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      Deep Brain Stimulation Improves the Symptoms and Sensory Signs of Persistent Central Neuropathic Pain from Spinal Cord Injury: A Case Report

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          Abstract

          Central neuropathic pain (CNP) is a significant problem after spinal cord injury (SCI). Pharmacological and non-pharmacological approaches may reduce the severity, but relief is rarely substantial. While deep brain stimulation (DBS) has been used to treat various chronic pain types, the technique has rarely been used to attenuate CNP after SCI. Here we present the case of a 54-year-old female with incomplete paraplegia who had severe CNP in the lower limbs and buttock areas since her injury 30 years prior. She was treated with bilateral DBS of the midbrain periaqueductal gray (PAG). The effects of this stimulation on CNP characteristics, severity and pain-related sensory function were evaluated using the International SCI Pain Basic Data Set (ISCIPBDS), Neuropathic Pain Symptom Inventory (NPSI), Multidimensional Pain Inventory and Quantitative Sensory Testing before and periodically after initiation of DBS. After starting DBS treatment, weekly CNP severity ratings rapidly decreased from severe to minimal, paralleled by a substantial reduction in size of the painful area, reduced pain impact and reversal of pain-related neurological abnormalities, i.e., dynamic-mechanical and cold allodynia. She discontinued pain medication on study week 24. The improvement has been consistent. The present study expands on previous findings by providing in-depth assessments of symptoms and signs associated with CNP. The results of this study suggest that activation of endogenous pain inhibitory systems linked to the PAG can eliminate CNP in some people with SCI. More research is needed to better-select appropriate candidates for this type of therapy. We discuss the implications of these findings for understanding the brainstem’s control of chronic pain and for future progress in using analgesic DBS in the central gray.

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          Descending control of persistent pain: inhibitory or facilitatory?

          The periaqueductal gray matter (PAG) and the nucleus raphe magnus and adjacent structures of the rostral ventromedial medulla (RVM), with their projections to the spinal dorsal horn, constitute the "efferent channel" of a pain-control system that "descends" from the brain onto the spinal cord. Considerable evidence has recently emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. Herein, this evidence is reviewed and organized to support the idea that persistent nociception simultaneously triggers descending facilitation and inhibition. In models of inflammation, descending inhibition predominates over facilitation in pain circuits with input from the inflamed tissue, and thus attenuates primary hyperalgesia, while descending facilitation predominates over inhibition in pain circuits with input from neighboring tissues, and thus facilitates secondary hyperalgesia. Both descending facilitation and inhibition mainly stem from RVM. The formalin-induced primary hyperalgesia, although considered a model for inflammation, is mainly facilitated from RVM. Also, formalin-induced secondary hyperalgesia is facilitated by RVM. Again, formalin triggers a concomitant but concealed descending inhibition. The (primary) hyperalgesia and allodynia of the neuropathic syndrome are also facilitated from RVM. Simultaneously, there is an inhibition of secondary neuronal pools that is partly supported from the PAG. Because in all these models of peripheral damage descending facilitation and inhibition are triggered simultaneously, it will be important to elucidate why inhibition predominates in some neuronal pools and facilitation in others. Therapies that enhance descending inhibition and/or attenuate descending facilitation are furthermore an important target for research in the future.
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            Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study.

