title: Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.
abstract: Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAAreceptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAAreceptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAAreceptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAAreceptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain.
  
  
  
  Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAAreceptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAAreceptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0C7, Canada, florence.pomares@gmail.com.|Faculty of Dentistry, McGill University, Montreal, Quebec H3A 0C7, Canada.
authors.forename: Florence B
authors.identifier: 0000-0002-1139-9825
authors.initials: FB
authors.lastname: Pomares
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Funck
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0C7, Canada.
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Feier
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0C7, Canada.
authors.forename: Steven
authors.identifier: 0000-0001-5559-4625
authors.initials: S
authors.lastname: Roy
authors.affiliation: Institute for Biomedical Engineering, École Polytechnique, Montreal, Quebec H3T 1J4, Canada.
authors.forename: Alexandre
authors.identifier: 0000-0002-1981-5758
authors.initials: A
authors.lastname: Daigle-Martel
authors.affiliation: Institute of Cognitive Science, University of Colorado, Boulder, Colorado 80309.
authors.forename: Marta
authors.identifier: 0000-0001-8679-8145
authors.initials: M
authors.lastname: Ceko
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
authors.forename: Sridar
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
authors.forename: David
authors.identifier: 0000-0002-1600-6138
authors.initials: D
authors.lastname: Araujo
authors.affiliation: Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec H3A 0C7, Canada.|Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Thiel
authors.affiliation: Institute for Biomedical Engineering, École Polytechnique, Montreal, Quebec H3T 1J4, Canada.|Montreal Heart Institute, Montreal, Quebec, H1T 1C8, Canada.
authors.forename: Nikola
authors.initials: N
authors.lastname: Stikov
authors.affiliation: Division of Rheumatology, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.|Alan Edwards Pain Management Unit, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada, and.
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Fitzcharles
authors.affiliation: Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 0C7, Canada.|Faculty of Dentistry, McGill University, Montreal, Quebec H3A 0C7, Canada.|Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec H3A 0C7, Canada.|Interdisciplinary Spinal Research, Department of Chiropractic Medicine, University Hospital Balgrist, 8008 Zurich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Schweinhardt
mesh_terms: D000368:Aged; D001834:Body Water / Q000378:metabolism; D001923:Brain Chemistry; D059350:Chronic Pain / Q000000981:diagnostic imaging / Q000523:psychology; D005260:Female; D005356:Fibromyalgia / Q000000981:diagnostic imaging* / Q000523:psychology; D005442:Flumazenil / Q000031:analogs & derivatives; D066128:Gray Matter / Q000737:chemistry / Q000000981:diagnostic imaging*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods*; D049268:Positron-Emission Tomography; D017698:Postmenopause; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: C483765:2'-fluoroflumazenil; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; D005442:Flumazenil
keywords: chronic pain; flumazenil PET; grey matter; neurodegeneration; voxel-based morphometry