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Concept: Vagus nerve

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Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Concepts: Inflammation, Cytokine, Interleukin 1, Rheumatoid arthritis, Vagus nerve, Autoimmune disease, Vagus nerve stimulation, Tumor necrosis factor-alpha

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Recent animal studies demonstrate that vagus nerve stimulation (VNS) paired with movement induces movement-specific plasticity in motor cortex and improves forelimb function after stroke. We conducted a randomized controlled clinical pilot study of VNS paired with rehabilitation on upper-limb function after ischemic stroke.

Concepts: Stroke, Traumatic brain injury, Vagus nerve, Cranial nerves, Vagus nerve stimulation, Vagus

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Objective. Hypertension is the largest threat to patient health and a burden to health care systems. Despite various options, 30% of patients do not respond sufficiently to medical treatment. Mechanoreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selective electrical stimulation of these nerve fibers reduced BP in rats. However, there is no technique described to localize and stimulate these fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. Approach. We present a novel method for selective VN stimulation to reduce BP without the aforementioned side effects. Baroreceptor compound activity of rat VN (n = 5) was localized using a multichannel cuff electrode, true tripolar recording and a coherent averaging algorithm triggered by BP or electrocardiogram. Main results. Tripolar stimulation over electrodes near the barofibers reduced the BP without triggering significant bradycardia and bradypnea. The BP drop was adjusted to 60% of the initial value by varying the stimulation pulse width and duration, and lasted up to five times longer than the stimulation. Significance. The presented method is robust to impedance changes, independent of the electrode’s relative position, does not compromise the nerve and can run on implantable, ultra-low power signal processors.

Concepts: Medicine, Electrochemistry, Vagus nerve, Carotid sinus, Vagus nerve stimulation, Electrochemical cell, Hypotension, Baroreflex

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The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy.

Concepts: Medicine, Cardiology, Heart failure, Ejection fraction, Randomized controlled trial, Muscle, Vagus nerve, Vagus nerve stimulation

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Pain is a complex common health problem, with important implications for quality of life and with huge economic consequences. Pain can be elicited due to tissue damage, as well as other multiple factors such as inflammation and oxidative stress. Can there be one therapeutic pathway which may target multiple etiologic factors in pain? In the present article, we review evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to or protective in pain. Specifically, vagal nerve activity inhibits inflammation, oxidative stress and sympathetic activity, activates brain regions that can oppose the brain “pain matrix”, and finally it might influence the analgesic effects of opioids. Together, these can explain the anti-nociceptive effects of vagal nerve activation or of acetylcholine, the principal vagal nerve neurotransmitter. These findings form an evidence-based neurobiological rationale for testing and possibly implementing different vagal nerve activating treatments in pain conditions. Perspective: In this article, we show evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and five factors which are etiologic to pain. Given the evidence and effects of the vagus nerve activation in pain, people involved in pain therapy may need to seriously consider activation of this nerve.

Concepts: Medicine, Neuroanatomy, Opioid, Pain, Vagus nerve, Cranial nerves, Acetylcholine, Vagus nerve stimulation

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Within a biopsychosocial model of pain, pain is seen as a conscious experience modulated by mental, emotional and sensory mechanisms. Recently, using a rodent visceral pain assay that combines the colorectal distension (CRD) model with the conditioned place avoidance (CPA) paradigms, we measured a learned behavior that directly reflects the affective component of visceral pain, and showed that perigenual anterior cingulate cortex (pACC) activation is critical for memory processing involved in long-term visceral affective state and prediction of aversive stimuli by contextual cue. Electrical vagus nerve stimulation (VNS) has become an established therapy for treatment-resistant epilepsy. VNS has also been shown to enhance memory performance in rats and humans. High-intensity VNS (400 μA) immediately following conditional training significantly increases the CRD-induced CPA scores, and enhanced the pain affective memory retention. In contrast, VNS (400 μA) had no effect on CPA induced by non-nociceptive aversive stimulus (U69,593). Low-intensity VNS (40 μA) had no effect on CRD-induced CPA. Electrophysiological recording showed that VNS (400 μA) had no effect on basal and CRD-induced ACC neuronal firing. Further, VNS did not alter CRD-induced visceral pain responses suggesting high intensity VNS facilitates visceral pain aversive memory independent of sensory discriminative aspects of visceral pain processing. The findings that vagus nerve stimulation facilities visceral pain-related affective memory underscore the importance of memory in visceral pain perception, and support the theory that postprandial factors may act on vagal afferents to modulate ongoing nature of visceral pain-induced affective disorder observed in the clinic, such as irritable bowel syndrome.

