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The Association Between Clinical Characteristics of Migraine and Brain GABA Levels: An Exploratory Study

      Highlights

      • Increased gamma-aminobutyric acid (GABA) levels were associated with increased pain and more frequent central sensitization symptoms in patients with migraine.
      • Our results provide preliminary evidence for the possible involvement of GABA in migraine pathophysiology.
      • GABA is a potential biomarker for migraine.
      • Measuring clinical characteristics of migraine using self-report questionnaires might be useful in characterizing migraine better and broadening the diagnostic process.

      Abstract

      Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker.

      Perspective

      Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker.

      Key words

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      References

        • Aguila M.E.
        • Lagopoulos J.
        • Leaver A.M.
        • Rebbeck T.
        • Hübscher M.
        • Brennan P.C.
        • Refshauge K.M.
        Elevated levels of GABA+ in migraine detected using 1H-MRS.
        NMR Biomed. 2015; 28: 890-897
        • Bigal M.E.
        • Hetherington H.
        • Pan J.
        • Tsang A.
        • Grosberg B.
        • Avdievich N.
        • Friedman B.
        • Lipton R.B.
        Occipital levels of GABA are related to severe headaches in migraine.
        Neurology. 2008; 70: 2078-2080
        • Biondi D.M.
        Is migraine a neuropathic pain syndrome?.
        Curr Pain Headache Rep. 2006; 10: 167-178
        • Borsook D.
        • Maleki N.
        • Becerra L.
        • McEwen B.
        Understanding migraine through the lens of maladaptive stress responses: A model disease of allostatic load.
        Neuron. 2012; 73: 219-234
        • Brennan K.C.
        • Charles A.
        An update on the blood vessel in migraine.
        Curr Opin Neurol. 2010; 23: 266-274
        • Bromberg J.
        • Wood M.E.
        • Black R.A.
        • Surette D.A.
        • Zacharoff K.L.
        • Chiauzzi E.J.
        A randomized trial of a web-based intervention to improve migraine self-management and coping.
        Headache. 2012; 52: 244-261
        • Burstein R.
        • Noseda R.
        • Borsook D.
        Migraine: Multiple processes, complex pathophysiology.
        J Neurosci. 2015; 35: 6619-6629
        • Buse D.C.
        • Silberstein S.D.
        • Manack A.N.
        • Papapetropoulos S.
        • Lipton R.B.
        Psychiatric comorbidities of episodic and chronic migraine.
        J Neurol. 2013; 260: 1960-1969
        • Coppola G.
        • Di Lorenzo C.
        • Schoenen J.
        • Pierelli F.
        Habituation and sensitization in primary headaches.
        J Headache Pain. 2013; 14: 65-77
        • Dodick D.
        • Silberstein S.
        Central sensitization theory of migraine: Clinical implications.
        Headache. 2006; 46: S182-S191
        • Durham P.
        • Papapetropoulos S.
        Biomarkers associated with migraine and their potential role in migraine management.
        Headache. 2013; 53: 1262-1267
        • Dworkin R.H.
        • Turk D.C.
        • Revicki D.A.
        • Harding G.
        • Coyne K.S.
        • Peirce-Sandner S.
        • Bhagwat D.
        • Everton D.
        • Burke L.B.
        • Cowan P.
        • Farrar J.T.
        • Hertz S.
        • Max M.B.
        • Rappaport B.A.
        • Melzack R.
        Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).
        Pain. 2009; 144: 35-42
        • Enna S.J.
        • McCarson K.E.
        The role of GABA in the mediation and perception of pain.
        Adv Pharmacol. 2006; 54: 1-27
        • Fayed N.
        • Andrés E.
        • Viguera L.
        • Modrego P.J.
        • Garcia-Campayo J.
