Exploring the vagus nerve and the inflammatory reflex for therapeutic benefit in chronic spinal cord injury

Abstract

Purpose of review

To describe features and implications of chronic systemic inflammation in individuals with spinal cord injury (SCI) and to summarize the growing therapeutic possibilities to explore the vagus nerve-mediated inflammatory reflex in this context.

Recent findings

The discovery of the inflammatory reflex provides a rationale to explore neuromodulation modalities, that is, electrical vagus nerve stimulation and pharmacological cholinergic modalities to regulate inflammation after SCI.

Summary

Inflammation in individuals with SCI may negatively impact functional recovery and medical consequences after SCI. Exploring the potential of the vagus nerve-based inflammatory reflex to restore autonomic regulation and control inflammation may provide a novel approach for functional improvement in SCI.

INTRODUCTION

There are an estimated 2.5 million individuals living with chronic traumatic spinal cord injury (SCI), and 17 730 new cases of SCI in the United States each year [1]. Neurologically incomplete tetraplegia is now the most common injury level and severity in the United States [1]. Despite advances in clinical care, life expectancy for people with SCI is significantly lower than for uninjured people [1]. Infections, which often cause pneumonia and sepsis, are the leading causes of mortality for individuals with SCI [1–3].

In addition to motor and sensory dysfunction, SCI is associated with descending supraspinal autonomic nervous system (ANS) dysregulation, resulting in multiorgan system dysfunction that promotes serious medical consequences [4–6]. These include autonomic dysreflexia, immune dysfunction and inflammation, hypertension, blood pressure instability, obesity and metabolic disorders, and an elevated risk of cardiovascular disease and stroke [4,6,7]. Inflammation potentiates many of these common medical consequences of SCI. A meta-analysis of data from more than 250 individuals with chronic SCI showed that 76% had elevated levels of the inflammatory biomarker C-reactive protein (CRP), in parallel with obesity and metabolic derangements [8]. Systemic inflammation can also promote CNS inflammation, that is, neuroinflammation [7,9]. In preclinical studies of lupus, studies have shown that stress or infection can cause breaches in the blood–brain barrier, enabling high molecular weight mediators, such as antibodies to enter the brain, where they are neurotoxic and alter neuronal function [10]. A similar scenario is possible in acute or chronic SCI, where environmental conditions promoting breach of the vascular permeability barriers (brain or spinal cord), such as infection are common. Increasing evidence indicates that persistent chronic inflammation may block neurological recovery and rehabilitation for people with SCI, both acutely and chronically [11–13].

Despite its clinical relevance, inflammation is often untreated in people with chronic SCI. Over the past 20 years, studies have shown that the vagus nerve, which belongs to the parasympathetic branch of the ANS, regulates inflammation within the inflammatory reflex [14–17]. Mechanistic preclinical studies showed that electrical vagus nerve stimulation (VNS) parameters can influence production of specific inflammatory cytokines systemically [18]. Recent clinical studies demonstrated safety and efficacy of bioelectronic VNS to reduce chronic inflammation in multiple clinical populations [19,20]. Of note, reduced vagal tone is reported in people with chronic SCI at rest and in response to orthostatic provocation [21,22].

Here, we provide an overview of inflammation in chronic SCI, the inflammatory reflex, and clinically available approaches, including bioelectronic VNS and the cholinergic drug galantamine, to target this physiological mechanism to control inflammation, which, when paired with rehabilitation or other therapeutic modalities, may provide the opportunity to improve functional abilities across the lifespan of people with SCI [23]. Then, we describe potential mechanisms and special considerations for alleviating inflammation targeting the inflammatory reflex in the SCI population.

INFLAMMATION IN CHRONIC SPINAL CORD INJURY: SOURCES AND POTENTIAL DOWNSTREAM EFFECTS

Inflammation is a protective mechanism against infection and injury when it is localized and resolved in a timely manner. However, various forms of excessive, unresolved, and chronic inflammation are implicated in the pathogenesis of many disorders. The regulation of inflammation involves a complex interplay between immune, hormonal, and neural mechanisms at organismal, cellular, and molecular levels. Both the sympathetic and parasympathetic branches of the ANS regulate inflammation as described in more detail below.

