in which stimulation is applied a terminal branch of the vagal nerve located in the ear.
It is important to distinguish between preclinical neuroprotective findings and established clinical applications. Most evidence suggesting reduction of penumbral injury comes from animal models of acute stroke. In humans, the strongest current evidence supports the use of VNS paired with rehabilitation to enhance neuroplasticity and motor recovery in chronic stroke. However, growing translational interest exists in whether earlier autonomic and inflammatory modulation may also improve tissue preservation and functional outcomes after acute stroke.
VNS after Stroke: Practical takeaways for patients and clinicians
- VNS is a promising adjunct therapy: preclinical evidence strongly supports penumbra reduction, and early clinical translation (especially when paired with rehabilitation) shows functional benefits.
- Reducing infarct expansion (i.e., reducing stroke’s penumbra) preserves brain tissue and improves the odds of meaningful recovery.
- Clinicians and researchers: the recent comprehensive review by Jelinek et al., 2023 is a useful one-stop summary of the mechanisms and animal evidence.
Selected references & further reading
- Jelinek M, Lipkova J, Duris K. Vagus nerve stimulation as immunomodulatory therapy for stroke: A comprehensive review. Experimental Neurology. 2023. doi:10.1016/j.expneurol.2023.114628
