What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of 'centralized' pain?

Vitaly Napadow, Richard E Harris, Vitaly Napadow, Richard E Harris

Abstract

Research suggests that fibromyalgia is a central, widespread pain syndrome supported by a generalized disturbance in central nervous system pain processing. Over the past decades, multiple lines of research have identified the locus for many functional, chronic pain disorders to the central nervous system, and the brain. In recent years, brain neuroimaging techniques have heralded a revolution in our understanding of chronic pain, as they have allowed researchers to non-invasively (or minimally invasively) evaluate human patients suffering from various pain disorders. While many neuroimaging techniques have been developed, growing interest in two specific imaging modalities has led to significant contributions to chronic pain research. For instance, resting functional connectivity magnetic resonance imaging (fcMRI) is a recent adaptation of fMRI that examines intrinsic brain connectivity - defined as synchronous oscillations of the fMRI signal that occurs in the resting basal state. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive magnetic resonance imaging technique that can quantify the concentration of multiple metabolites within the human brain. This review will outline recent applications of the complementary imaging techniques - fcMRI and 1H-MRS - to improve our understanding of fibromyalgia pathophysiology and how pharmacological and non-pharmacological therapies contribute to analgesia in these patients. A better understanding of the brain in chronic pain, with specific linkage as to which neural processes relate to spontaneous pain perception and hyperalgesia, will greatly improve our ability to develop novel therapeutics. Neuroimaging will play a growing role in the translational research approaches needed to make this a reality.

