Diminished corticomotor excitability in Gulf War Illness related chronic pain symptoms; evidence from TMS study

Karen Lei, Alphonsa Kunnel, Valerie Metzger-Smith, Shahrokh Golshan, Jennifer Javors, Jennie Wei, Roland Lee, Michael Vaninetti, Thomas Rutledge, Albert Leung, Karen Lei, Alphonsa Kunnel, Valerie Metzger-Smith, Shahrokh Golshan, Jennifer Javors, Jennie Wei, Roland Lee, Michael Vaninetti, Thomas Rutledge, Albert Leung

Abstract

Chronic diffuse body pain is unequivocally highly prevalent in Veterans who served in the 1990-91 Persian Gulf War and diagnosed with Gulf War Illness (GWI). Diminished motor cortical excitability, as a measurement of increased resting motor threshold (RMT) with transcranial magnetic stimulation (TMS), is known to be associated with chronic pain conditions. This study compared RMT in Veterans with GWI related diffuse body pain including headache, muscle and joint pain with their military counterparts without GWI related diffuse body pain. Single pulse TMS was administered over the left motor cortex, using anatomical scans of each subject to guide the TMS coil, starting at 25% of maximum stimulator output (MSO) and increasing in steps of 2% until a motor response with a 50 µV peak to peak amplitude, defined as the RMT, was evoked at the contralateral flexor pollicis brevis muscle. RMT was then analyzed using Repeated Measures Analysis of Variance (RM-ANOVA). Veterans with GWI related chronic headaches and body pain (N = 20, all males) had a significantly (P < 0.001) higher average RMT (% ± SD) of 77.2% ± 16.7% compared to age and gender matched military controls (N = 20, all males), whose average was 55.6% ± 8.8%. Veterans with GWI related diffuse body pain demonstrated a state of diminished corticomotor excitability, suggesting a maladaptive supraspinal pain modulatory state. The impact of this observed supraspinal functional impairment on other GWI related symptoms and the potential use of TMS in rectifying this abnormality and providing relief for pain and co-morbid symptoms requires further investigation.Trial registration: This study was registered on January 25, 2017, on ClinicalTrials.gov with the identifier: NCT03030794. Retrospectively registered. https://ichgcp.net/clinical-trials-registry/NCT03030794 .

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Box-and-whisker plot of the minimum value, lower quartile, median, mean, upper quartile, and the maximum value of the resting motor threshold amplitude percentages of veterans in the GWV-HAP and GWV-Control groups. Resting motor threshold was determined using electromyograph recordings on the contralateral flexor pollicis brevis muscle with the TMS coil positioned over the primary motor cortex (M1). GWV-HAP: Veterans in the Gulf War Illness-associated headache and pain group; GWV-Control: Gulf War Veterans not experiencing Gulf War Illness and associated headache and pain; **p < 0.001.

References

    1. White RF, et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: effects of toxicant exposures during deployment. Cortex. 2016;74:449–475. doi: 10.1016/j.cortex.2015.08.022.
    1. Steele L, Sastre A, Gerkovich MM, Cook MR. Complex factors in the etiology of Gulf War illness: wartime exposures and risk factors in veteran subgroups. Environ. Health Perspect. 2012;120:112–118. doi: 10.1289/ehp.1003399.
    1. Rayhan RU, Ravindran MK, Baraniuk JN. Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation. Front. Physiol. 2013;4:181. doi: 10.3389/fphys.2013.00181.
    1. Kuzma JM, Black DW. Chronic widespread pain and psychiatric disorders in veterans of the first Gulf War. Curr. Pain Headache Rep. 2006;10:85–89. doi: 10.1007/s11916-006-0017-z.
    1. Lei K, Metzger-Smith V, Golshan S, Javors J, Leung A. The prevalence of headaches, pain, and other associated symptoms in different Persian Gulf deployment periods and deployment durations. SAGE Open Med. 2019;7:2050312119871418. doi: 10.1177/2050312119871418.
    1. Galhardoni R, et al. Altered cortical excitability in persistent idiopathic facial pain. Cephalalgia. 2019;39:219–228. doi: 10.1177/0333102418780426.
    1. Schabrun SM, Burns E, Thapa T, Hodges P. The response of the primary motor cortex to neuromodulation is altered in chronic low back pain: a preliminary study. Pain Med. 2018;19:1227–1236. doi: 10.1093/pm/pnx168.
    1. Thibaut A, Zeng D, Caumo W, Liu J, Fregni F. Corticospinal excitability as a biomarker of myofascial pain syndrome. Pain Rep. 2017;2:e594. doi: 10.1097/PR9.0000000000000594.
