A novel cortical biomarker signature for predicting pain sensitivity: protocol for the PREDICT longitudinal analytical validation study

David A Seminowicz, Katarzyna Bilska, Nahian S Chowdhury, Patrick Skippen, Samantha K Millard, Alan K I Chiang, Shuo Chen, Andrew J Furman, Siobhan M Schabrun, David A Seminowicz, Katarzyna Bilska, Nahian S Chowdhury, Patrick Skippen, Samantha K Millard, Alan K I Chiang, Shuo Chen, Andrew J Furman, Siobhan M Schabrun

Abstract

Introduction: Temporomandibular disorder is a common musculoskeletal pain condition with development of chronic symptoms in 49% of patients. Although a number of biological factors have shown an association with chronic temporomandibular disorder in cross-sectional and case control studies, there are currently no biomarkers that can predict the development of chronic symptoms. The PREDICT study aims to undertake analytical validation of a novel peak alpha frequency (PAF) and corticomotor excitability (CME) biomarker signature using a human model of the transition to sustained myofascial temporomandibular pain (masseter intramuscular injection of nerve growth factor [NGF]). This article describes, a priori, the methods and analysis plan.

Methods: This study uses a multisite longitudinal, experimental study to follow individuals for a period of 30 days as they progressively develop and experience complete resolution of NGF-induced muscle pain. One hundred fifty healthy participants will be recruited. Participants will complete twice daily electronic pain diaries from day 0 to day 30 and undergo assessment of pressure pain thresholds, and recording of PAF and CME on days 0, 2, and 5. Intramuscular injection of NGF will be given into the right masseter muscle on days 0 and 2. The primary outcome is pain sensitivity.

Perspective: PREDICT is the first study to undertake analytical validation of a PAF and CME biomarker signature. The study will determine the sensitivity, specificity, and accuracy of the biomarker signature to predict an individual's sensitivity to pain.

Registration details: ClinicalTrials.gov: NCT04241562 (prospective).

Keywords: Biomarkers; Electroencephalography; Nerve growth factor; Orofacial pain; Susceptibility; Transcranial magnetic stimulation.

Conflict of interest statement

D.A. Seminowicz and A.J. Furman have a patent pending for “A Simple and Portable Biomarker for Pain Sensitivity”. The authors have no other conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Figures

Figure 1.
Figure 1.
Experimental protocol. Questionnaires—Health history form, Pain Catastrophising Scale, Brief Pain Inventory Pain Severity and 7-item Interference subscales; SF-8 Health Survey; Sleep Scale; Patient Health Questionnaire-2 item; Generalised Anxiety Disorder 2 item Questionnaire; Tobacco, Alcohol, Prescription Medications, and other Substances Questionnaire; Perceived Stress Scale; and Pennebaker Inventory of Limbic Languidness (PILL) questionnaire. DC-TMD, Diagnostic Criteria for Temporomandibular Disorder; EEG, electroencephalography; NGF, nerve growth factor; NRS, numerical rating scale; PPTs, pressure pain thresholds; TMS, transcranial magnetic stimulation.

