Advertisement

Gray Matter Abnormalities in Social Anxiety Disorder: Primary, Replication, and Specificity Studies

  • Ardesheer Talati
    Correspondence
    Address correspondence to Ardesheer Talati, Ph.D., Department of Psychiatry, Columbia University Medical Center, New York State Psychiatric Institute, 1051 Riverside Drive, Unit 24, New York, NY 10032
    Affiliations
    Department of Psychiatry, Columbia University Medical Center, New York, New York

    Division of Epidemiology, New York State Psychiatric Institute, New York, New York
    Search for articles by this author
  • Spiro P. Pantazatos
    Affiliations
    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, New York

    functional MRI Laboratory, Columbia University, New York, New York
    Search for articles by this author
  • Franklin R. Schneier
    Affiliations
    Department of Psychiatry, Columbia University Medical Center, New York, New York

    Division of Clinical Therapeutics, New York State Psychiatric Institute, New York, New York
    Search for articles by this author
  • Myrna M. Weissman
    Affiliations
    Department of Psychiatry, Columbia University Medical Center, New York, New York

    Department of Epidemiology, Columbia University Medical Center, New York, New York

    Division of Epidemiology, New York State Psychiatric Institute, New York, New York
    Search for articles by this author
  • Joy Hirsch
    Affiliations
    Department of Psychology, Columbia University Medical Center, New York, New York

    Department of Neuroscience, Columbia University Medical Center, New York, New York

    Department of Radiology, Columbia University Medical Center, New York, New York

    functional MRI Laboratory, Columbia University, New York, New York
    Search for articles by this author

      Background

      Despite increasing evidence that neuroanatomical abnormalities underlie pathological anxiety, social anxiety disorder (SAD)—although among the most common of anxiety disorders—has received little attention. With magnetic resonance imaging, we: 1) examined gray matter (GM) differences between generalized SAD and healthy control groups; 2) retested the findings in an independent clinical sample; and 3) tested for specificity by contrasting the SAD group to a separate group of panic disorder (PD) subjects.

      Methods

      The primary SAD group (n = 16) was required to meet DSM-IV criteria for SAD, with onset by age 30 years; control subjects (n = 20) had no lifetime history of anxiety. The replication sample included 17 generalized SAD and 17 control subjects. The PD comparison group (n = 16) was required to have no lifetime SAD. Images were acquired on a 1.5-Tesla GE Signa magnetic resonance imaging scanner with a three-dimensional T1-weighted spoiled gradient recalled pulse sequence. Morphological differences were determined with voxel-based morphometry, in SPM8.

      Results

      After adjusting for age, gender, and total intracranial volume, SAD (as compared with control) subjects had greater GM in the left parahippocampal and middle occipital, and bilateral supramarginal and angular cortices, and left cerebellum; and lower GM in bilateral temporal poles and left lateral orbitofrontal cortex. Cerebellar, parahippocampal, and temporal pole differences were observed in both samples, survived whole brain corrections, and were not observed in the PD group, pointing to relative specificity to SAD.

