Advertisement

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia

  • Arpana Gupta
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Davis C. Woodworth
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Benjamin M. Ellingson
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Department of Radiology at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Andrea J. Rapkin
    Affiliations
    Department of Obstetrics and Gynecology at UCLA, Los Angeles, California
    Search for articles by this author
  • Bruce Naliboff
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Lisa A. Kilpatrick
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Jean Stains
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California
    Search for articles by this author
  • Salome Masghati
    Affiliations
    Department of Obstetrics and Gynecology at UCLA, Los Angeles, California
    Search for articles by this author
  • Kirsten Tillisch
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Emeran A. Mayer
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
  • Jennifer S. Labus
    Correspondence
    Address reprint requests to Jennifer S. Labus PhD, G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Vatche and Tamar Manoukin Division of Digestive Diseases, David Geffen School of Medicine, UCLA CHS 42-210, 10833 Le Conte Avenue, MC737818, Los Angeles, CA 90095-7378.
    Affiliations
    G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA, Los Angeles, California

    Vatche and Tamar Manoukian Division of Digestive Diseases at UCLA, Los Angeles, California

    David Geffen School of Medicine at UCLA, Los Angeles, California
    Search for articles by this author
Published:February 03, 2018DOI:https://doi.org/10.1016/j.jpain.2017.12.269

      Highlights

      • Alterations in microstructure in provoked vestibulodynia (PVD) were observed.
      • Fibers associated with sensorimotor integration and pain processing were involved.
      • These alterations were associated with increased vaginal muscle tenderness and vulvar pain.
      • These alterations may contribute to increased pain sensitivity and tenderness.
      • These findings highlight the need for new therapies targeting the central nervous system.

      Abstract

      Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs.

      Perspective

      Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system.

      Key words

      To read this article in full you will need to make a payment
      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Alexander A.L.
        • Lee J.E.
        • Lazar M.
        • Field A.S.
        Diffusion tensor imaging of the brain.
        Neurother. 2007; 4: 316-329
        • Andrews J.C.
        Vulvodynia interventions—systematic review and evidence grading.
        Obstet Gynecol Surv. 2011; 66: 299-315
        • Apkarian A.V.
        • Sosa Y.
        • Sonty S.
        • Levy R.M.
        • Harden R.N.
        • Parrish T.B.
        • Gitelman D.R.
        Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.
        J Neurosci. 2004; 24: 10410-10415
        • Bachmann G.A.
        • Rosen R.
        • Pinn V.W.
        • Utian W.H.
        • Ayers C.
        • Basson R.
        • Binik Y.M.
        • Brown C.
        • Foster D.C.
        • Gibbons Jr, J.M.
        • Goldstein I.
        • Graziottin A.
        • Haefner H.K.
        • Harlow B.L.
        • Spadt S.K.
        • Leiblum S.R.
        • Masheb R.M.
        • Reed B.D.
        • Sobel J.D.
        • Veasley C.
        • Wesselmann U.
        • Witkin S.S.
        Vulvodynia: A state-of-the-art consensus on definitions, diagnosis and management.
        J Reprod Med. 2006; 51: 447-456
        • Basson R.
        The recurrent pain and sexual sequelae of provoked vestibulodynia: A perpetuating cycle.
        J Sex Med. 2012; 9: 2077-2092
        • Bergeron S.
        • Brown C.
        • Lord M.J.
        • Oala M.
        • Binik Y.M.
        • Khalife S.
        Physical therapy for vulvar vestibulitis syndrome: A retrospective study.
        J Sex Marital Ther. 2002; 28: 183-192
        • Behrens T.E.
        • Woolrich M.W.
        • Jenkinson M.
        • Johansen-Berg H.
        • Nunes R.G.
        • Clare S.
        • Matthews P.M.
        • Brady J.M.
        • Smith S.M.
        Characterization and propagation of uncertainty in diffusion-weighted MR imaging.
        Magn Reson Med. 2003; 50: 1077-1088
        • Bergeron S.
        • Binik Y.M.
        • Khalife S.
        • Pagidas K.
        • Glazer H.I.