References

    1. Bair E, Gaynor S, Slade GD, Ohrbach R, Fillingim RB, Greenspan JD, Dubner R, Smith SB, Diatchenko L, Maixner W. Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: the OPPERA study. PAIN 2016;157:1266–78.
    1. Castrillon EE, Ernberg M, Cairns BE, Wang K, Sessle BJ, Arendt-Nielsen L, Svensson P. Interstitial glutamate concentration is elevated in the masseter muscle of myofascial temporomandibular disorder patients. J Orofac Pain 2010;24:350–60.
    1. Chang WJ, Buscemi V, Liston MB, McAuley JH, Hodges PW, Schabrun SM. Sensorimotor cortical activity in acute low back pain: a cross-sectional study. J Pain 2019;20:819–29.
    1. Costa YM, Exposto FG, Kothari M, Castrillon EE, Conti PCR, Bonjardim LR, Svensson P. Masseter corticomotor excitability is decreased after intramuscular administration of nerve growth factor. Eur J Pain 2019;23:1619–30.
    1. D'Errico J. Surface fitting using gridfit. MATLAB central file exchange. Available at: . Accessed June 1, 2017.
    1. Davis KD, Flor H, Greely HT, Iannetti GD, Mackey S, Ploner M, Pustilnik A, Tracey I, Treede RD, Wager TD. Brain imaging tests for chronic pain: medical, legal and ethical issues and recommendations. Nat Rev Neurol 2017;13:624–38.
    1. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods 2004;134:9–21.
    1. Deng H, Gao S, Lu S, Kumar A, Zhang Z, Svensson P. Alteration of occlusal vertical dimension induces signs of neuroplastic changes in corticomotor control of masseter muscles: preliminary findings. J Oral Rehabil 2018;45:710–19.
    1. Dworkin SF. Research Diagnostic criteria for Temporomandibular Disorders: current status & future relevance. J Oral Rehabil 37:734–43, 2010.
    1. Fillingim RB, Slade GD, Greenspan JD, Dubner R, Maixner W, Bair E, Ohrbach R. Long-term changes in biopsychosocial characteristics related to temporomandibular disorder: findings from the OPPERA study. PAIN 2018;159:2403–13.
    1. Finan PH, Buenaver LF, Bounds SC, Hussain S, Park RJ, Haque UJ, Campbell CM, Haythornthwaite JA, Edwards RR, Smith MT. Discordance between pain and radiographic severity in knee osteoarthritis: findings from quantitative sensory testing of central sensitization. Arthritis Rheum 2013;65:363–72.
    1. Furman AJ, Krimmel J, Zhang M, Keaser R, Gullapalli D, Seminowicz DA. The relationship of sensorimotor peak alpha frequency to regions across the brain is modulated by pain. No. 391.21. 2018 neuroscience meeting planner. San Diego: Society for Neuroscience, 2018.
    1. Furman AJ, Thapa T, Summers SJ, Cavaleri R, Fogarty JS, Steiner GZ, Schabrun SM, Seminowicz DA. Cerebral peak alpha frequency reflects average pain severity in a human model of sustained, musculoskeletal pain. J Neurophysiol 2019;122:1784–93.
    1. Greenspan JD, Slade GD, Bair E, Dubner R, Fillingim RB, Ohrbach R, Knott C, Diatchenko L, Liu Q, Maixner W. Pain sensitivity and autonomic factors associated with development of TMD: the OPPERA prospective cohort study. J Pain 2013;14:T63–74 e61-66.
    1. Hastie T, Tibshirani R, Friedman J,: The elements of statistical learning, 2nd ed New York: Springer-Verlag, 2009.
    1. Keel JC, Smith MJ, Wassermann EM. A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 2001;112:720.
    1. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain 2004;20:309–18.
    1. Koes BW, van Tulder MW, Thomas S. Diagnosis and treatment of low back pain. BMJ 2006;332:1430–4.
    1. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care 2003;41:1284–92.
    1. Kroenke K, Spitzer RL, Williams JB, Monahan PO, Lowe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med 2007;146:317–25.
    1. Lin CS. Brain signature of chronic orofacial pain: a systematic review and meta-analysis on neuroimaging research of trigeminal neuropathic pain and temporomandibular joint disorders. PLoS One 2014;9:e94300.
    1. Maixner W, Greenspan JD, Dubner R, Bair E, Mulkey F, Miller V, Knott C, Slade GD, Ohrbach R, Diatchenko L, Fillingim RB. Potential autonomic risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case-control study. J Pain 2011;12:T75–91.
    1. Mann MK, Dong XD, Svensson P, Cairns BE. Influence of intramuscular nerve growth factor injection on the response properties of rat masseter muscle afferent fibers. J Orofac Pain 2006;20:325–36.
    1. Mazaheri A, Coffey-Corina S, Mangun GR, Bekker EM, Berry AS, Corbett BA. Functional disconnection of frontal cortex and visual cortex in attention-deficit/hyperactivity disorder. Biol Psychiatry 2010;67:617–23.
    1. Mazaheri A, Nieuwenhuis IL, van Dijk H, Jensen O. Prestimulus alpha and mu activity predicts failure to inhibit motor responses. Hum Brain Mapp 2009;30:1791–800.
    1. Mazaheri A, van Schouwenburg MR, Dimitrijevic A, Denys D, Cools R, Jensen O. Region-specific modulations in oscillatory alpha activity serve to facilitate processing in the visual and auditory modalities. Neuroimage 2014;87:356–62.
    1. Oostenveld R, Fries P, Maris E, Schoffelen JM. FieldTrip: open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. Comput Intell Neurosci 2011;2011:156869.
