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Manuscript Submission Deadline 31 January 2024

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This Research Topic is part of the Bioelectronic Medicines – New Frontiers in Autonomic Neuromodulation series:


This Research Topic is part of the Bioelectronic Medicines – New Frontiers in Autonomic Neuromodulation series:

Bioelectronic Medicines – New Frontiers in Autonomic Neuromodulation, Volume I

Bioelectronic Medicines – New Frontiers in Autonomic Neuromodulation, Volume II

Bioelectronic medicine is an interdisciplinary area of research that seeks to develop brand-new therapeutic approaches to resolve disease via the modulation of signals in peripheral nerves. While other non-electrical methods have been used to modulate nerves experimentally, electrical stimulation of the nerves has been employed for deep brain, spinal cord, and cranial nerve stimulation in therapeutic settings.

Traditional neuromodulation devices such as deep brain or spinal cord stimulation have evolved from cardiac pacemaker devices and stimulate large swathes of tissues/cells in a non-specific fashion. As a result, they present tolerability issues. In many cases, their mechanism of action is largely unknown.

In contrast, the influence of autonomic nerves on organ system physiology has long been appreciated via molecular drugs, but the lack of understanding of the wiring (anatomy) and translational studies has prevented innovation until the last decade. Theoretically, these autonomic nerves are ideal targets for intervention, providing greater specificity if appropriate targeting is used and might cause lower adverse effects (compared to pharmacological or neuromodulatory device approaches). Due to the anatomic diversity of these nerves, targeting technologies, as a result, must be bespoke for the disease need and target the patient population.

The foray of public (DARPA's ElectRx, NIH SPARC) and private companies in this innovation area is evidencing the promise of autonomic nerves as viable targets for therapy to complement and in certain cases replace existing molecular treatments, as a new source of intervention for chronic diseases treatment. In early feasibility studies, vagus nerve stimulation (cervical and auricular) has been shown to be efficacious in rheumatoid arthritis, stroke rehabilitation, and heart failure. Hypoglossal nerve stimulation has been approved for the treatment of sleep apnea. While these are examples of cranial nerve stimulation for chronic disorders, new evidence suggests that peripheral autonomic nerve targets beyond the cranial nerves have great potential too. Baroreflex activation therapy has successfully completed its pivotal trial in heart failure patients who are not candidates for existing device therapy (cardiac resynchronization therapy). Apical splenic modulation (immune modulation) has been shown to have preclinical efficacy in reducing arthritic scores and joint inflammation. Recently, in-silico and ex vivo human tissue studies have provided refinement of stimulation parameters for splenic nerve, spinal cord, and vagus nerve stimulation. Neural blocking technologies have been successfully applied in preclinical models of diabetes and cardiac arrhythmogenesis and shown to increase insulin tolerance and refractoriness to arrhythmia induction, respectively. Finally, stimulation of the pancreatic nerve leads to sequestration of antigen-presenting cells in the lymph nodes and reduces beta-cell destruction and insulitis in type 1 diabetic rodent model. All these studies demonstrate immense potential to treat chronic disorders in the future.

The development of neuromodulatory products (bioelectronic medicines) requires detailed knowledge of nerve targets, including their functional and topological organization across translative species, and demonstration of target engagement using neurostimulatory dose. We are at the cusp of this burgeoning understanding of autonomic neural target impact on physiology and pathophysiology. Beyond this biological understanding, there is the need to better categorize selectivity to improve and design the technical requirements needed for a product.

This Research Topic seeks to advance in the understanding and development of specific bioelectronic autonomic neuromodulatory clinical approaches by collecting key studies performed in the field. We welcome original research studies, method descriptions, and review articles focusing on, but not limited to:

• Viscerotopy in nerves to aid selective modulation of nerve fibers

• New understanding of immune, metabolic, cardio-respiratory neuromodulatory targets

• Parameter optimization examples for neuromodulation therapies

• Proof of nerve fiber activation selectivity via nerve stimulation in vivo or in-silico modeling of novel parameters for selective modulation of autonomic nerves

• Understanding and updating new wiring circuitry for autonomic nerves (interoceptive circuitry)

• Investigative or mechanistic clinical studies for novel disease conditions for a given nerve target

"Topic Editor Arun Sridhar is the Director at Artha. The other Topic Editors declare no competing interests with regard to the Research Topic subject."

Keywords: Neuromodulation, Bioelectronic medicines, Autonomic neuroscience, Neuro-immunology, Nerve stimulation

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