        • Meana M.
        • Amsel R.
        A randomized comparison of group cognitive—behavioral therapy, surface electromyographic biofeedback, and vestibulectomy in the treatment of dyspareunia resulting from vulvar vestibulitis.
        Pain. 2001; 91: 297-306
        • Bohm-Starke N.
        • Hilliges M.
        • Falconer C.
        • Rylander E.
        Increased intraepithelial innervation in women with vulvar vestibulitis syndrome.
        Gynecol Obstet Invest. 1998; 46: 256-260
        • Borsook D.
        • Upadhyay J.
        • Chudler E.H.
        • Becerra L.
        A key role of the basal ganglia in pain and analgesia—insights gained through human functional imaging.
        Mol Pain. 2010; 6: 27
        • Bullmore E.T.
        • Suckling J.
        • Overmeyer S.
        • Rabe-Hesketh S.
        • Taylor E.
        • Brammer M.J.
        Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain.
        IEEE Trans Med Imaging. 1999; 18: 32-42
        • Cavallari M.
        • Ceccarelli A.
        • Wang G.Y.
        • Moscufo N.
        • Hannoun S.
        • Matulis C.R.
        • Jackson J.S.
        • Glanz B.I.
        • Bakshi R.
        • Neema M.
        • Guttmann C.R.
        Microstructural changes in the striatum and their impact on motor and neuropsychological performance in patients with multiple sclerosis.
        PLoS One. 2014; 9: e101199
        • Chan L.L.
        • Rumpel H.
        • Yap K.
        • Lee E.
        • Loo H.V.
        • Ho G.L.
        • Fook-Chong S.
        • Yuen Y.
        • Tan E.K.
        Case control study of diffusion tensor imaging in Parkinson's disease.
        J Neurol Neurosurg Psychiatry. 2007; 78: 1383-1386
        • Chang L.
        • Lee O.Y.
        • Naliboff B.
        • Schmulson M.
        • Mayer E.A.
        Sensation of bloating and visible abdominal distension in patients with irritable bowel syndrome.
        Am J Gastroenterol. 2001; 96: 3341-3347
        • Chen J.Y.
        • Blankstein U.
        • Diamant N.E.
        • Davis K.D.
        White matter abnormalities in irritable bowel syndrome and relation to individual factors.
        Brain Res. 2011; 1392: 121-131
        • Chudler E.H.
        • Dong W.K.
        The role of the basal ganglia in nociception and pain.
        Pain. 1995; 60: 3-38
        • de Belilovsky C.
        2013 vulvodynia update.
        Gynecol Obstet Fertil. 2013; 41: 505-510
        • Deco G.
        • Jirsa V.K.
        • McIntosh A.R.
        Emerging concepts for the dynamical organization of resting-state activity in the brain.
        Nat Rev Neurosci. 2011; 12: 43-56
        • Dostrovsky J.O.
        Role of thalamus in pain.
        Prog Brain Res. 2000; 129: 245-257
        • Drossman D.A.
        The functional gastrointestinal disorders and the Rome III process.
        Gastroenterology. 2006; 130: 1377-1390
        • Ellingson B.M.
        • Mayer E.
        • Harris R.J.
        • Ashe-McNally C.
        • Naliboff B.D.
        • Labus J.S.
        • Tillisch K.
        Diffusion tensor imaging detects microstructural reorganization in the brain associated with chronic irritable bowel syndrome.
        Pain. 2013; 154: 1528-1541
        • Ellingson B.M.
        • Salamon N.
        • Woodworth D.C.
        • Holly L.T.
        Correlation between degree of subvoxel spinal cord compression measured with super-resolution tract density imaging and neurological impairment in cervical spondylotic myelopathy.
        J Neurosurg Spine. 2015; 22: 631-638
        • Falsetta M.L.
        • Foster D.C.
        • Woeller C.F.
        • Pollock S.J.
        • Bonham A.D.
        • Haidaris C.G.
        • Stodgell C.J.
        • Phipps R.P.
        Identification of novel mechanisms involved in generating localized vulvodynia pain.
        Am J Obstet Gynecol. 2015; 213: e1-e12
        • Farmer M.A.
