Gray Matter Correlates of Posttraumatic Stress Disorder: A Quantitative Meta-Analysis

  • Simone Kühn
    Address correspondence to Simone Kühn, Ph.D., Max Planck Institute for Human Development, Center for Lifespan Psychology, Lentzeallee 94, Berlin 14195, Germany
    Max Planck Institute for Human Development, Center for Lifespan Psychology, Berlin, Germany
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  • Jürgen Gallinat
    Charité University Medicine, St. Hedwig Krankenhaus, Clinic for Psychiatry and Psychotherapy, Berlin, Germany
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      Since the inception of the diagnosis posttraumatic stress disorder (PTSD), attempts have been undertaken to understand why only a subpopulation of individuals exposed to trauma develops PTSD. Cerebral gray matter reductions have been suggested to be a crucial pathobiological marker of PTSD. However, a quantitative meta-analysis of whole-brain voxel-based morphometry studies is lacking.


      Here, we investigated concurrence across voxel-based morphometry studies in PTSD compared with trauma-exposed individuals without PTSD (all together nine studies with 319 subjects) by means of activation likelihood estimation.


      We identified brain regions of consistent gray matter reduction in anterior cingulate cortex, ventromedial prefrontal cortex, left temporal pole/middle temporal gyrus, and left hippocampus in PTSD patients compared with individuals exposed to trauma without PTSD.


      This is the first quantitative whole-brain meta-analysis showing brain structure deficits in traumatized subjects with PTSD compared with trauma-exposed healthy control subjects. The gray matter deficit profile overlaps with brain networks of emotion processing, fear extinction, and emotion regulation known to be affected in PTSD. Although the data cannot clarify if this is a predisposition or a consequence of the disease, the results may facilitate the need to control for structural characteristics in future functional brain studies.

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        • Kessler R.C.
        • Berglund P.
        • Delmer O.
        • Jin R.
        • Merikangas K.R.
        • Walters E.E.
        Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
        Arch Gen Psychiatry. 2005; 62: 593-602
        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        4th ed. American Psychiatric Press, Washington, DC1994
        • Yehuda R.
        • Flory J.D.
        • Southwick S.
        • Charney D.S.
        Developing an agenda for translational studies of resilience and vulnerability following trauma exposure.
        Ann N Y Acad Sci. 2006; 1071: 379-396
        • Karl A.
        • Schaefer M.
        • Malta L.S.
        • Dörfel D.
        • Rohleder N.
        • Werner A.
        A meta-analysis of structural brain abnormalities in PTSD.
        Neurosci Biobehav Rev. 2006; 30: 1004-1031
        • Jelicic M.
        • Merckelbach H.
        Traumatic stress, brain changes, and memory deficits: A critical note.
        J Nerv Ment Dis. 2004; 192: 548-553
        • Bremner J.D.
        • Randall P.
        • Scott T.M.
        • Bronen R.A.
        • Seibyl J.P.
        • Southwick S.M.
        • et al.
        MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder.
        Am J Psychiatry. 1995; 152: 973-981
        • Gurvits T.V.
        • Shenton M.E.
        • Hokama H.
        • Ohta H.
        Magnetic resonance imaging study of hippocampal volume in chronic, combat related posttraumatic stress disorder.
        Biol Psychiatry. 1996; 40: 1091-1099
        • Stein M.B.
        • Koverola C.
        • Hanna C.
        • Torchia M.G.
        • McClarty B.
        Hippocampal volume in women victimized by childhood sexual abuse.
        Psychol Med. 1997; 27: 951-959
        • Pederson C.L.
        • Maurer S.H.
        • Kaminski P.L.
        • Zander K.A.
        • Peters C.M.
        • Stokes-Crowe L.A.
        • Osborn R.E.
        Hippocampal volume and memory performance in a community-based sample of women with posttraumatic stress disorder secondary to child abuse.
        J Trauma Stress. 2004; 17: 37-40
        • Schuff N.
        • Neylan T.C.
        • Lenoci M.A.
        • Du A.T.
        • Weiss D.S.
        • Marmar C.R.
        • Weiner M.W.
        Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder.
        Biol Psychiatry. 2001; 50: 952-959
        • Bremner J.D.
        • Vythilingam M.
        • Vermetten E.
        • Southwick S.M.
        • McGlashan T.
        • Nazeer A.
        • et al.
        MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder.
        Am J Psychiatry. 2003; 160: 924-932
        • Smith M.E.
        Bilateral hippocampal volume reduction in adults with posttraumatic stress disorder: A meta-analysis of structural MRI studies.
        Hippocampus. 2005; 15: 798-807
        • Kitayama N.
        • Vaccarino V.
        • Kutner M.
        • Weiss P.
        • Bremner J.D.
        Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: A meta-analysis.
        J Affect Disord. 2005; 88: 79-86
        • Woon F.L.
        • Sood S.
        • Hedges D.W.
        Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: A meta-analysis.
        Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 1181-1188
        • Woon F.L.
        • Hedges D.W.
        Amygdala volume in adults with posttraumatic stress disorder: A meta-analysis.
        J Neuropsychiatry Clin Neurosci. 2009; 21: 5-12
        • Woon F.L.
        • Hedges D.W.
        Hippocampal and amygdale volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: A meta-analysis.
        Hippocampus. 2008; 18: 729-736
        • Eickhoff S.B.
        • Laird A.R.
        • Grefkes C.
        • Wang L.E.
        • Zilles K.
        • Fox P.T.
        Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: A random effects approach based on empirical estimates of spatial uncertainty.
        Hum Brain Mapp. 2009; 30: 2907-2926
        • Laird A.R.
        • Fox P.M.
        • Price C.J.
        • Glahn D.C.
        • Uecker A.M.
        • Lancaster J.L.
        • et al.
        ALE meta-analysis: Controlling the false discovery rate and performing statistical contrasts.
        Hum Brain Mapp. 2005; 25: 155-164
        • Turkeltaub P.E.
        • Eden G.F.
        • Jones K.M.
        • Zeffiro T.A.
        Meta-analysis of the functional neuroanatomy of single-word reading: Method and validation.
        Neuroimage. 2002; 16: 765-780
        • Talairach J.
        • Tournoux P.
        Co-planar Stereotaxic Atlas of the Human Brain.
        Thieme, New York1998
        • Sui S.G.
        • Wu M.X.
        • King M.E.
        • Zhan Y.
        • Ling L.
        • Xu J.M.
        • et al.
        Abnormal grey matter in victims of rape with PTSD in Mainland China: A voxel-based morphometry study.
        Acta Neuropsychiatr. 2010; 22: 118-126
        • Carrion V.G.
        • Weems C.F.
        • Watson C.
        • Eliez S.
        • Menon V.
        • Reiss A.L.
        Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric PTSD: An MRI study.
        Psychiatry Res. 2009; 172: 226-234
        • Lancaster J.L.
        • Tordesillas-Guiérrez D.
        • Martinez M.
        • Salinas F.
        • Evans A.
        • Zilles K.
        • et al.
        Bias between MNI and Talairach coordinates analyzed using the ICBM-152 brain template.
        Hum Brain Mapp. 2007; 28: 1194-1205
        • Bryant R.A.
        • Felmingham K.
        • Whitford T.J.
        • Kemp A.
        • Hughes G.
        • Peduto A.
        • Williams L.M.
        Rostral anterior cingulate volume predicts treatment response to cognitive-behavioral therapy for posttraumatic stress disorder.
        J Psychiatry Neurosci. 2008; 33: 142-146
        • Chen S.
        • Xia W.
        • Li L.
        • Liu J.
        • He Z.
        • Zhang Z.
        • et al.
        Gray matter density reduction in the insula in fire survivors with posttraumatic stress disorder: A voxel-based morphometric study.
        Psychiatry Res. 2006; 146: 65-72
        • Chen S.
        • Li L.
        • Xu B.
        • Liu J.
        Insular cortex involvement in declarative memory deficits in patients with posttraumatic stress disorder.
        BMC Psychiatry. 2009; 9: 39-48
        • Hakamata Y.
        • Matsuoka Y.
        • Inagaki M.
        • Nagamine M.
        • Hara E.
        • Imoto S.
        • et al.
        Structure of orbitofrontal cortex and its longitudinal course in cancer-related posttraumatic stress disorder.
        Neurosci Res. 2007; 59: 383-389
        • Li L.
        • Chen S.
        • Liu J.
        • Zhang J.
        • He Z.
        • Lin X.
        Magnetic resonance imaging and magnetic resonance spectroscopy study of deficits in hippocampal structure in fire victims with recent-onset posttraumatic stress disorder.
        Can J Psychiatry. 2006; 51: 431-437
        • Nardo D.
        • Höberg G.
        • Looi J.C.L.
        • Larsson S.
        • Hällström T.
        • Pagani M.
        Gray matter density in limbic and paralimbic cortices is associated with trauma load and EMDR outcome in PTSD patients.
        J Psychiatr Res. 2010; 44: 477-485
        • Yamasue H.
        • Kasai K.
        • Iwanami A.
        • Ohtani T.
        • Yamada H.
        • Abe O.
        • et al.
        Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism.
        Proc Natl Acad Sci U S A. 2003; 100: 9039-9043
        • Zhang J.
        • Tan Q.
        • Yin H.
        • Zhang X.
        • Huan Y.
        • Tang L.
        • et al.
        Decreased gray matter volume in the left hippocampus and bilateral calcarine cortex in coal mine flood disaster survivors with recent onset PTSD.
        Psychiatry Res. 2011; 192: 84-90
        • Squire L.R.
        • Schacter D.L.
        The Neuropsychology of Memory.
        Guilford Press, New York2002
        • Samuelson K.W.
        Post-traumatic stress disorder and declarative memory functioning: A review.
        Dialogues Clin Neurosci. 2011; 13: 346-351
        • Bannerman D.M.
        • Rawlins J.N.P.
        • McHugh S.B.
        • Deacon R.M.J.
        • Yee B.K.
        • Bast R.
        • et al.
        Regional dissociations within the hippocampus - memory and anxiety.
        Neurosci Biobehav Rev. 2004; 28: 273-283
        • Fanselow M.S.
        • Dong H.W.
        Are the dorsal and ventral hippocampus functionally distinct structures?.
        Neuron. 2010; 65: 7-19
        • Gray J.A.
        • McNaughton N.
        The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-Hippocampal System.
        Oxford University Press, Oxford2000
        • Kishi T.
        • Tsumori T.
        • Yokota S.
        • Yasui Y.
        Topographical projection from the hippocampal formation to the amygdala: A combined anterograde and retrograde tracing study in the rat.
        J Comp Neurol. 2006; 496: 349-368
        • Milad M.R.
        • Wright C.I.
        • Orr S.P.
        • Pitman R.K.
        • Quirk G.J.
        • Rauch S.L.
        Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert.
        Biol Psychiatry. 2007; 62: 446-454
        • 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
        • Milad M.R.
        • Pitman R.K.
        • Ellis C.B.
        • Gold A.L.
        • Shin L.M.
        • Lasko N.B.
        • et al.
        Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder.
        Biol Psychiatry. 2009; 66: 1075-1982
        • Norrholm S.D.
        • Jovanociv T.
        • Olin I.W.
        • Sands L.A.
        • Karapanou I.
        • Brandley B.
        • Ressler K.J.
        Fear extinction in traumatized civilians with posttraumatic stress disorder: Relation to symptom severity.
        Biol Psychiatry. 2011; 69: 556-563
        • Myers-Schulz B.
        • Koenigs M.
        Functional anatomy of ventromedial prefrontal cortex: Implications for mood and anxiety disorders.
        Mol Psychiatry. 2012; 17: 132-141
        • Carter C.S.
        • Botvinick M.M.
        • Cohen J.D.
        The contribution of the anterior cingulate cortex to executive processes in cognition.
        Rev Neurosci. 1999; 10: 49-57
        • Diekhof E.K.
        • Geier K.
        • Falkai P.
        • Gruber O.
        Fear is only as deep as the mind allows: A coordinate-based meta-analysis of neuroimaging studies on the regulation of negative affect.
        Neuroimage. 2011; 58: 275-285
        • Bush G.
        • Luu P.
        • Posner M.I.
        Cognitive and emotional influences in anterior cingulate cortex.
        Trends Cogn Sci. 2000; 4: 215-222
        • Carmichael S.T.
        • Price J.L.
        Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys.
        J Comp Neurol. 1995; 363: 615-641
        • Hariri A.R.
        • Mattay V.S.
        • Tessitore A.
        • Fera F.
        • Weinberger D.R.
        Neocortical modulation of the amygdale response to fearful stimuli.
        Biol Psychiatry. 2003; 53: 494-501
        • 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
        • Olson I.R.
        • Plotzker A.
        • Ezzyat Y.
        The enigmatic temporal pole: A review of findings on social and emotional processing.
        Brain. 2007; 130: 1718-1731
        • Klüver H.
        • Bucy P.
        Preliminary analysis of functions of the temporal lobes in monkeys.
        Arch Neurol Psychiatry. 1939; 41: 979-1000
        • Fletcher P.C.
        • Happe F.
        • Frith U.
        • Baker S.C.
        Other minds in the brain: A functional imaging study of “theory of mind” in story comprehension.
        Cognition. 1995; 57: 109-121
        • Frith U.
        • Frith C.
        Development and neurophysiology of mentalizing.
        Philos Trans R Soc Lond B Biol Sci. 2003; 358: 459-473
        • Saxe R.
        • Powell L.J.
        It's the thought that counts: Specific brain regions for one component of theory of mind.
        Psychol Sci. 2006; 17: 692-699