Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate

Nicolas Fayed, Javier Garcia-Campayo, Rosa Magallón, Helena Andrés-Bergareche, Juan V Luciano, Eva Andres, Julián Beltrán, Nicolas Fayed, Javier Garcia-Campayo, Rosa Magallón, Helena Andrés-Bergareche, Juan V Luciano, Eva Andres, Julián Beltrán

Abstract

Introduction: The purpose of this study was to investigate whether single-voxel (SV) proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI) detected differences between fibromyalgia (FM) patients and healthy controls. We also searched for correlations between neuroimaging abnormalities and neuropsychological variables.

Methods: Ten patients with FM and 10 gender- and age-matched control subjects were studied. A neuropsychological examination, DWI, DTI, and proton MRS were performed on the brain areas known to be associated with pain processing.

Results: Compared with healthy controls, FM patients had significantly higher levels of glutamate + glutamine (Glx) (mean ± SD, 10.71 ± 0.50 arbitrary institutional units versus 9.89 ± 1.04; P = 0.049) and higher glutamate + glutamine/creatine (Glx/Cr) ratios (1.90 ± 0.12 versus 1.72 ± 0.23; P = 0.034) in the posterior gyrus. Myoinositol (Ins) levels of the right and left hippocampi were significantly lower in FM patients (4.49 ± 0.74 versus 5.17 ± 0.62; P = 0.008 and 4.91 ± 0.85 versus 6.09 ± 0.78; P = 0.004, respectively). In FM patients, decreased myoinositol/creatine (Ins/Cr) ratios were found in the left sensorimotor area (P = 0.05) and the left hippocampus (P = 0.002) and lower levels of choline (P = 0.019) and N-acetyl aspartate + N-acetyl aspartyl glutamate (NAA + NAG) (P = 0.034) in the left hippocampus. Significant correlations between depression, pain, and global function and the posterior gyrus Glx levels and Glx/Cr ratios were observed.

Conclusions: Glx within the posterior gyrus could be a pathologic factor in FM. Hippocampal dysfunction may be partially responsible for the depressive symptoms of FM. Additional studies with larger samples are required to confirm these preliminary data.

Figures

Figure 1
Figure 1
Voxel placement in the different brain regions. The hippocampus (a, b), thalamus (c, d), posterior gyrus (e), and left sensorimotor (f) (red) after functional magnetic resonance imaging during finger-tapping tasks.
Figure 2
Figure 2
Left hippocampus spectrum. A control patient (a) and a patient with fibromyalgia (FM) (b). For the patient with FM, a decrease in the myoinositol peak amplitude and in the relation to creatine was noted. The black line indicates the averaged spectrum; the red line indicates the LCModel fit. The residuals, calculated as a subtraction of the fit from the average spectrum, are plotted at the top.
Figure 3
Figure 3
Axial images showing the different locations of the equal-sized regions of interest (ROIs). The ROI placements for the periaqueductal gray and amygdale (a), the orbitofrontal cortex and insular cortex (b), the internal capsule and ventral and dorsolateral thalamus (c), the gyrus cortex and corpus callosum (d), the frontal white matter, parietal white matter, and dorsolateral prefrontal cortex (e), and the sensorimotor area (f).
Figure 4
Figure 4
Scatterplot of the correlations between brain metabolites and psychological variables in patients with FM. FIQ, Fibromyalgia Impact Questionnaire; Glx, glutamate+glutamine; Glx-Cr, glutamate+glutamine/creatine; HADS-dep: Hospital Anxiety Depression Scale (depression subscale); Sphig, pain assessed with sphygmomanometer (the pressure that is needed to evoke pain). Blue circles represent patients with FM.

