65 results on '"Thomas M. Hyde"'
Search Results
2. GENE CONNECTIVITY ANALYSIS OF CO-EXPRESSION NETWORKS PROVIDES INSIGHTS INTO THE OMNIGENIC MODEL AND IDENTIFIES NOVEL GENETIC HUBS OF SCHIZOPHRENIA RISK
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Christopher Borcuk, Madhur Parihar, Leonardo Sportelli, Joel E. Kleinman, Joo Heon Shin, Thomas M. Hyde, Alessandro Bertolino, Daniel R. Weinberger, and Giulio Pergola
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Pharmacology ,Psychiatry and Mental health ,Neurology ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Published
- 2022
3. A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan
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Yijing Su, Yi Zhou, Mariko L. Bennett, Shiying Li, Marc Carceles-Cordon, Lu Lu, Sooyoung Huh, Dennisse Jimenez-Cyrus, Benjamin C. Kennedy, Sudha K. Kessler, Angela N. Viaene, Ingo Helbig, Xiaosong Gu, Joel E. Kleinman, Thomas M. Hyde, Daniel R. Weinberger, David W. Nauen, Hongjun Song, and Guo-li Ming
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Alzheimer Disease ,Astrocytes ,Longevity ,Genetics ,Humans ,Molecular Medicine ,Cell Biology ,Transcriptome ,Neuroglia ,Hippocampus ,Article - Abstract
The molecular diversity of glia in the human hippocampus and their temporal dynamics over the lifespan remain largely unknown. Here, we performed single-nucleus RNA sequencing to generate a transcriptome atlas of the human hippocampus across the postnatal lifespan. Detailed analyses of astrocytes, oligodendrocyte lineages, and microglia identified subpopulations with distinct molecular signatures and revealed their association with specific physiological functions, age-dependent changes in abundance, and disease relevance. We further characterized spatiotemporal heterogeneity of GFAP-enriched astrocyte subpopulations in the hippocampal formation using immunohistology. Leveraging glial subpopulation classifications as a reference map, we revealed the diversity of glia differentiated from human pluripotent stem cells and identified dysregulated genes and pathological processes in specific glial subpopulations in Alzheimer's disease (AD). Together, our study significantly extends our understanding of human glial diversity, population dynamics across the postnatal lifespan, and dysregulation in AD and provides a reference atlas for stem-cell-based glial differentiation.
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- 2022
4. Association of a Noncoding RNA Postmortem With Suicide by Violent Means and In Vivo With Aggressive Phenotypes
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Gianluca Ursini, Tiziana Quarto, Joo Heon Shin, Andrew E. Jaffe, Giuseppe Blasi, Eugenia Radulescu, Giovanna Punzi, Joel E. Kleinman, Alessandro Bertolino, Giovanna Viscanti, Thomas M. Hyde, Roberto Catanesi, Daniel R. Weinberger, and Amy Deep-Soboslay
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Adult ,Male ,0301 basic medicine ,RNA, Untranslated ,Genotype ,Prefrontal Cortex ,Poison control ,Brodmann area 10 ,Single-nucleotide polymorphism ,Violence ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Cause of Death ,medicine ,Humans ,Gene Regulatory Networks ,Prefrontal cortex ,Gene ,Biological Psychiatry ,Genetics ,medicine.diagnostic_test ,Sequence Analysis, RNA ,Aggression ,Functional Neuroimaging ,Mental Disorders ,Brain ,Non-coding RNA ,Magnetic Resonance Imaging ,Suicide ,Phenotype ,030104 developmental biology ,Female ,medicine.symptom ,Functional magnetic resonance imaging ,030217 neurology & neurosurgery - Abstract
Background Previous findings suggest that differences in brain expression of a human-specific long intergenic noncoding RNA (LINC01268; GRCh37/hg19: LOC285758) may be linked to suicide by violent methods. We sought to replicate and extend these findings in a new sample and translate the results to the behavioral level in living healthy subjects. Methods We examined RNA sequencing data in human brains to confirm the prior postmortem association of the long intergenic noncoding RNA specifically with suicide by violent means. In addition, we used a genetic variant associated with LINC01268 expression to detect association in healthy subjects with trait aggression and with in vivo prefrontal physiology related to behavioral control. Finally, we performed weighted gene