        • Huang L.
        • Martucci K.
        • Yang C.C.
        • Maravilla K.R.
        • Harris R.E.
        • Clauw D.J.
        • Mackey S.
        • Ellingson B.M.
        • Mayer E.A.
        • Schaeffer A.J.
        • Apkarian A.V.
        • Network M.R.
        Brain white matter abnormalities in female interstitial cystitis/bladder pain syndrome: A MAPP network neuroimaging study.
        J Urol. 2015; 194: 118-126
        • Farmer M.A.
        • Maykut C.A.
        • Huberman J.S.
        • Huang L.
        • Khalife S.
        • Binik Y.M.
        • Apkarian A.V.
        • Schweinhardt P.
        Psychophysical properties of female genital sensation.
        Pain. 2013; 154: 2277-2286
        • Ford J.C.
        • Hackney D.B.
        Numerical model for calculation of apparent diffusion coefficients (ADC) in permeable cylinders—comparison with measured ADC in spinal cord white matter.
        Magn Reson Med. 1997; 37: 387-394
        • Ford J.C.
        • Hackney D.B.
        • Lavi E.
        • Phillips M.
        • Patel U.
        Dependence of apparent diffusion coefficients on axonal spacing, membrane permeability, and diffusion time in spinal cord white matter.
        J Magn Reson Imaging. 1998; 8: 775-782
        • Foster D.C.
        • Kotok M.B.
        • Huang L.S.
        • Watts A.
        • Oakes D.
        • Howard F.M.
        • Stodgell C.J.
        • Dworkin R.H.
        The tampon test for vulvodynia treatment outcomes research: Reliability, construct validity, and responsiveness.
        Obstet Gynecol. 2009; 113: 825-832
        • Friedrich Jr, E.G.
        Vulvar vestibulitis syndrome.
        J Reprod Med. 1987; 32: 110-114
        • Gerber S.
        • Witkin S.S.
        • Stucki D.
        Immunological and genetic characterization of women with vulvodynia.
        J Med Life. 2008; 1: 432-438
        • Goldstein A.T.
        • Burrows L.
        Vulvodynia.
        J Sex Med. 2008; 5 (quiz 15): 5-14
        • Gracely R.H.
        • Kwilosz D.M.
        The Descriptor Differential Scale: Applying psychophysical principles to clinical pain assessment.
        Pain. 1988; 35: 279-288
        • Grinberg K.
        • Granot M.
        • Lowenstein L.
        • Abramov L.
        • Weissman-Fogel I.
        A common pronociceptive pain modulation profile typifying subgroups of chronic pelvic pain syndromes is interrelated with enhanced clinical pain.
        Pain. 2017; 158: 1021-1029
        • Gupta A.
        • Rapkin A.J.
        • Gill Z.
        • Kilpatrick L.
        • Fling C.
        • Stains J.
        • Masghati S.
        • Tillisch K.
        • Mayer E.A.
        • Labus J.S.
        Disease-related differences in resting-state networks: A comparison between localized provoked vulvodynia, irritable bowel syndrome, and healthy control subjects.
        Pain. 2015; 156: 809-819
        • Halperin R.
        • Zehavi S.
        • Vaknin Z.
        • Ben-Ami I.
        • Pansky M.
        • Schneider D.
        The major histopathologic characteristics in the vulvar vestibulitis syndrome.
        Gynecol Obstet Invest. 2005; 59: 75-79
        • Hampson J.P.
        • Reed B.D.
        • Clauw D.J.
        • Bhavsar R.
        • Gracely R.H.
        • Haefner H.K.
        • Harris R.E.
        Augmented central pain processing in vulvodynia.
        J Pain. 2013; 14: 579-589
        • Harlow B.L.
        • Stewart E.G.
        A population-based assessment of chronic unexplained vulvar pain: Have we underestimated the prevalence of vulvodynia?.
        J Am Med Womens Assoc. 2003; 58: 82-88
        • Hong J.Y.
        • Kilpatrick L.A.
        • Labus J.
        • Gupta A.
        • Jiang Z.G.
        • Ashe-McNalley C.