References

    1. Wolfe F, Smythe HA, Yunus MB, Bennet RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM. The American College of Rheumatology 1990 Criteria for the classification of fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160–172. doi: 10.1002/art.1780330203.
    1. Wolfe F, Ross K, Anderson J, Russell IJ. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38:19–28. doi: 10.1002/art.1780380104.
    1. Wolfe F. Fibromyalgia, the clinical syndrome. Rheum Dis Clin North Am. 1989;15:1–18.
    1. García Campayo J, Magdalena J, Magallón R, Fernandez-García E, Salas M, Andrés E. A meta-analysis of the efficacy of fibromyalgia treatment according to level of care. Arthritis Res Ther. 2008;10:R81. doi: 10.1186/ar2455.
    1. García Campayo J, Fayed N, Serrano-Blanco A, Roca M. Brain dysfunction behind functional symptoms: neuroimaging and somatoform, conversive, and dissociative disorders. Curr Opin Psychiatry. 2009;22:224–231. doi: 10.1097/YCO.0b013e3283252d43.
    1. Jones AK, Brown WD, Friston KJ, Qi LY, Frackowiak RS. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc Biol Sci. 1991;244:39–44. doi: 10.1098/rspb.1991.0048.
    1. Kwiatek R, Barnden L, Tedman R, Jarrett R, Chew J, Rowe C, Pile K. Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum. 2000;43:2823–2833. doi: 10.1002/1529-0131(200012)43:12<2823::AID-ANR24>;2-E.
    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. Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol. 2004;31:364–378.
    1. Lutz J, Jäger L, de Quervain D, Krauseneck T, Padberg F, Wichnalek M, Beyer A, Stahl R, Zirngibl B, Morhard D, Reiser M, Schelling G. White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study. Arthritis Rheum. 2008;58:3960–3969. doi: 10.1002/art.24070.
    1. Hadjipavlou G, Dunckley P, Behrens TE, Tracey I. Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: a diffusion tensor imaging study in healthy controls. Pain. 2006;123:169–178. doi: 10.1016/j.pain.2006.02.027.
    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. 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. Basser PJ, Pierpaoli C. Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B. 1996;111:209–219. doi: 10.1006/jmrb.1996.0086.
    1. Jones DK, Williams SC, Gasston D, Horsfield MA, Simmons A, Howard R. Isotropic resolution diffusion tensor imaging with whole brain acquisition in a clinically acceptable time. Hum Brain Mapp. 2002;15:216–230. doi: 10.1002/hbm.10018.
    1. Sundgren PC, Petrou M, Harris RE, Fan X, Foerster B, Mehrotra N, Sen A, Clauw DJ, Welsh RC. Diffusion-weighted and diffusion tensor imaging in fibromyalgia patients: a prospective study of whole brain diffusivity, apparent diffusion coefficient, and fraction anisotropy in different regions of the brain and correlation with symptom severity. Acad Radiol. 2007;14:839–846. doi: 10.1016/j.acra.2007.03.015.
    1. Gordis L. In: Epidemiology. Gordis L, editor. Philadelphia: WB Saunders; 1996. Case-control and cross-sectional studies; pp. 124–140.
    1. Sullivan MJ, Bishop S, Pivik J. The Pain Catastrophizing Scale: development and validation. Psychol Assess. 1995;7:524–532. doi: 10.1037/1040-3590.7.4.524.
    1. García Campayo J, Rodero B, Alda M, Sobradiel N, Montero J, Moreno S. Validación de la versión española de la Escala de Catastrofización ante el Dolor en la fibromialgia. Med Clin (Barc) 2008;131:487–492. doi: 10.1157/13127277.
    1. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983;67:361–370. doi: 10.1111/j.1600-0447.1983.tb09716.x.
    1. Tejero A, Guimerá EM, Farré JM, Peri JM. Uso clínico del HAD (Hospital Anxiety and Depression Scale) en población psiquiátrica: un estudio de su sensibilidad, fiabilidad y validez. Rev Dep Psiquiatr Fac Med Barc. 1986;13:233–238.
    1. Huskisson EC. In: Pain Measurement and Assessment. Melzack R, editor. New York: Raven; 1983. Visual analog scales; pp. 33–37.
    1. Vargas A, Vargas A, Hernández-Paz R, Sánchez-Huerta JM, Romero-Ramírez R, Amezcua-Guerra L, Kooh M, Nava A, Pineda C, Rodríguez-Leal G, Martínez-Lavín M. Sphygmomanometry-evoked allodynia: a simple bedside test indicative of fibromyalgia: a multicenter developmental study. J Clin Rheumatol. 2006;12:272–274. doi: 10.1097/01.rhu.0000249770.86652.3b.
    1. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–198. doi: 10.1016/0022-3956(75)90026-6.
    1. Lobo A, Saz P, Marcos G, Día JL, de la Cámara C, Ventura T, Morales Asín F, Fernando Pascual L, Montañés JA, Aznar S. Revalidation and standardization of the cognition mini-exam (first Spanish version of the Mini-Mental Status Examination) in the general geriatric population. Med Clin (Barc) 1999;112:767–774.
    1. Burckhardt CS, Clark SR, Bennet RM. The Fibromyalgia Impact Questionnaire: development and validation. J Rheumatol. 1991;18:728–733.
    1. Rivera J, Gonzalez T. The Fibromyalgia Impact Questionnaire: a validated Spanish version to assess the health status in women with fibromyalgia. Clin Exp Rheumatol. 2004;22:554–560.
    1. Adalsteinsson E, Sullivan EV, Kleinhans N, Spielman DM, Pfefferbaum A. Longitudinal decline of the neuronal marker N-acetyl aspartate in Alzheimer's disease. Lancet. 2000;355:1696–1697. doi: 10.1016/S0140-6736(00)02246-7.
    1. Kantarci K, Weigand SD, Petersen RC, Boeve BF, Knopman DS, Gunter J, Reyes D, Shiung M, O'Brien PC, Smith GE, Ivnik RJ, Tangalos EG, Jack CR Jr. Longitudinal 1 H MRS changes in mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2007;28:1330–1339. doi: 10.1016/j.neurobiolaging.2006.06.018.
    1. Fayed N, Dávila J, Oliveros A Jr, Medrano J, Castillo J. Correlation of findings in advanced MR techniques with global severity scales in patients with some grade of cognitive impairment. Neurol Res. 2010;32:157–165. doi: 10.1179/174313209X405164.
    1. Provencher SW. Estimation of metabolite concentrations from localised in vivo proton NMR spectra. Magn Reson Med. 1993;30:672–679. doi: 10.1002/mrm.1910300604.
    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. Fayed N, Modrego PJ, Medrano J. Comparative test-retest reliability of metabolite values assessed with magnetic resonance spectroscopy of the brain: the LCModel versus the manufacturer software. Neurol Res. 2009;31:472–477. doi: 10.1179/174313209X395481.
    1. Coyle JT, Bird SJ, Evans RH, Gulley RL, Nadler JV, Nicklas WJ, Olney JW. Excitatory amino acid neurotoxins: selectively and mechanisms of action. Based on an NRP one-day conference held June 30, 1980. Neurosci Res Program Bull. 1981;19:1–427.
    1. Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets. 2007;6:219–233. doi: 10.2174/187152707780619326.
    1. Yildiz-Yesiloglu A, Ankerst DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:969–995. doi: 10.1016/j.pnpbp.2006.03.012.
    1. Dickenson AH. Gate Control Theory of pain stands the test of time. Br J Anaesth. 2002;88:755–757. doi: 10.1093/bja/88.6.755.
    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. Häussinger D, Kircheis G, Fischer R, Schliess F, vom Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol. 2000;32:1035–1038. doi: 10.1016/S0168-8278(00)80110-5.
    1. Cordoba J, Blei AT. Brain edema and hepatic encephalopathy. Semin Liver Dis. 1996;16:271–280. doi: 10.1055/s-2007-1007240.
    1. Mullins PG, Rowland LM, Jung RE, Sibbitt WL Jr. A novel technique to study the brain's response to pain: proton magnetic resonance spectroscopy. Neuroimage. 2005;26:642–646. doi: 10.1016/j.neuroimage.2005.02.001.
    1. Córdoba J, Sanpedro F, Alonso J, Rovira A. 1 H magnetic resonance in the study of hepatic encephalopathy in humans. Metab Brain Dis. 2002;17:415–429. doi: 10.1023/A:1021926405944.
    1. Bosman DK, Deutz NE, De Graaf AA, Van der Hulst RWN, Van Eijk HM, Bovee WM. Changes in brain metabolism during hyperammonemia and acute liver failure: results of a comparative 1 H NMR spectroscopy and biochemical investigation. Hepatology. 1990;12:281–290. doi: 10.1002/hep.1840120215.
    1. Kreis R, Ross BD, Farrow NA, Ackerman Z. Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy. Radiology. 1992;182:19–27.
    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. AJNR Am J Neuroradiol. 2008;29:913–918. doi: 10.3174/ajnr.A0959.
    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.
    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. Ogura A, Miyamoto M, Kudo Y. Neuronal death in vitro: parallelism between survivability of hippocampal neurones and sustained elevation of cytosolic Ca2+ after exposure to glutamate receptor agonist. Exp Brain Res. 1988;73:447–458. doi: 10.1007/BF00406601.
    1. Mattson MP, Murrain M, Guthrie PB, Kater SB. Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture. J Neurosci. 1989;9:3728–3740.
    1. McKenna JE, Melzack R. Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test. Exp Neurol. 2001;172:92–99. doi: 10.1006/exnr.2001.7777.
    1. Silverstone PH, McGrath BM, Kim H. Bipolar disorder and myo-inositol: a review of the magnetic resonance spectroscopy findings. Bipolar Disord. 2005;7:1–10. doi: 10.1111/j.1399-5618.2004.00174.x.
    1. Harwood AJ. Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited. Mol Psychiatry. 2005;10:117–126. doi: 10.1038/sj.mp.4001618.
    1. Barkai IA, Dunner DL, Gross HA, Mayo P, Fieve RR. Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psychiatry. 1978;13:65–72.
    1. Gormsen L, Rosenberg R, Bach FW, Jensen TS. Depression, anxiety, health-related quality of life and pain in patients with chronic fibromyalgia and neuropathic pain. Eur J Pain. 2010;14:127. doi: 10.1016/j.ejpain.2009.03.010. e1-8.

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