Advertisement

Preliminary Evidence of White Matter Abnormality in the Uncinate Fasciculus in Generalized Social Anxiety Disorder

      Background

      Individuals with generalized social anxiety disorder (GSAD) exhibit exaggerated amygdala reactivity to aversive social stimuli. These findings could be explained by microstructural abnormalities in white matter (WM) tracts that connect the amygdala and prefrontal cortex, which is known to modulate the amygdala's response to threat. The goal of this study was to investigate brain frontal WM abnormalities using diffusion tensor imaging (DTI) in patients with social anxiety disorder.

      Methods

      A Turboprop DTI sequence was used to acquire diffusion tensor images in 30 patients with GSAD and 30 matched healthy control subjects. Fractional anisotropy, an index of axonal organization, within WM was quantified in individual subjects, and an automated voxel-based, whole-brain method was used to analyze group differences.

      Results

      Compared with healthy control subjects, patients had significantly lower fractional anisotropy localized to the right uncinate fasciculus WM near the orbitofrontal cortex. There were no areas of higher fractional anisotropy in patients than controls.

      Conclusions

      These findings point to an abnormality in the uncinate fasciculus, the major WM tract connecting the frontal cortex to the amygdala and other limbic temporal regions, in GSAD, which could underlie the aberrant amygdala-prefrontal interactions resulting in dysfunctional social threat processing in this illness.

      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

        • Stein M.B.
        • Stein D.J.
        Social anxiety disorder.
        Lancet. 2008; 371: 1115-1125
        • 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
        • Stein M.B.
        • Goldin P.R.
        • Sareen J.
        • Zorrilla L.T.
        • Brown G.G.
        Increased amygdala activation to angry and contemptuous faces in generalized social phobia.
        Arch Gen Psychiatry. 2002; 59: 1027-1034
        • Phan K.L.
        • Fitzgerald D.A.
        • Nathan P.J.
        • Tancer M.E.
        Association between amygdala hyperactivity to harsh faces and severity of social anxiety in generalized social phobia.
        Biol Psychiatry. 2006; 59: 424-429
        • 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
        • Ochsner K.N.
        • Gross J.J.
        The cognitive control of emotion.
        Trends Cogn Sci. 2005; 9: 242-249
        • Phelps E.A.
        • Delgado M.R.
        • Nearing K.I.
        • LeDoux J.E.
        Extinction learning in humans: Role of the amygdala and vmPFC.
        Neuron. 2004; 43: 897-905
        • Goldin P.R.
        • Hakimi S.
        • Manber T.
        • 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
        • Ghashghaei H.T.
        • Hilgetag C.C.
        • Barbas H.
        Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala.
        Neuroimage. 2007; 34: 905-923
        • Lim K.O.
        • Helpern J.A.
        Neuropsychiatric applications of DTI—A review.
        NMR Biomed. 2002; 15: 587-593
        • Mori S.
        • Zhang J.
        Principles of diffusion tensor imaging and its applications to basic neuroscience research.
        Neuron. 2006; 51: 527-539
        • Arfanakis K.
        • Gui M.
        • Lazar M.
        White matter tractography by means of turboprop diffusion tensor imaging.
        Ann N Y Acad Sci. 2005; 1064: 78-87
        • 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
        • Fresco D.M.
        • Coles M.E.
        • Heimberg R.G.
        • Liebowitz M.R.
        • Hami S.
        • Stein M.B.
        • et al.
        The Liebowitz social anxiety scale: A comparison of the psychometric properties of self-report and clinician-administered formats.
        Psychol Med. 2001; 31: 1025-1035
        • Pipe J.G.
        • Zwart N.
        Turboprop: Improved PROPELLER imaging.
        Magn Reson Med. 2006; 55: 380-385
        • Arfanakis K.
        • Gui M.
        • Tamhane A.A.
        • Carew J.D.
        Investigating the medial temporal lobe in Alzheimer's disease and mild cognitive impairment, with turboprop diffusion tensor imaging, MRI-volumetry, and T 2-relaxometry.
        Brain Imaging Behav. 2007; 1: 11-21
        • Sullivan E.V.
        • Adalsteinsson E.
        • Hedehus M.
        • Ju C.
        • Moseley M.
        • Lim K.O.
        • et al.
        Equivalent disruption of regional white matter microstructure in ageing healthy men and women.
        Neuroreport. 2001; 12: 99-104
        • Nakamae T.
        • Narumoto J.
        • Shibata K.
        • Matsumoto R.
        • Kitabayashi Y.
        • Yoshida T.
        • et al.
        Alteration of fractional anisotropy and apparent diffusion coefficient in obsessive-compulsive disorder: A diffusion tensor imaging study.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 1221-1226
        • Wang F.
        • Kalmar J.H.
        • Edmiston E.
        • Chepenik L.G.
        • Bhagwagar Z.
        • Spencer L.
        • et al.
        Abnormal corpus callosum integrity in bipolar disorder: A diffusion tensor imaging study.
        Biol Psychiatry. 2008; 64: 730-733
        • Murphy C.F.
        • Gunning-Dixon F.M.
        • Hoptman M.J.
        • Lim K.O.
        • Ardekani B.
        • Shields J.K.
        • et al.
        White-matter integrity predicts Stroop performance in patients with geriatric depression.
        Biol Psychiatry. 2007; 61: 1007-1010
        • Ashtari M.
        • Kumra S.
        • Bhaskar S.L.
        • Clarke T.
        • Thaden E.
        • Cervellione K.L.
        • et al.
        Attention-deficit/hyperactivity disorder: A preliminary diffusion tensor imaging study.
        Biol Psychiatry. 2005; 57: 448-455
        • Hubl D.
        • Koenig T.
        • Strik W.
        • Federspiel A.
        • Kreis R.
        • Boesch C.
        • et al.
        Pathways that make voices: White matter changes in auditory hallucinations.
        Arch Gen Psychiatry. 2004; 61: 658-668
        • Mori S.
        • Wakana S.
        • Nagae-Poetscher L.M.
        • Van Zijl P.C.
        MRI Atlas of Human White Matter.
        Elsevier B.B, Amsterdam2005
        • Ghashghaei H.T.
        • Barbas H.
        Pathways for emotion: Interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey.
        Neuroscience. 2002; 115: 1261-1279
        • Evans K.C.
        • Simon N.M.
        • Dougherty D.D.
        • Hoge E.A.
        • Worthington J.J.
        • Chow C.
        • et al.
        A PET study of tiagabine treatment implicates ventral medial prefrontal cortex in generalized social anxiety disorder.
        Neuropsychopharmacology. 2009; 34: 390-398
        • Quadflieg S.
        • Mohr A.
        • Mentzel H.J.
        • Miltner W.H.
        • Straube T.
        Modulation of the neural network involved in the processing of anger prosody: The role of task-relevance and social phobia.
        Biol Psychol. 2008; 78: 129-137
        • Versace A.
        • Almeida J.R.
        • Hassel S.
        • Walsh N.D.
        • Novelli M.
        • Klein C.R.
        • et al.
        Elevated left and reduced right orbitomedial prefrontal fractional anisotropy in adults with bipolar disorder revealed by tract-based spatial statistics.
        Arch Gen Psychiatry. 2008; 65: 1041-1052
        • Kanaan R.A.
        • Kim J.S.
        • Kaufmann W.E.
        • Pearlson G.D.
        • Barker G.J.
        • McGuire P.K.
        Diffusion tensor imaging in schizophrenia.
        Biol Psychiatry. 2005; 58: 921-929
        • Gurrera R.J.
        • Nakamura M.
        • Kubicki M.
        • Dickey C.C.
        • Niznikiewicz M.A.
        • Voglmaier M.M.
        • et al.
        The uncinate fasciculus and extraversion in schizotypal personality disorder: A diffusion tensor imaging study.
        Schizophr Res. 2007; 90: 360-362
        • Nakamura M.
        • McCarley R.W.
        • Kubicki M.
        • Dickey C.C.
        • Niznikiewicz M.A.
        • Voglmaier M.M.
        • et al.
        Fronto-temporal disconnectivity in schizotypal personality disorder: A diffusion tensor imaging study.
        Biol Psychiatry. 2005; 58: 468-478
        • Hoptman M.J.
        • Ardekani B.A.
        • Butler P.D.
        • Nierenberg J.
        • Javitt D.C.
        • Lim K.O.
        DTI and impulsivity in schizophrenia: A first voxelwise correlational analysis.
        Neuroreport. 2004; 15: 2467-2470
        • Hoptman M.J.
        • Volavka J.
        • Johnson G.
        • Weiss E.
        • Bilder R.M.
        • Lim K.O.
        Frontal white matter microstructure, aggression, and impulsivity in men with schizophrenia: A preliminary study.
        Biol Psychiatry. 2002; 52: 9-14
        • Kyriakopoulos M.
        • Bargiotas T.
        • Barker G.J.
        • Frangou S.
        Diffusion tensor imaging in schizophrenia.
        Eur Psychiatry. 2008; 23: 255-273
        • Schlosser R.G.
        • Nenadic I.
        • Wagner G.
        • Gullmar D.
        • von Consbruch K.
        • Kohler
        • et al.
        White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study.
        Schizophr Res. 2007; 89: 1-11
        • Forstmann B.U.
        • Jahfari S.
        • Scholte H.S.
        • Wolfensteller U.
        • van den Wildenberg W.P.
        • Ridderinkhof K.R.
        Function and structure of the right inferior frontal cortex predict individual differences in response inhibition: A model-based approach.
        J Neurol Sci. 2008; 28: 9790-9796
        • Westlye L.T.
        • Walhovd K.B.
        • Bjornerud A.
        • Due-Tonnessen P.
        • Fjell A.M.
        Error-related negativity is mediated by fractional anisotropy in the posterior cingulate gyrus—A study combining diffusion tensor imaging and electrophysiology in healthy adults.
        Cereb Cortex. 2009; 19: 293-304
        • Smith S.M.
        • Jenkinson M.
        • Johansen-Berg H.
        • Rueckert D.
        • Nichols T.E.
        • Mackay C.E.
        • et al.
        Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data.
        Neuroimage. 2006; 31: 1487-1505