A detailed understanding of immune dysfunction and inflammation in acute SCI is growing [9,13,24] but much less is known in chronic SCI [7]. As recently reviewed elsewhere [7], relatively small clinical studies have demonstrated elevated systemic inflammatory proteins (cytokines and adipokines) in persons with chronic SCI, including IL-2, IL-6, TNF, MIF, and HMGB1, using reliable but low-throughput methods. More recently, functional genomics studies identified broader changes in whole blood or white blood cell gene expression in persons with chronic SCI compared with uninjured persons [25,26]. For example, there is upregulation of pattern recognition receptor genes that are essential to innate immunity, the Toll-like receptors (TLR), as well as downregulation of natural killer cell genes and adaptive immunity pathways [26].

SCI is characterized by a pronounced sympathetic dysfunction because of the loss of supraspinal control [4]. Dysregulation of the sympathetic outflow (which could be because of injury to the SNS itself or in its regulation), in SCI results in disruption of cardiovascular and immune homeostasis and inflammation – higher level injuries are associated with a more profound alterations [3,27–30] (Fig. 1). Systemic inflammation in chronic SCI correlates inversely with mobility status and is higher in persons who are nonambulatory [31–33]. Autonomic dysreflexia, blood pressure fluctuations, episodes of hypertension and orthostatic hypotension, and persistent hypertension are characteristic manifestations of cardiovascular dysfunction in chronic SCI [4,6,34] (Fig. 1). In preclinical models, acute SCI at thoracic level 3 (T3) is linked to enhanced catecholaminergic output to the spleen, which leads to impaired antibody production, lymphocyte apoptosis, and immune suppression [27,35,36]. Immunosuppression in chronic SCI coexists with increased levels of inflammation and may be mechanistically linked, as inflammation induces suppressive immune cell phenotypes [29,37].

FIGURE 1.

A role for the vagus nerve and the inflammatory reflex in alleviating inflammation and cardiometabolic derangements in chronic spinal cord injury – anatomical and functional considerations. Chronic SCI is associated with profound autonomic dysfunction, cardiometabolic, and immune dysregulation, as well as inflammation, which are related to interruption of the normal function of sympathetic preganglionic neurons. These neurons synapse (not shown) in paravertebral ganglia and through postganglionic catecholaminergic fibers innervate the heart, lungs, blood vessels, glands, and other tissues. Other preganglionic neurons, that is, specifically those residing at the thoracic level T5–T12, forming the greater splanchnic nerve and the lesser splanchnic nerve, pass through the paravertebral ganglia and make synaptic contacts with postganglionic fibers in prevertebral ganglia, including the celiac-superior mesenteric ganglion complex. These postganglionic fibers innervate the spleen (via the splenic nerve), and (not shown) the liver, kidney, pancreas, and parts of the gastrointestinal tract and control immune and metabolic processes. Chronic SCI is also associated with obesity and development of metabolic syndrome. The efferent vagus nerve originating in the brainstem dorsal motor nucleus of the vagus (DMN) and nucleus ambiguus (NA) innervates the heart, lungs, and many other visceral organs and plays a critical role in the regulation of cardiometabolic homeostasis. The efferent vagus nerve also innervates the celiac-superior mesenteric ganglion complex and interacts with the splenic nerve. This interaction is key for the vagus nerve regulation of immune function and inflammation within the inflammatory reflex. Bioelectronic vagus nerve stimulation of the cervical vagus nerve has been shown to suppress pro-inflammatory cytokine levels and alleviate aberrant inflammation and to have overall beneficial effects in many chronic conditions in preclinical settings and lately in people with chronic inflammatory disorders. The cholinergic drug galantamine also suppresses inflammation acting through a brain-mediated activation of the efferent vagus nerve-based arm of the inflammatory reflex. Galantamine alleviates inflammatory and metabolic derangements and improves the sympatho/vagal balance in people with metabolic syndrome. These anatomical and functional considerations and experimental evidence for beneficial effects of vagus nerve stimulation and galantamine in SCI indicate new possibilities for utilizing these two approaches in future studies for improving functional outcomes of chronic spinal cord injury patients. See the main text for details. SCI, spinal cord injury.