        Higher glutamate+glutamine and reduction of N-acetylaspartate in posterior cingulate according to age range in patients with cognitive impairment and/or pain.
        Acad Radiol. 2014; 21: 1211-1217
        • Foerster B.R.
        • Petrou M.
        • Edden R.A.
        • Sundgren P.C.
        • Schmidt-Wilcke T.
        • Lowe S.E.
        • Harte S.E.
        • Clauw D.J.
        • Harris R.E.
        Reduced insular γ-aminobutyric acid in fibromyalgia.
        Arthritis Rheum. 2012; 64: 579-583
        • Gustin S.M.
        • Wrigley P.J.
        • Youssef A.M.
        • McIndoe L.
        • Wilcox S.L.
        • Rae C.D.
        • Edden R.
        • Siddall P.J.
        • Henderson L.A.
        Thalamic activity and biochemical changes in individuals with neuropathic pain after spinal cord injury.
        Pain. 2014; 155: 1027-1036
        • Hamedi V.
        • Asghari A.
        • Sheeri M.R.
        An investigation of the effectiveness of a composed model of cognitive-behavior headache management on the treatment of anxiety, depression, stress and migraine symptoms.
        Proc Soc Behav Sci. 2013; 84: 1850-1855
        • Headache Classification Committee of the International Headache Society
        The International Classification of Headache Disorders: 2nd edition.
        Cephalalgia. 2004; 24: 9-160
        • Headache Classification Committee of the International Headache Society
        The International Classification of Headache Disorders, 3rd edition (beta version).
        Cephalalgia. 2013; 33: 629-808
        • Henry J.D.
        • Crawford J.R.
        The short-form version of the Depression Anxiety Stress Scales (DASS-21): Construct validity and normative data in a large non-clinical sample.
        Br J Clin Psychol. 2005; 44: 227-239
        • Hlatky M.A.
        • Greenland P.
        • Arnett D.K.
        • Ballantyne C.M.
        • Criqui M.H.
        • Elkind M.S.
        • Go A.S.
        • Harrell Jr., F.E.
        • Hong Y.
        • Howard B.V.
        • Howard V.J.
        • Hsue P.Y.
        • Kramer C.M.
        • McConnell J.P.
        • Norman S.T.
        • O’Donnell C.J.
        • Smith S.C.J.R.
        • Wilson P.W.
        • on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council
        Criteria for evaluation of novel markers of cardiovascular risk: A scientific statement from the American Heart Association.
        Circulation. 2009; 119: 2408-2416
        • Kocharyan A.
        • Fernandes P.
        • Tong X.K.
        • Vaucher E.
        • Hamel E.
        Specific subtypes of cortical GABA interneurons contribute to the neurovascular coupling response to basal forebrain stimulation.
        J Cereb Blood Flow Metab. 2008; 28: 221-231
        • Kolotylo C.J.
        • Broome M.E.
        Exploration of migraine pain, disability, depressive symptomatology, and coping: A pilot study.
        Health Care Women Int. 2000; 21: 203-218
        • Kosinski M.
        • Bayliss M.S.
        • Bjorner J.B.
        • Ware Jr., J.E.
        • Garber W.H.
        • Batenhorst A.
        • Cady R.
        • Dahlöf C.G.
        • Dowson A.
        • Tepper S.
        A six-item short-form survey for measuring headache impact: the HIT-6.
        Qual Life Res. 2003; 12: 963-974
        • Leonardi M.
        • Raggi A.
        Burden of migraine: International perspectives.
        Neurol Sci. 2013; 34: S117-S118
        • Lipton R.B.
        • Bigal M.E.
        Migraine: Epidemiology, impact, and risk factors for progression.
        Headache. 2005; 45: S3-S13
        • Lipton R.B.
        • Bigal M.E.
        • Ashina S.
        • Burstein R.
        • Silberstein S.
        • Reed M.L.
        • Serrano D.
        • Stewart W.F.
        • on behalf of the American Migraine Prevalence Prevention Advisory Group
        Cutaneous allodynia in the migraine population.
        Ann Neurol. 2008; 63: 148-158