coexpression network analysis and gene ontology analysis to identify biological processes associated with a LINC01268 coexpression network. Results In the replication sample, prefrontal expression of LINC01268 was again higher in suicides by violent means (n = 65) than in both nonsuicides (n = 78; p = 1.29 × 10−6) and suicides by nonviolent means (n = 46; p = 1.4 × 10−6). In the living cohort, carriers of the minor allele of a single nucleotide polymorphism associated with increased LINC01268 expression in brain scored higher on a lifetime aggression questionnaire and show diminished engagement of prefrontal cortex (Brodmann area 10) when viewing angry faces during functional magnetic resonance imaging. Weighted gene coexpression network analysis highlighted the immune response. Conclusions These results suggest that LINC01268 influences emotional regulation, aggressive behavior, and suicide by violent means; the underlying biological dynamics may include modulation of genes potentially engaged in the immune response.
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- 2019
5. Differential expression of NPAS4 in the dorsolateral prefrontal cortex following opioid overdose
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David W. Sosnowski, Andrew E. Jaffe, Ran Tao, Amy Deep-Soboslay, Chang Shu, Sarven Sabunciyan, Joel E. Kleinman, Thomas M. Hyde, and Brion S. Maher
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- 2022
6. P89. Spatial Landscape of Gene Expression in the Human Locus Coeruleus
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Heena R. Divecha, Lukas M. Weber, Sang Ho Kwon, Matthew N. Tran, Madhavi Tippani, Abby Spangler, Kelsey D. Montgomery, Thomas M. Hyde, Leonardo Collado-Torres, Kristen R. Maynard, Stephanie C. Hicks, and Keri Martinowich
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Biological Psychiatry - Published
- 2022
7. Exploiting the Variability of CACNA1C Splicing to Identify Novel, Brain-Selective Targets for Schizophrenia and Bipolar Disorder
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Michael B. Clark, Tomasz Wrzesinski, Wilfried Haerty, Syed M. Husain, Paul Harrison, Daniel R. Weinberger, Thomas M. Hyde, Joel E. Kleinman, Aintzane B. Garcia, Elizabeth M. Tunbridge, and Nicola A. L. Hall
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Schizophrenia ,business.industry ,RNA splicing ,medicine ,Bipolar disorder ,medicine.disease ,business ,Neuroscience ,Biological Psychiatry - Published
- 2020
8. BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders
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Patricio O'Donnell, Christian Schubert, Tony Kam-Thong, Wayne C. Drevets, Amy Deep-Soboslay, Nicholas J. Brandon, David C. Airey, Andrew E. Jaffe, Laurent Essioux, James E. Scherschel, Mitsuyuki Matsumoto, Thomas M. Hyde, David A. Collier, Philip J. Ebert, Hartmuth C. Kolb, Michael Didriksen, Yushi Liu, Hui-Rong Qian, Alan J. Cross, Joo Heon Shin, Daniel R. Weinberger, Qi Wang, Kalpana M. Merchant, Laura Nisenbaum, Jens R. Wendland, Hualin S. Xi, Maura L. Furey, Richard E. Straub, John N. Calley, Ryan M. Smith, Cara L. Ruble, Jie Quan, Enrico Domenici, Ashley R. Winslow, Joel E. Kleinman, Husseini K. Manji, Takeshi Saito, Brian J. Eastwood, Hong Wang, and Yankai Jia
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Neurogenomics ,medicine.medical_specialty ,Mood Disorders ,Mental Disorders ,General Neuroscience ,Genomic data ,Brain ,Computational biology ,Medical research ,medicine.disease ,Epigenesis, Genetic ,Mood disorders ,Drug Discovery ,Gene Targeting ,medicine ,Animals ,Humans ,Psychiatry ,Psychology - Abstract
We outline an ambitious project to characterize the genetic and epigenetic regulation of multiple facets of transcription in distinct brain regions across the human lifespan in samples of major neuropsychiatric disorders and controls. Initially focused on schizophrenia and mood disorders, the goal of this consortium is to elucidate the underlying molecular mechanisms of genetic associations with the goal of identifying novel therapeutic targets. The consortium currently consists of seven pharmaceutical companies and a not-for-profit medical research institution working as a precompetitive team to generate and analyze publicly available archival brain genomic data related to neuropsychiatric illness.
