Neuromodulation for Intractable Neuromodulation for Pain • Tipu Aziz and Alex Green Neuromodulation for Intractable Pain Edited by Tipu Aziz and Alex Green Printed Edition of the Special Issue Published in Brain Sciences www.mdpi.com/journal/brainsci Neuromodulation for Intractable Pain Neuromodulation for Intractable Pain Special Issue Editors Tipu Aziz Alex Green MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin Special Issue Editors Tipu Aziz Alex Green University of Oxford University of Oxford UK UK Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Brain Sciences (ISSN 2076-3425) (available at: https://www.mdpi.com/journal/brainsci/special issues/neuromodulation pain). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03936-950-8 (Hbk) ISBN 978-3-03936-951-5 (PDF) c 2020 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ..................................... vii Alexander L. Green and Tipu Z. Aziz Neuromodulation for Intractable Pain Reprinted from: Brain Sci. 2020, 10, 267, doi:10.3390/brainsci10050267 ................ 1 Tariq Parker, Yongzhi Huang, Ashley L.B. Raghu, James J. FitzGerald, Alexander L. Green and Tipu Z. Aziz Dorsal Root Ganglion Stimulation Modulates Cortical Gamma Activity in the Cognitive Dimension of Chronic Pain Reprinted from: Brain Sci. 2020, 10, 95, doi:10.3390/brainsci10020095 ................ 5 Afonso S. I. Salgado, Juliana Stramosk, Daniela D. Ludtke, Ana C. C. Kuci, Daiana C. Salm, Lisandro A. Ceci, Fabricia Petronilho, Drielly Florentino, Lucineia G. Danielski, Aline Gassenferth, et al. Manual Therapy Reduces Pain Behavior and Oxidative Stress in a Murine Model of Complex Regional Pain Syndrome Type I Reprinted from: Brain Sci. 2019, 9, 197, doi:10.3390/brainsci9080197 ................. 19 Salvo Danilo Lombardo, Emanuela Mazzon, Maria Sofia Basile, Eugenio Cavalli, Placido Bramanti, Riccardo Nania, Paolo Fagone, Ferdinando Nicoletti and Maria Cristina Petralia Upregulation of IL-1 Receptor Antagonist in a Mouse Model of Migraine Reprinted from: Brain Sci. 2019, 9, 172, doi:10.3390/brainsci9070172 ................. 31 Yongzhi Huang, Binith Cheeran, Alexander L. Green, Timothy J. Denison and Tipu Z. Aziz Applying a Sensing-Enabled System for Ensuring Safe Anterior Cingulate Deep Brain Stimulation for Pain Reprinted from: Brain Sci. 2019, 9, 150, doi:10.3390/brainsci9070150 ................. 43 Timothy R. Deer, Sameer Jain, Corey Hunter and Krishnan Chakravarthy Neurostimulation for Intractable Chronic Pain Reprinted from: Brain Sci. 2019, 9, 23, doi:10.3390/brainsci9020023 .................. 55 Sarah Marie Farrell, Alexander Green and Tipu Aziz The Use of Neuromodulation for Symptom Management Reprinted from: Brain Sci. 2019, 9, 232, doi:10.3390/brainsci9090232 ................. 75 Holly Roy, Ifeoma Offiah and Anu Dua Neuromodulation for Pelvic and Urogenital Pain Reprinted from: Brain Sci. 2018, 8, 180, doi:10.3390/brainsci8100180 ................. 95 Sarah Marie Farrell, Alexander Green and Tipu Aziz The Current State of Deep Brain Stimulation for Chronic Pain and Its Context in Other Forms of Neuromodulation Reprinted from: Brain Sci. 2018, 8, 158, doi:10.3390/brainsci8080158 .................111 Ivano Dones and Vincenzo Levi Spinal Cord Stimulation for Neuropathic Pain: Current Trends and Future Applications Reprinted from: Brain Sci. 2018, 8, 138, doi:10.3390/brainsci8080138 .................131 v About the Special Issue Editors Tipu Aziz, D Med Sci, FRCS(SN), is the founder and head of Oxford functional neurosurgery. His primate work was central to confirming the subthalamic nucleus as a possible surgical target for deep brain stimulation in Parkinson’s disease and more recently the pedunculopontine nucleus. OFN is currently one of the busiest centres for such surgery in the UK and academically very productive. Research Interests are the role of the upper brain stem in the control of movement, the clinical neurophysiology of movement disorders and neuropathic pain and autonomic responses to deep brain stimulation, use of MR and MEG imaging in functional neurosurgery. Alex Green MD FRCS(SN)., has been looking at the neurocircuitry underlying autonomic function and pain in humans undergoing Deep Brain Stimulation (DBS) over the past ten years. There are several aims of this research. Firstly, he wishes to understand both the mechanisms underlying the pathophysiology of