Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications

Abstract

Vagus nerve stimulation (VNS) is a technology that provides electrical stimulation to the cervical vagus nerve and can be applied in the treatment of a wide variety of neuropsychiatric and systemic diseases. VNS exerts its effect by stimulating vagal afferent and efferent fibers, which project upward to the brainstem nuclei and the relayed circuits and downward to the internal organs to influence the autonomic, neuroendocrine, and neuroimmunology systems. The neuroimmunomodulation effect of VNS is mediated through the cholinergic anti-inflammatory pathway that regulates immune cells and decreases pro-inflammatory cytokines. Traditional and non-invasive VNS have Food and Drug Administration (FDA)-approved indications for patients with drug-refractory epilepsy, treatment-refractory major depressive disorders, and headaches. The number of clinical trials and translational studies that explore the therapeutic potentials and mechanisms of VNS is increasing. In this review, we first introduced the anatomical and physiological bases of the vagus nerve and the immunomodulating functions of VNS. We covered studies that investigated the mechanisms of VNS and its therapeutic implications for a spectrum of brain disorders and systemic diseases in the context of neuroimmunomodulation.

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD)

“…Our results are preliminary and should be interpreted with caution due to the small sample size and uncontrolled design, but they provide an encouraging approach for severely affected patients. In contrast to the majority of previous VNS studies involving animal models or in vitro investigations [42], our study is one of the first to investigate treatment responses in real-world patients according to cytokine profiles and clusters rather than single cytokines. Given the complex interplay between cytokines in the complex pathophysiological mechanism of depression [20], this approach to investigate clusters of cytokines may be more useful and appropriate than attempting to predict responses to anti-depressant treatment based on single cytokines.…”

Autonomic dysfunction and treatment strategies in intracerebral hemorrhage

“…Vagus nerve stimulation (VNS) has long been approved for the treatment of refractory epilepsy, primary headache, depression, and obesity 128,129 . In addition, VNS has been indicated to regulate immune cells and reduce proinflammatory cytokines through cholinergic anti‐inflammatory pathway, thus exerting neuroimmunomodulatory effects in a spectrum of brain disorders 130 . Recent studies have indicated that VNS paired with rehabilitation is a promising treatment option for people with moderate‐to‐severe neurological impairment after stroke 131–134 .…”

“… 128 , 129 In addition, VNS has been indicated to regulate immune cells and reduce proinflammatory cytokines through cholinergic anti‐inflammatory pathway, thus exerting neuroimmunomodulatory effects in a spectrum of brain disorders. 130 Recent studies have indicated that VNS paired with rehabilitation is a promising treatment option for people with moderate‐to‐severe neurological impairment after stroke. 131 , 132 , 133 , 134 The US Food and Drug Administration (FDA) then approved the use of VNS paired with upper limb rehabilitation for the treatment of moderate‐to‐severe upper extremity motor deficits associated with chronic ischemic stroke in 2021.…”

Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies

“…Innovative bioelectronic methods of CAP harnessing for clinical use were also assessed [ 115 ]. Bioelectronic medicine, via vagus nerve stimulation (VNS), may have an interest in the non-pharmacological therapeutic approach [ 116 ]. A recent double-blind, randomized clinical trial examined the effect of chronic low-level transcutaneous VNS on cardiac function in patients with heart failure demonstrating that VNS can have the potential to counteract cardiovascular-inflammaging [ 117 ].…”