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- 2015
9. RNA Sequencing of the Limbic System in Major Depressive Disorder
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Emily E. Burke, Thomas M. Hyde, Leonardo Collado Torres, Peter P. Zandi, Andrew E. Jaffe, Joel E. Kleinman, and Fernando S. Goes
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Limbic system ,medicine.anatomical_structure ,business.industry ,Medicine ,RNA ,Major depressive disorder ,business ,medicine.disease ,Neuroscience ,Biological Psychiatry - Published
- 2020
10. T57IDENTIFYING CAUSAL GENETIC VARIANTS IN PSYCHIATRIC DISORDERS USING SUMMARY DATA BASED MENDELIAN RANDOMIZATION
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Daniel R. Weinberger, Eugenia Radulescu, Andrew E. Jaffe, Qiang Chen, Joo Heon Shin, Vijay Sadashivaiah, Joel E. Kleinman, Richard E. Straub, Thomas M. Hyde, and Giulio Pergola
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Pharmacology ,Genetics ,Psychiatry and Mental health ,Neurology ,Summary data ,Mendelian randomization ,Genetic variants ,Pharmacology (medical) ,Neurology (clinical) ,Biology ,Biological Psychiatry - Published
- 2019
11. Investigation of the Prenatal Expression Patterns of 108 Schizophrenia-Associated Genetic Loci
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Andrew E. Jaffe, Rebecca Birnbaum, Joel E. Kleinman, Daniel R. Weinberger, Thomas M. Hyde, and Qiang Chen
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Regulation of gene expression ,Genetics ,Fetus ,Pregnancy ,business.industry ,Schizophrenia (object-oriented programming) ,Gene Expression Regulation, Developmental ,Genome-wide association study ,Biology ,medicine.disease ,Text mining ,Expression (architecture) ,Genetic Loci ,Expression quantitative trait loci ,Schizophrenia ,medicine ,Humans ,Female ,Genetic Predisposition to Disease ,business ,Biological Psychiatry ,Genome-Wide Association Study - Published
- 2015
12. Myelin, myelin-related disorders, and psychosis
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Joel E. Kleinman, Michelle I. Mighdoll, Thomas M. Hyde, and Ran Tao
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Phenocopy ,Psychosis ,medicine.disease ,Nerve Fibers, Myelinated ,White Matter ,behavioral disciplines and activities ,Oligodendrocyte ,White matter ,Oligodendroglia ,Psychiatry and Mental health ,Myelin ,Diffusion Tensor Imaging ,medicine.anatomical_structure ,Psychotic Disorders ,Schizophrenia ,mental disorders ,medicine ,Humans ,Psychology ,Pathological ,Neuroscience ,Myelin Sheath ,Biological Psychiatry ,Demyelinating Diseases ,Diffusion MRI - Abstract
The neuropathological basis of schizophrenia and related psychoses remains elusive despite intensive scientific investigation. Symptoms of psychosis have been reported in a number of conditions where normal myelin development is interrupted. The nature, location, and timing of white matter pathology seem to be key factors in the development of psychosis, especially during the critical adolescent period of association area myelination. Numerous lines of evidence implicate myelin and oligodendrocyte function as critical processes that could affect neuronal connectivity, which has been implicated as a central abnormality in schizophrenia. Phenocopies of schizophrenia with a known pathological basis involving demyelination or dysmyelination may offer insights into the biology of schizophrenia itself. This article reviews the pathological changes in white matter of patients with schizophrenia, as well as demyelinating diseases associated with psychosis. In an attempt to understand the potential role of dysmyelination in schizophrenia, we outline the evidence from a number of both clinically-based and post-mortem studies that provide evidence that OMR genes are genetically associated with increased risk for schizophrenia. To further understand the implication of white matter dysfunction and dysmyelination in schizophrenia, we examine diffusion tensor imaging (DTI), which has shown volumetric and microstructural white matter differences in patients with schizophrenia. While classical clinical-neuropathological correlations have established that disruption in myelination can produce a high fidelity phenocopy of psychosis similar to schizophrenia, the role of dysmyelination in schizophrenia remains controversial.