References

    1. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38:19–28. doi: 10.1002/art.1780380104.
    1. Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL, Russell IJ, Yunus MB. A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia. Arthritis Rheum. 1997;40:1560–1570. doi: 10.1002/art.1780400904.
    1. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333–1343. doi: 10.1002/art.10225.
    1. Harris RE, Clauw DJ, Scott DJ, McLean SA, Gracely RH, Zubieta JK. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci. 2007;27:10000–10006. doi: 10.1523/JNEUROSCI.2849-07.2007.
    1. Yunus MB. Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation. J Rheumatol. 1992;19:846–850.
    1. Krienen FM, Buckner RL. Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. CerebCortex. 2009;19:2485–2497.
    1. Raichle ME. A paradigm shift in functional brain imaging. J Neurosci. 2009;29:12729–12734. doi: 10.1523/JNEUROSCI.4366-09.2009.
    1. Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8:700–711. doi: 10.1038/nrn2201.
    1. Buckner RL, Vincent JL. Unrest at rest: default activity and spontaneous network correlations. Neuroimage. 2007;37:1091–1096. doi: 10.1016/j.neuroimage.2007.01.010.
    1. Beckmann CF, DeLuca M, Devlin JT, Smith SM. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci. 2005;360:1001–1013. doi: 10.1098/rstb.2005.1634.
    1. Bandettini PA. What's new in neuroimaging methods? Ann N Y Acad Sci. 2009;1156:260–293. doi: 10.1111/j.1749-6632.2009.04420.x.
    1. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995;34:537–541. doi: 10.1002/mrm.1910340409.
    1. Beckmann CF, DeLuca M, Devlin JT, Smith SM. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci. 2005;360:1001–1013. doi: 10.1098/rstb.2005.1634.
    1. de Graaf RA. In Vivo NMR Spectroscopy: Principles and Techniques. New York: John Wiley & Sons; 1998.
    1. Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed. 2001;14:260–264. doi: 10.1002/nbm.698.
    1. Ross AJ, Sachdev PS. Magnetic resonance spectroscopy in cognitive research. Brain Res Brain Res Rev. 2004;44:83–102. doi: 10.1016/j.brainresrev.2003.11.001.
    1. Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol. 2007;81:89–131. doi: 10.1016/j.pneurobio.2006.12.003.
    1. Grachev ID, Apkarian AV. Multi-chemical networking profile of the living human brain: potential relevance to molecular studies of cognition and behavior in normal and diseased brain. J Neural Transm. 2002;109:15–33. doi: 10.1007/s702-002-8233-y.
    1. Pattany PM, Yezierski RP, Widerstrom-Noga EG, Bowen BC, Martinez-Arizala A, Garcia BR, Quencer RM. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. Am J Neuroradiol. 2002;23:901–905.
    1. Gu T, Ma XX, Xu YH, Xiu JJ, Li CF. Metabolite concentration ratios in thalami of patients with migraine and trigeminal neuralgia measured with 1H-MRS. Neurol Res. 2008;30:229–233. doi: 10.1179/016164107X235473.
    1. Wang SJ, Lirng JF, Fuh JL, Chen JJ. Reduction in hypothalamic 1H-MRS metabolite ratios in patients with cluster headache. J Neurol Neurosurg Psychiatry. 2006;77:622–625. doi: 10.1136/jnnp.2005.081836.
    1. Dichgans M, Herzog J, Freilinger T, Wilke M, Auer DP. 1H-MRS alterations in the cerebellum of patients with familial hemiplegic migraine type 1. Neurology. 2005;64:608–613. doi: 10.1212/01.WNL.0000151855.98318.50.
    1. Fayed N, Garcia-Campayo J, Magallon R, Andres-Bergareche H, Luciano JV, Andres E, Beltran J. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res Ther. 2010;12:R134. doi: 10.1186/ar3072.
    1. Fayed N, Andres E, Rojas G, Moreno S, Serrano-Blanco A, Roca M, Garcia-Campayo J. Brain dysfunction in fibromyalgia and somatization disorder using proton magnetic resonance spectroscopy: a controlled study. Acta Psychiatr Scand. 2012;126:115–125. doi: 10.1111/j.1600-0447.2011.01820.x.
    1. Emad Y, Ragab Y, Zeinhom F, El-Khouly G, Abou-Zeid A, Rasker JJ. Hippocampus dysfunction may explain symptoms of fibromyalgia syndrome. A study with single-voxel magnetic resonance spectroscopy. J Rheumatol. 2008;35:1371–1377.
    1. Wood PB, Ledbetter CR, Glabus MF, Broadwell LK, Patterson JC. Hippocampal metabolite abnormalities in fibromyalgia: correlation with clinical features. J Pain. 2009;10:47–52. doi: 10.1016/j.jpain.2008.07.003.
    1. Aoki Y, Inokuchi R, Suwa H. Reduced N-acetylaspartate in the hippocampus in patients with fibromyalgia: a meta-analysis. Psychiatry Res. 2013;213:242–248. doi: 10.1016/j.pscychresns.2013.03.008.
    1. Petrou M, Harris RE, Foerster BR, McLean SA, Sen A, Clauw DJ, Sundgren PC. Proton MR spectroscopy in the evaluation of cerebral metabolism in patients with fibromyalgia: comparison with healthy controls and correlation with symptom severity. Am J Neuroradiol. 2008;29:913–918. doi: 10.3174/ajnr.A0959.
    1. Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926. doi: 10.1016/j.jpain.2009.06.012.
