Evidence of altered prefrontal–thalamic circuitry in schizophrenia: An optimized diffusion MRI study

MRI diffusion tensor imaging (DTI), optimized for measuring the trace of the diffusion tensor, was used to investigate microstructural changes in the brains of 12 individuals with schizophrenia compared with 12 matched control subjects. To control for the effects of anatomic variation between subject groups, all participants' diffusion images were nonlinearly registered to standard anatomical space. Significant statistical differences in mean diffusivity (MD) measures between the two groups were determined on a pixel-by-pixel basis, using Gaussian random field theory. We found significantly elevated MD measures within temporal, parietal and prefrontal cortical regions in the schizophrenia group (P > 0.001), especially within the medial frontal gyrus and anterior cingulate. The dorsal medial and anterior nucleus of the thalamus, including the caudate, also exhibited significantly increased MD in the schizophrenia group (P > 0.001). This study has shown for the first time that MD measures offer an alternative strategy for investigating altered prefrontal-thalamic circuitry in schizophrenia.

[1]  F. Benes,et al.  Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. , 1991, Archives of general psychiatry.

[2]  J. Hallmayer,et al.  Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study. , 1993, Archives of general psychiatry.

[3]  Adam M. Brickman,et al.  Thalamus size and outcome in schizophrenia , 2004, Schizophrenia Research.

[4]  William Byne,et al.  Magnetic resonance imaging of mediodorsal, pulvinar, and centromedian nuclei of the thalamus in patients with schizophrenia. , 2003, Archives of general psychiatry.

[5]  B. Pakkenberg,et al.  Total nerve cell number in neocortex in chronic schizophrenics and controls estimated using optical disectors , 1993, Biological Psychiatry.

[6]  R. Gur,et al.  Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. , 1998, The American journal of psychiatry.

[7]  Bente Pakkenberg,et al.  Glial cell loss in the anterior cingulate cortex, a subregion of the prefrontal cortex, in subjects with schizophrenia. , 2004, The American journal of psychiatry.

[8]  Tyrone D. Cannon,et al.  Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  F. Benes,et al.  A cross-study meta-analysis and three-dimensional comparison of cell counting in the anterior cingulate cortex of schizophrenic and bipolar brain , 2005, Schizophrenia Research.

[10]  Daniel R Weinberger,et al.  Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? , 2002, Archives of general psychiatry.

[11]  C. Pariante,et al.  Glial cell abnormalities in major psychiatric disorders: the evidence and implications , 2001, Brain Research Bulletin.

[12]  David M. Smith,et al.  Cerebellar, prefrontal cortex, and thalamic volumes over two time points in adolescent-onset schizophrenia. , 2004, The American journal of psychiatry.

[13]  M. Keshavan,et al.  Changes in caudate volume with neuroleptic treatment , 1994, The Lancet.

[14]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[15]  A. Mcghie,et al.  Disorders of attention and perception in early schizophrenia. , 1961, The British journal of medical psychology.

[16]  E. Syková,et al.  Extrasynaptic volume transmission and diffusion parameters of the extracellular space , 2004, Neuroscience.

[17]  C. Jack,et al.  Mild cognitive impairment and Alzheimer disease: regional diffusivity of water. , 2001, Radiology.

[18]  Judith M. Ford,et al.  Delayed hemodynamic responses in schizophrenia , 2005, NeuroImage.

[19]  K. Krishnan,et al.  Diffusion tensor imaging: background, potential, and utility in psychiatric research , 2003, Biological Psychiatry.

[20]  Derek K. Jones,et al.  The effect of filter size on VBM analyses of DT-MRI data , 2005, NeuroImage.

[21]  N. Andreasen The Role of the Thalamus in Schizophrenia , 1997, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[22]  P. Basser,et al.  Parametric and non-parametric statistical analysis of DT-MRI data. , 2003, Journal of magnetic resonance.

[23]  M. Weissman,et al.  Best estimate of lifetime psychiatric diagnosis: a methodological study. , 1982, Archives of general psychiatry.

[24]  R. Kikinis,et al.  A review of diffusion tensor imaging studies in schizophrenia. , 2007, Journal of psychiatric research.

[25]  R. Coppola,et al.  Thalamic and Caudate Volumes in Monozygotic Twins Discordant for Schizophrenia , 2001, The Australian and New Zealand journal of psychiatry.

[26]  P. Goldman-Rakic,et al.  Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: Application of a three‐dimensional, stereologic counting method , 1998, The Journal of comparative neurology.

[27]  M. Horsfield,et al.  Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging , 1999, Magnetic resonance in medicine.

[28]  B. Pakkenberg,et al.  Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. , 1990, Archives of general psychiatry.

[29]  P. Goldman-Rakic,et al.  Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. , 1995, Archives of general psychiatry.

[30]  John Suckling,et al.  For personal use. Only reproduce with permission from The Lancet Publishing Group. Effect of sunlight and season on serotonin turnover in the brain , 2002 .

[31]  Eve C. Johnstone,et al.  Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives , 2004, Biological Psychiatry.

[32]  Richard S. J. Frackowiak,et al.  Cortical and subcortical gray matter abnormalities in schizophrenia determined through structural magnetic resonance imaging with optimized volumetric voxel-based morphometry. , 2002, The American journal of psychiatry.

[33]  Lei Wang,et al.  Abnormalities of thalamic volume and shape in schizophrenia. , 2004, The American journal of psychiatry.

[34]  H. Möller,et al.  Thalamic volume in first-episode and chronic schizophrenic subjects: a volumetric MRI study , 2005, Schizophrenia Research.

[35]  Alan C. Evans,et al.  A General Statistical Analysis for fMRI Data , 2000, NeuroImage.

[36]  P. Goldman-Rakic,et al.  Increased volume and glial density in primate prefrontal cortex associated with chronic antipsychotic drug exposure , 1999, Biological Psychiatry.

[37]  P. Goldman-Rakic,et al.  The reduced neuropil hypothesis: a circuit based model of schizophrenia , 1999, Biological Psychiatry.

[38]  J Mazziotta,et al.  A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). , 2001, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[39]  Adolf Pfefferbaum,et al.  Diffusion tensor imaging in normal aging and neuropsychiatric disorders. , 2003, European journal of radiology.

[40]  J. Nurnberger,et al.  Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. , 1994, Archives of general psychiatry.

[41]  L. DeLisi,et al.  A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. , 1988, Archives of general psychiatry.

[42]  Dennis Velakoulis,et al.  Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. , 2005, Schizophrenia bulletin.

[43]  Mario Mascalchi,et al.  Diffusion-weighted MR of the brain: methodology and clinical application. , 2005, La Radiologia medica.

[44]  Peter Falkai,et al.  Volumes of association thalamic nuclei in schizophrenia: a postmortem study , 2003, Schizophrenia Research.

[45]  K. Davis,et al.  Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry. , 2003, Archives of general psychiatry.