Neuroinflammatory activation in sensory and motor regions of the cortex is related to sensorimotor function in individuals with low back pain maintained by nociplastic mechanisms: A preliminary proof-of-concept study.

BACKGROUND Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function. METHODS Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered. RESULTS Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41). CONCLUSION This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype. SIGNIFICANCE STATEMENT Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation.

[1]  E. Aronica,et al.  Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases , 2023, Nature communications.

[2]  N. Jahanshad,et al.  Mapping Brain Structure Variability in Chronic Pain: The Role of Widespreadness and Pain Type and Its Mediating Relationship With Suicide Attempt , 2023, Biological Psychiatry.

[3]  M. Simoneau,et al.  The influence of experimental low back pain on neural networks involved in the control of lumbar erector spinae muscles. , 2022, Journal of neurophysiology.

[4]  P. Hodges,et al.  Can training of a skilled pelvic movement change corticomotor control of back muscles? Comparison of single and paired‐pulse transcranial magnetic stimulation , 2022, The European journal of neuroscience.

[5]  N. Gasson,et al.  Motor cortex excitability in chronic low back pain , 2022, bioRxiv.

[6]  A. Philipsen,et al.  Stress vulnerability shapes disruption of motor cortical neuroplasticity , 2022, Translational Psychiatry.

[7]  S. Salomoni,et al.  Characterisation of motor cortex organisation in patients with different presentations of persistent low back pain , 2021, The European journal of neuroscience.

[8]  H. Massé-Alarie,et al.  Influence of different transcranial magnetic stimulation current directions on the corticomotor control of lumbar erector spinae muscles during a static task , 2021, Brain Stimulation.

[9]  R. Sclocco,et al.  Neuro-immune signatures in chronic low back pain subtypes. , 2021, Brain : a journal of neurology.

[10]  Richard E. Harris,et al.  Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system. , 2021, Pain.

[11]  J. Karch.  Psychologists Should Use Brunner-Munzel’s Instead of Mann-Whitney’s U Test as the Default Nonparametric Procedure , 2021, Advances in Methods and Practices in Psychological Science.

[12]  S. Schabrun,et al.  Low somatosensory cortex excitability in the acute stage of low back pain causes chronic pain , 2021, medRxiv.

[13]  K. Hirata,et al.  Central Sensitization in Neurological, Psychiatric, and Pain Disorders: A Multicenter Case-Controlled Study , 2021, Pain research & management.

[14]  T. Yin,et al.  Quantitative assessment of inter-individual variability in fMRI-based human brain atlas. , 2021, Quantitative imaging in medicine and surgery.

[15]  V. Papadopoulos,et al.  Cellular sources of TSPO expression in healthy and diseased brain , 2021, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  M. Rychlik,et al.  Female Overrepresentation in Low Back-Related Leg Pain: A Retrospective Study of the Autonomic Response to a Minimally Invasive Procedure , 2020, Journal of pain research.

[17]  J. Cholewicki,et al.  Cohort profile: why do people keep hurting their back? , 2020, BMC Research Notes.

[18]  P. Hodges,et al.  Methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a systematic review. , 2020, Pain.

[19]  S. Schabrun,et al.  Corticomotor reorganization during short‐term visuomotor training in the lower back: A randomized controlled study , 2020, Brain and behavior.

[20]  P. Hodges,et al.  Systematic Review and Synthesis of Mechanism-based Classification Systems for Pain Experienced in the Musculoskeletal System , 2020, The Clinical journal of pain.

[21]  K. Thomas,et al.  Neuronal activity increases translocator protein (TSPO) levels , 2020, Molecular Psychiatry.

[22]  B. Rosen,et al.  Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy , 2020, NeuroImage.

[23]  D. Bennett,et al.  Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer’s dementia , 2019, Science Advances.

[24]  Rob Herbert.  Research Note: Significance testing and hypothesis testing: meaningless, misleading and mostly unnecessary. , 2019, Journal of physiotherapy.