neuropathic pain as well as why some patients get much better than results than others. Secondly, by understanding the autonomic nervous system, it may be possible to control diseases such as hypertension, respiratory and bladder disease by brain manipulation in the future. Most of the research to date has involved stimulating brain areas under different experimental conditions and also recording local field potentials to understand the underlying neurophysiology. This work has resulted in a number of publications including improvement in peak expiratory flow with stimulation, the effect of stimulation on blood pressure and baroreceptors sensitivity and novel electrical signals associated with pain states. vii brain sciences Editorial Neuromodulation for Intractable Pain Alexander L. Green * and Tipu Z. Aziz Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK; [email protected] * Correspondence: [email protected] Received: 22 April 2020; Accepted: 29 April 2020; Published: 30 April 2020 Over 7% of the Western population suffer from intractable pain and despite pharmacotherapy, many patients’ pain is refractory [1]. In addition to the pain, patients often suffer from depression and anxiety, poor quality of life and loss of employment. An ever-enlarging problem is that of opiate use, which in the US has been labelled as a “crisis” [2]. In order to tackle these issues, we require a greater understanding of the underlying pathophysiology of pain, novel treatments (pharmacological and otherwise), and a greater evidence base for both the efficacy of non-pharmacological treatments alongside a better understanding of the mechanisms of action. In this issue, Deer et al. [3] provide an up-to-date literature review on spinal cord stimulation (SCS), dorsal root ganglion (DRG) stimulation, and peripheral nerve stimulation (PNS), which are all well-established neuromodulatory techniques for treating chronic neuropathic pain. Deer et al. provide a comprehensive report, demonstrating that SCS has well-established efficacy for specific pain subtypes such as failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), and a number of other conditions. They point out that although SCS is not a new therapy, there are a multitude of new advancements in the field such as novel waveforms, new closed-loop technologies, and many recent advances in the understanding of its mechanisms. Whilst DRG stimulation and PNS are somewhat more recent additions to the armamentarium, there is good early evidence for efficacy, although the authors point out that trial designs (especially subject blinding) can be a challenge. Dones and Levi, in their review of SCS, echo the conclusions of Deer et al. and also discuss in depth the technical nuances of SCS therapy. Controversies include the choice between percutaneous and paddle electrodes, and the choice between awake implantation and implantation under general anaesthetic. The authors present the evidence on different sides of the argument, providing the advantages and disadvantages of each technique. This also makes the point that trials need to be evaluated in the context of the specific technique. Regarding the mechanisms of action of DRG stimulation, Parker et al. [4] report a study in which magnetoencephalography (MEG) was used to measure cortical activity during periods of DRG stimulation compared with a control whilst performing a cognitive task (the “N-Back task”). The authors elegantly show that DRG stimulation modulates cortical gamma activity in the cognitive dimension of pain. This study has implications for the way in which peripheral neuromodulation works and implies that the modulation of cortical networks is important (either as a cause or consequence), and not just local DRG effects. Salgado et al. [5], in their study on CRPS in mice, bring to our attention that there are alternatives to medication, other than neuromodulation. One such intervention is manual therapy such as ankle joint mobilization. The authors show that mobilization 48 hours after an ischemia–reperfusion injury reduced the pain behaviour and oxidative stress. This study outlines the importance of therapy in the acute phase after injury in order to prevent the build-up of chronic pain in the first place. For those patients who do not respond to SCS and other forms of more “peripheral” neuromodulation, deep brain stimulation