The Role of Transcutaneous Vagus Nerve Stimulation in Treatment of Acute Brain Injury

Overview

Acute brain injury is a major global health problem associated with high mortality and morbidity, limited therapeutic options, prolonged hospital stays, and long-term disability that significantly impairs quality of life and increases healthcare costs. Noninvasive transcutaneous VNS developed as a safer approach for treating cerebral edema, epileptic seizures, and blood-brain barrier disruption, for facilitating the recovery of motoric and cognitive functions, and for immunomodulation. Transcutaneous VNS improves cerebral perfusion pressure and tissue oxygenation, supports reperfusion of the penumbral zone, and reduces neuronal hyperexcitability, thereby suppressing seizures.It may exert anti-inflammatory effects by reducing microglial cytokine and chemokine production. Additionally, vagal stimulation promotes acetylcholine-mediated suppression of pro-inflammatory cytokines, including TNF, IL-1β, IL-6, and IL-18. Another anti-inflammatory mechanism involves ghrelin, a peptide hormone whose serum levels increase under vagal stimulation. Elevated ghrelin reduces TNF-α and other pro-inflammatory cytokines and may limit intracerebral hemorrhage by inhibiting the NLRP3 inflammasome and activating the Nrf2/ARE signaling pathway. Biomarkers such as S100 protein and neuron-specific enolase (NSE) are valuable indicators of brain tissue damage and clinical outcomes; tVNS may reduce their levels and support non-invasive monitoring of disease progression. The technique is considered safe in patients . To date, tVNS has not been evaluated in clinical trials in Croatia, nor reported in case studies or cohort analyses. Study outcomes will be correlated with patients' clinical status, duration and course of hospitalization, complication rates, and overall treatment outcomes.

Acute brain injury is one of the leading health problems of today. It presents with high mortality and morbidity, limited therapeutic options, and prolonged hospital stays, leaving patients with disabilities that impair quality of life and increase healthcare costs. The etiology of brain injury may be traumatic or non-traumatic. The global incidence of traumatic brain injury (TBI) is estimated at 27 to 69 million cases per year, mainly due to falls and traffic accidents. Among the most challenging non-traumatic brain injuries is aneurysmal subarachnoid hemorrhage (aSAH), with an incidence of 10-15 patients per 100,000 per year. In the treatment of primary and secondary brain injury, both surgical and non-surgical procedures are important. Limited therapeutic options in the treatment of brain injury have opened the door to consideration of new non-invasive methods. Recent studies show that neuromodulation induced by vagus nerve stimulation (VNS) may contribute to better outcomes in patients with brain injury. The first application of VNS in a clinical setting was an invasive procedure used in the treatment of pharmacoresistant epilepsy. Subsequently, a non-invasive method of transcutaneous VNS (tVNS) was developed, which may have neuroprotective and immunoprotective effects. According to existing research, tVNS provides a safer approach in the treatment of cerebral edema, epileptic seizures, disorders of the cerebral blood-brain barrier, recovery of motor and cognitive functions, and immunomodulation. Transcutaneous VNS induces enhanced regulation of endogenous noradrenergic activity through activation of the locus coeruleus and the release of noradrenaline in the amygdala, as well as higher overall concentrations of noradrenaline in the brain. Accordingly, an increase in cerebral perfusion pressure (CPP) enables better oxygenation of brain tissue and reperfusion of the penumbral zone. Noradrenaline suppresses seizures by protecting GABAergic neurons and reducing neuronal hyperexcitability. In addition, it exerts anti-inflammatory effects on microglial cells, reducing the production of cytokines and chemokines. Acetylcholine (ACh), under vagal stimulation, also reduces pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukins IL-1β, IL-6, and IL-18. At the same time, it influences the microglial phenotype, reducing the pro-inflammatory M1 microglial phenotype, which promotes oxidative stress and mitochondrial damage, in favor of the neuroprotective M2 phenotype. Recent studies show that tVNS also significantly modulates serum inflammatory cytokines in patients with sepsis. Another anti-inflammatory mechanism is the interaction of VNS with the peptide hormone ghrelin. Serum ghrelin concentrations increase under vagal stimulation, leading to a subsequent reduction in TNF-α levels and other pro-inflammatory cytokines after brain injury. Ghrelin also plays an important role in reducing intracerebral hemorrhage by inhibiting NLRP3 and stimulating the Nrf2/ARE signaling pathway. Analysis of biomarkers of brain tissue damage, such as S100 protein and neuron-specific enolase (NSE), can be used to assess mortality and morbidity, as well as outcomes of neurointensive care, and non-invasive tVNS stimulation could result in a reduction of their values and serve in monitoring the clinical condition of patients with brain injury. Motor recovery depends on brain neuroplasticity, and the results of previous studies indicate significantly better functional motor recovery when rehabilitation therapy is combined with tVNS. Non-invasive tVNS can also alleviate cognitive dysfunction, as it reduces neuroinflammation and improves memory function through stimulation of peripheral and central cholecystokinin (CCK) receptors. The use of tVNS is safe in patients with aSAH and stroke, and it significantly improves functional recovery in patients in a minimally conscious state after transauricular tVNS administered for a duration of four weeks. To the best of our knowledge, tVNS has not yet been used in clinical trials in Croatia, nor has it been described in case reports or small cohort studies. The obtained results will be correlated with collected data on patients' clinical status, the course and duration of hospital treatment, the occurrence of complications, and treatment outcomes.