[25]  R. Gunn,et al.  Building a database for brain 18 kDa translocator protein imaged using [11C]PBR28 in healthy subjects , 2019, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  J. V. van Dieën,et al.  Motor Control Changes in Low Back Pain: Divergence in Presentations and Mechanisms. , 2019, The Journal of orthopaedic and sports physical therapy.

[27]  P. Hodges.  Hybrid Approach to Treatment Tailoring for Low Back Pain: A Proposed Model of Care. , 2019, The Journal of orthopaedic and sports physical therapy.

[28]  P. Hodges,et al.  Diverse Role of Biological Plasticity in Low Back Pain and Its Impact on Sensorimotor Control of the Spine. , 2019, The Journal of orthopaedic and sports physical therapy.

[29]  M. James,et al.  Microglial Modulation as a Target for Chronic Pain: From the Bench to the Bedside and Back. , 2019, Anesthesia and analgesia.

[30]  Yiyun Huang,et al.  Effects of age, BMI and sex on the glial cell marker TSPO — a multicentre [11C]PBR28 HRRT PET study , 2019, bioRxiv.

[31]  Robert R. Edwards,et al.  Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation , 2019, Brain, Behavior, and Immunity.

[32]  S. Skou,et al.  Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis , 2018, Disability and rehabilitation.

[33]  W. Maixner,et al.  Neuroinflammation and Central Sensitization in Chronic and Widespread Pain. , 2018, Anesthesiology.

[34]  W. Drevets,et al.  PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects , 2018, EJNMMI Research.

[35]  N. Kettner,et al.  Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients , 2018, Pain.

[36]  P. Hodges,et al.  Individual Variation in Pain Sensitivity and Conditioned Pain Modulation in Acute Low Back Pain: Effect of Stimulus Type, Sleep, and Psychological and Lifestyle Factors. , 2018, The journal of pain : official journal of the American Pain Society.

[37]  L. Arendt-Nielsen,et al.  Assessment and manifestation of central sensitisation across different chronic pain conditions , 2018, European journal of pain.

[38]  Nicole R. Zürcher,et al.  Pseudoreference Regions for Glial Imaging with 11C-PBR28: Investigation in 2 Clinical Cohorts , 2018, The Journal of Nuclear Medicine.

[39]  Sophie E. Holmes,et al.  Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study , 2018, Biological Psychiatry.

[40]  D. Perani,et al.  An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia , 2017, Annals of clinical and translational neurology.

[41]  Olivier A. Coubard,et al.  Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights , 2017, Neuroscience & Biobehavioral Reviews.

[42]  E. Tolosa,et al.  Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study , 2017, The Lancet Neurology.

[43]  S. Schabrun,et al.  Smudging of the Motor Cortex Is Related to the Severity of Low Back Pain , 2017, Spine.

[44]  S. Schabrun,et al.  Is the Organization of the Primary Motor Cortex in Low Back Pain Related to Pain, Movement, and/or Sensation? , 2017, The Clinical journal of pain.

[45]  Hyun Woo Kwon,et al.  [11C]-(R)-PK11195 positron emission tomography in patients with complex regional pain syndrome , 2017, Medicine.

[46]  Yu-Qiu Zhang,et al.  Pain regulation by non-neuronal cells and inflammation , 2016, Science.

[47]  Young T. Hong,et al.  Neuroinflammatory and morphological changes in late-life depression: the NIMROD study , 2016, British Journal of Psychiatry.

[48]  C. Schneider,et al.  Revisiting the Corticomotor Plasticity in Low Back Pain: Challenges and Perspectives , 2016, Healthcare.

[49]  L. Macedo,et al.  Motor Control Exercise for Nonspecific Low Back Pain: A Cochrane Review , 2016, Spine.

[50]  P. Hodges,et al.  Paired-Pulse TMS and Fine-Wire Recordings Reveal Short-Interval Intracortical Inhibition and Facilitation of Deep Multifidus Muscle Fascicles , 2016, PloS one.

