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Dana M Tilley,1 Ricardo Vallejo,1,2 Francesco Vetri,3 David C Platt,1,2 David L Cedeno1,2 1Research and Development, SGX Medical, Bloomington, IL, USA; 2Neuroscience, Illinois Wesleyan University, Bloomington, IL, USA; 3Research Department, National Spine and Pain Centers, Bloomington, IL, USACorrespondence: David L Cedeno, SGX Medical, 2406 E. Empire St, Bloomington, IL, 61704, USA, Tel +1 309 826 6974, Email dclumbrera@gmail.comIntroduction: Spinal cord stimulation (SCS) has been used for decades to treat neuropathic pain conditions with limited understanding of its mechanisms of action. The mTOR pathway is a well-known co-factor in chronic pain and has not been previously linked to SCS therapy. Proteomic and phosphorylation analyses allow capturing a broad view of tissue response to an injury model and subsequent therapies such as SCS. Here, we evaluated the effect of differential target multiplexed SCS programming (DTMP) and traditional low-rate spinal cord stimulation (LR-SCS) on the mTOR pathway using proteomic and phosphoproteomic analyses.Methods: The spared nerve injury (SNI) model of neuropathic pain in animals was established followed by continuous treatment with either DTMP or LR-SCS for 48 hours. Control groups included sham-stimulated (No-SCS) and uninjured animals (No-SNI). Proteins were extracted from spinal cord tissue removed post-stimulation and subjected to liquid chromatography/tandem mass spectrometry to assess changes in protein expression and states of phosphorylation. Bioinformatics tools and literature were used to identify mTOR-related proteins in the various groups.Results: Over 7000 proteins were identified and filtered to find 1451 and 705 proteins significantly affected by DTMP and LR-SCS (p < 0.05), respectively, relative to No-SCS. Literature and bioinformatic tools yielded 192 mTOR-related proteins that were cross-referenced to the list of DTMP and LR-SCS affected proteins. Of these proteins, 49 were found in the proteomic dataset. Eight of these proteins showed a significant response to the pain model, 25 were significantly modulated by DTMP, and 8 by LR-SCS. Phosphoproteomic analyses yielded 119 mTOR-related phosphoproteins affected by the injury model with a 66% reversal following DTMP versus a 58% reversal by LR-SCS.Conclusion: Proteomic and phosphoproteomic analyses support the hypothesis that DTMP, and to a lesser extent LR-SCS, reverse injury induced changes of the mTOR pathway while treating neuropathic pain.Keywords: proteomic analysis, phosphoproteomic analysis, nerve injury, central sensitization, inflammation

David L Cedeño,1,2 Dana M Tilley,2 Francesco Vetri,3 David C Platt,1,2 Ricardo Vallejo1– 3 1Neuroscience, Illinois Wesleyan University, Bloomington, IL, USA; 2Research and Development, SGX Medical, Bloomington, IL, USA; 3Research Department, National Spine and Pain Centers, Bloomington, IL, USACorrespondence: Ricardo Vallejo; David L Cedeño, Email vallejo1019@yahoo.com; dclumbrera@gmail.comIntroduction: Neuropathic pain initiates an interplay of pathways, involving MAP kinases and NFκB-signaling, leading to expression of immune response factors and activation and inactivation of proteins via phosphorylation. Neuropathic pain models demonstrated that spinal cord stimulation (SCS) may provide analgesia by modulating gene and protein expression in neuroinflammatory processes. A differential target multiplexed programming (DTMP) approach was more effective than conventional SCS treatments at modulating these. This work investigated the effect of DTMP and low rate SCS (LR-SCS) on proteins associated with MAP kinases and NFκB-signaling relevant to neuroinflammation.Methods: Animals subjected to the spared nerve injury model (SNI) of neuropathic pain were treated continuously (48h) with either DTMP or LR-SCS. No-SNI and No-SCS groups were included as controls. Proteomics and phosphoproteomics of stimulated spinal cord tissues were performed via liquid chromatography/tandem mass spectrometry. Proteins were identified from mass spectra using bioinformatics. Expression levels and fold changes (No-SCS/No-SNI and SCS/No-SCS) were obtained from spectral intensities.Results: Analyses identified 7192 proteins, with 1451 and 705 significantly changed by DTMP and LR-SCS, respectively. Eighty-one proteins, including MAP kinases, facilitating NFκB-signaling as part of inflammatory processes