            Pain is a serious consequence of spinal cord injury (SCI). Our aim was to investigate the temporal aspects of different types of pain following traumatic SCI and to determine possible predictors of neuropathic pain. Prospective data on 90 patients were collected at 1, 6, and 12 months after traumatic SCI. The patients completed questionnaires on pain severity, descriptors, and impact and underwent clinical examination with bedside sensory testing. Eighty-eight patients completed the 12-month follow-up. Approximately 80% of patients reported any type of pain at all 3 time points. Neuropathic pain related to SCI increased over time, and musculoskeletal pain decreased slightly, with both being present in 59% of patients at 12 months; other neuropathic pain not related to SCI and visceral pain were present in 1 to 3%. At-level neuropathic pain present at 1 month resolved in 45% and below-level pain resolved in 33%. Early (1 month) sensory hypersensitivity (particularly cold-evoked dysesthesia) was a predictor for the development of below-level, but not at-level, SCI pain at 12 months. In conclusion, the present study demonstrates phenotypical differences between at-level and below-level SCI pain, which is important for future studies aiming to uncover underlying pain mechanisms. The finding that early sensory hypersensitivity predicts later onset of below-level central neuropathic pain may help to identify patients at risk of developing neuropathic pain conditions after traumatic spinal cord injury. Information about onset of pain may help to identify different phenotypes in neuropathic pain conditions. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
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              Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury.

              Central neuropathic pain (CNP) developing after spinal cord injury (SCI) is described by the region affected: above-level, at-level and below-level pain occurs in dermatomes rostral, at/near, or below the SCI level, respectively. People with SCI and rodent models of SCI develop above-level pain characterized by mechanical allodynia and thermal hyperalgesia. Mechanisms underlying this pain are unknown and the goals of this study were to elucidate components contributing to the generation of above-level CNP. Following a thoracic (T10) contusion, forelimb nociceptors had enhanced spontaneous activity and were sensitized to mechanical and thermal stimulation of the forepaws 35 days post-injury. Cervical dorsal horn neurons showed enhanced responses to non-noxious and noxious mechanical stimulation as well as thermal stimulation of receptive fields. Immunostaining dorsal root ganglion (DRG) cells and cord segments with activating transcription factor 3 (ATF3, a marker for neuronal injury) ruled out neuronal damage as a cause for above-level sensitization since few C8 DRG cells expressed AFT3 and cervical cord segments had few to no ATF3-labeled cells. Finally, activated microglia and astrocytes were present in thoracic and cervical cord at 35 days post-SCI, indicating a rostral spread of glial activation from the injury site. Based on these data, we conclude that peripheral and central sensitization as well as reactive glia in the uninjured cervical cord contribute to CNP. We hypothesize that reactive glia in the cervical cord release pro-inflammatory substances which drive chronic CNP. Thus a complex cascade of events spanning many cord segments underlies above-level CNP.
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                Author and article information

                Contributors
                Journal
                Front Hum Neurosci
                Front Hum Neurosci
                Front. Hum. Neurosci.
                Frontiers in Human Neuroscience
                Frontiers Media S.A.
                1662-5161
                06 April 2017
                2017
                : 11
                : 177
                Affiliations
                [1] 1The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami Miami, FL, USA
                [2] 2Department of Neurological Surgery, Miller School of Medicine, University of Miami Miami, FL, USA
                [3] 3Research Service, Bruce W. Carter Department of Veterans Affairs Medical Center Miami, FL, USA
                [4] 4Department of Neurology, Miller School of Medicine, University of Miami Miami, FL, USA
                Author notes

                Edited by: Mikhail Lebedev, Duke University, USA

                Reviewed by: Lorys Castelli, University of Turin, Italy; Filippo Brighina, University of Palermo, Italy

                *Correspondence: Eva Widerström-Noga ewiderstrom-noga@ 123456med.miami.edu
                Article
                10.3389/fnhum.2017.00177
                5382156
                28428749
                a65e5f7e-e5c5-4aa4-89e3-432d761600e7
                Copyright © 2017 Jermakowicz, Hentall, Jagid, Luca, Adcock, Martinez-Arizala and Widerström-Noga.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 December 2016
                : 27 March 2017
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 35, Pages: 7, Words: 4940
                Funding
                Funded by: U.S. Department of Defense 10.13039/100000005
                Award ID: SC110131
                Categories
                Neuroscience
                Case Report

                Neurosciences
                neuromodulation,low-frequency stimulation,periaqueductal gray,pain severity,evoked pain,chronic pain

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