Harnessing the Inflammatory Reflex for the Treatment of Inflammation-Mediated Diseases.

Treating diseases nonpharmacologically, using targeted neurostimulation instead of systemic drugs, is a hallmark of the burgeoning field of bioelectronic medicine. In this review, we provide a brief overview of the discovery and function of the prototypical neuroimmune reflex, the "inflammatory reflex." We discuss various biomarkers developed and used to translate early physiological discoveries into dosing parameters used in experimental settings, from the treatment of animal models of disease through a proof-of-concept clinical study in rheumatoid arthritis (RA). Finally, we relate how unique aspects of this form of therapy enabled the design of a next-generation implanted pulse generator using integrated electrodes, currently under evaluation in a U.S.-based clinical study for patients with drug refractory RA.

Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase+ T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h in vitro attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.

Neurophysiologic and Chronic Safety Testing of a Miniaturized Active Implanted Device with Integrated Electrodes for Bioelectronic Medicine Applications.

New dosing paradigms in bioelectronic medicine applications, such as low duty cycle stimulation of the vagus nerve to treat inflammatory disorders, enable architectural shifts in active implantable devices that benefit patients. Herein, we describe various features of the MicroRegulator (MR), an innovative neurostimulation system that includes a unique electrode-integrated implantable nerve stimulator. To verify efficient activation of neuronal targets within the vagus nerve, a geometric emulator of the MR (identical form and electrical contact properties as the clinical MR device) was tested in situ and neurophysiologic outcomes were compared to a control electrode in wide clinical use. The data demonstrated comparable patterns of compound potentials evoked from the MR emulator and the control electrode, with the MR emulator requiring a lower threshold current to depolarize the nerve. To verify chronic mechanical safety, the MR emulator was implanted for 2 months on the vagus nerves of canines. Blood flow through the major cervical vessels was unaffected, and pathologic and histologic findings included normal foreign body encapsulation and an absence of demyelination and nerve damage. Together these finding support the feasibility of the MR system for clinical translation.

Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.

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-1ß, 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.

Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

INTRODUCTION: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model. METHODS: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed. RESULTS: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01). CONCLUSIONS: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.

A low-power asynchronous interleaved sampling algorithm for cochlear implants that encodes envelope and phase information.

Cochlear implants currently fail to convey phase information, which is important for perceiving music, tonal languages, and for hearing in noisy environments. We propose a bio-inspired asynchronous interleaved sampling (AIS) algorithm that encodes both envelope and phase information, in a manner that may be suitable for delivery to cochlear implant users. Like standard continuous interleaved sampling (CIS) strategies, AIS naturally meets the interleaved-firing requirement, which is to stimulate only one electrode at a time, minimizing electrode interactions. The majority of interspike intervals are distributed over 1-4 ms, thus staying within the absolute refractory limit of neurons, and form a more natural, pseudostochastic pattern of firing due to complex channel interactions. Stronger channels are selected to fire more often but the strategy ensures that weaker channels are selected to fire in proportion to their signal strength as well. The resulting stimulation rates are considerably lower than those of most modern implants, saving power yet delivering higher potential performance. Correlations with original sounds were found to be significantly higher in AIS reconstructions than in signal reconstructions using only envelope information. Two perceptual tests on normal-hearing listeners verified that the reconstructed signals enabled better melody and speech recognition in noise than those processed using tone-excited envelope-vocoder simulations of cochlear implant processing. Thus, our strategy could potentially save power and improve hearing performance in cochlear implant users.