Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study

Abstract

Objective: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. Methods: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/ month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. Results: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1b was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p < 0.05]. Concentrations of high-mobility group box-1 (HMGB-1), IL-6, tumor-necrosis factor-a (TNF-a), leptin, adiponectin, ghrelin remained unchanged [p > 0.05]. No severe device-/stimulation-related adverse events occurred. Conclusion: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/ month. Pro-inflammatory IL-1b plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro-[IL-6, HMGB-1, TNF-a, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics].

Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain

“…Contrary, decreased concentrations of adiponectin (AN), another member of the adipokine family and a neuropeptide solely synthetized by adipocytes, has been suspected of inducing metabolic disorders (e.g., type 2 diabetes, arterial hypertension, and coronary artery disease). Whether concentration changes in circulating AN relate to changes in body weight (body mass index; BMI) or only represent an epiphenomenon is still largely unknown [4,5,6,41,42,43]. AN affects the resistance of insulin receptors (anti-diabetic effect), lipid oxidation, vasodilatation, and anti-arteriosclerosis effects [34,41,42].…”

“…There is increasing evidence that migraine, a neurological disorder of the trigeminal-nociceptive system, is associated with the contribution of adipose tissue cellular components of systemic inflammation. Circulating mediators of inflammation involved in the mechanisms of migraine pathology are secreted from adipocytes and adipose tissue-derived immune cells [4]. It is widely recognized, white adipose tissue (WAT), an endocrine-active organ, not only functions as a site of energy storage but also has the capability to exacerbate or reduce systemic inflammation.…”

“…To date, there exist a few randomized-controlled and uncontrolled observational neurostimulation human studies, which have quantified peripheral circulating markers of inflammation related to metabolic homeostasis in chronic pain patients [4,5,6,7,75,76,77,78,79] (Table 1).…”

“…For instance, Il-1 β and leptin (pro-inflammatory) and oxytocin (anti-inflammatory) exert their effects through specific receptors located either at the terminal C-fibers (neuropathic pain) or the trigeminal ganglion (migraine). Pharmacological treatment with a variety of classes of drugs and behavioral therapy are first-line treatments for neuropathic pain [3,4,5,6,7,8], but many patients fail to experience clinically meaningful pain relief from these treatments alone. Drug resistance and loss of efficacy in chronic pain treatment are perhaps due to the involvement of multiple disturbed physiological and psychological interrelated pathways that contribute to the severity of chronic pain.…”

“…In addition to their role in the transition and maintenance of chronic pain, most of the described mediators have been associated with a broad range of chronic disorders (neurological, psychiatric, cardiovascular, and metabolic) due to their multifunctional characteristics, which in turn may explain the clinically observed co-occurrence of the so-called comorbidities [9,10,11,12]. Spinal and peripheral neurostimulation therapies have repeatedly shown meaningful pain relief in recent studies to treat various chronic pain disorders (failed back surgery, complex regional pain syndrome (CRPS), and migraine) targeting the spinal cord, the dorsal root ganglia (DRG), and peripheral nerves (vagus nerve stimulation; VNS) [3,4,5,6,7,8]. The strongest rationale for considering neurostimulation approaches to treat chronic pain is the growing understanding that all forms of pain are ultimately the result of an interplay of central and peripheral properties of the nervous system, which in turn allows neurostimulation therapies to interact with inflammatory pain signaling [13,14,15,16,17,18].…”