        • Lovibond S.
        • Lovibond P.
        Manual for the Depression Anxiety Stress Scales.
        2nd ed. Psychology Foundation of Australia, Sydney1995
        • Mann E.O.
        • Paulsen O.
        Role of GABAergic inhibition in hippocampal network oscillations.
        Trends Neurosci. 2007; 30: 343-349
        • Mayer T.G.
        • Neblett R.
        • Cohen H.
        • Howard K.J.
        • Choi Y.H.
        • Williams M.J.
        • Perez Y.
        • Gatchel R.J.
        The development and psychometric validation of the Central Sensitization Inventory.
        Pain Pract. 2012; 12: 276-285
        • Möhler H.
        The GABA system in anxiety and depression and its therapeutic potential.
        Neuropharmacology. 2012; 62: 42-53
        • Nachit-Ouinekh F.
        • Dartigues J.F.
        • Henry P.
        • Chastan B.G.
        • Lemaire N.
        • El Hasnaoui A.
        Use of the headache impact test (HIT-6) in general practice: Relationship with quality of life and severity.
        Eur J Neurol. 2005; 12: 189-193
        • Neblett R.
        • Cohen H.
        • Choi Y.
        • Hartzell M.M.
        • Williams M.
        • Mayer T.G.
        • Gatchel R.J.
        The Central Sensitization Inventory (CSI): Establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample.
        J Pain. 2013; 14: 438-445
        • Neblett R.
        • Hartzell M.M.
        • Cohen H.
        • Mayer T.G.
        • Williams M.
        • Choi Y.H.
        • Gatchel R.J.
        Ability of the Central Sensitization Inventory to identify central sensitivity syndromes in an outpatient chronic pain sample.
        Clin J Pain. 2014; 31: 323-332
        • Orta O.R.
        • Gelaye B.
        • Qiu C.
        • Stoner L.
        • Williams M.A.
        Depression, anxiety and stress among pregnant migraineurs in a pacific-northwest cohort.
        J Affect Disord. 2014; 172: 390-396
        • Pietrobon D.
        • Moskowitz M.A.
        Pathophysiology of migraine.
        Annu Rev Physiol. 2013; 75: 365-391
        • Pletcher M.J.
        • Pignone M.
        Evaluating the clinical utility of a biomarker: A review of methods for estimating health impact.
        Circulation. 2011; 123: 1116-1124
        • Portney L.G.
        • Watkins M.P.
        Foundations of Clinical Research: Applications to Practice.
        3rd ed. Pearson/Prentice Hall, Upper Saddle River, NJ2009
        • Pryse-Phillips W.
        • Findlay H.
        • Tugwell P.
        • Edmeads J.
        • Murray T.J.
        • Nelson RF A.
        Canadian population survey on the clinical, epidemiologic and societal impact of migraine and tension-type headache.
        Can J Neurol Sci. 1992; 19: 333-339
        • Steiner T.J.
        Headache in the world: Public health and research priorities.
        Expert Rev Pharmacoecon Outcomes Res. 2013; 13: 51-57
        • Vecchia D.
        • Pietrobon D.
        Migraine: A disorder of brain excitatory-inhibitory balance?.
        Trends Neurosci. 2012; 35: 507-520
        • Vos T.
        • Flaxman A.D.
        • Naghavi M.
        • Lozano R.
        • Michaud C.
        • Ezzati M.
        • Shibuya K.
        • Salomon J.A.
        • Abdalla S.
        • Aboyans V.
        • Abraham J.
        • Ackerman I.
        • Aggarwal R.
        • Ahn S.Y.
        • Ali M.K.
        • AlMazroa M.A.
        • Alvarado M.
        • Anderson H.R.
        • Anderson L.M.
        • Andrews K.G.
        • Atkinson C.
        • Baddour L.M.
        • Bahalim A.N.
        • Barker-Collo S.
        • Barrero L.H.
        • Bartels D.H.
        • Basáñez M.G.
        • Baxter A.
        • Bell M.L.
        • Benjamin E.J.
        • Bennett D.
        • Bernabé E.
        • Bhalla K.
        • Bhandari B.
        • Bikbov B.
        • Bin Abdulhak A.
        • Birbeck G.
        • Black J.A.
        • Blencowe H.
        • Blore J.D.
        • Blyth F.
        • Bolliger I.
        • Bonaventure A.
        • Boufous S.
        • Bourne R.
        • Boussinesq M.
        • Braithwaite T.
        • Brayne C.
        • Bridgett L.
        • Brooker S.
        • Brooks P.
        • Brugha T.S.
        • Bryan-Hancock C.
        • Bucello C.
        • Buchbinder R.
        • Buckle G.
        • Budke C.M.
        • Burch M.
        • Burney P.
        • Burstein R.
        • Calabria B.
        • Campbell B.
        • Canter C.E.
        • Carabin H.
        • Carapetis J.
        • Carmona L.
        • Cella C.
        • Charlson F.
        • Chen H.
        • Cheng A.T.
        • Chou D.
        • Chugh S.S.
        • Coffeng L.E.
        • Colan S.D.
        • Colquhoun S.
        • Colson K.E.
        • Condon J.
        • Connor M.D.
        • Cooper L.T.
        • Corriere M.
        • Cortinovis M.
        • de Vaccaro K.C.
        • Couser W.
        • Cowie B.C.
        • Criqui M.H.
        • Cross M.
        • Dabhadkar K.C.
        • Dahiya M.
        • Dahodwala N.
        • Damsere-Derry J.
        • Danaei G.
        • Davis A.
        • De Leo D.
        • Degenhardt L.
        • Dellavalle R.
        • Delossantos A.
        • Denenberg J.
        • Derrett S.
        • Des Jarlais D.C.
        • Dharmaratne S.D.
        • Dherani M.
        • Diaz-Torne C.
        • Dolk H.
        • Dorsey E.R.
        • Driscoll T.
        • Duber H.
        • Ebel B.
        • Edmond K.
        • Elbaz A.
        • Ali S.E.
        • Erskine H.
        • Erwin P.J.
        • Espindola P.
        • Ewoigbokhan S.E.
        • Farzadfar F.
        • Feigin V.
        • Felson D.T.
        • Ferrari A.
        • Ferri C.P.
        • Fèvre E.M.
        • Finucane M.M.
        • Flaxman S.
        • Flood L.
        • Foreman K.
        • Forouzanfar M.H.
        • Fowkes F.G.
        • Franklin R.
        • Fransen M.
        • Freeman M.K.
        • Gabbe B.J.
        • Gabriel S.E.
        • Gakidou E.
        • Ganatra H.A.
        • Garcia B.
        • Gaspari F.
        • Gillum R.F.
        • Gmel G.
        • Gosselin R.
        • Grainger R.
        • Groeger J.
        • Guillemin F.
        • Gunnell D.
        • Gupta R.
        • Haagsma J.
        • Hagan H.
        • Halasa Y.A.
        • Hall W.
        • Haring D.
        • Haro J.M.
        • Harrison J.E.
        • Havmoeller R.
        • Hay R.J.
        • Higashi H.
        • Hill C.
        • Hoen B.
        • Hoffman H.
        • Hotez P.J.
        • Hoy D.
        • Huang J.J.
        • Ibeanusi S.E.
        • Jacobsen K.H.
        • James S.L.
        • Jarvis D.
        • Jasrasaria R.
        • Jayaraman S.
        • Johns N.
        • Jonas J.B.
        • Karthikeyan G.
        • Kassebaum N.
        • Kawakami N.
        • Keren A.
        • Khoo J.P.
        • King C.H.
        • Knowlton L.M.
        • Kobusingye O.
        • Koranteng A.
        • Krishnamurthi R.
        • Lalloo R.
        • Laslett L.L.
        • Lathlean T.
        • Leasher J.L.
        • Lee Y.Y.
        • Leigh J.
        • Lim S.S.
        • Limb E.
        • Lin J.K.
        • Lipnick M.
        • Lipshultz S.E.
        • Liu W.
        • Loane M.
        • Ohno S.L.
        • Lyons R.
        • Ma J.
        • Mabweijano J.
        • MacIntyre M.F.
        • Malekzadeh R.
        • Mallinger L.
        • Manivannan S.
        • Marcenes W.
        • March L.
        • Margolis D.J.
        • Marks G.B.
        • Marks R.
        • Matsumori A.
        • Matzopoulos R.
        • Mayosi B.M.
        • McAnulty J.H.
        • McDermott M.M.
        • McGill N.
        • McGrath J.
        • Medina-Mora M.E.
        • Meltzer M.
        • Mensah G.A.
        • Merriman T.R.
        • Meyer A.C.
        • Miglioli V.
        • Miller M.
        • Miller T.R.