[51]  C. Schneider,et al.  Corticomotor control of lumbar multifidus muscles is impaired in chronic low back pain: concurrent evidence from ultrasound imaging and double-pulse transcranial magnetic stimulation , 2016, Experimental Brain Research.

[52]  B. Stevens,et al.  New insights on the role of microglia in synaptic pruning in health and disease , 2016, Current Opinion in Neurobiology.

[53]  Blair H. Smith,et al.  Neuropathic pain: an updated grading system for research and clinical practice , 2016, Pain.

[54]  A. Strafella,et al.  TMS and drugs revisited 2014 , 2015, Clinical Neurophysiology.

[55]  P. Hodges,et al.  Organisation of the motor cortex differs between people with and without knee osteoarthritis , 2015, Arthritis Research & Therapy.

[56]  F. Wolfe,et al.  The Use of Polysymptomatic Distress Categories in the Evaluation of Fibromyalgia (FM) and FM Severity , 2015, The Journal of Rheumatology.

[57]  M. Grey,et al.  TMS Brain Mapping in Less Than Two Minutes , 2015, Brain Stimulation.

[58]  Nicole R. Zürcher,et al.  Evidence for brain glial activation in chronic pain patients. , 2015, Brain : a journal of neurology.

[59]  Alan A. Wilson,et al.  Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. , 2015, JAMA psychiatry.

[60]  E. Rabiner,et al.  Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer’s disease patients and control subjects , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[61]  S. Rossi,et al.  Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee , 2015, Clinical Neurophysiology.

[62]  Maiken Nedergaard,et al.  Glia and pain: Is chronic pain a gliopathy? , 2013, PAIN®.

[63]  Karmen K. Yoder,et al.  Influence of TSPO Genotype on 11C-PBR28 Standardized Uptake Values , 2013, The Journal of Nuclear Medicine.

[64]  T. Mayer,et al.  The Central Sensitization Inventory (CSI): establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample. , 2013, The journal of pain : official journal of the American Pain Society.

[65]  Kimberly J. Jenko,et al.  A Genetic Polymorphism for Translocator Protein 18 Kda Affects both in Vitro and in Vivo Radioligand Binding in Human Brain to this Putative Biomarker of Neuroinflammation , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[66]  Jian Kong,et al.  S1 is associated with chronic low back pain: a functional and structural MRI study , 2013, Molecular pain.

[67]  Luke A Henderson,et al.  Pain and Plasticity: Is Chronic Pain Always Associated with Somatosensory Cortex Activity and Reorganization? , 2012, The Journal of Neuroscience.

[68]  Edgar Brunner,et al.  Nonparametric analysis of longitudinal data in factorial experiments , 2012 .

[69]  Philippe Hantraye,et al.  Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging , 2012, The Journal of Neuroscience.

[70]  U. Ziemann,et al.  A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee , 2012, Clinical Neurophysiology.

[71]  David L. H. Bennett,et al.  The mechanisms of microgliosis and pain following peripheral nerve injury , 2012, Experimental Neurology.

[72]  T. Mayer,et al.  The Development and Psychometric Validation of the Central Sensitization Inventory , 2012, Pain practice : the official journal of World Institute of Pain.

[73]  H. Moffet,et al.  Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments , 2012, Experimental Brain Research.

[74]  Roger N Gunn,et al.  An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28 , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[75]  Anthony Staines,et al.  The Discriminative Validity of “Nociceptive,” “Peripheral Neuropathic,” and “Central Sensitization” as Mechanisms-based Classifications of Musculoskeletal Pain , 2011, The Clinical journal of pain.

[76]  P. Hodges,et al.  ISSLS Prize Winner: Smudging the Motor Brain in Young Adults With Recurrent Low Back Pain , 2011, Spine.

[77]  C. Woolf.  Central sensitization: Implications for the diagnosis and treatment of pain , 2011, PAIN.