    1. Cosentino G, et al. Cyclical changes of cortical excitability and metaplasticity in migraine: evidence from a repetitive transcranial magnetic stimulation study. Pain. 2014;155:1070–1078. doi: 10.1016/j.pain.2014.02.024.
    1. Castillo Saavedra L, Mendonca M, Fregni F. Role of the primary motor cortex in the maintenance and treatment of pain in fibromyalgia. Med. Hypotheses. 2014;83:332–336. doi: 10.1016/j.mehy.2014.06.007.
    1. Granovsky Y, Sprecher E, Sinai A. Motor corticospinal excitability: a novel facet of pain modulation? Pain Rep. 2019;4:e725. doi: 10.1097/PR9.0000000000000725.
    1. Bushnell MC, Ceko M, Low LA. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 2013;14:502–511. doi: 10.1038/nrn3516.
    1. Leung A, et al. Diminished supraspinal pain modulation in patients with mild traumatic brain injury. Mol. Pain. 2016 doi: 10.1177/1744806916662661.
    1. Parker RS, Lewis GN, Rice DA, McNair PJ. Is motor cortical excitability altered in people with chronic pain? A systematic review and meta-analysis. Brain Stimul. 2016;9:488–500. doi: 10.1016/j.brs.2016.03.020.
    1. Badawy RA, Loetscher T, Macdonell RA, Brodtmann A. Cortical excitability and neurology: insights into the pathophysiology. Funct. Neurol. 2012;27:131–145.
    1. King R, et al. Longitudinal assessment of cortical excitability in children and adolescents with mild traumatic brain injury and persistent post-concussive symptoms. Front. Neurol. 2019;10:451. doi: 10.3389/fneur.2019.00451.
    1. Li M, et al. Effect of electro-acupuncture on lateralization of the human swallowing motor cortex excitability in healthy subjects: study protocol for a single-blind, randomized controlled trial. Trials. 2019;20:180. doi: 10.1186/s13063-019-3267-x.
    1. Du J, et al. Aberrances of cortex excitability and connectivity underlying motor deficit in acute stroke. Neural Plast. 2018;2018:1318093. doi: 10.1155/2018/1318093.
    1. Brighina F, Palermo A, Daniele O, Aloisio A, Fierro B. High-frequency transcranial magnetic stimulation on motor cortex of patients affected by migraine with aura: a way to restore normal cortical excitability? Cephalalgia. 2010;30:46–52. doi: 10.1111/j.1468-2982.2009.01870.x.
    1. Chistyakov AV, et al. Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: a double-blind sham-controlled study. J. Affect. Disord. 2015;170:225–229. doi: 10.1016/j.jad.2014.08.035.
    1. Fierro B, et al. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) during capsaicin-induced pain: modulatory effects on motor cortex excitability. Exp. Brain Res. 2010;203:31–38. doi: 10.1007/s00221-010-2206-6.
    1. Lefaucheur JP, et al. Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: influence of theta burst stimulation priming. Eur. J. Pain. 2012;16:1403–1413. doi: 10.1002/j.1532-2149.2012.00150.x.
    1. Fukuda K, et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998;280:981–988. doi: 10.1001/jama.280.11.981.
    1. Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am. J. Epidemiol. 2000;152:992–1002. doi: 10.1093/aje/152.10.992.
    1. Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia38, 1–211, doi: 10.1177/0333102417738202 (2018).
    1. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J. Clin. Nurs. 2005;14:798–804. doi: 10.1111/j.1365-2702.2005.01121.x.
    1. Reijonen J, Saisanen L, Kononen M, Mohammadi A, Julkunen P. The effect of coil placement and orientation on the assessment of focal excitability in motor mapping with navigated transcranial magnetic stimulation. J. Neurosci. Methods. 2020;331:108521. doi: 10.1016/j.jneumeth.2019.108521.
    1. Leung A, et al. Left dorsolateral prefrontal cortex rTMS in alleviating MTBI related headaches and depressive symptoms. Neuromodulation. 2018;21:390–401. doi: 10.1111/ner.12615.
    1. Leung A, et al. Repetitive transcranial magnetic stimulation in managing mild traumatic brain injury-related headaches. Neuromodulation. 2015 doi: 10.1111/ner.12364.
    1. Khedr EM, et al. Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain. J. Neurol. Neurosurg. Psychiatry. 2005;76:833–838. doi: 10.1136/jnnp.2004.055806.
    1. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain. 2005;9:463–484. doi: 10.1016/j.ejpain.2004.11.001.
