Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation

The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation

Investigational Treatment of Rheumatoid Arthritis with a Vibrotactile Device Applied to the External Ear

Abstract Rheumatoid arthritis (RA) is a debilitating polyarthritis characterized by joint tissue inflammation. Here, we assessed the effect of applying a vibrotactile device to the external ear on inflammatory responses in healthy subjects, as well as its effect on disease activity in patients with RA. We enrolled 19 healthy subjects in a randomized cross-over study, delivered vibrotactile treatment at either the external ear or gastrocnemius, and performed ex vivo whole blood assays. Vibrotactile treatment at the external ear significantly reduced TNF, IL-1β, and IL-6 levels compared to pre-treatment baseline (TNF p&amp;lt;0.05, IL-1β p&amp;lt;0.005, IL-6 p&amp;lt;0.005), whereas treatment at the gastrocnemius did not attenuate inflammatory responses. Vibrotactile treatment at the external ear inhibited TNF by 80% (mean ± SD: pre-treatment = 4541 ± 2721 pg/ml vs. post-treatment = 3624 ± 2810 pg/ml), IL-6 by 73% (mean ± SD: pre-treatment = 5979 ± 2094 pg/ml vs post-treatment = 4342 ± 2600 pg/ml), and IL-1β by 50% (mean ± SD: pre-treatment = 1527 ± 1429 pg/ml vs post-treatment = 765 ± 968 pg/ml) as compared to pre-treatment baseline levels. 9 patients with RA were enrolled in a prospective interventional study. Vibrotactile treatment at the external ear significantly decreased DAS28-CRP scores two days post-treatment (DAS28-CRP score mean ± SD: pre-treatment = 3.4 ± 1.4 [1.27–5.67] vs. post-treatment = 2.7 ± 0.9 [1.24–4.37], p&amp;lt;0.005). DAS28-CRP scores remained significantly reduced 7 days post-treatment (DAS28-CRP score mean ± SD: 7 days post-treatment = 2.4 ± 0.7 [1.21–3.68]; p&amp;lt;0.005). These data demonstrate that application of a vibrotactile device to the external ear attenuates systemic inflammatory responses in both healthy subjects and patients with RA.</jats:p

Specific vagus nerve stimulation parameters alter serum cytokine levels in the absence of inflammation

Abstract Background Electrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Methods Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Results Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor (TNF), while other parameters selectively lowered serum TNF levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. Conclusions These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes. </jats:sec

Serum cytokine levels are modulated by specific frequencies, amplitudes, and pulse widths of vagus nerve stimulation

ABSTRACTElectrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), while other parameters selectively lowered serum TNFα levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.</jats:p

Brain-computer interaction for online enhancement of visuospatial attention performance

International audienceObjective. this study on real-time decoding of visuospatial attention has two objectives: first, to reliably decode self-directed shifts of attention from electroencephalography (EEG) data, and second, to analyze whether this information can be used to enhance visuospatial performance. Visuospatial performance was measured in a target orientation discrimination task, in terms of reaction time, and error rate. Approach. Our experiment extends the Posner paradigm by introducing a new type of ambiguous cues to indicate upcoming target location. The cues are designed so that their ambiguity is imperceptible to the user. This entails endogenous shifts of attention which are truly self-directed. Two protocols were implemented to exploit the decoding of attention shifts. The first ‘adaptive’ protocol uses the decoded locus to display the target. In the second ‘warning’ protocol, the target position is defined in advance, but a warning is flashed when the target mismatches the decoded locus. Main results. Both protocols were tested in an online experiment involving ten subjects. The reaction time improved in both the adaptive and the warning protocol. The error rate was improved in the adaptive protocol only. Significance.This proof of concept study brings evidence that visuospatial brain–computer interfaces (BCIs) can be used to enhance improving human–machine interaction in situations where humans must react to off-center events in the visual fiel

Transient Receptor Potential Ankyrin 1 Mediates Afferent Signals in the Inflammatory Reflex

ABSTRACTSurvival of an organism requires mechanisms to sense damaging factors in the environment. In mammals, bacterial toxins and inflammatory mediators stimulate nociceptive sensory neurons to activate protective reflexes. Whereas the vagus nerve reflex circuit that protects against damaging inflammation, termed the “inflammatory reflex,” was described more than twenty years ago1,2, how the vagus nerve detects inflammation to initiate the inflammatory reflex has remained unknown. Here we show that transient receptor potential ankyrin 1 (TRPA1) in sensory vagus neurons is required to sense interleukin-1β (IL-1β), a central cytokine mediator of inflammation and injury. Selective activation of vagus nerve TRPA1 using optopharmacology stimulated the inflammatory reflex to inhibit innate inflammatory responses to bacterial lipopolysaccharide and IL-1β. Proximity ligation assay and immunohistochemistry revealed that IL-1 receptors are co-expressed with TRPA1 in vagus sensory neurons. Whole-cell patch-clamp recordings reveal that TRPA1 is required to mediate IL-1β-dependent depolarization of vagus sensory neurons. Further, TRPA1-deficient mice lack inflammatory reflex attenuation of inflammation, fail to restrain cytokine release, and have significantly enhanced lethality to bacterial sepsis. Therefore, vagus neurons expressing TRPA1 are necessary and sufficient to activate the sensory arc of the inflammatory reflex to protect against harmful inflammation.</jats:p

Identification of a brainstem locus that inhibits tumor necrosis factor

Significance Electronic devices that stimulate electrical activity in the vagus nerve are being studied for clinical use in rheumatoid arthritis, inflammatory bowel disease, and other inflammatory syndromes because vagus nerve signals inhibit inflammation and cytokine production. A vagus nerve mechanism, termed the inflammatory reflex, has been widely studied, but the origin and functional neuroanatomy of vagus nerve fibers controlling inflammation were previously unknown. Here we reveal cholinergic neurons in the brainstem dorsal motor nucleus (DMN) of the vagus projecting to the celiac-superior mesenteric ganglia and transmitting cytokine-inhibiting signals to the splenic nerve. By combining optogenetics, anatomical and functional mapping, and measurement of TNF production, our data show the DMN is an important brainstem locus controlling anti-inflammatory signals in the inflammatory reflex.</jats:p