    1. Oostenveld R, Praamstra P. The five percent electrode system for high-resolution EEG and ERP measurements. Clin Neurophysiol 2001;112:713–19.
    1. Pennebaker J: The psychology of physical symptoms. New York: Springer-Verlag, 1982.
    1. Raphael KG, Janal MN, Anathan S, Cook DB, Staud R. Temporal summation of heat pain in temporomandibular disorder patients. J Orofac Pain 2009;23:54–64.
    1. Rogachov A, Cheng JC, Erpelding N, Hemington KS, Crawley AP, Davis KD. Regional brain signal variability: a novel indicator of pain sensitivity and coping. PAIN 2016;157:2483–92.
    1. Sarlani E, Grace EG, Reynolds MA, Greenspan JD. Evidence for up-regulated central nociceptive processing in patients with masticatory myofascial pain. J Orofac Pain 2004;18:41–55.
    1. Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, John MT, De Laat A, de Leeuw R, Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, Smith B, Visscher CM, Zakrzewska J, Dworkin SF; International Rdc/Tmd Consortium Network IafDR, Orofacial Pain Special Interest Group IAftSoP. Diagnostic criteria for temporomandibular disorders (DC/TMD) for clinical and research applications: recommendations of the international RDC/TMD consortium network* and orofacial pain special interest groupdagger. J Oral Facial Pain Headache 2014;28:6–27.
    1. Seminowicz DA, Thapa T, Schabrun SM. Corticomotor depression is associated with higher pain severity in the transition to sustained pain: a longitudinal exploratory study of individual differences. J Pain 2019;20:1498–1506.
    1. Seminowicz DA, Thapa T, Furman A, Summers S, Cavaleri R, Fogarty J, Steiner G, Schabrun SM. Slow peak alpha frequency and corticomotor depression linked to high pain susceptibility in transition to sustained pain. bioRXiv 2017. doi: 10.1101/278598.
    1. Slade GD, Bair E, Greenspan JD, Dubner R, Fillingim RB, Diatchenko L, Maixner W, Knott C, Ohrbach R. Signs and symptoms of first-onset TMD and sociodemographic predictors of its development: the OPPERA prospective cohort study. J Pain 2013;14:T20–32 e21-23.
    1. Slade GD, Conrad MS, Diatchenko L, Rashid NU, Zhong S, Smith S, Rhodes J, Medvedev A, Makarov S, Maixner W, Nackley AG. Cytokine biomarkers and chronic pain: association of genes, transcription, and circulating proteins with temporomandibular disorders and widespread palpation tenderness. PAIN 2011;152:2802–12.
    1. Slade GD, Ohrbach R, Greenspan JD, Fillingim RB, Bair E, Sanders AE, Dubner R, Diatchenko L, Meloto CB, Smith S, Maixner W. Painful temporomandibular disorder: decade of discovery from OPPERA studies. J Dent Res 2016;95:1084–92.
    1. Slade GD, Sanders AE, Ohrbach R, Fillingim RB, Dubner R, Gracely RH, Bair E, Maixner W, Greenspan JD. Pressure pain thresholds fluctuate with, but do not usefully predict, the clinical course of painful temporomandibular disorder. PAIN 2014;155:2134–43.
    1. Smith SB, Maixner DW, Greenspan JD, Dubner R, Fillingim RB, Ohrbach R, Knott C, Slade GD, Bair E, Gibson DG, Zaykin DV, Weir BS, Maixner W, Diatchenko L. Potential genetic risk factors for chronic TMD: genetic associations from the OPPERA case control study. J Pain 2011;12:T92–101.
    1. Smith SM, Dworkin RH, Turk DC, Baron R, Polydefkis M, Tracey I, Borsook D, Edwards RR, Harris RE, Wager TD, Arendt-Nielsen L, Burke LB, Carr DB, Chappell A, Farrar JT, Freeman R, Gilron I, Goli V, Haeussler J, Jensen T, Katz NP, Kent J, Kopecky EA, Lee DA, Maixner W, Markman JD, McArthur JC, McDermott MP, Parvathenani L, Raja SN, Rappaport BA, Rice ASC, Rowbotham MC, Tobias JK, Wasan AD, Witter J. The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT considerations. J Pain 2017;18:757–77.
    1. Stepan L, Shaw CL, Oue S. Temporomandibular disorder in otolaryngology: systematic review. J Laryngol Otol 2017;131:S50–6.
    1. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess 1995;7:524–32.
    1. Svensson P, Wang MW, Dong XD, Kumar U, Cairns BE. Human nerve growth factor sensitizes masseter muscle nociceptors in female rats. PAIN 2010;148:473–80.
    1. Tan G, Jensen MP, Thornby JI, Shanti BF. Validation of the brief pain inventory for chronic nonmalignant pain. J Pain 2004;5:133–7.
    1. Taylor JM. Psychometric analysis of the Ten-item perceived stress scale. Psychol Assess 2015;27:90–101.
    1. van de Ruit M, Perenboom MJ, Grey MJ. TMS brain mapping in less than two minutes. Brain Stimul 2015;8:231–9.
    1. van Diepen RM, Mazaheri A. Cross-sensory modulation of alpha oscillatory activity: suppression, idling, and default resource allocation. Eur J Neurosci 2017;45:1431–8.
    1. Walton KD, Dubois M, Llinas RR. Abnormal thalamocortical activity in patients with complex regional pain syndrome (CRPS) type I. Pain 2010;150:41–51.
    1. Ware JKM, Dewey J, Gandek B. How to score and interpret single-item health status measures: A manual for users of the SF-8 health Survey. Boston: QualyMetric, 2001.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi