This post is about VNS after stroke and how VNS helps with recovery. VNS is short for vagal nerve stimulation. VNS is a form of bioelectric neuromodulation, a remarkable treatment for brain disorders. It’s been around for decades, but recent discoveries mean it no longer requires surgery. We’ve been using the noninvasive form of VNS at Ormond Neuroscience for a few years now. It’s safe, gentle and best of all, the patient controls the intensity.
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 (13%) of strokes. We distinguish between ischaemic and haemorrhagic strokes. Obviously, haemorrhage diverts blood from where it should be, causing similar damage to an ischaemic stroke. In fact, ischaemia underpins much of the damage caused by a haemorrhagic stroke. It is the toxic effects of blood products in the interstitial space that complicate haemorrhagic stroke.
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 in the penumbra have reduced blood flow and function but are not yet dead. The main goal of acute stroke care is to protect and rescue this penumbra, because saving that tissue preserves brain networks and improves long-term functional outcome.
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 an incredible aspect of how VNS works: “shrinking the penumbra.” That sounds exotic, and it is! VNS aids stroke recovery because:
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
Spreading depolarisations refers to a pathological process occurring in the context of stroke, traumatic brain injury, and related conditions. It’s a wave of electrophysiological hyperactivity followed by a wave of inhibition. A massive slow wave of cellular depolarisation propagates through the brain’s grey matter, breaking down ion gradients and silencing neurons (inhibition). These neural waves expand injury into the penumbra (Lindemann et al., 2020, Jelinek et al., 2023). VNS reduces the spread of depolarising waves that otherwise hit the penumbra repeatedly and expand the lesion.
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. VNS limits this vasogenic injury, preserving blood–brain barrier integrity and microvascular function, preventing vasogenic injury and microvascular collapse that would doom penumbral 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 factors all contribute to reducing the penumbra (Zhang, et al., 2022, Zhoa 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, 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: non-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). Interestingly, VNS also improved limb function even when not paired with physio (Meyers et al., 2018).
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