        • Mitchell P.B.
        • Mocumbi A.O.
        • Moffitt T.E.
        • Mokdad A.A.
        • Monasta L.
        • Montico M.
        • Moradi-Lakeh M.
        • Moran A.
        • Morawska L.
        • Mori R.
        • Murdoch M.E.
        • Mwaniki M.K.
        • Naidoo K.
        • Nair M.N.
        • Naldi L.
        • Narayan K.M.
        • Nelson P.K.
        • Nelson R.G.
        • Nevitt M.C.
        • Newton C.R.
        • Nolte S.
        • Norman P.
        • Norman R.
        • O'Donnell M.
        • O'Hanlon S.
        • Olives C.
        • Omer S.B.
        • Ortblad K.
        • Osborne R.
        • Ozgediz D.
        • Page A.
        • Pahari B.
        • Pandian J.D.
        • Rivero A.P.
        • Patten S.B.
        • Pearce N.
        • Padilla R.P.
        • Perez-Ruiz F.
        • Perico N.
        • Pesudovs K.
        • Phillips D.
        • Phillips M.R.
        • Pierce K.
        • Pion S.
        • Polanczyk G.V.
        • Polinder S.
        • Pope 3rd, C.A.
        • Popova S.
        • Porrini E.
        • Pourmalek F.
        • Prince M.
        • Pullan R.L.
        • Ramaiah K.D.
        • Ranganathan D.
        • Razavi H.
        • Regan M.
        • Rehm J.T.
        • Rein D.B.
        • Remuzzi G.
        • Richardson K.
        • Rivara F.P.
        • Roberts T.
        • Robinson C.
        • De Leòn F.R.
        • Ronfani L.
        • Room R.
        • Rosenfeld L.C.
        • Rushton L.
        • Sacco R.L.
        • Saha S.
        • Sampson U.
        • Sanchez-Riera L.
        • Sanman E.
        • Schwebel D.C.
        • Scott J.G.
        • Segui-Gomez M.
        • Shahraz S.
        • Shepard D.S.
        • Shin H.
        • Shivakoti R.
        • Singh D.
        • Singh G.M.
        • Singh J.A.
        • Singleton J.
        • Sleet D.A.
        • Sliwa K.
        • Smith E.
        • Smith J.L.
        • Stapelberg N.J.
        • Steer A.
        • Steiner T.
        • Stolk W.A.
        • Stovner L.J.
        • Sudfeld C.
        • Syed S.
        • Tamburlini G.
        • Tavakkoli M.
        • Taylor H.R.
        • Taylor J.A.
        • Taylor W.J.
        • Thomas B.
        • Thomson W.M.
        • Thurston G.D.
        • Tleyjeh I.M.
        • Tonelli M.
        • Towbin J.A.
        • Truelsen T.
        • Tsilimbaris M.K.
        • Ubeda C.
        • Undurraga E.A.
        • van der Werf M.J.
        • van Os J.
        • Vavilala M.S.
        • Venketasubramanian N.
        • Wang M.
        • Wang W.
        • Watt K.
        • Weatherall D.J.
        • Weinstock M.A.
        • Weintraub R.
        • Weisskopf M.G.
        • Weissman M.M.
        • White R.A.
        • Whiteford H.
        • Wiersma S.T.
        • Wilkinson J.D.
        • Williams H.C.
        • Williams S.R.
        • Witt E.
        • Wolfe F.
        • Woolf A.D.
        • Wulf S.
        • Yeh P.H.
        • Zaidi A.K.
        • Zheng Z.J.
        • Zonies D.
        • Lopez A.D.
        • Murray C.J.
        Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380: 2163-2196
        • World Health Organization
        Atlas of headache disorders and resources in the world 2011.
        World Health Organization, Geneva2011: 40-42
        • Wu J.
        • Gao M.
        • Shen J.X.
        • Qiu S.F.
        • Kerrigan J.F.
        Mechanisms of intrinsic epileptogenesis in human gelastic seizures with hypothalamic hamartoma.
        CNS Neurosci Ther. 2015; 21: 104-111
        • Yavuz B.G.
        • Aydinlar E.I.
        • Dikmen P.Y.
        • Incesu C.
        Association between somatic amplification, anxiety, depression, stress and migraine.
        J Headache Pain. 2013; 14: 53
        • Zweig M.H.
        • Campbell G.
        Receiver-operating characteristic (ROC) plots: A fundamental evaluation tool in clinical medicine.
        Clin Chem. 1993; 39: 561-577