A causal relationship has been described and proposed between SCI level-dependent changes in autonomic and immune system dysfunction [3,24,27,28,38–40]. People with SCI rostral to thoracic level 6 (T6), where sympathetic nervous system (SNS) fibers exit the spinal cord and (after synapsing with postganglionic fibers) innervate many organs (Fig. 1), have the greatest inflammation and infection susceptibility acutely after SCI [3,24,27,28,41]. This is important in light of the fact that the most common level of injury is cervical and the most common neurological status is incomplete tetraplegia [1]. Deconditioning, because of reduced physical activity with long-term paralysis also promotes autonomic downregulation, which may further promote inflammation [42]. Immune cells are regulated by noradrenaline, and changes in catecholamines may modulate inflammation directly and indirectly [17,43–45]. Autonomic injury severity in people with chronic SCI has been characterized using supine plasma noradrenaline levels to indicate ‘autonomic completeness’ [34,46]. More recently, the International Standards to Document Remaining Autonomic Function after SCI (ISAFSCI) has been developed to aid in the clinical description of ANS dysfunction in people with SCI [5,47]. In a recent study, TLR-signaling genes were most elevated in persons with chronic SCI rostral to T6 [26]. In that study, there were also distinct differences in gene expression by injury severity.

Preclinical data supports the concept that systemic inflammation negatively impacts functional recovery and systemic anti-inflammatory interventions promote functional improvements. For example, minocycline is neuroprotective in acute SCI and improved locomotor function in mice after SCI [48,49]. Inhibition of regulatory T-cell function with anti-CD25 antibodies promoted locomotor recovery in mice after chronic SCI [49]. In a rat model of chronic SCI, systemic administration of lipopolysaccharide (LPS) triggered intraspinal inflammation [50]. In that study, animals that received LPS together with high-intensity rehabilitation training had better neurological recovery, suggesting to the authors that ‘mild neuroinflammation’ that resolves may enhance rehabilitation after SCI. In contrast, LPS alone was administered alone or in combination with low-intensity rehabilitation training, animals had worse recovery. In a recent double-blind placebo-controlled clinical trial of acute intermittent hypoxia (AIH), a new strategy to induce neuroplasticity in individuals with chronic SCI, pretreatment with the anti-inflammatory steroid prednisolone increased serum levels of IL-10 and enhanced plasticity induced by AIH, indicated by increased ankle strength [12]. There is also growing literature indicating that inflammation promotes neuropathic pain [51,52], which is widely experienced in chronic SCI and often unresolved by pharmacological treatments [53,54].

Of note, newly injured individuals with SCI are at increased risk for developing rapid obesity concurrent with muscle atrophy, osteoporosis, and other medical consequences that promote metabolic syndrome (Fig. 1) [6,55–58]. Hepatic dysfunction and inflammation has been also documented in SCI acutely and chronically, and linked to dysfunctional ANS regulation [59–61]. Individuals with SCI gain an average of 10 kg in total fat mass, including abdominal fat, within the first 2 years after injury and lose 3.2% of lean body tissue per decade [56]. The prevalence of obesity is estimated to be 40–60% in the SCI population [62–65]. Fat tissue itself is a potent source of inflammation, and weight loss reduces inflammation [66]. Thus, fat reduction in individuals SCI is considered an important strategy to reduce inflammation [65,67]. However, interventions that reduce body fat and inflammation, remain challenging in individuals with SCI.

NEURAL CONTROL OF INFLAMMATION

The sympathetic and parasympathetic parts of the ANS and the brain are critically involved in the regulation of immunity and inflammation [44]. As previously reviewed, the sympathetic part of the ANS regulates immune responses through the release of norepinephrine from postganglionic sympathetic nerve fibers innervating many organs, and via epinephrine secreted in the adrenal medulla and acting as a hormone [4,27,29,45]. The vagus nerve – the main nerve of the parasympathetic part of the ANS is also importantly implicated in the regulation of inflammation as recently reviewed [17] and described in more detail below.

