The Human Brain Revisited: Opportunities and Challenges in Postmortem Studies of Psychiatric Disorders

Studies of the postmortem human brain have become an increasingly essential element of the effort to understand the neurobiology of psychiatric disorders, especially in light of advances in our knowledge of functional brain circuitry and the new opportunities to apply the approaches of genomics and proteomics. This Perspective reviews some of the opportunities afforded by investigations of the postmortem human brain, and offers suggestions for improving the quality of future studies through the use of well-characterized brain specimens, well-constructed experimental designs and well-controlled confounds.

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

[2]  Mark J. West,et al.  Stereological methods for estimating the total number of neurons and synapses: issues of precision and bias , 1999, Trends in Neurosciences.

[3]  R W Guillery,et al.  Quantification without pontification: Choosing a method for counting objects in sectioned tissues , 1997, The Journal of comparative neurology.

[4]  Daniel R Weinberger,et al.  Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study , 2002, Schizophrenia Research.

[5]  T. Crow,et al.  CEREBRAL VENTRICULAR SIZE AND COGNITIVE IMPAIRMENT IN CHRONIC SCHIZOPHRENIA , 1976, The Lancet.

[6]  F. Benes.  Post-mortem structural analyses of schizophrenic brain: study designs and the interpretation of data. , 1988, Psychiatric developments.

[7]  D. German,et al.  Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia , 2000, Biological Psychiatry.

[8]  J. Stevens.  An anatomy of schizophrenia? , 1973, Archives of general psychiatry.

[9]  J. Kleinman,et al.  The neuropathology of schizophrenia: A critical assessment of research methodologies , 1990, Biological Psychiatry.

[10]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

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

[12]  Richard J. Haier,et al.  Schizophrenia: The epigenetic puzzle Cambridge University Press, Cambridge (1982). 258 pp. by Irving I. Gottesman and James Shields , 1982, Psychiatry Research.

[13]  A. Levey,et al.  Postnatal development of tyrosine hydroxylase- and dopamine transporter-immunoreactive axons in monkey rostral entorhinal cortex. , 1998, Cerebral cortex.

[14]  J. Haycock,et al.  Expression and distribution of two isoforms of tyrosine hydroxylase in macaque monkey brain , 1994, Brain Research.

[15]  A. Sampson,et al.  Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia. , 2000, Archives of general psychiatry.

[16]  Pat Levitt,et al.  Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse , 2001, Trends in Neurosciences.

[17]  E. G. Jones,et al.  Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. , 1995, Archives of general psychiatry.

[18]  D. Lewis,et al.  Heterogeneity of layer II neurons in human entorhinal cortex , 1992, The Journal of comparative neurology.

[19]  K. Davis,et al.  Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. , 1997, Archives of general psychiatry.

[20]  M S Buchsbaum,et al.  PET and MRI of the thalamus in never-medicated patients with schizophrenia. , 1996, The American journal of psychiatry.

[21]  R. Straub,et al.  Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Sampson,et al.  Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia. , 2001, Archives of general psychiatry.

[23]  Nicholas Lange,et al.  Two-dimensional versus three-dimensional cell counting: a practical perspective , 2001, Trends in Neurosciences.

[24]  R. Harris,et al.  Gene expression in human alcoholism: microarray analysis of frontal cortex. , 2000, Alcoholism, clinical and experimental research.

[25]  J. Miller,et al.  Effect of pre- and postmortem variables on specific mRNA levels in human brain. , 1991, Brain research. Molecular brain research.

[26]  Yogesh K. Dwivedi,et al.  Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study. , 2000, Archives of general psychiatry.

[27]  K. Davis,et al.  Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients , 2000, Biological Psychiatry.

[28]  L Kruglyak,et al.  Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  J. Price,et al.  Glial reduction in the subgenual prefrontal cortex in mood disorders. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Pierri,et al.  Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. , 1999, The American journal of psychiatry.

[31]  D. Lewis,et al.  Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia , 2001, Molecular Psychiatry.

[32]  L. Siever,et al.  Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. , 2001, Archives of general psychiatry.

[33]  C. Yates,et al.  Enzyme Activities in Relation to pH and Lactate in Postmortem Brain in Alzheimer‐Type and Other Dementias , 1990, Journal of neurochemistry.

[34]  Paul J. Harrison,et al.  The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins , 1995, Neuroscience Letters.

[35]  E. Perry,et al.  The influence of agonal status on some neurochemical activities of postmortem human brain tissue , 1982, Neuroscience Letters.

[36]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[37]  Pat Levitt,et al.  Molecular Characterization of Schizophrenia Viewed by Microarray Analysis of Gene Expression in Prefrontal Cortex , 2000, Neuron.

[38]  P. Goldman-Rakic,et al.  Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. , 1998, Archives of general psychiatry.

[39]  R. Kerwin,et al.  Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. , 2001, Archives of general psychiatry.

[40]  L. Glantz,et al.  Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. , 1997, Archives of general psychiatry.

[41]  J. Sweeney,et al.  Thalamic volumes in patients with first-episode schizophrenia. , 2001, The American journal of psychiatry.

[42]  F Plum,et al.  Prospects for research on schizophrenia. 3. Neurophysiology. Neuropathological findings. , 1972, Neurosciences Research Program bulletin.

[43]  N. Perrone-Bizzozero,et al.  Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Ravid,et al.  Brain banking and the human hypothalamus--factors to match for, pitfalls and potentials. , 1992, Progress in brain research.

[45]  C D Marsden,et al.  Tissue pH as an indicator of mRNA preservation in human post-mortem brain. , 1995, Brain research. Molecular brain research.

[46]  M. Akil,et al.  Cortical dopamine in schizophrenia: strategies for postmortem studies. , 1997, Journal of psychiatric research.

[47]  E G Jones,et al.  Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[48]  T. Kelly,et al.  Validity of DSM‐III‐R diagnosis by psychological autopsy: a comparison with clinician ante‐mortem diagnosis , 1996, Acta psychiatrica Scandinavica.

[49]  J. Haycock,et al.  Four isoforms of tyrosine hydroxylase are expressed in human brain , 1993, Neuroscience.

[50]  W Q Sturner,et al.  Alterations in synaptic proteins and their encoding mRNAs in prefrontal cortex in schizophrenia: a possible neurochemical basis for ‘hypofrontality’ , 1999, Molecular Psychiatry.

[51]  J. Cameron,et al.  A comparative analysis of the distribution of prosomatostatin‐derived peptides in human and monkey neocortex , 1991, The Journal of comparative neurology.

[52]  J. Trojanowski,et al.  Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. , 1998, Archives of general psychiatry.

[53]  T. Woo,et al.  A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[54]  J. Sweeney,et al.  Drug abuse in schizophrenic patients: clinical correlates and reasons for use. , 1991, The American journal of psychiatry.