Vagus Nerve Stimulation and Neuroplasticity: Rewiring the Brain

Introduction: Neuroplasticity and the Promise of Vagus Nerve Stimulation

The human brain is not a fixed organ. Throughout life, neural circuits continuously reorganise in response to experience, injury, and learning — a phenomenon known as neuroplasticity. This capacity for rewiring underpins our ability to acquire new skills, recover from brain injury, and adapt to changing environments. It also lies at the heart of many neurological and psychiatric conditions, where maladaptive plasticity can entrench pathological patterns of neural activity.

For decades, researchers have sought reliable methods to harness and direct neuroplasticity for therapeutic purposes. The challenge has always been precision: how do you encourage the brain to reorganise in beneficial ways without disrupting healthy circuits?

Vagus nerve stimulation (VNS) has emerged as one of the most promising tools for addressing this challenge. By delivering timed electrical pulses to the vagus nerve, VNS activates neuromodulatory systems in the brainstem that are known to gate plasticity — the noradrenergic locus coeruleus, the cholinergic nucleus basalis, and the serotonergic dorsal raphe nucleus. When paired with specific sensory or motor experiences, VNS appears to enhance the brain's capacity to reorganise circuits in a targeted, experience-dependent manner.

This concept, termed targeted plasticity therapy, has moved from preclinical studies in rodents to landmark clinical trials in stroke rehabilitation, and research continues to expand into areas such as tinnitus, learning and memory, and fear extinction. This article examines the evidence linking VNS to neuroplasticity — the molecular mechanisms, the clinical applications, and the limitations that remain.

Mechanisms: How VNS Promotes Neural Plasticity

The plasticity-enhancing effects of VNS are thought to arise from its ability to activate multiple neuromodulatory systems simultaneously, with precise temporal control. Understanding these mechanisms requires a brief overview of the neurochemistry of plasticity itself.

Noradrenergic and Cholinergic Gating of Plasticity

Neural plasticity does not occur indiscriminately. The brain employs neuromodulatory "gating" systems that signal when a particular experience is important enough to warrant lasting neural changes. Two of the most critical gating systems involve noradrenaline (released from the locus coeruleus) and acetylcholine (released from the nucleus basalis of Meynert).

When the vagus nerve is electrically stimulated, afferent signals travel to the nucleus tractus solitarius (NTS) in the brainstem, which projects to both the locus coeruleus and the nucleus basalis. Hulsey et al. (2017) demonstrated that even brief trains of VNS (0.5 seconds) drive rapid, phasic firing of locus coeruleus neurons, triggering the release of noradrenaline throughout the cortex. The same group showed that VNS-dependent reorganisation of motor cortex requires intact cholinergic innervation from the nucleus basalis — lesioning this pathway completely prevents VNS-driven plasticity (Hulsey et al., 2016).

These findings suggest that VNS engages the same neuromodulatory mechanisms that the brain naturally uses to mark experiences as significant. The difference is that VNS provides external, precisely timed control over these systems — allowing researchers and clinicians to pair neuromodulatory activation with specific therapeutic activities.

BDNF and Neurotrophic Factor Expression

Beyond acute neuromodulatory effects, VNS also promotes the expression of molecules that support the structural basis of plasticity. Brain-derived neurotrophic factor (BDNF) is a key neurotrophin involved in synaptic strengthening, dendritic growth, and neuronal survival. BDNF is essential for long-term potentiation (LTP) — the cellular mechanism widely considered the foundation of learning and memory.

In a foundational study, Follesa et al. (2007) demonstrated that acute VNS significantly increased the expression of BDNF and basic fibroblast growth factor (bFGF) in the rat hippocampus and cerebral cortex. VNS also increased noradrenaline concentrations in the prefrontal cortex, an effect comparable to that of the antidepressant venlafaxine. This dual action — activating neuromodulatory systems while simultaneously upregulating neurotrophic factors — may explain why VNS produces particularly robust and durable plasticity.