were identified. The pain model significantly increased expression levels of complement pathway-related proteins (LBP, NRG1, APP, CFH, C3, C5), which were significantly reversed by DTMP. Expression levels of other complement pathway-related proteins (HMGB1, S100A8, S100A9, CRP, C4) were decreased by DTMP, although not significantly affected by SNI. Other proteins (ORM1, APOE, NG2, CNTF) involved in NFκB-signaling were increased by SNI and decreased by DTMP. Expression levels of phosphorylated protein kinases involved in NFκB-signaling (including MAP kinases, PKC, MARK1) were affected by the pain model and reverse modulated by DTMP. LR-SCS modulated inflammatory-related proteins although to a lesser extent than DTMP.Conclusion: Proteomic analyses support the profound effect of the DTMP approach on neuroinflammation via MAP kinases and NFκB-mediated signaling to alleviate neuropathic pain.Keywords: differential target multiplexed spinal cord stimulation, proteomics, neuropathic pain, neuroinflammation, mitogen activated protein kinase, nuclear factor-kappa B

Ricardo Vallejo,1 Krishnan Chakravarthy,2 Andrew Will,3 Karen Trutnau,3 David Dinsmoor4 1Millennium Pain Center, Bloomington, IL, USA; 2Anesthesiology and Pain Management, University of California San Diego, San Diego, CA, USA; 3Twin Cities Pain Clinic, Edina, MN, USA; 4Neuromodulation Research & Technology, Medtronic plc, Minneapolis, MN, USACorrespondence: David DinsmoorNeuromodulation Research & Technology, Medtronic plc, 7000 Central Ave NE RCE275, Minneapolis, MN, 55432, USATel +1 763 526-8801Email david.a.dinsmoor@medtronic.comAbstract: Spinal cord stimulation (SCS) utilizes the delivery of mild electrical pulses via epidural electrodes placed on the dorsal side of the spinal cord, typically to treat chronic pain. The first clinical use of SCS involved the delivery of paresthesia inducing, low-frequency waveforms to the neural targets corresponding to the painful areas. Contemporary SCS therapies now leverage novel therapeutic pathways to limit paresthesia and deliver superior clinical outcomes. Historically, SCS has largely been delivered with fixed stimulation parameters. This approach, referred to as open-loop (OL) SCS, does not account for the fluctuations in spacing—driven by postural changes and activity—between the electrodes and the cord. These fluctuations result in variability in the delivered dose and the volume of tissue activation (VTA) that manifests with each stimulation pulse. Inconsistent dosing may lead to suboptimal therapeutic efficacy and durability. To address this clinical need, closed-loop (CL) SCS systems have been developed to automatically adjust stimulation parameters to compensate for this variability. The evoked compound action potential (ECAP), a biopotential generated by the synchronous activation of dorsal column fibers, is indicative of the VTA resulting from the stimulation pulse. The ECAP may be utilized as a control signal in CL SCS systems to adjust stimulation parameters to reduce variability in the ECAP, and in turn, variability in the VTA. While investigational CL SCS systems with ECAP sensing have so far focused solely on managing paresthesia-based SCS, such systems must also incorporate the stimulation approaches that now define the contemporary clinical practice of SCS. Accordingly, we describe here a flexible, next-generation framework for neural responsive SCS that blends science-based methodologies for pain management with real-time CL control for biophysical variation. We conclude with a clinical example of such a system and the associated performance characteristics.Keywords: spinal cord stimulation, evoked potentials, closed-loop, neuromodulation

Yashar Eshraghi,1– 3 Krishnan Chakravarthy,4,5 Natalie H Strand,6 Prasad Shirvalkar,7 Nathaniel M Schuster,4 Rany T Abdallah,8 Ricardo Vallejo,9,10 Dawood Sayed,11 David Kim,11 Chong Kim,12 Kathleen Meacham,13 Timothy Deer14,15 On Behalf of Translational Research Committee American Society of Pain and Neuroscience (ASPN)1Department of Anesthesia, Interventional Pain Management, Ochsner Health System, New Orleans, LA, USA; 2University of Queensland Ochsner Clinical School. Academics Department, Ochsner Health System, New Orleans, LA, USA; 3Louisiana State University School of Medicine, New Orleans, LA, USA; 4Division of Pain Medicine, Department of Anesthesiology, University of California San Diego, San Diego, CA, USA; 5VA San