      Conclusions

      These findings parallel the functional literature on SAD and suggest structural abnormalities underlying the functional disturbances.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Psychiatric Disorders.
        American Psychiatric Association, Washington, DC1994
        • Delgado M.R.
        • Nearing K.I.
        • Ledoux J.E.
        • Phelps E.A.
        Neural circuitry underlying the regulation of conditioned fear and its relation to extinction.
        Neuron. 2008; 59: 829-838
        • Bienvenu O.J.
        • Samuels J.F.
        • Wuyek L.A.
        • Liang K.Y.
        • Wang Y.
        • Grados M.A.
        • et al.
        Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions?.
        Psychol Med. 2012; 42: 1-13
        • Stein D.J.
        • Craske M.G.
        • Friedman M.J.
        • Phillips K.A.
        Meta-structure issues for the DSM-5: How do anxiety disorders, obsessive-compulsive and related disorders, post-traumatic disorders, and dissociative disorders fit together?.
        Curr Psychiatry Rep. 2011; 13: 248-250
        • Jefferys D.
        Social phobia.
        Aust Fam Physician. 1997; 26 (4–7): 1061
        • Weissman M.M.
        • Bland R.C.
        • Canino G.J.
        • Greenwald S.
        • Lee C.K.
        • Newman S.C.
        • et al.
        The cross-national epidemiology of social phobia: A preliminary report.
        Int Clin Psychopharmacol. 1996; 11: 9-14
        • Kessler R.C.
        • Chiu W.T.
        • Demler O.
        • Merikangas K.R.
        • Walters E.E.
        Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 617-627
        • Filho A.S.
        • Hetem L.A.
        • Ferrari M.C.
        • Trzesniak C.
        • Martin-Santos R.
        • Borduqui T.
        • et al.
        Social anxiety disorder: What are we losing with the current diagnostic criteria?.
        Acta Psychiatr Scand. 2010; 121: 216-226
        • Schneier F.R.
        Clinical practice.
        N Engl J Med. 2006; 355: 1029-1036
        • Stein M.B.
        • Chartier M.J.
        • Hazen A.L.
        • Kozak M.V.
        • Tancer M.E.
        • Lander S.
        • et al.
        A direct-interview family study of generalized social phobia.
        Am J Psychiatry. 1998; 155: 90-97
        • Freitas-Ferrari M.C.
        • Hallak J.E.
        • Trzesniak C.
        • Filho A.S.
        • Machado-de-Sousa J.P.
        • Chagas M.H.
        • et al.
        Neuroimaging in social anxiety disorder: A systematic review of the literature.
        Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 565-580
        • Pietrini F.
        • Godini L.
        • Lazzeretti L.
        • Benni L.
        • Pracucci C.
        • Talamba G.A.
        • et al.
        [Neuroimaging and neurobiology of social anxiety].
        Riv Psichiatr. 2010; 45: 349-360
        • Safren S.A.
        • Heimberg R.G.
        • Horner K.J.
        • Juster H.R.
        • Schneier F.R.
        • Liebowitz M.R.
        Factor structure of social fears: The Liebowitz Social Anxiety Scale.
        J Anxiety Disord. 1999; 13: 253-270
        • Lorberbaum J.P.
        • Kose S.
        • Johnson M.R.
        • Arana G.W.
        • Sullivan L.K.
        • Hamner M.B.
        • et al.
        Neural correlates of speech anticipatory anxiety in generalized social phobia.
        Neuroreport. 2004; 15: 2701-2705
        • Tillfors M.
        • Furmark T.
        • Marteinsdottir I.
        • Fischer H.
        • Pissiota A.
        • Langstrom B.
        • et al.
        Cerebral blood flow in subjects with social phobia during stressful speaking tasks: A PET study.
        Am J Psychiatry. 2001; 158: 1220-1226
        • Schneier F.R.
        • Pomplun M.
        • Sy M.
        • Hirsch J.
        Neural response to eye contact and paroxetine treatment in generalized social anxiety disorder.
        Psychiatry Res. 2011; 194: 271-278
        • Andrews-Hanna J.R.
        • Reidler J.S.
        • Sepulcre J.
        • Poulin R.
        • Buckner R.L.
        Functional-anatomic fractionation of the brain's default network.
        Neuron. 2010; 65: 550-562
        • Whitfield-Gabrieli S.
        • Moran J.M.
        • Nieto-Castanon A.
        • Triantafyllou C.
        • Saxe R.
        • Gabrieli J.D.
        Associations and dissociations between default and self-reference networks in the human brain.