    1. Harris RE, Sundgren PC, Pang Y, Hsu M, Petrou M, Kim SH, McLean SA, Gracely RH, Clauw DJ. Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia. Arthritis Rheum. 2008;58:903–907. doi: 10.1002/art.23223.
    1. Northoff G, Walter M, Schulte RF, Beck J, Dydak U, Henning A, Boeker H, Grimm S, Boesiger P. GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci. 2007;10:1515–1517. doi: 10.1038/nn2001.
    1. Harris RE, Sundgren PC, Craig AD, Kirshenbaum E, Sen A, Napadow V, Clauw DJ. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum. 2009;60:3146–3152. doi: 10.1002/art.24849.
    1. Valdes M, Collado A, Bargallo N, Vazquez M, Rami L, Gomez E, Salamero M. Increased glutamate/glutamine compounds in the brains of patients with fibromyalgia: a magnetic resonance spectroscopy study. Arthritis Rheum. 2010;62:1829–1836. doi: 10.1002/art.27430.
    1. Fayed N, Garcia-Campayo J, Magallon R, Andres-Bergareche H, Luciano JV, Andres E, Beltran J. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res Ther. 2010;12:R134. doi: 10.1186/ar3072.
    1. Feraco P, Bacci A, Pedrabissi F, Passamonti L, Zampogna G, Malavolta N, Leonardi M. Metabolic abnormalities in pain-processing regions of patients with fibromyalgia: a 3 T MR spectroscopy study. Am J Neuroradiol. 2011;32:1585–1590. doi: 10.3174/ajnr.A2550.
    1. Zhuo M. Cortical excitation and chronic pain. Trends Neurosci. 2008;31:199–207. doi: 10.1016/j.tins.2008.01.003.
    1. Muthukumaraswamy SD, Edden RA, Jones DK, Swettenham JB, Singh KD. Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc Natl Acad Sci U S A. 2009;106:8356–8361. doi: 10.1073/pnas.0900728106.
    1. Potes CS, Neto FL, Castro-Lopes JM. Administration of baclofen, a gamma-aminobutyric acid type B agonist in the thalamic ventrobasal complex, attenuates allodynia in monoarthritic rats subjected to the ankle-bend test. J Neurosci Res. 2006;83:515–523. doi: 10.1002/jnr.20737.
    1. Jasmin L, Rabkin SD, Granato A, Boudah A, Ohara PT. Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature. 2003;424:316–320. doi: 10.1038/nature01808.
    1. Foerster BR, Petrou M, Edden RA, Sundgren PC, Schmidt-Wilcke T, Lowe SE, Harte SE, Clauw DJ, Harris RE. Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum. 2011;64:579–583. doi: 10.1002/art.33339.
    1. Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 2010;62:2545–2555. doi: 10.1002/art.27497.
    1. Buckner RL, Andrews-Hanna JR, Schacter DL. The brain's default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci. 2008;1124:1–38. doi: 10.1196/annals.1440.011.
    1. Seminowicz DA, Davis KD. Interactions of pain intensity and cognitive load: the brain stays on task. Cereb Cortex. 2007;17:1412–1422. doi: 10.1093/cercor/bhl052.
    1. Baliki M, Geha P, Apkarian A, Chialvo D. Society for Neuroscience Annual Meeting. San Diego, CA, USA: Society for Neuroscience; 2007. Impaired brain de-activation in chronic pain.
    1. Pujol J, Macia D, Garcia-Fontanals A, Blanco-Hinojo L, Lopez-Sola M, Garcia-Blanco S, Poca-Dias V, Harrison BJ, Contreras-Rodriguez O, Monfort J, Garcia-Fructuoso F, Deus J. The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia. Pain. 2014;155:1492–1503. doi: 10.1016/j.pain.2014.04.028.
    1. Cifre I, Sitges C, Fraiman D, Munoz MA, Balenzuela P, Gonzalez-Roldan A, Martinez-Jauand M, Birbaumer N, Chialvo DR, Montoya P. Disrupted functional connectivity of the pain network in fibromyalgia. Psychosom Med. 2012;74:55–62. doi: 10.1097/PSY.0b013e3182408f04.
    1. Kucyi A, Moayedi M, Weissman-Fogel I, Goldberg MB, Freeman BV, Tenenbaum HC, Davis KD. Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination. J Neurosci. 2014;34:3969–3975. doi: 10.1523/JNEUROSCI.5055-13.2014.
    1. Ceko M, Bushnell MC, Fitzcharles MA, Schweinhardt P. Fibromyalgia interacts with age to change the brain. Neuroimage Clin. 2013;3:249–260. doi: 10.1016/j.nicl.2013.08.015.
    1. Kim JY, Kim SH, Seo J, Kim SH, Han SW, Nam EJ, Kim SK, Lee HJ, Lee SJ, Kim YT, Chang Y. Increased power spectral density in resting-state pain-related brain networks in fibromyalgia. Pain. 2013;154:1792–1797. doi: 10.1016/j.pain.2013.05.040.
    1. Kapogiannis D, Reiter DA, Willette AA, Mattson MP. Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network. Neuroimage. 2013;64:112–119. doi: 10.1016/j.neuroimage.2012.09.029.
    1. Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum. 2012;64:2398–2403. doi: 10.1002/art.34412.
    1. Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, Sundgren PC, Foerster B, Petrou M, Schmidt-Wilcke T, Clauw DJ. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology. 2013;119:1453–1464. doi: 10.1097/ALN.0000000000000017.
    1. Kim J, Van Dijk KR, Libby A, Napadow V. Frequency-dependent relationship between resting-state functional magnetic resonance imaging signal power and head motion is localized within distributed association networks. Brain Connect. 2013;4:30–39.

Source: PubMed

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