    1. Tracey I. Nociceptive processing in the human brain. Curr. Opin. Neurobiol. 2005;15:478–487. doi: 10.1016/j.conb.2005.06.010.
    1. Neugebauer V, Galhardo V, Maione S, Mackey SC. Forebrain pain mechanisms. Brain Res. Rev. 2009;60:226–242. doi: 10.1016/j.brainresrev.2008.12.014.
    1. Tracey I. Neuroimaging of pain mechanisms. Curr. Opin. Support Palliat Care. 2007;1:109–116. doi: 10.1097/SPC.0b013e3282efc58b.
    1. Seifert F, et al. A functional magnetic resonance imaging navigated repetitive transcranial magnetic stimulation study of the posterior parietal cortex in normal pain and hyperalgesia. Neuroscience. 2010;170:670–677. doi: 10.1016/j.neuroscience.2010.07.024.
    1. Moulton EA, Pendse G, Becerra LR, Borsook D. BOLD responses in somatosensory cortices better reflect heat sensation than pain. J. Neurosci. 2012;32:6024–6031. doi: 10.1523/JNEUROSCI.0006-12.2012.
    1. Mhalla A, de Andrade DC, Baudic S, Perrot S, Bouhassira D. Alteration of cortical excitability in patients with fibromyalgia. Pain. 2010;149:495–500. doi: 10.1016/j.pain.2010.03.009.
    1. Van Riper SM, et al. Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain. Pain. 2017;158:2364–2375. doi: 10.1097/j.pain.0000000000001038.
    1. Rayhan RU, et al. Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness. PLoS ONE. 2013;8:e58493. doi: 10.1371/journal.pone.0058493.
    1. Voss HU, et al. Possible axonal regrowth in late recovery from the minimally conscious state. J. Clin. Investig. 2006;116:2005–2011. doi: 10.1172/JCI27021.
    1. Bosch B, et al. Multiple DTI index analysis in normal aging, amnestic MCI and AD. Relationship with neuropsychological performance. Neurobiol. Aging. 2012;33:61–74. doi: 10.1016/j.neurobiolaging.2010.02.004.
    1. Taylor WD, MacFall JR, Gerig G, Krishnan RR. Structural integrity of the uncinate fasciculus in geriatric depression: relationship with age of onset. Neuropsychiatr. Dis. Treat. 2007;3:669–674.
    1. Pardini M, Krueger F, Raymont V, Grafman J. Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury. Neurology. 2010;74:749–754. doi: 10.1212/WNL.0b013e3181d25b6b.
    1. Tajima S, et al. Medial orbitofrontal cortex is associated with fatigue sensation. Neurol. Res. Int. 2010;2010:671421. doi: 10.1155/2010/671421.
    1. Aron AR, Fletcher PC, Bullmore ET, Sahakian BJ, Robbins TW. Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nat. Neurosci. 2003;6:115–116. doi: 10.1038/nn1003.
    1. Weissman DH, Prado J. Heightened activity in a key region of the ventral attention network is linked to reduced activity in a key region of the dorsal attention network during unexpected shifts of covert visual spatial attention. Neuroimage. 2012;61:798–804. doi: 10.1016/j.neuroimage.2012.03.032.
    1. Matsushita M, Hosoda K, Naitoh Y, Yamashita H, Kohmura E. Utility of diffusion tensor imaging in the acute stage of mild to moderate traumatic brain injury for detecting white matter lesions and predicting long-term cognitive function in adults. J. Neurosurg. 2011;115:130–139. doi: 10.3171/2011.2.JNS101547.
    1. Gu L, et al. Detection of white matter lesions in the acute stage of diffuse axonal injury predicts long-term cognitive impairments: a clinical diffusion tensor imaging study. J. Trauma Acute Care Surg. 2013;74:242–247. doi: 10.1097/TA.0b013e3182684fe8.
    1. Caeyenberghs K, Siugzdaite R, Drijkoningen D, Marinazzo D, Swinnen SP. Functional connectivity density and balance in young patients with traumatic axonal injury. Brain Connect. 2015;5:423–432. doi: 10.1089/brain.2014.0293.
    1. Levin HS, et al. Mental state attributions and diffusion tensor imaging after traumatic brain injury in children. Dev. Neuropsychol. 2011;36:273–287. doi: 10.1080/87565641.2010.549885.
    1. Ljubisavljevic M, et al. Central changes in muscle fatigue during sustained submaximal isometric voluntary contraction as revealed by transcranial magnetic stimulation. Electroencephalogr. Clin. Neurophysiol. 1996;101:281–288. doi: 10.1016/0924-980x(96)95627-1.