Biggio et al. (2009) extended these findings to chronic VNS, demonstrating that one month of continuous vagus nerve stimulation increased BDNF immunoreactivity in the CA1 and CA3 subregions of the hippocampus, promoted cell proliferation in the dentate gyrus, and increased the number and dendritic complexity of doublecortin-positive (DCX+) neurons — newly generated cells that are markers of adult neurogenesis. These results indicate that VNS does not merely facilitate transient synaptic changes but can promote the birth and integration of new neurons into existing circuits.

Enhancement of Long-Term Potentiation

Long-term potentiation (LTP) — the sustained strengthening of synaptic connections following repeated activation — is the best-characterised cellular mechanism of learning and memory. If VNS truly enhances neuroplasticity, it should be expected to potentiate LTP.

Zuo, Smith, and Jensen (2007) tested this directly by measuring LTP in the dentate gyrus of freely moving rats. They found that VNS delivered at a moderate intensity (0.4 mA) significantly enhanced the potentiation of population spike amplitude for at least 24 hours following tetanic stimulation. Notably, lower (0.2 mA) and higher (0.8 mA) intensities were less effective, suggesting an inverted-U dose–response relationship — a pattern consistent with the broader literature on arousal-mediated memory modulation.

This finding is significant because it demonstrates that VNS does not simply increase neural excitability in a non-specific way. Rather, it selectively enhances the strengthening of synapses that are actively engaged — precisely the kind of targeted plasticity that would be most therapeutically useful.

Stroke Rehabilitation: The VNS-REHAB Trial

Perhaps the most clinically significant application of VNS-driven neuroplasticity is in stroke rehabilitation. Long-term upper limb impairment is one of the most common and disabling consequences of ischaemic stroke, affecting approximately two-thirds of stroke survivors. Despite intensive rehabilitation, many patients plateau in their recovery, suggesting that conventional therapy alone is insufficient to drive the neural reorganisation needed to restore motor function.

Preclinical Foundations

The concept of pairing VNS with motor rehabilitation emerged from the work of Porter et al. (2012), who demonstrated that repeatedly pairing VNS with specific forelimb movements in rats produced lasting reorganisation of movement representations in the primary motor cortex. Critically, rats receiving identical motor training without VNS showed no such reorganisation — the pairing with vagus nerve stimulation was essential for driving cortical map plasticity.

Khodaparast et al. (2013) then tested whether this plasticity could be harnessed for stroke recovery. In rats with ischaemic lesions of the motor cortex, VNS paired with rehabilitative training restored forelimb function to pre-lesion levels, while equivalent rehabilitation without VNS failed to achieve the same degree of recovery. The pairing had to be temporally precise: delivering VNS after the rehabilitation session, rather than during it, provided no benefit.

These studies established the principle that VNS paired with rehabilitation could enhance recovery by driving targeted, task-specific plasticity in damaged motor circuits.

The Landmark VNS-REHAB Trial

In 2021, Dawson et al. published the results of the VNS-REHAB trial in The Lancet — the first adequately powered, multicentre, randomised, triple-blind, sham-controlled trial of VNS paired with rehabilitation for post-stroke upper limb recovery.

The trial enrolled 108 participants across 19 rehabilitation centres in the United Kingdom and the United States. All participants were at least 9 months post-ischaemic stroke with moderate-to-severe arm weakness. Critically, all participants were implanted with a VNS device and underwent identical rehabilitation protocols — the only difference was whether the device delivered active stimulation or sham stimulation during therapy.

The results were striking:

- After six weeks of in-clinic therapy, participants in the VNS group showed a mean improvement of 5.0 points on the Fugl-Meyer Assessment Upper Extremity (FMA-UE) scale, compared with 2.4 points in the control group (p = 0.0014).
- At 90 days post-therapy, 47% of VNS participants achieved a clinically meaningful response, compared with 24% of controls (p = 0.0098).

These findings were particularly noteworthy given the chronicity of the participants' strokes — many were years post-injury, a stage at which conventional rehabilitation typically yields minimal further gains. The results suggested that VNS could reopen a window of plasticity that had otherwise closed.