Concepts: Psychology, Pain, Vagus nerve, Irritable bowel syndrome, Vagus nerve stimulation, Brodmann area 24, Anterior cingulate cortex, Cingulate cortex

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Abstract Conclusions: This pilot study shows that transcutaneous vagus nerve stimulation (tVNS), if combined with sound therapy (ST), reduces the severity of tinnitus and tinnitus-associated distress. Our magnetoencephalography (MEG) results show that auditory cortical activation can be modulated by the application of tVNS. Thus, tVNS might offer a new avenue to treat tinnitus and tinnitus-associated distress. Objectives: Recent studies suggest that tinnitus can be improved by tailored ST or by VNS plus ST. Our aims were to study whether tVNS has therapeutic effects on patients with tinnitus and, additionally, if tVNS has effects on acoustically evoked neuronal activity of the auditory cortex. Methods: The clinical efficacy was studied by a short-term tVNS plus ST trial in 10 patients with tinnitus using disease-specific and general well-being questionnaires. tVNS was delivered to the left tragus. The acute effects of tVNS were evaluated in eight patients in the MEG study in which the N1m response was analyzed in terms of source level amplitude and latency in the presence or absence of tVNS. Results: The treatment with tVNS plus ST produced improved mood and decreased tinnitus handicap scores, indicating reduced tinnitus severity. The application of tVNS decreased the amplitude of auditory N1m responses in both hemispheres.

Concepts: Effectiveness, Therapy, Cerebral cortex, Auditory system, Vagus nerve, Cranial nerves, Vagus nerve stimulation, Cultural studies

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BACKGROUND: Vagus nerve stimulation is capable of regulating autonomic nerve function. In Traditional Chinese Medicine, the effect of auricular acupuncture (AA) is mediated by the vagus. This study was designed to investigate the effect of AA on gastrointestinal (GI) motility and the relationship of this effect with the vagus nerve. METHODS: 50 rats were divided into five groups for observation of the effects of different types of acupuncture and influencing factors: control, AA, somatic acupuncture (SA), atropine and atropine+AA. The acupuncture points used for AA were ST (Stomach) and SI (Small intestine), while the acupuncture point used for SA was ST36. Electroacupuncture was performed for 15 min. A model of reduced GI motility was established using ethanol, and GI transit rate was used to measure GI motility. Heart rate variability (HRV) and the effect of atropine administration were investigated to study the relationship between AA and vagal activity. RESULTS: The GI transit rate increased in both the AA and SA groups compared with control, and no significant difference was found between their effects. In addition, after atropine administration, AA was found to be ineffective in influencing the GI transit rate. In the HRV analysis, no significant differences were found in the absolute low frequency normalised units, high frequency normalised units or the low frequency/high frequency component ratio in the AA or SA groups compared with control. After administration of atropine AA still had no effect on HRV. CONCLUSIONS: The function of AA in improving GI motility is similar to that of SA, and this effect can be blocked by the presence of atropine, indicating that this effect is regulated by the vagus. However, HRV did not reflect the acupuncture-induced changes in vagal nerve function.

Concepts: Statistical significance, Vagus nerve, Acupuncture, Vagus nerve stimulation, Alternative medicine, Atropine, Moxibustion, Meridian

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BACKGROUND: The vagus nerve is important in maintaining HPA axis and sympatho-adrenal system (SAS) homeostasis, however little is known about the effect of vagus nerve stimulation (VNS), as used therapeutically, on these functions. Accordingly, the effect of VNS on plasma indices of HPA axis (ACTH, corticosterone), and SAS (norepinephrine, epinephrine) function were evaluated in rats. METHODS: Male rats, on day-0 (D0), underwent surgeries for implantation of catheters into the right jugular vein and programmable (VNP) or non-programmable (VND) neurocybernetic devices encircling the left cervical vagus. On D7, after a blood sample, the device in VNP rats was programmed to deliver 500μs width, 0.25mA current pulses at 20Hz (‘on’ 30s, ‘off’ 5min) followed by timed blood samples during the next 90min. In acute studies, VNS was stopped at 60min and the rats were perfused at 90min to evaluate neuronal Fos immunoreactivity (Fos-IR). In chronic studies, the probe remained active. In these rats, the HPA axis response to airpuff-startle stressor (D17) and anterior pituitary CRF-receptor binding (D26) were evaluated. RESULTS: During acute VNS, plasma indices of HPA axis and SAS activity, as well as Fos-IR activation pattern in brain regions known to increase after stress, were not different between VND and VNP rats. During chronic VNS, stress-induced HPA axis responses exhibited a tendency toward faster recovery to baseline in VNP rats. CONCLUSIONS: Therapeutic VNS is not a stressor and does not compromise HPA axis or SAS homeostasis. Chronic VNS may facilitate development of efficient feedback mechanisms.

Concepts: Hypothalamus, Vagus nerve, Cranial nerves, Acetylcholine, Computer program, Internal jugular vein, Vagus nerve stimulation, Program

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Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via α7-nicotinic acetylcholine receptors (α7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or α7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the α7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity.

Concepts: Gene, Insulin, Hormone, Vagus nerve, Acetylcholine, Muscarinic acetylcholine receptor, Nicotinic acetylcholine receptor, Atropine