The inflammatory reflex and its therapeutic exploration

Insights during the last 20 years have highlighted the role of the vagus nerve and the brain in the regulation of immunity and inflammation [14,15]. The vagus nerve constitutes afferent (about 80%) and efferent fibers. The efferent vagus nerve originates in two brainstem nuclei – the dorsal motor nucleus of the vagus (DMN) and nucleus ambiguus, innervates major peripheral organs, and controls vital physiological functions, including heart rate, breathing, gastrointestinal and pancreatic secretion, and hepatic metabolism through the release of acetylcholine (Fig. 1). The inflammatory reflex is a brain-integrated physiological mechanism based on afferent and efferent vagus nerve circuitry that detects and controls peripheral inflammatory alterations, for example, pro-inflammatory cytokines [15]. This control is mediated through the release of acetylcholine, which interacts with the alpha7 nicotinic acetylcholine receptor (α7nAChR) on macrophages and other immune cells. Consequent suppression of NF-κB nuclear translocation and other intracellular mechanisms ultimately leads to inhibition of tumor necrosis factor (TNF) and other pro-inflammatory cytokine production [43]. Acetylcholine is released from efferent vagus nerve cholinergic axonal endings in organs innervated by the vagus nerve, such as the liver, gastrointestinal tract, and pancreas. The efferent vagus nerve also interacts with the splenic nerve in the celiac-superior mesenteric ganglion complex, and this interaction facilitates the suppression of pro-inflammatory cytokines in the spleen within the inflammatory reflex [15,68] (Fig. 1). In the spleen, norepinephrine released from catecholaminergic splenic nerve endings binds to beta adrenergic receptors expressed on a subset of T cells, which contain the enzyme choline acetyltransferase (ChAT) that synthesizes acetylcholine [69]. This interaction triggers the release of acetylcholine that suppresses TNF and other pro-inflammatory cytokine production as demonstrated in endotoxemia, colitis, and other inflammatory conditions [45,69,70].

VNS applied to the cervical portion of the nerve has been instrumental in studying the inflammatory reflex and delineating physiological and cellular mechanisms of neuroimmune communication [14] (Fig. 1). The anti-inflammatory and disease-alleviating efficacy of VNS has been demonstrated in many animal models, including endotoxemia, sepsis, arthritis, inflammatory bowel disease (colitis). In addition to VNS, pharmacological cholinergic modalities including α7nAChR agonists and acetylcholinesterase inhibitors have been shown to suppress aberrant inflammation and alleviate disease severity in preclinical models of numerous diseases [23,71]. One of these compounds is galantamine – a centrally acting acetylcholinesterase inhibitor that is clinically approved for the symptomatic treatment of cognitive impairment in Alzheimer’s disease [71]. Galantamine has a significant anti-inflammatory efficacy that has been demonstrated in many animal models of diseases characterized by immune and metabolic dysregulation as recently reviewed in detail [23] (Fig. 1). Chronic inflammation as a result of immune and metabolic dysregulation plays a central role in promoting insulin resistance, and other metabolic derangements in obesity, metabolic syndrome, and type 2 diabetes [71]. Galantamine has been shown to alleviate the chronic inflammatory state, abdominal fat accumulation, insulin resistance, hepatic steatosis, and other metabolic abnormalities in mice with high-fat diet-induced obesity and features of metabolic syndrome [72]. These preclinical insights and the fact that galantamine is a clinically approved drug provided a rationale and facilitated performing recent clinical studies with galantamine in individuals with metabolic syndrome as described in detail below [72,73]. VNS has been also actively explored in treating obesity and obesity-associated inflammation and metabolic manifestations as previously summarized [17,43]. Both VNS and pharmacological cholinergic modalities have been currently explored in the treatment of COVID-19, and these approaches may be of specific interest for obese individuals with this viral disease [71].

Current clinical exploration of vagus nerve stimulation and galantamine in chronic inflammatory diseases

Abundant preclinical evidence with VNS has provided a rationale for performing clinical trials employing bioelectronic VNS in patients with rheumatoid arthritis, inflammatory bowel disease, and other disorders [19,20] within the growing field of Bioelectronic Medicine [19,20,74]. In a study with rheumatoid arthritis patients who had previously failed treatments with anti-TNF antibody and other biological treatments, implanted device VNS carried out one to four times daily significantly improved the disease scores that were correlated with suppressed TNF production [19]. These findings were recently complemented in a 12-week implanted miniaturized device VNS study with rheumatoid arthritis patients, which also included a sham-stimulated group [75]. The efficacy of bioelectronic VNS for 6 months is also demonstrated in a study with patients with Crohn’s disease [20]. Patients subjected to VNS with documented remission at 6 months remain in remission at 12-month follow-up and their vagal tone (assessed by heart rate variability analysis) is increased [76]. In addition, implanted device-generated VNS has been used in rehabilitation of patients postischemic stroke [77,78]. Recently, in a pivotal, sham-controlled trial, patients were implanted with VNS devices and subjected to standard rehabilitation paired with either VNS or with sham stimulation three times per week for 6 weeks at in-clinic settings followed by a home exercise program. Patients in the group with added VNS had significantly better clinical responses compared with the control group that was retained even 90 days after the in-clinic therapy [77]. In addition to implanted bioelectronic device VNS, noninvasive approaches have been utilized. One of these approaches is transcutaneous auricular VNS in which the stimulation is applied on an area of the ear that is innervated by the auricular sensory branch of the vagus nerve. Another noninvasive method is using a device on the neck that delivers electrical current to the cervical vagus nerve. These two approaches have been successfully explored in treating patients with rheumatoid arthritis, lupus, and several other chronic inflammatory and autoimmune disorders [79–83]. Noninvasive electrical transcutaneous stimulation has also been approved by the Food and Drug Administration (FDA) for the adjunct treatment of symptoms of acute opioid withdrawal [83]. These studies demonstrate the utility of bioelectronic VNS as a new, efficient, relatively nonexpensive, and well tolerated therapeutic alternative.