Following publication of the VNS-REHAB trial, the MicroTransponder Vivistim Paired VNS System received FDA clearance in August 2021 for the treatment of chronic ischaemic stroke — the first application of targeted plasticity therapy to receive regulatory approval.

Mechanism of Paired VNS in Stroke

The proposed mechanism is that VNS, delivered during specific motor movements, triggers precisely timed release of noradrenaline and acetylcholine from the locus coeruleus and nucleus basalis. These neuromodulators act on the motor cortex and corticospinal pathways to strengthen the specific synaptic connections being activated by the rehabilitation exercise. Over many repetitions across weeks of therapy, this targeted reinforcement drives the reorganisation of perilesional cortex to take over functions previously served by damaged tissue.

Long-term follow-up data from the earlier pilot study (Kimberley et al., 2018) are encouraging: participants continued to improve for years after initial therapy, with mean FMA-UE improvements of 11.4 points at 2 years and 14.8 points at 3 years, and 85.7% of participants qualifying as responders by year 3 (Francisco et al., 2023). These sustained gains are consistent with durable neuroplastic reorganisation rather than transient symptomatic relief.

Tinnitus: Reversing Maladaptive Auditory Cortex Plasticity

Chronic tinnitus — the persistent perception of sound in the absence of an external source — is thought to arise from maladaptive plasticity in the auditory cortex. Following noise-induced hearing loss, the brain's tonotopic maps reorganise, with neurons that previously responded to the damaged frequency range being "recruited" by neighbouring frequencies. This reorganisation, combined with increased neural synchrony, may generate the phantom sound percept that characterises tinnitus.

If tinnitus is caused by maladaptive plasticity, the logical therapeutic question becomes: can we use targeted plasticity to reverse it?

Preclinical Evidence

Engineer et al. (2011) provided a landmark demonstration that VNS-driven plasticity could reverse the pathological neural changes underlying tinnitus. In rats with noise-induced tinnitus, repeatedly pairing VNS with tones at various frequencies — excluding the tinnitus frequency — eliminated both the behavioural and physiological signs of tinnitus. The therapy sharpened auditory neuron tuning curves, normalised tonotopic maps, and reduced the pathological neural synchrony that is a hallmark of the condition.

The key insight was that by selectively expanding the cortical representation of non-tinnitus frequencies through VNS-paired tone exposure, the expanded representation at the tinnitus frequency could be reversed. The changes persisted for at least three weeks after cessation of therapy, indicating lasting cortical reorganisation.

Clinical Translation

De Ridder et al. (2014) conducted the first clinical application of this approach, implanting VNS devices in 10 patients with severe, treatment-resistant chronic tinnitus. Over 20 days of therapy (2.5 hours daily), patients heard tones — excluding their tinnitus-matched frequency — paired with brief electrical stimulation of the vagus nerve.

Four of the ten patients exhibited clinically meaningful improvements in both tinnitus distress (measured by the Tinnitus Handicap Inventory) and the loudness of the tinnitus percept (measured by minimum masking level). These improvements were stable for more than two months after therapy ended. Notably, five of the non-responding patients were taking medications (muscarinic antagonists, noradrenaline agonists, or GABA agonists) that may have interfered with the neuromodulatory mechanisms required for VNS-driven plasticity.

While the clinical results were modest compared to the dramatic preclinical findings, this study provided proof-of-concept that VNS-paired sound therapy can induce beneficial auditory cortex reorganisation in humans with chronic tinnitus. Research continues into optimising stimulation parameters, treatment duration, and patient selection to improve outcomes.

Learning and Memory: VNS as a Cognitive Enhancer

The neuroplasticity-enhancing properties of VNS have also attracted interest as a means of augmenting learning and memory — a concept with implications ranging from educational neuroscience to the treatment of cognitive decline.

The Clark et al. Study

The foundational human study in this area was conducted by Clark et al. (1999), who tested whether VNS could enhance recognition memory in epilepsy patients with implanted VNS devices. Participants underwent a verbal learning task and then received either active VNS at varying intensities or no stimulation.