        • Stains J.
        • Heendeniya N.
        • Ebrat B.
        • Smith S.
        • Tillisch K.
        • Naliboff B.
        • Mayer E.A.
        Patients with chronic visceral pain show sex-related alterations in intrinsic oscillations of the resting brain.
        J Neurosci. 2013; 33: 11994-12002
        • Hong J.Y.
        • Kilpatrick L.A.
        • Labus J.S.
        • Gupta A.
        • Katiban D.
        • Ashe-McNalley C.
        • Stains J.
        • Heendeniya N.
        • Smith S.
        • Tillisch K.
        • Naliboff B.
        • Mayer E.A.
        Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.
        J Neurosci. 2014; 34: 14252-14259
        • Horn A.
        • Ostwald D.
        • Reisert M.
        • Blankenburg F.
        The structural-functional connectome and the default mode network of the human brain.
        Neuroimage. 2014; 102: 142-151
        • Iadarola M.J.
        • Max M.B.
        • Berman K.F.
        • Byassmith M.G.
        • Coghill R.C.
        • Gracely R.H.
        • Bennett G.J.
        Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain.
        Pain. 1995; 63: 55-64
        • Icenhour A.
        • Witt S.T.
        • Elsenbruch S.
        • Lowen M.
        • Engstrom M.
        • Tillisch K.
        • Mayer E.A.
        • Walter S.
        Brain functional connectivity is associated with visceral sensitivity in women with irritable bowel syndrome.
        Neuroimage Clin. 2017; 15: 449-457
        • Inui K.
        • Wang X.H.
        • Qiu Y.H.
        • Nguyen B.T.
        • Ojima S.
        • Tamura Y.
        • Nakata H.
        • Wasaka T.
        • Tran T.D.
        • Kakigi R.
        Pain processing within the primary somatosensory cortex in humans.
        Eur J Neurosci. 2003; 18: 2859-2866
        • Irimia A.
        • Labus J.S.
        • Torgerson C.M.
        • Van Horn J.D.
        • Mayer E.A.
        Altered viscerotopic cortical innervation in patients with irritable bowel syndrome.
        Neurogastroenterol Motil. 2015; 27: 1075-1081
        • Jenkinson M.
        • Bannister P.
        • Brady M.
        • Smith S.
        Improved optimization for the robust and accurate linear registration and motion correction of brain images.
        Neuroimage. 2002; 17: 825-841
        • Jiang Z.
        • Dinov I.D.
        • Labus J.
        • Shi Y.
        • Zamanyan A.
        • Gupta A.
        • Ashe-McNalley C.
        • Hong J.Y.
        • Tillisch K.
        • Toga A.W.
        • Mayer E.A.
        Sex-related differences of cortical thickness in patients with chronic abdominal pain.
        PLoS One. 2013; 8: e73932
        • Kairys A.E.
        • Schmidt-Wilcke T.
        • Puiu T.
        • Ichesco E.
        • Labus J.S.
        • Martucci K.
        • Farmer M.A.
        • Ness T.J.
        • Deutsch G.
        • Mayer E.A.
        • Mackey S.
        • Apkarian A.V.
        • Maravilla K.
        • Clauw D.J.
        • Harris R.E.
        Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome.
        J Urol. 2015; 193: 131-137
        • Kilpatrick L.A.
        • Kutch J.J.
        • Tillisch K.
        • Naliboff B.D.
        • Labus J.S.
        • Jiang Z.
        • Farmer M.A.
        • Apkarian A.V.
        • Mackey S.
        • Martucci K.T.
        • Clauw D.J.
        • Harris R.E.
        • Deutsch G.
        • Ness T.J.
        • Yang C.C.
        • Maravilla K.
        • Mullins C.
        • Mayer E.A.
        Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome.
        J Urol. 2014; 192: 947-955
        • Kim H.J.
        • Kim S.J.
        • Kim H.S.
        • Choi C.G.
        • Kim N.
        • Han S.
        • Jang E.H.
        • Chung S.J.
        • Lee C.S.
        Alterations of mean diffusivity in brain white matter and deep gray matter in Parkinson's disease.