In addition to VNS, the FDA-approved drug galantamine has been clinically explored – in treating people with metabolic syndrome [72,73]. The metabolic syndrome is a constellation of conditions, including obesity, hypertension, dyslipidemia, and hyperglycosemia, that is associated with significantly higher risks for cardiovascular disease, type 2 diabetes, cancer, and other debilitating and lethal diseases [71]. The metabolic syndrome has reached pandemic proportions, and many people are unsuccessful in controlling it with behavioral interventions, such as weight loss and exercise. Chronic inflammation is a major underlying pathological event that drives further pathogenesis in patients with metabolic syndrome [71]. Performing a clinical trial with galantamine in people with metabolic syndrome supported by findings from animal studies and the fact that this centrally acting acetylcholinesterase inhibitor is a clinically approved drug for Alzheimer’s disease [23,84]. In a randomized, double-blind, placebo-controlled trial treatments of patients with the metabolic syndrome with relatively low galantamine doses (8 mg, escalated to 16 mg daily) for 12 weeks significantly suppressed plasma TNF and leptin levels, increased plasma adiponectin levels, and ameliorates oxidative stress [72,73]. These beneficial effects are associated with a decrease in insulin levels and alleviated insulin resistance [72,73]. In addition, analysis of heart rate variability reveals that galantamine treatment modulates the autonomic regulation and sympathovagal balance towards lower sympathetic and higher vagal activity [72,73] (Fig. 1). The well established safety profile of galantamine that stretches back for decades and abundant rationale from preclinical investigations drive active clinical exploration of galantamine in many other disorders characterized by inflammatory, metabolic, and cognitive derangements, including Parkinson disease, schizophrenia, and autism spectrum disorder [23].

TOWARDS CLINICAL TRIALS WITH BIOELECTRONIC VAGUS NERVE STIMULATION AND PHARMACOLOGICAL CHOLINERGIC MODALITIES IN CHRONIC SPINAL CORD INJURY

Preclinical studies have generated experimental evidence for efficacy of VNS and galantamine in SCI [85–87]. VNS in a closed-loop configuration combined with rehabilitative training considerably improve recovery of forelimb motor function compared with rehabilitation alone in models of contusive SCI at spinal level C5/6 [86]. Utilizing bioelectronic technological advances, the real-time closed-loop VNS paradigm in this study was designed to generate VNS immediately after the most successful forelimb movements as a result of motor rehabilitation [86]. The proposed mechanism of VNS is through strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb [86]. VNS delivered through cuff electrodes implanted 7 weeks after bilateral C7/8 SCI (that damages distal motor neuron pools) in combination with rehabilitative training results in better recovery of forelimb function compared with rehabilitative training alone [86]. A recent preclinical study investigated the safety of acute VNS on cardiovascular parameters in a rat model of complete transection at the level of T3, 1 month after SCI [88]. A dose response of continuous VNS showed decreases in sensitivity for heart rate and blood pressure in SCI compared with control (uninjured animals). Intermittent VNS stimulation showed heart rate reduction in rat SCI and no change in blood pressure. Importantly, VNS did not trigger or exacerbate autonomic dysreflexia and the effects lasted only while VNS was present. In a rat model of cervical contusion SCI, compared with rehabilitation alone, rehabilitation along with VNS promoted functional recovery of forelimb strength [87]. Of note, treatment with galantamine results in improved functional recovery and decreased lesion sizes in rats subjected to SCI [85].