The results showed that when VNS was delivered after the encoding phase, participants exhibited significantly enhanced word recognition compared to the no-stimulation condition. As with the LTP studies, moderate stimulation intensities were most effective, while lower and higher intensities produced less benefit — consistent with an inverted-U arousal–memory relationship.

This study was the first to demonstrate in humans that VNS could enhance memory formation, paralleling decades of animal research showing that post-learning vagal activation strengthens memory consolidation through modulation of the amygdala–hippocampal system.

Proposed Mechanisms

The memory-enhancing effects of VNS are likely mediated by several complementary mechanisms:

1. Noradrenergic modulation of the amygdala and hippocampus: VNS-driven noradrenaline release from the locus coeruleus enhances the encoding and consolidation of memories, particularly for emotionally salient information (McIntyre et al., 2012).

2. Enhanced hippocampal LTP: As demonstrated by Zuo et al. (2007), VNS potentiates synaptic strengthening in the dentate gyrus — a region critical for the formation of new episodic memories.

3. Increased BDNF expression: The VNS-driven upregulation of BDNF in the hippocampus (Follesa et al., 2007; Biggio et al., 2009) supports the structural changes required for long-term memory storage.

4. Neurogenesis in the dentate gyrus: The increased cell proliferation and dendritic complexity observed following chronic VNS (Biggio et al., 2009) may expand the hippocampal circuitry available for memory encoding.

While the prospect of VNS as a cognitive enhancer is intriguing, it is important to note that most human studies to date have been conducted in clinical populations with implanted devices. Research into non-invasive transcutaneous VNS for memory enhancement in healthy individuals has yielded mixed results, and further investigation is needed to determine optimal parameters and the magnitude of effects that can be reliably achieved.

Progressive Improvement: Evidence for Slow Neuroplastic Changes

One of the most intriguing features of VNS therapy across multiple clinical applications is that its effects tend to improve progressively over months and years — a temporal pattern highly suggestive of ongoing neuroplastic reorganisation rather than acute pharmacological modulation.

Epilepsy

In the treatment of drug-resistant epilepsy, the efficacy of VNS increases substantially with prolonged use. Englot, Chang, and Auguste (2011) conducted the first comprehensive meta-analysis of VNS efficacy in epilepsy, pooling data from 74 clinical studies encompassing 3,321 patients. They found that longer follow-up periods were significantly associated with greater seizure reduction. This progressive improvement has been confirmed in long-term registry data: in a 17-year follow-up study, the proportion of patients achieving at least 50% seizure reduction rose from 38.4% at 1 year to 77.8% at 17 years (Morris et al., 2013).

This temporal pattern is difficult to explain through conventional pharmacological mechanisms, which would be expected to reach a steady state relatively quickly. Instead, the gradual accrual of benefit suggests that VNS is driving slow, cumulative reorganisation of epileptogenic networks — progressively strengthening inhibitory circuits and normalising the balance between excitation and inhibition.

Depression

A similar pattern is observed in the treatment of treatment-resistant depression (TRD). In the largest and longest naturalistic study of VNS for TRD, Aaronson et al. (2017) followed 795 patients for five years. The adjunctive VNS group achieved a cumulative 5-year response rate of 67.6%, compared with 40.9% for treatment as usual alone. Remission rates were also significantly higher in the VNS group (43.3% versus 25.7%).

Importantly, response and remission rates continued to increase over the full five-year observation period — a strikingly different trajectory from conventional antidepressant therapies, transcranial magnetic stimulation, or electroconvulsive therapy, all of which tend to reach peak efficacy relatively quickly. This progressive improvement is consistent with the hypothesis that VNS promotes slow neuroplastic changes in the limbic and prefrontal circuits that are dysregulated in depression — including BDNF-mediated synaptic remodelling and, potentially, neurogenesis in the hippocampus.