Diego Health Care, San Diego, CA, USA; 6Division of Pain Medicine, Department of Anesthesiology, Mayo Clinic, Phoenix, Arizona, USA; 7Department of Anesthesiology (Pain Management), Department of Neurology, UCSF School of Medicine, San Francisco, CA, USA; 8Center for Interventional Pain and Spine, Wilmington, DE, USA; 9National Spine and Pain Center, Bloomington, IL, USA; 10Psychology Department, Illinois Wesleyan University, Bloomington, IL, USA; 11University of Kansas Medical Center, Kansas City, KS, USA; 12Departments of Physical Medicine and Rehabilitation and Anesthesiology, Case Western Reserve University/MetroHealth, Cleveland, OH, USA; 13Division of Pain Management, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO; 14The Spine and Nerve Center of the Virginias, Charleston, WV, USA; 15West Virginia University, School of Medicine, Charleston, WV, USACorrespondence: Yashar Eshraghi Email Yashar.Eshraghi@gmail.comBackground: Healthcare clinical and even policy decisions are progressively made based on research-based evidence. The process by which the appropriate trials are developed and well-written manuscripts by means of evidence-based medicine recommendations has resulted in unprecedented necessity in evidence-based medicine in neuromodulation.Methods: The essential considerations in the planning of neuromodulation research are discussed in the light of available scientific literature as well as the authors’ scientific expertise regarding research study design and scientific manuscript preparation.Conclusion: This article should enable the reader to understand how to appropriately design a clinical research study and prepare scientific manuscripts. The high-quality and well-designed studies, when performed and reported effectively, support evidence-based medicine and foster improved patient outcomes.Keywords: research, study design, neuromodulation, neurostimulation, clinical evidence review

Nagy A Mekhail,1 Shrif J Costandi,1 Sherif Armanyous,1 Ricardo Vallejo,2 Lawrence R Poree,3 Lora L Brown,4 Stanley Golovac,5 Timothy R Deer6 1Evidence-Based Pain Management Research, Cleveland Clinic, Cleveland, OH, USA; 2Millennium Pain Center, Bloomington, IL, USA; 3Pain Management Center, UCSF Health, San Francisco, CA, USA; 4TruWell Health, St. Petersburg, FL, USA; 5Florida Pain Institute, Merritt Island, FL, USA; 6Center for Pain Relief, Charleston, WV, USACorrespondence: Nagy A Mekhail Email mekhain@ccf.orgBackground and Purpose: Minimally invasive lumbar decompression (mild®) is an effective long-term therapy for patients with symptomatic lumbar spinal stenosis (LSS) resulting primarily from hypertrophic ligamentum flavum (HLF). Most subjects in clinical studies of the mild procedure have been older adults (age≥ 65). While the incidence of LSS increases with age, a substantial number of adults (age< 65) also suffer from neurogenic claudication secondary to HLF. In this report, outcomes of mild were compared between adults and older adults.Patients and Methods: All prospective studies of the mild procedure with a 1-year follow-up completed since the beginning of 2012 that allowed the inclusion of adult patients of all ages were reviewed. Outcomes of visual analog scale (VAS), Oswestry Disability Index (ODI), Pain Disability Index (PDI), Roland Morris Low Back Pain and Disability Questionnaire (RMQ), standing time and walking distance were compared for adults and older adults.Results: Four studies met the inclusion criteria, resulting in an analysis of 49 adults and 160 older adults. Patients in both age groups experienced significant mean improvements in all but one outcome measure at 6- and 12-month follow-up. Differences between the two age groups in all scores at 6 and 12 months were not statistically significant.Conclusion: Analysis of the four studies indicated that symptom improvements for adults and older adults were significant from baseline, and no statistically significant difference was observed between the two age groups. These results illustrate that mild can be an effective treatment for LSS due primarily to HLF, regardless of the adult patient age.Keywords: mild, neurogenic claudication, ligamentum flavum, LSS