        Neurosci Lett. 2013; 550: 64-68
        • Krhut J.
        • Holy P.
        • Tintera J.
        • Zachoval R.
        • Zvara P.
        Brain activity during bladder filling and pelvic floor muscle contractions: A study using functional magnetic resonance imaging and synchronous urodynamics.
        Int J Urol. 2014; 21: 169-174
        • Kuhtz-Buschbeck J.P.
        • van der Horst C.
        • Wolff S.
        • Filippow N.
        • Nabavi A.
        • Jansen O.
        • Braun P.M.
        Activation of the supplementary motor area (SMA) during voluntary pelvic floor muscle contractions—an fMRI study.
        Neuroimage. 2007; 35: 449-457
        • Labus J.S.
        • Dinov I.D.
        • Jiang Z.
        • Ashe-McNalley C.
        • Zamanyan A.
        • Shi Y.
        • Hong J.Y.
        • Gupta A.
        • Tillisch K.
        • Ebrat B.
        • Hobel S.
        • Gutman B.A.
        • Joshi S.
        • Thompson P.M.
        • Toga A.W.
        • Mayer E.A.
        Irritable bowel syndrome in female patients is associated with alterations in structural brain networks.
        Pain. 2014; 155: 137-149
        • Labus J.S.
        • Naliboff B.
        • Kilpatrick L.
        • Liu C.
        • Ashe-McNalley C.
        • dos Santos I.R.
        • Alaverdyan M.
        • Woodworth D.
        • Gupta A.
        • Ellingson B.M.
        • Tillisch K.
        • Mayer E.A.
        Pain and Interoception Imaging Network (PAIN): A multimodal, multisite, brain-imaging repository for chronic somatic and visceral pain disorders.
        Neuroimage. 2016; 124: 1232-1237
        • Lamvu G.
        • Nguyen R.H.
        • Burrows L.J.
        • Rapkin A.
        • Witzeman K.
        • Marvel R.P.
        • Hutchins D.
        • Witkin S.S.
        • Veasely C.
        • Fillingim R.
        • Zoulnoun D.
        The EVA (evidence-based vulvodynia assessment) project: A national registry for the study of vulvodynia.
        J Reprod Med. 2015; 60: 223-235
        • Leclair C.M.
        • Leeborg N.J.
        • Jacobson-Dunlop E.
        • Goetsch M.F.
        • Morgan T.K.
        CD4-positive T-cell recruitment in primary-provoked localized vulvodynia: Potential insights into disease triggers.
        J Low Genit Tract Dis. 2014; 18: 195-201
        • Lester R.A.
        • Brotto L.A.
        • Sadownik L.A.
        Provoked vestibulodynia and the health care implications of comorbid pain conditions.
        J Obstet Gynaecol Can. 2015; 37: 995-1005
        • Lutz J.
        • Jager 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
        • Ma X.
        • Li S.
        • Tian J.
        • Jiang G.
        • Wen H.
        • Wang T.
        • Fang J.
        • Zhan W.
        • Xu Y.
        Altered brain spontaneous activity and connectivity network in irritable bowel syndrome patients: A resting-state fMRI study.
        Clin Neurophysiol. 2015; 126: 1190-1197
        • Mansour A.R.
        • Baliki M.N.
        • Huang L.
        • Torbey S.
        • Herrmann K.M.
        • Schnitzer T.J.
        • Apkarian A.V.
        Brain white matter structural properties predict transition to chronic pain.
        Pain. 2013; 154: 2160-2168
        • Mayer E.A.
        • Bushnell M.C.
        Functional Pain Syndromes : Presentation and Pathophysiology.
        IASP Press, Seattle2009
        • Moayedi M.
        • Weissman-Fogel I.
        • Salomons T.V.
        • Crawley A.P.
        • Goldberg M.B.
        • Freeman B.V.
        • Tenenbaum H.C.
        • Davis K.D.
        White matter brain and trigeminal nerve abnormalities in temporomandibular disorder.
        Pain. 2012; 153: 1467-1477
        • Mori S.
        • Crain B.J.
        MRI Atlas of Human White Matter.