These observations support the possibility of performing clinical trials utilizing VNS in combination with rehabilitation approaches for functional recovery of patients with incomplete cervical SCI. In addition, considering the anti-inflammatory and beneficial metabolic efficacy of VNS [43,71] and cholinergic drugs, for example, galantamine [23,72,73], these two approaches can be evaluated in future clinical trials for alleviating the interrelated inflammatory and cardiovascular and metabolic burdens in patients with chronic SCI (Fig. 1).

In planning potential clinical application of VNS or other modalities to influence the inflammatory reflex, there may be special considerations in the SCI population, who have been demonstrated to have altered vagal tone. The high frequency component of heart rate variability (HRV), indicating cardiac vagal control, correlated with other outcomes of autonomic regulation in people with SCI, such as supine and upright heart rates, blood pressures, and plasma catecholamine levels [46]. Cardiac autonomic control in people with SCI has been investigated during orthostatic provocation, where the expected increase in heart rate was diminished in those with tetraplegia [22]. Individuals with chronic SCI did not have a vagal activation in response to the cold face test, which could be because of reduced physical activity and/or from the injury itself [21]. Another subset of people with SCI, that is, those with obesity and metabolic syndrome, may also specifically benefit from therapeutic strategies utilizing VNS or galantamine.

Of course, in addition to efficacy, the safety of bioelectronic VNS and the use of galantamine should be considered and evaluated specifically in people with chronic SCI. As reviewed here, bioelectronic VNS is an emerging therapy for chronic inflammatory disorders and the safety and efficacy of this approach were recently evaluated in patients with multidrug-refractory rheumatoid arthritis [75]. Surgery-related adverse symptoms were Horner’s syndrome (in one patient) and vocal cord paralysis (in another patient) that were resolved without clinically significant sequelae. No device-related or treatment-related serious adverse events were found. As the authors summarized ‘VNS with a miniaturised neurostimulator was safe and well tolerated and reduced signs and symptoms of rheumatoid arthritis in patients with multidrug-refractory disease’. In another recent study with noninvasive VNS in 30 patients with rheumatoid arthritis, four adverse effects, including a superficial skin abrasion at the point of contact where the device touched the ear and other three (most likely not related to the device) were observed [74]. Of note, no patient dropped out of the study because of adverse effects. In both studies, the need for further evaluation in larger randomized sham-controlled studies was emphasized. The abundant information available from prior studies of galantamine in the context of Alzheimer’s disease indicates that relatively high drug doses – 24 and 32 mg/day may cause gastrointestinal disturbances, such as nausea and other adverse effects [89]. However, these adverse effects can be considerably reduced using a lower galantamine dose or slowly escalating the drug dose to achieve a favorable tolerability profile [90]. Of note, no significant adverse effects were observed in the study of galantamine in patients with MetS in which the initial drug dose (8 mg/day) for 4 weeks was subsequently increased to 16 mg/day for the remaining period of the study [72]. In addition, in a randomized, double-blind, placebo-controlled study with galantamine (up to 24 mg/day) for 10 weeks in children with autism, no significant difference in the frequency of adverse effects between the galantamine and the placebo arms was observed [91].

CONCLUSION

Persistent systemic inflammation is present in individuals with chronic SCI, where it accompanies autonomic dysfunction. It is increasingly appreciated that in addition to the correlation between inflammation and metabolic syndrome, which is common in individuals with SCI, inflammation may also dampen neuroplasticity and functional recovery. In many other clinical areas, including neurological disorders/conditions, such as stroke, therapeutic exploration of the vagus nerve-mediated inflammatory reflex is being successfully applied; VNS appears to increase neuroplasticity (albeit the underlying mechanisms remain to be elucidated) and to suppress chronic inflammation. Interest is growing in understanding the multimodal effects of VNS and cholinergic drugs, such as galantamine in the context of SCI, where they may suppress inflammation, alleviate cardiometabolic derangements, increase neuroplasticity, and have an overall beneficial health impact.

KEY POINTS.

• Aberrant inflammation is a major but modifiable health issue in chronic SCI.

• The vagus nerve-based inflammatory reflex can be modulated to reduce inflammation in preclinical settings and in patients with chronic diseases.

• There is autonomic nervous system (ANS) dysfunction linked to inflammatory and cardiometabolic dysregulation in chronic SCI.

• Electrical vagus nerve stimulation (VNS) or pharmacological modalities, such as galantamine can be explored to activate the inflammatory reflex for therapeutic benefit in chronic SCI.