Marta Mellides González,1 Marta Elena Losa Iglesias,2 Inmaculada Corral-Liria,2 Ricardo Becerro-de-Bengoa-Vallejo,3 Eva Maria Martinez-Jimenez,3 Sandra Fares-Medina,2 Sara González-Martín,2 Marta San-Antolín,4 Raquel Jiménez-Fernández2 1Hospital Universitario 12 de Octubre, Usera, Madrid, 28041, Spain; 2Faculty of Health Sciences, Universidad Rey Juan Carlos, Alcorcon, 28922, Spain; 3Facultad de Enfermería, Fisioterapia y Podología, Universidad Complutense de Madrid, Madrid, 28040, Spain; 4Department of Psychology, Universidad de Valladolid, Valladolid, 47002, SpainCorrespondence: Inmaculada Corral-Liria, Faculty of Health Sciences, Universidad Rey Juan Carlos, Alcorcon, 28922, Spain, Email inmaculada.corral.liria@urjc.esObjective: To evaluate the moral distress (MD)in health professionals of pediatric and adult units to show how the complexity of care in the pediatric field causes the professionals who carry out their activity in these units to present a higher level of moral distress and a worse climate ethical.Design: Observational study with health professionals who currently work in Spanish Hospitals.Methods: A 58-item questionnaire was electronically distributed which included sociodemographic and employment characteristics, the Spanish version of the Measure of Moral Unrest for Healthcare Professionals (MMD-HP-SPA) and the Hospital Ethical Climate Survey (HECS).Results: A total of 169 health professionals completed the questionnaire. The moral distress was significantly higher among nurses than among physicians and nursing assistant care technicians. Focusing on the type of unit, moral distress it was only significantly higher for those physicians treating adult patients compared to those treating pediatric patients. Regarding the total score of the HECS survey, the medical group shows higher scores compared to the nursing group.Conclusion: Statistically significant differences have been found only in the medical group that treats adult patients, presenting a higher level of moral unrests than the pediatrician group. The MMD-HP-SPA questionnaire is a valid and useful instrument to detect MD in our hospital units in order to be able to implement strategies/interventions that improve the ethical climate and other factors that can mitigate and prevent this MD.Keywords: moral unrest, ethical climate, surveys, questionnaires, pediatrics

Every year about 45 000 forest fires occur in Europe, burning half a million hectares of forests and rural lands; between 1995 and 2004, more than 4 million hectares burned in the Mediterranean Region alone. Post-fire management of burned areas has been given much lesser attention than combating or preventing fires. However, important questions raise public concern and call for sound scientific knowledge to undertake appropriate post-fire actions: e.g., how to evaluate fire damages in economical terms? How to manage burned areas? Is it possible to establish, in the long-term, less flammable and more fire resilient forests and landscapes? To address these questions, a network of researchers and practitioners working in the field of fire ecology and forest management from all around Europe has been established in the frame of “COST Action FP0701-Post-Fire Forest Management in Southern Europe”, supported by the European Union Research and Technology Development Framework Program. The Action aims to: i) develop and disseminate scientifically based decision criteria for planning post-fire forest management, from the stand to the landscape level; ii) translate this scientific knowledge into management practices; iii) connect scientists and stakeholders for exchanging experiences, evaluating these practices, and putting them into practice. To achieve these objectives the scientific groups involved will a) review and summarize the current scientific knowledge on post-fire management in Europe, by gathering and evaluating the results of previous and ongoing research; b) translate this knowledge into technical recommendations, by producing thematic reports, a book on the state-of-the-art of scientific knowledge on post fire assessment, and an electronic handbook on post-fire restoration; c) disseminate this knowledge to stakeholders, practitioners and decision makers. Besides publications and a project website already active (http://uaeco.biol.uoa.gr/cost/), training schools and one major conference will be organized. Although focused on Southern Europe, the outcomes of this Action will be crucial for central and northern European countries as well, as climate change and land use changes often leading to more homogeneous and expanding forest areas are already increasing fire hazard in those regions.