        1st ed. Elsevier, Amsterdam; Boston2005
        • Morin A.
        • Leonard G.
        • Gougeon V.
        • Waddell G.
        • Bureau Y.A.
        • Girard I.
        • Morin M.
        Efficacy of transcranial direct-current stimulation (tDCS) in women with provoked vestibulodynia: Study protocol for a randomized controlled trial.
        Trials. 2016; 17: 243
        • Morin M.
        • Bergeron S.
        • Khalife S.
        • Mayrand M.H.
        • Binik Y.M.
        Morphometry of the pelvic floor muscles in women with and without provoked vestibulodynia using 4D ultrasound.
        J Sex Med. 2014; 11: 776-785
        • Nagae L.M.
        • Honce J.M.
        • Tanabe J.
        • Shelton E.
        • Sillau S.H.
        • Berman B.D.
        Microstructural changes within the basal ganglia differ between Parkinson disease subtypes.
        Front Neuroanat. 2016; 10
        • Phillips K.
        • Clauw D.J.
        Central pain mechanisms in chronic pain states—maybe it is all in their head.
        Best Pract Res Clin Rheumatol. 2011; 25: 141-154
        • Pike N.
        Using false discovery rates for multiple comparisons in ecology and evolution.
        Methods Ecol Evol. 2011; 2: 278-282
        • Pukall C.F.
        Primary and secondary provoked vestibulodynia: A review of overlapping and distinct factors.
        Sex Med Rev. 2016; 4: 36-44
        • Pukall C.F.
        • Strigo I.A.
        • Binik Y.M.
        • Amsel R.
        • Khalife S.
        • Bushnell M.C.
        Neural correlates of painful genital touch in women with vulvar vestibulitis syndrome.
        Pain. 2005; 115: 118-127
        • Reed B.D.
        • Harlow S.D.
        • Plegue M.A.
        • Sen A.
        Remission, relapse, and persistence of vulvodynia: A longitudinal population-based study.
        J Womens Health. 2016; 25: 276-283
        • Reed B.D.
        • Plegue M.A.
        • Williams D.A.
        • Sen A.
        Presence of spontaneous pain and comorbid pain conditions identifies vulvodynia subgroups.
        J Low Genit Tract Dis. 2016; 20: 57-63
        • Schmahmann J.D.
        • Smith E.E.
        • Eichler F.S.
        • Filley C.M.
        Cerebral white matter neuroanatomy, clinical neurology, and neurobehavioral correlates.
        Ann N Y Acad Sci. 2008; 1142: 266-309
        • Schmidt-Wilcke T.
        • Leinisch E.
        • Ganssbauer S.
        • Draganski B.
        • Bogdahn U.
        • Altmeppen J.
        • May A.
        Affective components and intensity of pain correlate with structural differences in gray matter in chronic back pain patients.
        Pain. 2006; 125: 89-97
        • Schwartz E.D.
        • Hackney D.B.
        Diffusion-weighted MRI and the evaluation of spinal cord axonal integrity following injury and treatment.
        Exp Neurol. 2003; 184: 570-589
        • Schweinhardt P.
        • Kuchinad A.
        • Pukall C.F.
        • Bushnell M.C.
        Increased gray matter density in young women with chronic vulvar pain.
        Pain. 2008; 140: 411-419
        • Smart O.C.
        • MacLean A.B.
        Vulvodynia.
        Curr Opin Obstet Gynecol. 2003; 15: 497-500
        • Smith S.M.
        • Jenkinson M.
        • Woolrich M.W.
        • Beckmann C.F.
        • Behrens T.E.
        • Johansen-Berg H.
        • Bannister P.R.
        • De Luca M.
        • Drobnjak I.
        • Flitney D.E.
        • Niazy R.K.
        • Saunders J.
        • Vickers J.
        • Zhang Y.
        • De Stefano N.
        • Brady J.M.
        • Matthews P.M.
        Advances in functional and structural MR image analysis and implementation as FSL.
        Neuroimage. 2004; 23: S208-S219
        • Sutton K.
        • Pukall C.
        • Wild C.
        • Johnsrude I.
        • Chamberlain S.