        Neuroimage. 2011; 55: 225-232
        • Ferrari M.C.
        • Busatto G.F.
        • McGuire P.K.
        • Crippa J.A.
        Structural magnetic resonance imaging in anxiety disorders: An update of research findings.
        Rev Bras Psiquiatr. 2008; 30: 251-264
        • Potts N.L.
        • Davidson J.R.
        • Krishnan K.R.
        • Doraiswamy P.M.
        Magnetic resonance imaging in social phobia.
        Psychiatry Res. 1994; 52: 35-42
        • Radua J.
        • van den Heuvel O.A.
        • Surguladze S.
        • Mataix-Cols D.
        Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders.
        Arch Gen Psychiatry. 2010; 67: 701-711
        • van Tol M.J.
        • van der Wee N.J.
        • van den Heuvel O.A.
        • Nielen M.M.
        • Demenescu L.R.
        • Aleman A.
        • et al.
        Regional brain volume in depression and anxiety disorders.
        Arch Gen Psychiatry. 2010; 67: 1002-1011
        • Cassimjee N.
        • Fouche J.P.
        • Burnett M.
        • Lochner C.
        • Warwick J.
        • Dupont P.
        • et al.
        Changes in regional brain volumes in social anxiety disorder following 12 weeks of treatment with escitalopram.
        Metab Brain Dis. 2010; 25: 369-374
        • Roy-Byrne P.P.
        • Craske M.G.
        • Stein M.B.
        Panic disorder.
        Lancet. 2006; 368: 1023-1032
        • Weissman M.M.
        Family genetic studies of panic disorder.
        J Psychiatr Res. 1993; 27: 69-78
        • Schneier F.R.
        • Johnson J.
        • Hornig C.D.
        • Liebowitz M.R.
        • Weissman M.M.
        Social phobia.
        Arch Gen Psychiatry. 1992; 49: 282-288
        • Kendler K.S.
        • Walters E.E.
        • Neale M.C.
        • Kessler R.C.
        • Heath A.C.
        • Eaves L.J.
        The structure of the genetic and environmental risk factors for six major psychiatric disorders in women.
        Arch Gen Psychiatry. 1995; 52: 374-383
        • Goldstein R.B.
        • Wickramaratne P.J.
        • Horwath E.
        • Weissman M.M.
        Familial aggregation and phenomenology of ‘early’-onset (at or before age 20 years) panic disorder.
        Arch Gen Psychiatry. 1997; 54: 271-278
        • Talati A.
        • Ponniah K.
        • Strug L.J.
        • Hodge S.E.
        • Fyer A.J.
        • Weissman M.M.
        Panic disorder, social anxiety disorder, and a possible medical syndrome previously linked to chromosome 13.
        Biol Psychiatry. 2008; 63: 594-601
        • Fyer A.
        • Endicott J.
        • Mannuzza S.
        • Klein D.F.
        Schedule for Affective Disorders and Schizophrenia-Lifetime Version, Modified for the Study of Anxiety Disorders (SADS-LA).
        Anxiety Disorders Clinic, New York State Psychiatric Institute, New York1985
        • Weissman M.M.
        • Wickramaratne P.
        • Adams P.
        • Wolk S.
        • Verdeli H.
        • Olfson M.
        Brief screening for family psychiatric history: The family history screen.
        Arch Gen Psychiatry. 2000; 57: 675-682
        • Leckman J.F.
        • Sholomskas D.
        • Thompson W.D.
        • Belanger A.
        • Weissman M.M.
        Best estimate of lifetime psychiatric diagnosis: A methodological study.
        Arch Gen Psychiatry. 1982; 39: 879-883
        • Spielberger C.
        • Gorsuch R.L.
        • Lushene R.E.
        Manual for the State-Trait Anxiety Inventory.
        Consulting Psychologists Press, Palo Alto, CA1970
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • Willians J.B.W.
        Structured Clinical Interview for DSM-IV Axis 1 Disorders.
        American Psychiatric Press, Washington, DC1997
        • Liebowitz M.R.
        Social phobia.
        Mod Probl Pharmacopsychiatry. 1987; 22: 141-173
        • Ashburner J.
        • Friston K.J.
        Voxel-based morphometry—the methods.
        Neuroimage. 2000; 11: 805-821
        • Ashburner J.
        • Friston K.J.
        Why voxel-based morphometry should be used.
        Neuroimage. 2001; 14: 1238-1243
        • Ashburner J.
        • Friston K.J.
        Unified segmentation.
        Neuroimage. 2005; 26: 839-851
        • Ashburner J.
        A fast diffeomorphic image registration algorithm.
        Neuroimage. 2007; 38: 95-113
        • Keller S.S.
        • Wilke M.
        • Wieshmann U.C.
        • Sluming V.A.
        • Roberts N.
        Comparison of standard and optimized voxel-based morphometry for analysis of brain changes associated with temporal lobe epilepsy.
        Neuroimage. 2004; 23: 860-868
        • Mikl M.
        • Marecek R.
        • Hlustik P.
        • Pavlicova M.
        • Drastich A.
        • Chlebus P.
        • et al.
        Effects of spatial smoothing on fMRI group inferences.
        Magn Reson Imaging. 2008; 26: 490-503
        • Lazaro L.
        • Castro-Fornieles J.
        • Cullell C.
        • Andres S.
        • Falcon C.
        • Calvo R.
        • et al.
        A voxel-based morphometric MRI study of stabilized obsessive-compulsive adolescent patients.
        Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35: 1863-1869
        • Yoo H.K.
        • Kim M.J.
        • Kim S.J.
        • Sung Y.H.
        • Sim M.E.
        • Lee Y.S.
        • et al.
        Putaminal gray matter volume decrease in panic disorder: An optimized voxel-based morphometry study.
        Eur J Neurosci. 2005; 22: 2089-2094
        • Henley S.M.
        • Ridgway G.R.
        • Scahill R.I.
        • Kloppel S.
        • Tabrizi S.J.
        • Fox N.C.
        • et al.
        Pitfalls in the use of voxel-based morphometry as a biomarker: Examples from huntington disease.
        AJNR Am J Neuroradiol. 2010; 31: 711-719
        • Silver M.
        • Montana G.
        • Nichols T.E.
        False positives in neuroimaging genetics using voxel-based morphometry data.
        Neuroimage. 2011; 54: 992-1000
        • Hayasaka S.
        • Phan K.L.
        • Liberzon I.
        • Worsley K.J.
        • Nichols T.E.
        Nonstationary cluster-size inference with random field and permutation methods.
        Neuroimage. 2004; 22: 676-687
        • Warwick J.M.
        • Carey P.
        • Jordaan G.P.
        • Dupont P.
        • Stein D.J.
        Resting brain perfusion in social anxiety disorder: A voxel-wise whole brain comparison with healthy control subjects.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1251-1256
        • Kilts C.D.
        • Kelsey J.E.
        • Knight B.
        • Ely T.D.
        • Bowman F.D.
        • Gross R.E.
        • et al.
        The neural correlates of social anxiety disorder and response to pharmacotherapy.
        Neuropsychopharmacology. 2006; 31: 2243-2253
        • Baldacara L.
        • Borgio J.G.
        • Lacerda A.L.
        • Jackowski A.P.
        Cerebellum and psychiatric disorders.
        Rev Bras Psiquiatr. 2008; 30: 281-289
        • Goldin P.R.
        • Manber T.
        • Hakimi S.
        • Canli T.
        • Gross J.J.
        Neural bases of social anxiety disorder: Emotional reactivity and cognitive regulation during social and physical threat.
        Arch Gen Psychiatry. 2009; 66: 170-180
        • Straube T.
        • Kolassa I.T.
        • Glauer M.
        • Mentzel H.J.
        • Miltner W.H.
        Effect of task conditions on brain responses to threatening faces in social phobics: An event-related functional magnetic resonance imaging study.
        Biol Psychiatry. 2004; 56: 921-930
        • Polosan M.
        • Baciu M.
        • Cousin E.
        • Perrone M.
        • Pichat C.
        • Bougerol T.
        An fMRI study of the social competition in healthy subjects.
        Brain Cogn. 2011; 77: 401-411
        • Fairhall S.L.
        • Ishai A.
        Effective connectivity within the distributed cortical network for face perception.
        Cereb Cortex. 2007; 17: 2400-2406
        • Gentili C.
        • Gobbini M.I.
        • Ricciardi E.
        • Vanello N.
        • Pietrini P.
        • Haxby J.V.
        • et al.
        Differential modulation of neural activity throughout the distributed neural system for face perception in patients with Social Phobia and healthy subjects.
        Brain Res Bull. 2008; 77: 286-292
        • Lai C.H.
        Gray matter deficits in panic disorder: A pilot study of meta-analysis.
        J Clin Psychopharmacol. 2011; 31: 287-293
        • Massana G.
        • Serra-Grabulosa J.M.
        • Salgado-Pineda P.
        • Gasto C.
        • Junque C.
        • Massana J.
        • et al.
        Parahippocampal gray matter density in panic disorder: A voxel-based morphometric study.
        Am J Psychiatry. 2003; 160: 566-568
        • Uchida R.R.
        • Del-Ben C.M.
        • Busatto G.F.
        • Duran F.L.
        • Guimaraes F.S.
        • Crippa J.A.
