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      The Evolution of Neuromodulation in the Treatment of Chronic Pain: Forward-Looking Perspectives

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          Abstract

          Background

          The field of neuromodulation is continually evolving, with the past decade showing significant advancement in the therapeutic efficacy of neuromodulation procedures. The continued evolution of neuromodulation technology brings with it the promise of addressing the needs of both patients and physicians, as current technology improves and clinical applications expand.

          Design

          This review highlights the current state of the art of neuromodulation for treating chronic pain, describes key areas of development including stimulation patterns and neural targets, expanding indications and applications, feedback-controlled systems, noninvasive approaches, and biomarkers for neuromodulation and technology miniaturization.

          Results and Conclusions

          The field of neuromodulation is undergoing a renaissance of technology development with potential for profoundly improving the care of chronic pain patients. New and emerging targets like the dorsal root ganglion, as well as high-frequency and patterned stimulation methodologies such as burst stimulation, are paving the way for better clinical outcomes. As we look forward to the future, neural sensing, novel target-specific stimulation patterns, and approaches combining neuromodulation therapies are likely to significantly impact how neuromodulation is used. Moreover, select biomarkers may influence and guide the use of neuromodulation and help objectively demonstrate efficacy and outcomes.

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          Most cited references135

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          Novel 10-kHz High-frequency Therapy (HF10 Therapy) Is Superior to Traditional Low-frequency Spinal Cord Stimulation for the Treatment of Chronic Back and Leg Pain: The SENZA-RCT Randomized Controlled Trial.

          Current treatments for chronic pain have limited effectiveness and commonly known side effects. Given the prevalence and burden of intractable pain, additional therapeutic approaches are desired. Spinal cord stimulation (SCS) delivered at 10 kHz (as in HF10 therapy) may provide pain relief without the paresthesias typical of traditional low-frequency SCS. The objective of this randomized, parallel-arm, noninferiority study was to compare long-term safety and efficacy of SCS therapies in patients with back and leg pain.
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            Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.

            The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit alpha7, a mechanism termed "the cholinergic antiinflammatory pathway." Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of alpha7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiac-superior mesenteric plexus, and projecting in the splenic nerve.
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              Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.

              To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm(3)) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (<1 °C). We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.
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                Author and article information

                Journal
                Pain Med
                Pain Med
                painmedicine
                Pain Medicine: The Official Journal of the American Academy of Pain Medicine
                Oxford University Press
                1526-2375
                1526-4637
                June 2019
                01 June 2019
                01 June 2019
                : 20
                : Suppl 1 , Neuromodulation of the Spine and Nervous System
                : S58-S68
                Affiliations
                [1 ]Center for Interventional Pain and Spine, Exton, Pennsylvania
                [2 ]University of Florida, Gainesville, Florida
                [3 ]Florida Pain Institute, Melbourne, Florida
                [4 ]The Spine and Nerve Center of the Virginias, Charleston, West Virginia
                [5 ]Institute for Neuromodulation, Boca Raton, Florida, USA
                Author notes
                Correspondence to: Michael Fishman, MD, Center for Interventional Pain and Spine Exton, 100 Arrandale Blvd, Suite 108, Exton, PA 19341, USA. Tel: 610-280-0360; Fax: 610-280-0181; E-mail: mafishman@ 123456gmail.com .
                Article
                pnz074
                10.1093/pm/pnz074
                6600066
                31152176
                efabe7bc-b0ee-4c54-8b3a-2c070a0a5198
                © 2019 American Academy of Pain Medicine.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Pages: 17
                Funding
                Funded by: Abbott 10.13039/100001316
                Categories
                Review Articles

                Anesthesiology & Pain management
                technology,stimulation patterns,closed-loop,miniaturization,noninvasive,optogenetics

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