        Cognitive, psychophysical, and neural correlates of vulvar pain in primary and secondary provoked vestibulodynia: A pilot study.
        J Sex Med. 2015; 12: 1283-1297
        • Tommola P.
        • Unkila-Kallio L.
        • Paavonen J.
        Long-term well-being after surgical or conservative treatment of severe vulvar vestibulitis.
        Acta Obstet Gynecol Scand. 2012; 91: 1086-1093
        • Tovar-Moll F.
        • Evangelou I.E.
        • Chiu A.W.
        • Richert N.D.
        • Ostuni J.L.
        • Ohayon J.M.
        • Auh S.
        • Ehrmantraut M.
        • Talagala S.L.
        • McFarland H.F.
        • Bagnato F.
        Thalamic involvement and its impact on clinical disability in patients with multiple sclerosis: A diffusion tensor imaging study at 3T.
        AJNR Am J Neuroradiol. 2009; 30: 1380-1386
        • Tympanidis P.
        • Terenghi G.
        • Dowd P.
        Increased innervation of the vulval vestibule in patients with vulvodynia.
        Br J Dermatol. 2003; 148: 1021-1027
        • Vierck C.J.
        • Whitsel B.L.
        • Favorov O.V.
        • Brown A.W.
        • Tommerdahl M.
        Role of primary somatosensory cortex in the coding of pain.
        Pain. 2013; 154: 334-344
        • Wang X.H.
        • Pathak S.
        • Stefaneanu L.
        • Yeh F.C.
        • Li S.T.
        • Fernandez-Miranda J.C.
        Subcomponents and connectivity of the superior longitudinal fasciculus in the human brain.
        Brain Struct Funct. 2016; 221: 2075-2092
        • Weaver K.R.
        • Sherwin L.B.
        • Walitt B.
        • Melkus G.D.
        • Henderson W.A.
        Neuroimaging the brain-gut axis in patients with irritable bowel syndrome.
        World J Gastrointest Pharmacol Ther. 2016; 7: 320-333
        • Wesselmann U.
        • Bonham A.
        • Foster D.
        Vulvodynia: Current state of the biological science.
        Pain. 2014; 155: 1696-1701
        • Woodworth D.
        • Mayer E.
        • Leu K.
        • Ashe-McNalley C.
        • Naliboff B.D.
        • Labus J.S.
        • Tillisch K.
        • Kutch J.J.
        • Farmer M.A.
        • Apkarian A.V.
        • Johnson K.A.
        • Mackey S.C.
        • Ness T.J.
        • Landis J.R.
        • Deutsch G.
        • Harris R.E.
        • Clauw D.J.
        • Mullins C.
        • Ellingson B.M.
        • Network M.R.
        Unique microstructural changes in the brain associated with urological chronic pelvic pain syndrome (UCPPS) revealed by diffusion tensor MRI, super-resolution track density imaging, and statistical parameter mapping: A MAPP network neuroimaging study.
        PLoS One. 2015; 10 (e0140250)
        • Yamada K.
        • Nagakane Y.
        • Yoshikawa K.
        • Kizu O.
        • Ito H.
        • Kubota T.
        • Akazawa K.
        • Oouchi H.
        • Matsushima S.
        • Nakagawa M.
        • Nishimura T.
        Somatotopic organization of thalamocortical projection fibers as assessed with MR tractography.
        Radiology. 2007; 242: 840-845
        • Zhang Z.
        • Zolnoun D.A.
        • Francisco E.M.
        • Holden J.K.
        • Dennis R.G.
        • Tommerdahl M.
        Altered central sensitization in subgroups of women with vulvodynia.
        Clin J Pain. 2011; 27: 755-763
        • Zigmond A.S.
        • Snaith R.P.
        The hospital anxiety and depression scale.
        Acta Psychiatr Scand. 1983; 67: 361-370
        • Zolnoun D.
        • Bair E.
        • Essick G.
        • Gracely R.
        • Goyal V.
        • Maixner W.
        Reliability and reproducibility of novel methodology for assessment of pressure pain sensitivity in pelvis.
        J Pain. 2012; 13: 910-920