    1. Pal D, et al. Diffusion tensor tractography indices in patients with frontal lobe injury and its correlation with neuropsychological tests. Clin. Neurol. Neurosurg. 2012;114:564–571. doi: 10.1016/j.clineuro.2011.12.002.
    1. Palacios EM, et al. Diffusion tensor imaging differences relate to memory deficits in diffuse traumatic brain injury. BMC Neurol. 2011;11:24. doi: 10.1186/1471-2377-11-24.
    1. Tallus J, Lioumis P, Hamalainen H, Kahkonen S, Tenovuo O. Long-lasting TMS motor threshold elevation in mild traumatic brain injury. Acta Neurol. Scand. 2012;126:178–182. doi: 10.1111/j.1600-0404.2011.01623.x.
    1. Tallus J, Lioumis P, Hamalainen H, Kahkonen S, Tenovuo O. Transcranial magnetic stimulation-electroencephalography responses in recovered and symptomatic mild traumatic brain injury. J. Neurotrauma. 2013;30:1270–1277. doi: 10.1089/neu.2012.2760.
    1. Bernabeu M, et al. Abnormal corticospinal excitability in traumatic diffuse axonal brain injury. J. Neurotrauma. 2009;26:2185–2193. doi: 10.1089/neu.2008.0859.
    1. Ah Sen CB, et al. Active and resting motor threshold are efficiently obtained with adaptive threshold hunting. PLoS ONE. 2017;12:e0186007. doi: 10.1371/journal.pone.0186007.
    1. Amourette C, et al. Gulf War illness: effects of repeated stress and pyridostigmine treatment on blood-brain barrier permeability and cholinesterase activity in rat brain. Behav. Brain Res. 2009;203:207–214. doi: 10.1016/j.bbr.2009.05.002.
    1. Ferguson E, Cassaday HJ. Theoretical accounts of Gulf War Syndrome: from environmental toxins to psychoneuroimmunology and neurodegeneration. Behav. Neurol. 2001;13:133–147. doi: 10.1155/2002/418758.
    1. Lewine JD, et al. Objective documentation of traumatic brain injury subsequent to mild head trauma: multimodal brain imaging with MEG, SPECT, and MRI. J. Head Trauma Rehabil. 2007;22:141–155. doi: 10.1097/01.HTR.0000271115.29954.27.
    1. George MS, Taylor JJ, Short EB. The expanding evidence base for rTMS treatment of depression. Curr. Opin. Psychiatry. 2013;26:13–18. doi: 10.1097/YCO.0b013e32835ab46d.
    1. Lipton RB, Pearlman SH. Transcranial magnetic simulation in the treatment of migraine. Neurotherapeutics. 2010;7:204–212. doi: 10.1016/j.nurt.2010.03.002.
    1. Lefaucheur JP, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) Clin. Neurophysiol. 2014;125:2150–2206. doi: 10.1016/j.clinph.2014.05.021.
    1. Leung A, et al. rTMS in alleviating mild TBI related headaches–a case series. Pain Physician. 2016;19:E347–354. doi: 10.36076/ppj/2016.19.E347.
    1. Leung A, et al. Repetitive transcranial magnetic stimulation in managing mild traumatic brain injury-related headaches. Neuromodulation. 2016;19:133–141. doi: 10.1111/ner.12364.
    1. Fumal A, et al. Induction of long-lasting changes of visual cortex excitability by five daily sessions of repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers and migraine patients. Cephalalgia. 2006;26:143–149. doi: 10.1111/j.1468-2982.2005.01013.x.
    1. Hosomi K, et al. Cortical excitability changes after high-frequency repetitive transcranial magnetic stimulation for central poststroke pain. Pain. 2013;154:1352–1357. doi: 10.1016/j.pain.2013.04.017.
    1. Coughlin SS, et al. A review of epidemiologic studies of the health of gulf war women veterans. J. Environ. Health Sci. 2017 doi: 10.15436/2378-6841.17.1551.
    1. Nahin RL. Severe pain in veterans: the effect of age and sex, and comparisons with the general population. J. Pain. 2017;18:247–254. doi: 10.1016/j.jpain.2016.10.021.
    1. Haskell SG, Heapy A, Reid MC, Papas RK, Kerns RD. The prevalence and age-related characteristics of pain in a sample of women veterans receiving primary care. J. Womens Health (Larchmt) 2006;15:862–869. doi: 10.1089/jwh.2006.15.862.
    1. Ly JQM, et al. Circadian regulation of human cortical excitability. Nat. Commun. 2016;7:11828. doi: 10.1038/ncomms11828.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner