Advertisement

Mapping Corticocortical Structural Integrity in Schizophrenia and Effects of Genetic Liability

  • Owen R. Phillips
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Keith H. Nuechterlein
    Affiliations
    Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry; Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Robert F. Asarnow
    Affiliations
    Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry; Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Kristi A. Clark
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Ryan Cabeen
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Yaling Yang
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Roger P. Woods
    Affiliations
    Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Arthur W. Toga
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California

    Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author
  • Katherine L. Narr
    Correspondence
    Address correspondence to Katherine L. Narr, Ph.D., Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, 635 Charles Young Drive South, Suite 225, Los Angeles, California 90095-7334
    Affiliations
    Laboratory of Neuro Imaging, Department of Neurology, Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California
    Search for articles by this author

      Background

      Structural and diffusion tensor imaging studies implicate gray and white matter (WM) abnormalities and disruptions of neural circuitry in schizophrenia. However, the structural integrity of the superficial WM, comprising short-range association (U-fibers) and intracortical axons, has not been investigated in schizophrenia.

      Methods

      High-resolution structural and diffusion tensor images and sophisticated cortical pattern matching methods were used to measure and compare global and local variations in superficial WM fractional anisotropy between schizophrenia patients and their relatives and community comparison subjects and their relatives (n = 150).

      Results

      Compared with control subjects, patients showed reduced superficial WM fractional anisotropy distributed across each hemisphere, particularly in left temporal and bilateral occipital regions (all p < .05, corrected). Furthermore, by modeling biological risk for schizophrenia in patients, patient relatives, and control subjects, fractional anisotropy was shown to vary in accordance with relatedness to a patient in both hemispheres and in the temporal and occipital lobes (p < .05, corrected). However, effects did not survive correction procedures for two-group comparisons between patient relatives and control subjects.

      Conclusions

      Results extend previous findings restricted to deep WM pathways to demonstrate that disturbances in corticocortical connectivity are associated with schizophrenia and might indicate a genetic predisposition for the disorder. Because the structural integrity of WM plays a crucial role in the functionality of networks linking gray matter regions, disturbances in the coherence and organization of fibers at the juncture of the neuropil might relate to features of schizophrenia at least partially attributable to disease-related genetic factors.

      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

        • Ellison-Wright I.
        • Glahn D.C.
        • Laird A.R.
        • Thelen S.M.
        • Bullmore E.
        The anatomy of first-episode and chronic schizophrenia: An anatomical likelihood estimation meta-analysis.
        Am J Psychiatry. 2008; 165: 1015-1023
        • Honea R.
        • Crow T.J.
        • Passingham D.
        • Mackay C.E.
        Regional deficits in brain volume in schizophrenia: A meta-analysis of voxel-based morphometry studies.
        Am J Psychiatry. 2005; 162: 2233-2245
        • Shenton M.E.
        • Dickey C.C.
        • Frumin M.
        • McCarley R.W.
        A review of MRI findings in schizophrenia.
        Schizophr Res. 2001; 49: 1-52
        • Ashburner J.
        • Friston K.J.
        Voxel-based morphometry—The methods.
        Neuroimage. 2000; 11: 805-821
        • Basser P.J.
        • Pierpaoli C.
        Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI.
        J Magn Reson B. 1996; 111: 209-219
        • Catani M.
        • Howard R.J.
        • Pajevic S.
        • Jones D.K.
        Virtual in vivo interactive dissection of white matter fasciculi in the human brain.
        Neuroimage. 2002; 17: 77-94
        • Conturo T.E.
        • Lori N.F.
        • Cull T.S.
        • Akbudak E.
        • Snyder A.Z.
        • Shimony J.S.
        • et al.
        Tracking neuronal fiber pathways in the living human brain.
        Proc Natl Acad Sci U S A. 1999; 96: 10422-10427
        • Wakana S.
        • Jiang H.
        • Nagae-Poetscher L.M.
        • van Zijl P.C.
        • Mori S.
        Fiber tract-based atlas of human white matter anatomy.
        Radiology. 2004; 230: 77-87
        • Dong Q.
        • Welsh R.C.
        • Chenevert T.L.
        • Carlos R.C.
        • Maly-Sundgren P.
        • Gomez-Hassan D.M.
        • et al.
        Clinical applications of diffusion tensor imaging.
        J Magn Reson Imaging. 2004; 19: 6-18
        • Neil J.J.
        • Shiran S.I.
        • McKinstry R.C.
        • Schefft G.L.
        • Snyder A.Z.
        • Almli C.R.
        • et al.
        Normal brain in human newborns: Apparent diffusion coefficient and diffusion anisotropy measured by using diffusion tensor MR imaging.
        Radiology. 1998; 209: 57-66
        • Song S.K.
        • Sun S.W.
        • Ju W.K.
        • Lin S.J.
        • Cross A.H.
        • Neufeld A.H.
        • et al.
        Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia.
        Neuroimage. 2003; 20: 1714-1722
        • Takahashi M.
        • Hackney D.B.
        • Zhang G.
        • Wehrli S.L.
        • Wright A.C.
        • O'Brien W.T.
        • et al.
        Magnetic resonance microimaging of intraaxonal water diffusion in live excised lamprey spinal cord.
        Proc Natl Acad Sci U S A. 2002; 99: 16192-16196
        • Takahashi M.
        • Ono J.
        • Harada K.
        • Maeda M.
        • Hackney D.B.
        Diffusional anisotropy in cranial nerves with maturation: Quantitative evaluation with diffusion MR imaging in rats.
        Radiology. 2000; 216: 881-885
        • Catani M.
        • ffytche D.H.
        The rises and falls of disconnection syndromes.
        Brain. 2005; 128: 2224-2239
        • Friston K.J.
        • Frith C.D.
        Schizophrenia: A disconnection syndrome?.
        Clin Neurosci. 1995; 3: 89-97
        • Hakak Y.
        • Walker J.R.
        • Li C.
        • Wong W.H.
        • Davis K.L.
        • Buxbaum J.D.
        • et al.
        Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia.
        Proc Natl Acad Sci U S A. 2001; 98: 4746-4751
        • Kubicki M.
        • McCarley R.
        • Westin C.F.
        • Park H.J.
        • Maier S.
        • Kikinis R.
        • et al.
        A review of diffusion tensor imaging studies in schizophrenia.
        J Psychiatr Res. 2007; 41: 15-30
        • Uranova N.A.
        • Vostrikov V.M.
        • Orlovskaya D.D.
        • Rachmanova V.I.
        Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: A study from the Stanley Neuropathology Consortium.
        Schizophr Res. 2004; 67: 269-275
        • Walterfang M.
        • Wood S.J.
        • Velakoulis D.
        • Pantelis C.
        Neuropathological, neurogenetic and neuroimaging evidence for white matter pathology in schizophrenia.
        Neurosci Biobehav Rev. 2006; 30: 918-948
        • Di X.
        • Chan R.C.
        • Gong Q.Y.
        White matter reduction in patients with schizophrenia as revealed by voxel-based morphometry: An activation likelihood estimation meta-analysis.
        Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33: 1390-1394
        • Ellison-Wright I.
        • Bullmore E.
        Meta-analysis of diffusion tensor imaging studies in schizophrenia.
        Schizophr Res. 2009; 108: 3-10
        • Phillips O.R.
        • Nuechterlein K.H.
        • Clark K.A.
        • Hamilton L.S.
        • Asarnow R.F.
        • Hageman N.S.
        • et al.
        Fiber tractography reveals disruption of temporal lobe white matter tracts in schizophrenia.
        Schizophr Res. 2009; 107: 30-38
        • Rametti G.
        • Junque C.
        • Falcon C.
        • Bargallo N.
        • Catalan R.
        • Penades R.
        • et al.
        A voxel-based diffusion tensor imaging study of temporal white matter in patients with schizophrenia.
        Psychiatry Res. 2009; 171: 166-176
        • White T.
        • Nelson M.
        • Lim K.O.
        Diffusion tensor imaging in psychiatric disorders.
        Top Magn Reson Imaging. 2008; 19: 97-109
        • Kyriakopoulos M.
        • Frangou S.
        Recent diffusion tensor imaging findings in early stages of schizophrenia.
        Curr Opin Psychiatry. 2009; 22: 168-176
        • Cheung V.
        • Cheung C.
        • McAlonan G.M.
        • Deng Y.
        • Wong J.G.
        • Yip L.
        • et al.
        A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia.
        Psychol Med. 2008; 38: 877-885
        • Hao Y.
        • Liu Z.
        • Jiang T.
        • Gong G.
        • Liu H.
        • Tan L.
        • et al.
        White matter integrity of the whole brain is disrupted in first-episode schizophrenia.
        Neuroreport. 2006; 17: 23-26
        • Price G.
        • Cercignani M.
        • Parker G.J.
        • Altmann D.R.
        • Barnes T.R.
        • Barker G.J.
        • et al.
        White matter tracts in first-episode psychosis: A DTI tractography study of the uncinate fasciculus.
        Neuroimage. 2008; 39: 949-955
        • Szeszko P.R.
        • Robinson D.G.
        • Ashtari M.
        • Vogel J.
        • Betensky J.
        • Sevy S.
        • et al.
        Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia.
        Neuropsychopharmacology. 2008; 33: 976-984
        • Cardno A.G.
        • Gottesman I.I.
        Twin studies of schizophrenia: From bow-and-arrow concordances to star wars Mx and functional genomics.
        Am J Med Genet. 2000; 97: 12-17
        • Kendler K.S.
        • Diehl S.R.
        The genetics of schizophrenia: A current, genetic-epidemiologic perspective.
        Schizophr Bull. 1993; 19: 261-285
        • Bertisch H.
        • Li D.
        • Hoptman M.J.
        • Delisi L.E.
        Heritability estimates for cognitive factors and brain white matter integrity as markers of schizophrenia.
        Am J Med Genet B Neuropsychiatr Genet. 2010; 153B: 885-894
        • Kochunov P.
        • Glahn D.C.
        • Lancaster J.L.
        • Winkler A.M.
        • Smith S.
        • Thompson P.M.
        • et al.
        Genetics of microstructure of cerebral white matter using diffusion tensor imaging.
        Neuroimage. 2010; 53: 1109-1116
        • Marenco S.
        • Radulescu E.
        Imaging genetics of structural brain connectivity and neural integrity markers.
        Neuroimage. 2009; 53: 848-856
        • McIntosh A.M.
        • Maniega S.M.
        • Lymer G.K.
        • McKirdy J.
        • Hall J.
        • Sussmann J.E.
        • et al.
        White matter tractography in bipolar disorder and schizophrenia.
        Biol Psychiatry. 2008; 64: 1088-1092
        • Peters B.D.
        • de Haan L.
        • Vlieger E.J.
        • Majoie C.B.
        • den Heeten G.J.
        • Linszen D.H.
        • et al.
        Recent-onset schizophrenia and adolescent cannabis use: MRI evidence for structural hyperconnectivity?.
        Psychopharmacol Bull. 2009; 42: 75-88
        • Camchong J.
        • Lim K.O.
        • Sponheim S.R.
        • Macdonald A.W.
        Frontal white matter integrity as an endophenotype for schizophrenia: Diffusion tensor imaging in monozygotic twins and patients' nonpsychotic relatives.
        Front Hum Neurosci. 2009; 3: 35
        • Hao Y.
        • Yan Q.
        • Liu H.
        • Xu L.
        • Xue Z.
        • Song X.
        • et al.
        Schizophrenia patients and their healthy siblings share disruption of white matter integrity in the left prefrontal cortex and the hippocampus but not the anterior cingulate cortex.
        Schizophr Res. 2009; 114: 128-135
        • Hoptman M.J.
        • Nierenberg J.
        • Bertisch H.C.
        • Catalano D.
        • Ardekani B.A.
        • Branch C.A.
        • et al.
        A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia.
        Schizophr Res. 2008; 106: 115-124
        • Karlsgodt K.H.
        • Niendam T.A.
        • Bearden C.E.
        • Cannon T.D.
        White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis.
        Biol Psychiatry. 2009; 66: 562-569
        • Parent A.
        • Carpenter M.B.
        Carpenter's Human Neuroanatomy.
        Williams & Wilkins, Baltimore1996
        • Mori S.
        • Wakena S.
        • Van Zijl P.C.M.
        • Nagae-Poetscher L.M.
        MRI Atlas of Human White Matter.
        Elsevier, Amsterdam2005
        • Oishi K.
        • Zilles K.
        • Amunts K.
        • Faria A.
        • Jiang H.
        • Li X.
        • et al.
        Human brain white matter atlas: Identification and assignment of common anatomical structures in superficial white matter.
        Neuroimage. 2008; 43: 447-457
        • Axel L.
        MRI of the microarchitecture of myocardial infarction: Are we seeing new kinds of structures?.
        Circ Cardiovasc Img. 2009; 2: 169-170
        • Fornito A.
        • Yucel M.
        • Pantelis C.
        Reconciling neuroimaging and neuropathological findings in schizophrenia and bipolar disorder.
        Curr Opin Psychiatry. 2009; 22: 312-319
        • Harrison P.J.
        The neuropathology of schizophrenia.
        Brain. 1999; 122: 593-624
        • Honea R.A.
        • Meyer-Lindenberg A.
        • Hobbs K.B.
        • Pezawas L.
        • Mattay V.S.
        • Egan M.F.
        • et al.
        Is gray matter volume an intermediate phenotype for schizophrenia?.
        Biol Psychiatry. 2008; 63: 465-474
        • Narr K.L.
        • Bilder R.M.
        • Toga A.W.
        • Woods R.P.
        • Rex D.E.
        • Szeszko P.R.
        • et al.
        Mapping cortical thickness and gray matter concentration in first episode schizophrenia.
        Cereb Cortex. 2005; 15: 708-719
        • Narr K.L.
        • Toga A.W.
        • Szeszko P.
        • Thompson P.M.
        • Woods R.P.
        • Robinson D.
        • et al.
        Cortical thinning in cingulate and occipital cortices in first episode schizophrenia.
        Biol Psychiatry. 2005; 58: 32-40
        • Steen R.G.
        • Mull C.
        • McClure R.
        • Hamer R.M.
        • Lieberman J.A.
        Brain volume in first-episode schizophrenia: Systematic review and meta-analysis of magnetic resonance imaging studies.
        Br J Psychiatry. 2006; 188: 510-518
        • Boos H.B.
        • Aleman A.
        • Cahn W.
        • Hulshoff Pol H.
        • Kahn R.S.
        Brain volumes in relatives of patients with schizophrenia: A meta-analysis.
        Arch Gen Psychiatry. 2007; 64: 297-304
        • Goghari V.M.
        • Rehm K.
        • Carter C.S.
        • MacDonald 3rd, A.W.
        Regionally specific cortical thinning and GM matter abnormalities in the healthy relatives of schizophrenia patients.
        Cereb Cortex. 2007; 17: 415-424
        • 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
        • Thompson P.M.
        • Vidal C.
        • Giedd J.N.
        • Gochman P.
        • Blumenthal J.
        • Nicolson R.
        • et al.
        Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.
        Proc Natl Acad Sci U S A. 2001; 98: 11650-11655
        • Apostolova L.G.
        • Thompson P.M.
        • Rogers S.A.
        • Dinov I.D.
        • Zoumalan C.
        • Steiner C.A.
        • et al.
        Surface feature-guided mapping of cerebral metabolic changes in cognitively normal and mildly impaired elderly.
        Mol Imaging Biol. 2010; 12: 218-224
        • Lu L.H.
        • Dapretto M.
        • O'Hare E.D.
        • Kan E.
        • McCourt S.T.
        • Thompson P.M.
        • et al.
        Relationships between brain activation and brain structure in normally developing children.
        Cereb Cortex. 2009; 19: 2595-2604
        • Phillips O.R.
        • Clark K.A.
        • Woods R.P.
        • Subotnik K.L.
        • Asarnow R.F.
        • Nuechterlein K.H.
        • et al.
        Topographical relationships between arcuate fasciculus connectivity and cortical thickness [published online ahead of print September 30].
        Hum Brain Mapp. 2010;
        • Rasser P.E.
        • Schall U.
        • Peck G.
        • Cohen M.
        • Johnston P.
        • Khoo K.
        • et al.
        Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching.
        Neuroimage. 2010; 53: 1175-1180
        • Rasser P.E.
        • Schall U.
        • Todd J.
        • Michie P.T.
        • Ward P.B.
        • Johnston P.
        • et al.
        Gray matter deficits, mismatch negativity, and outcomes in schizophrenia.
        Schizophr Bull. 2009; 37: 131-140
        • Thompson P.M.
        • Hayashi K.M.
        • Sowell E.R.
        • Gogtay N.
        • Giedd J.N.
        • Rapoport J.L.
        • et al.
        Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia.
        Neuroimage. 2004; 23: S2-S18
        • Kuperberg G.R.
        • Broome M.R.
        • McGuire P.K.
        • David A.S.
        • Eddy M.
        • Ozawa F.
        • et al.
        Regionally localized thinning of the cerebral cortex in schizophrenia.
        Arch Gen Psychiatry. 2003; 60: 878-888
        • Nesvag R.
        • Lawyer G.
        • Varnas K.
        • Fjell A.M.
        • Walhovd K.B.
        • Frigessi A.
        • et al.
        Regional thinning of the cerebral cortex in schizophrenia: Effects of diagnosis, age and antipsychotic medication.
        Schizophr Res. 2008; 98: 16-28
        • Ventura J.
        • Liberman R.P.
        • Green M.F.
        • Shaner A.
        • Mintz J.
        Training and quality assurance with the Structured Clinical Interview for DSM-IV(SCID-I/P).
        Psychiatry Res. 1998; 79: 163-173
        • First M.B.
        • Frances A.J.
        • Pincus H.A.
        • Vettorello N.
        • Davis W.W.
        DSM-IV in progress.
        Hosp Community Psychiatry. 1994; 45: 18-20
        • Ventura J.
        • Lukoff D.
        • Nuechterlein K.H.
        • Liberman R.P.
        • Green M.F.
        • Shaner A.
        Brief Psychiatric Rating Scale (BPRS) expanded version: Scales, anchor points, and administration manual.
        Int J Methods Psychiatr Res. 1993; 3: 227-243
        • Ventura J.
        • Nuechterlein K.H.
        • Subotnik K.L.
        • Gutkind D.
        • Gilbert E.A.
        Symptom dimensions in recent-onset schizophrenia and mania: A principal components analysis of the 24-item Brief Psychiatric Rating Scale.
        Psychiatry Res. 2000; 97: 129-135
        • Burger G.K.
        • Calsyn R.J.
        • Morse G.A.
        • Klinkenberg W.D.
        • Trusty M.L.
        Factor structure of the expanded Brief Psychiatric Rating Scale.
        J Clin Psychol. 1997; 53: 451-454
        • Oldfield R.C.
        The assessment and analysis of handedness: The Edinburgh inventory.
        Neuropsychologia. 1971; 9: 97-113
        • Stevens G.
        • Cho J.H.
        Socioeconomic indexes and the new 1980 census occupational classification scheme.
        Social Science Research. 1985; 14: 142-168
        • Reese T.G.
        • Heid O.
        • Weisskoff R.M.
        • Wedeen V.J.
        Reduction of eddy-current-induced distortion in diffusion MRI using a twice-refocused spin echo.
        Magn Reson Med. 2003; 49: 177-182
        • Sled J.G.
        • Pike G.B.
        Standing-wave and RF penetration artifacts caused by elliptic geometry: An electrodynamic analysis of MRI.
        IEEE Trans Med Imaging. 1998; 17: 653-662
        • Woods R.P.
        • Grafton S.T.
        • Holmes C.J.
        • Cherry S.R.
        • Mazziotta J.C.
        Automated image registration: I.
        J Comput Assist Tomogr. 1998; 22: 139-152
        • Woods R.P.
        • Grafton S.T.
        • Watson J.D.
        • Sicotte N.L.
        • Mazziotta J.C.
        Automated image registration: II.
        J Comput Assist Tomogr. 1998; 22: 153-165
        • Narr K.L.
        • Woods R.P.
        • Thompson P.M.
        • Szeszko P.
        • Robinson D.
        • Dimtcheva T.
        • et al.
        Relationships between IQ and regional cortical gray matter thickness in healthy adults.
        Cereb Cortex. 2007; 17: 2163-2171
        • Narr K.L.
        • Bilder R.M.
        • Luders E.
        • Thompson P.M.
        • Woods R.P.
        • Robinson D.
        • et al.
        Asymmetries of cortical shape: Effects of handedness, sex and schizophrenia.
        Neuroimage. 2007; 34: 939-948
        • Jezzard P.
        • Barnett A.S.
        • Pierpaoli C.
        Characterization of and correction for eddy current artifacts in echo planar diffusion imaging.
        Magn Reson Med. 1998; 39: 801-812
        • Shattuck D.W.
        • Sandor-Leahy S.R.
        • Schaper K.A.
        • Rottenberg D.A.
        • Leahy R.M.
        Magnetic resonance image tissue classification using a partial volume model.
        Neuroimage. 2001; 13: 856-876
        • Shattuck D.W.
        • Mirza M.
        • Adisetiyo V.
        • Hojatkashani C.
        • Salamon G.
        • Narr K.L.
        • et al.
        Construction of a 3D probabilistic atlas of human cortical structures.
        Neuroimage. 2008; 39: 1064-1080
        • Anderson M.J.
        • Legendre P.
        An empirical comparison of permutation methods for tests of partial regression coefficients in a linear model.
        J Stat Comput Simul. 1999; 62: 271-303
        • Anderson M.J.
        • Ter Braak C.J.F.
        Permutation tests for multi-factorial analysis of variance.
        J Stat Comput Simul. 2003; 73: 85-113
        • Ashtari M.
        • Cervellione K.L.
        • Hasan K.M.
        • Wu J.
        • McIlree C.
        • Kester H.
        • et al.
        White matter development during late adolescence in healthy males: A cross-sectional diffusion tensor imaging study.
        Neuroimage. 2007; 35: 501-510
        • Burns J.
        • Job D.
        • Bastin M.E.
        • Whalley H.
        • Macgillivray T.
        • Johnstone E.C.
        • et al.
        Structural disconnectivity in schizophrenia: A diffusion tensor magnetic resonance imaging study.
        Br J Psychiatry. 2003; 182: 439-443
        • Friedman J.I.
        • Tang C.
        • Carpenter D.
        • Buchsbaum M.
        • Schmeidler J.
        • Flanagan L.
        • et al.
        Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients.
        Am J Psychiatry. 2008; 165: 1024-1032
        • Karlsgodt K.H.
        • van Erp T.G.
        • Poldrack R.A.
        • Bearden C.E.
        • Nuechterlein K.H.
        • Cannon T.D.
        • et al.
        Diffusion tensor imaging of the superior longitudinal fasciculus and working memory in recent-onset schizophrenia.
        Biol Psychiatry. 2008; 63: 512-518
        • Mitelman S.A.
        • Torosjan Y.
        • Newmark R.E.
        • Schneiderman J.S.
        • Chu K.W.
        • Brickman A.M.
        • et al.
        Internal capsule, corpus callosum and long associative fibers in good and poor outcome schizophrenia: A diffusion tensor imaging survey.
        Schizophr Res. 2007; 92: 211-224
        • Mori T.
        • Ohnishi T.
        • Hashimoto R.
        • Nemoto K.
        • Moriguchi Y.
        • Noguchi H.
        • et al.
        Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging.
        Psychiatry Res. 2007; 154: 133-145
        • Shergill S.S.
        • Kanaan R.A.
        • Chitnis X.A.
        • O'Daly O.
        • Jones D.K.
        • Frangou S.
        • et al.
        A diffusion tensor imaging study of fasciculi in schizophrenia.
        Am J Psychiatry. 2007; 164: 467-473
        • Antonova E.
        • Sharma T.
        • Morris R.
        • Kumari V.
        The relationship between brain structure and neurocognition in schizophrenia: A selective review.
        Schizophr Res. 2004; 70: 117-145
        • Cirillo M.A.
        • Seidman L.J.
        Verbal declarative memory dysfunction in schizophrenia: From clinical assessment to genetics and brain mechanisms.
        Neuropsychol Rev. 2003; 13: 43-77
        • Hugdahl K.
        • Loberg E.M.
        • Nygard M.
        Left temporal lobe structural and functional abnormality underlying auditory hallucinations in schizophrenia.
        Front Neurosci. 2009; 3: 34-45
        • Kuperberg G.
        • Heckers S.
        Schizophrenia and cognitive function.
        Curr Opin Neurobiol. 2000; 10: 205-210
        • Sun J.
        • Maller J.J.
        • Guo L.
        • Fitzgerald P.B.
        Superior temporal gyrus volume change in schizophrenia: A review on region of interest volumetric studies.
        Brain Res Rev. 2009; 61: 14-32
        • Ardekani B.A.
        • Nierenberg J.
        • Hoptman M.J.
        • Javitt D.C.
        • Lim K.O.
        MRI study of white matter diffusion anisotropy in schizophrenia.
        Neuroreport. 2003; 14: 2025-2029
        • Butler P.D.
        • Hoptman M.J.
        • Nierenberg J.
        • Foxe J.J.
        • Javitt D.C.
        • Lim K.O.
        • et al.
        Visual white matter integrity in schizophrenia.
        Am J Psychiatry. 2006; 163: 2011-2013
        • Kunimatsu N.
        • Aoki S.
        • Kunimatsu A.
        • Yoshida M.
        • Abe O.
        • Yamada H.
        • et al.
        Tract-specific analysis of the superior occipitofrontal fasciculus in schizophrenia.
        Psychiatry Res. 2008; 164: 198-205
        • Lim K.O.
        • Hedehus M.
        • Moseley M.
        • de Crespigny A.
        • Sullivan E.V.
        • Pfefferbaum A.
        • et al.
        Compromised white matter tract integrity in schizophrenia inferred from diffusion tensor imaging.
        Arch Gen Psychiatry. 1999; 56: 367-374
        • Minami T.
        • Nobuhara K.
        • Okugawa G.
        • Takase K.
        • Yoshida T.
        • Sawada S.
        • et al.
        Diffusion tensor magnetic resonance imaging of disruption of regional white matter in schizophrenia.
        Neuropsychobiology. 2003; 47: 141-145
        • Ashtari M.
        • Cottone J.
        • Ardekani B.A.
        • Cervellione K.
        • Szeszko P.R.
        • Wu J.
        • et al.
        Disruption of white matter integrity in the inferior longitudinal fasciculus in adolescents with schizophrenia as revealed by fiber tractography.
        Arch Gen Psychiatry. 2007; 64: 1270-1280
        • Butler P.D.
        • Javitt D.C.
        Early-stage visual processing deficits in schizophrenia.
        Curr Opin Psychiatry. 2005; 18: 151-157
        • Chen Y.
        • Levy D.L.
        • Sheremata S.
        • Holzman P.S.
        Compromised late-stage motion processing in schizophrenia.
        Biol Psychiatry. 2004; 55: 834-841
        • Green M.F.
        • Lee J.
        • Cohen M.S.
        • Engel S.A.
        • Korb A.S.
        • Nuechterlein K.H.
        • et al.
        Functional neuroanatomy of visual masking deficits in schizophrenia.
        Arch Gen Psychiatry. 2009; 66: 1295-1303
        • Martinez A.
        • Hillyard S.A.
        • Dias E.C.
        • Hagler Jr, D.J.
        • Butler P.D.
        • Guilfoyle D.N.
        • et al.
        Magnocellular pathway impairment in schizophrenia: Evidence from functional magnetic resonance imaging.
        J Neurosci. 2008; 28: 7492-7500
        • Slaghuis W.L.
        Spatio-temporal luminance contrast sensitivity and visual backward masking in schizophrenia.
        Exp Brain Res. 2004; 156: 196-211
        • Kawashima T.
        • Nakamura M.
        • Bouix S.
        • Kubicki M.
        • Salisbury D.F.
        • Westin C.F.
        • et al.
        Uncinate fasciculus abnormalities in recent onset schizophrenia and affective psychosis: A diffusion tensor imaging study.
        Schizophr Res. 2009; 110: 119-126
        • Reichenberg A.
        • Harvey P.D.
        • Bowie C.R.
        • Mojtabai R.
        • Rabinowitz J.
        • Heaton R.K.
        • et al.
        Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders.
        Schizophr Bull. 2009; 35: 1022-1029
        • Sullivan P.F.
        • Kendler K.S.
        • Neale M.C.
        Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies.
        Arch Gen Psychiatry. 2003; 60: 1187-1192
        • Ebner F.
        • Tepest R.
        • Dani I.
        • Pfeiffer U.
        • Schulze T.G.
        • Rietschel M.
        • et al.
        The hippocampus in families with schizophrenia in relation to obstetric complications.
        Schizophr Res. 2008; 104: 71-78
        • Lawrie S.M.
        • McIntosh A.M.
        • Hall J.
        • Owens D.G.
        • Johnstone E.C.
        Brain structure and function changes during the development of schizophrenia: The evidence from studies of subjects at increased genetic risk.
        Schizophr Bull. 2008; 34: 330-340
        • Narr K.L.
        • Cannon T.D.
        • Woods R.P.
        • Thompson P.M.
        • Kim S.
        • Asunction D.
        • et al.
        Genetic contributions to altered callosal morphology in schizophrenia.