        • et al.
        Regional gray matter abnormalities in panic disorder: A voxel-based morphometry study.
        Psychiatry Res. 2008; 163: 21-29
        • Zahn R.
        • Moll J.
        • Krueger F.
        • Huey E.D.
        • Garrido G.
        • Grafman J.
        Social concepts are represented in the superior anterior temporal cortex.
        Proc Natl Acad Sci U S A. 2007; 104: 6430-6435
        • Zahn R.
        • Moll J.
        • Paiva M.
        • Garrido G.
        • Krueger F.
        • Huey E.D.
        • et al.
        The neural basis of human social values: Evidence from functional MRI.
        Cereb Cortex. 2009; 19: 276-283
        • Liu W.
        • Miller B.L.
        • Kramer J.H.
        • Rankin K.
        • Wyss-Coray C.
        • Gearhart R.
        • et al.
        Behavioral disorders in the frontal and temporal variants of frontotemporal dementia.
        Neurology. 2004; 62: 742-748
        • Tillfors M.
        • Furmark T.
        • Marteinsdottir I.
        • Fredrikson M.
        Cerebral blood flow during anticipation of public speaking in social phobia: A PET study.
        Biol Psychiatry. 2002; 52: 1113-1119
        • Meda S.A.
        • Pryweller J.R.
        • Thornton-Wells T.A.
        Regional brain differences in cortical thickness, surface area and subcortical volume in individuals with Williams syndrome.
        PLoS One. 2012; 7: e31913
        • Reiss A.L.
        • Eckert M.A.
        • Rose F.E.
        • Karchemskiy A.
        • Kesler S.
        • Chang M.
        • et al.
        An experiment of nature: brain anatomy parallels cognition and behavior in Williams syndrome.
        J Neurosci. 2004; 24: 5009-5015
        • Blackmon K.
        • Barr W.B.
        • Carlson C.
        • Devinsky O.
        • Dubois J.
        • Pogash D.
        • et al.
        Structural evidence for involvement of a left amygdala-orbitofrontal network in subclinical anxiety.
        Psychiatry Res. 2011; 194: 296-303
        • Milad M.R.
        • Rauch S.L.
        The role of the orbitofrontal cortex in anxiety disorders.
        Ann N Y Acad Sci. 2007; 1121: 546-561
        • Baur V.
        • Bruhl A.B.
        • Herwig U.
        • Eberle T.
        • Rufer M.
        • Delsignore A.
        • et al.
        Evidence of frontotemporal structural hypoconnectivity in social anxiety disorder: A quantitative fiber tractography study [published online ahead of print November 11].
        Hum Brain Mapp. 2011;
        • Baur V.
        • Hanggi J.
        • Rufer M.
        • Delsignore A.
        • Jancke L.
        • Herwig U.
        • et al.
        White matter alterations in social anxiety disorder.
        J Psychiatr Res. 2011; 45: 1366-1372
        • Biederman J.
        • Hirshfeld-Becker D.R.
        • Rosenbaum J.F.
        • Herot C.
        • Friedman D.
        • Snidman N.
        • et al.
        Further evidence of association between behavioral inhibition and social anxiety in children.
        Am J Psychiatry. 2001; 158: 1673-1679
        • Schwartz C.E.
        • Snidman N.
        • Kagan J.
        Adolescent social anxiety as an outcome of inhibited temperament in childhood.
        J Am Acad Child Adolesc Psychiatry. 1999; 38: 1008-1015
        • Schwartz C.E.
        • Kunwar P.S.
        • Greve D.N.
        • Moran L.R.
        • Viner J.C.
        • Covino J.M.
        • et al.
        Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age.
        Arch Gen Psychiatry. 2010; 67: 78-84
        • Etkin A.
        • Wager T.D.
        Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
        Am J Psychiatry. 2007; 164: 1476-1488
        • Weissman M.M.
        • Brown A.S.
        • Talati A.
        Translational epidemiology in psychiatry: Linking population to clinical and basic sciences.
        Arch Gen Psychiatry. 2011; 68: 600-608
        • Davatzikos C.
        Why voxel-based morphometric analysis should be used with great caution when characterizing group differences.
        Neuroimage. 2004; 23: 17-20
        • Crum W.R.
        • Griffin L.D.
        • Hill D.L.
        • Hawkes D.J.
        Zen and the art of medical image registration: Correspondence, homology, and quality.
        Neuroimage. 2003; 20: 1425-1437
        • Ioannidis J.P.
        Excess significance bias in the literature on brain volume abnormalities.
        Arch Gen Psychiatry. 2011; 68: 773-780