[78]  R. Fields,et al.  Physiological function of microglia. , 2011, Neuron glia biology.

[79]  J. Nabekura,et al.  Functions of microglia in the central nervous system--beyond the immune response. , 2011, Neuron glia biology.

[80]  Paul Kinahan,et al.  Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. , 2010, Seminars in ultrasound, CT, and MR.

[81]  P. Schwenkreis,et al.  Cortical disinhibition occurs in chronic neuropathic, but not in chronic nociceptive pain , 2010, BMC Neuroscience.

[82]  Sharon M. Henry,et al.  Low back pain associates with altered activity of the cerebral cortex prior to arm movements that require postural adjustment , 2010, Clinical Neurophysiology.

[83]  Shuxing Wang,et al.  Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis , 2009, Brain Research.

[84]  R. Dubner,et al.  Neuron-glia crosstalk gets serious: role in pain hypersensitivity. , 2008, Current opinion in anaesthesiology.

[85]  P. Hodges,et al.  Reorganization of the motor cortex is associated with postural control deficits in recurrent low back pain. , 2008, Brain : a journal of neurology.

[86]  R. Treede,et al.  The Kyoto protocol of IASP Basic Pain Terminology , 2008, PAIN®.

[87]  S. Cherry,et al.  Simultaneous in vivo positron emission tomography and magnetic resonance imaging , 2008, Proceedings of the National Academy of Sciences of the United States of America.

[88]  N. O’Connell,et al.  Towards a mechanisms-based classification of pain in musculoskeletal physiotherapy? , 2008 .

[89]  R. Ji,et al.  p38 MAPK, microglial signaling, and neuropathic pain , 2007, Molecular pain.

[90]  R. Baron,et al.  painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain , 2006, Current medical research and opinion.

[91]  Jacek Cholewicki,et al.  Muscle activation imbalance and low-back injury in varsity athletes. , 2006, Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology.

[92]  S. Waxman,et al.  Activated Microglia Contribute to the Maintenance of Chronic Pain after Spinal Cord Injury , 2006, The Journal of Neuroscience.

[93]  N. Davey,et al.  Corticospinal Excitability in Patients With Chronic Low Back Pain , 2005, Journal of spinal disorders & techniques.

[94]  L. Garcia-Segura,et al.  Ro5‐4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity , 2005, Journal of neuroscience research.

[95]  N. Davey,et al.  Corticospinal excitability in patients with unilateral sciatica , 2003, Neuroscience Letters.

[96]  M. Norenberg,et al.  Effects on free radical generation by ligands of the peripheral benzodiazepine receptor in cultured neural cells , 2002, Journal of neurochemistry.

[97]  E. Wassermann.  Variation in the response to transcranial magnetic brain stimulation in the general population , 2002, Clinical Neurophysiology.

[98]  R. Dallel,et al.  Towards a Pain Treatment Based on the Identification of the Pain-Generating Mechanisms? , 2001, European Neurology.

[99]  P. Pynsent,et al.  The Oswestry Disability Index. , 2000, Spine.

[100]  A. Apkarian,et al.  Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus , 2000, Pain.

[101]  S. Kohsaka,et al.  Functional roles of microglia in the central nervous system. , 1998, Human cell.

[102]  R. Lipton,et al.  Towards a mechanism-based classification of pain? , 1998, Pain.

[103]  M. Gavish,et al.  Biochemical, Physiological, and Pathological Aspects of the Peripheral Benzodiazepine Receptor , 1992, Journal of neurochemistry.

[104]  Daniel J Buysse,et al.  The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research , 1989, Psychiatry Research.

[105]  C. Woolf,et al.  Towards a mechanism-based approach to pain diagnosis , 2016 .

[106]  P. Matthews,et al.  Imaging brain microglial activation using positron emission tomography and translocator protein-specific radioligands. , 2011, International review of neurobiology.

[107]  Y. Kawasaki,et al.  Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. , 2006, Neuron glia biology.