        J Neurosci. 2002; 22: 3720-3729
        • Narr K.L.
        • van Erp T.G.
        • Cannon T.D.
        • Woods R.P.
        • Thompson P.M.
        • Jang S.
        • et al.
        A twin study of genetic contributions to hippocampal morphology in schizophrenia.
        Neurobiol Dis. 2002; 11: 83-95
        • Seidman L.J.
        • Faraone S.V.
        • Goldstein J.M.
        • Goodman J.M.
        • Kremen W.S.
        • Toomey R.
        • et al.
        Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: An MRI-based morphometric analysis.
        Biol Psychiatry. 1999; 46: 941-954
        • van Haren N.E.
        • Hulshoff Pol H.E.
        • Schnack H.G.
        • Cahn W.
        • Mandl R.C.
        • Collins D.L.
        • et al.
        Focal gray matter changes in schizophrenia across the course of the illness: A 5-year follow-up study.
        Neuropsychopharmacology. 2007; 32: 2057-2066
        • van Haren N.E.
        • Picchioni M.M.
        • McDonald C.
        • Marshall N.
        • Davis N.
        • Ribchester T.
        • et al.
        A controlled study of brain structure in monozygotic twins concordant and discordant for schizophrenia.
        Biol Psychiatry. 2004; 56: 454-461
        • Karoutzou G.
        • Emrich H.M.
        • Dietrich D.E.
        The myelin-pathogenesis puzzle in schizophrenia: A literature review.
        Mol Psychiatry. 2008; 13: 245-260
        • Munoz Maniega S.
        • Lymer G.K.
        • Bastin M.E.
        • Marjoram D.
        • Job D.E.
        • Moorhead T.W.
        • et al.
        A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia.
        Schizophr Res. 2008; 106: 132-139
        • Narr K.L.
        • Hageman N.
        • Woods R.P.
        • Hamilton L.S.
        • Clark K.
        • Phillips O.
        • et al.
        Mean diffusivity: A biomarker for CSF-related disease and genetic liability effects in schizophrenia.
        Psychiatry Res. 2009; 171: 20-32
        • Bassett D.S.
        • Bullmore E.
        • Verchinski B.A.
        • Mattay V.S.
        • Weinberger D.R.
        • Meyer-Lindenberg A.
        • et al.
        Hierarchical organization of human cortical networks in health and schizophrenia.
        J Neurosci. 2008; 28: 9239-9248
        • Lewis D.A.
        • Sweet R.A.
        Schizophrenia from a neural circuitry perspective: Advancing toward rational pharmacological therapies.
        J Clin Invest. 2009; 119: 706-716
        • Reichenberg A.
        • Harvey P.D.
        Neuropsychological impairments in schizophrenia: Integration of performance-based and brain imaging findings.
        Psychol Bull. 2007; 133: 833-858
        • Schlosser R.G.
        • Nenadic I.
        • Wagner G.
        • Gullmar D.
        • von Consbruch K.
        • Kohler S.
        • et al.
        White matter abnormalities and brain activation in schizophrenia: A combined DTI and fMRI study.
        Schizophr Res. 2007; 89: 1-11
        • White T.
        • Magnotta V.A.
        • Bockholt H.J.
        • Williams S.
        • Wallace S.
        • Ehrlich S.
        • et al.
        Global white matter abnormalities in schizophrenia: A multisite diffusion tensor imaging study.
        Schizophr Bull. 2011; 37: 222-232
        • Konrad A.
        • Winterer G.
        Disturbed structural connectivity in schizophrenia primary factor in pathology or epiphenomenon?.
        Schizophr Bull. 2008; 34: 72-92
        • Hof P.R.
        • Haroutunian V.
        • Friedrich Jr, V.L.
        • Byne W.
        • Buitron C.
        • Perl D.P.
        • et al.
        Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia.
        Biol Psychiatry. 2003; 53: 1075-1085
        • Vostrikov V.M.
        • Uranova N.A.
        • Orlovskaya D.D.
        Deficit of perineuronal oligodendrocytes in the prefrontal cortex in schizophrenia and mood disorders.
        Schizophr Res. 2007; 94: 273-280
        • Kuroki T.
        [Pharmacological study on second-generation antipsychotic agents and the effects on improvement of cognitive function in patients with schizophrenia].
        Seishin Shinkeigaku Zasshi. 2006; 108: 1323-1329