Implications

The progressive efficacy pattern across epilepsy and depression provides indirect but compelling evidence that neuroplasticity is a central mechanism of VNS therapy, not merely a secondary effect. It also has practical clinical implications: patients and clinicians should be counselled that the full benefit of VNS may take months or years to manifest, and that early non-response does not necessarily predict long-term failure.

Limitations and Future Directions

Despite the promising evidence, several important limitations and open questions remain.

Parameter Optimisation

The effects of VNS on plasticity are highly parameter-dependent. Stimulation intensity, frequency, pulse width, train duration, and the timing of stimulation relative to the paired activity all influence outcomes. The inverted-U dose–response relationship observed in LTP and memory studies (Zuo et al., 2007; Clark et al., 1999) suggests that more stimulation is not necessarily better — an observation with important implications for clinical protocol design. Systematic research into optimal parameters for different applications remains an ongoing priority.

Translation from Invasive to Non-Invasive VNS

Much of the foundational plasticity research has been conducted using invasive, surgically implanted VNS devices. Whether non-invasive transcutaneous approaches — particularly transcutaneous auricular VNS (taVNS) — can achieve comparable effects on plasticity is not yet fully established. While taVNS activates many of the same brainstem structures as invasive VNS, the degree and consistency of neuromodulatory engagement may differ. Clinical trials directly comparing invasive and non-invasive approaches for plasticity-dependent applications are needed.

Individual Variability

Not all patients respond equally to VNS therapy. The De Ridder et al. (2014) tinnitus study illustrated this clearly: only four of ten patients showed meaningful improvement, and concurrent medications may have interfered with the neuromodulatory mechanisms required for plasticity. Understanding the sources of individual variability — including genetics, medication interactions, baseline neural circuit integrity, and stimulation parameter sensitivity — will be critical for improving outcomes and identifying the patients most likely to benefit.

Mechanistic Understanding

While the broad outlines of VNS-driven plasticity are increasingly well characterised, many molecular and circuit-level details remain unclear. The relative contributions of noradrenergic, cholinergic, and serotonergic systems at different stages of plasticity induction and consolidation are not fully understood. Similarly, the relationship between acute neuromodulatory effects and longer-term structural changes (neurogenesis, dendritic remodelling, synaptic reorganisation) requires further investigation.

Expanding Applications

Research into VNS-driven targeted plasticity continues to expand beyond its current clinical applications. Preclinical studies have explored VNS-paired interventions for post-traumatic stress disorder — with Pena et al. (2013) demonstrating that VNS paired with extinction training significantly enhances the extinction of conditioned fear responses in rats. Other emerging areas include spinal cord injury, traumatic brain injury, and even language learning. The coming years are likely to see a broadening of the conditions for which VNS-driven plasticity is tested clinically.

Conclusion

Vagus nerve stimulation occupies a unique position at the intersection of neuromodulation and neuroplasticity. By engaging the brain's endogenous plasticity-gating systems — noradrenaline, acetylcholine, serotonin, and BDNF — with precise temporal control, VNS offers a means of directing neural reorganisation in ways that are specific to the sensory or motor experiences with which it is paired.

The evidence base spans multiple levels of analysis: from molecular changes in BDNF expression and hippocampal neurogenesis, through cellular-level enhancement of long-term potentiation, to systems-level reorganisation of motor and auditory cortical maps, and ultimately to clinical outcomes in stroke rehabilitation that have earned regulatory approval.

What makes the VNS–neuroplasticity story particularly compelling is its convergence across diverse applications. Whether the target is recovering arm movement after stroke, reversing maladaptive auditory cortex changes in tinnitus, enhancing memory consolidation, or the progressive improvement observed over years of epilepsy and depression treatment, the underlying principle is the same: VNS enhances the brain's capacity to rewire itself in response to experience.

Significant challenges remain — particularly in optimising stimulation parameters, translating invasive findings to non-invasive approaches, and understanding individual variability in response. But the trajectory of the field is clear. Vagus nerve stimulation is no longer merely a treatment that modulates neural activity in the moment. It is increasingly understood as a tool for reshaping the brain itself.

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