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- 2015
13. Modeling a Genetic Risk for Schizophrenia in iPSCs and Mice Reveals Neural Stem Cell Deficits Associated with Adherens Junctions and Polarity
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Joel E. Kleinman, Dan Rujescu, Maxwell Towe, Namshik Kim, Joo Heon Shin, Gianluca Ursini, Eva Pekle, Gregory L. Krauss, Kimberly M. Christian, Georgia Makri, Syed Mohammed Qasim Hussaini, Thomas M. Hyde, Guo Li Ming, Hongjun Song, David W. Nauen, Ki-Jun Yun, Yohan Lee, Fengyu Zhang, Youngbin Park, Ce Zhang, Zhexing Wen, Judith L. Rapoport, Raeeun Chung, Daniel R. Weinberger, Ha Nam Nguyen, and David St Clair
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Adult ,Risk ,Male ,DNA Copy Number Variations ,Polarity (physics) ,Cell ,Induced Pluripotent Stem Cells ,Mice, Inbred Strains ,Haploinsufficiency ,Biology ,White People ,Article ,Cell Line ,Adherens junction ,Mice ,Mediator ,Neural Stem Cells ,Intellectual Disability ,medicine ,Genetics ,Animals ,Humans ,Copy-number variation ,Genetic risk ,Autistic Disorder ,Progenitor cell ,Induced pluripotent stem cell ,Genetic Association Studies ,Adaptor Proteins, Signal Transducing ,Chromosome Aberrations ,Chromosomes, Human, Pair 15 ,Cell Polarity ,Epistasis, Genetic ,Adherens Junctions ,Cell Biology ,Middle Aged ,medicine.disease ,Neural stem cell ,Wiskott-Aldrich Syndrome Protein Family ,Cell biology ,medicine.anatomical_structure ,Schizophrenia ,Actin-Related Protein 2 ,Molecular Medicine ,Stem cell ,Neuroscience - Abstract
SummaryDefects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.
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- 2014
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14. 236. Molecular Dissection of Schizophrenia GWAS Significant Loci
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J H Shin, Thomas M. Hyde, Daniel R. Weinberger, Andrew E. Jaffe, Leo Collado-Torres, and Joel E. Kleinman
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Genetics ,business.industry ,Schizophrenia (object-oriented programming) ,Medicine ,Genome-wide association study ,Dissection (medical) ,business ,medicine.disease ,Biological Psychiatry - Published
- 2019
15. Characterization of miRNA Isoform Expression In Schizophrenia Using Postmortem Human Brain Tissue
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Daniel R. Weinberger, Joo Heon Shin, Alan J. Cross, Andrew E. Jaffe, Anandita Rajpurohit, Joel E. Kleinman, Courtney M. Williams, Carrie Wright, Nicholas J. Brandon, and Thomas M. Hyde
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Pharmacology ,Regulation of gene expression ,Gene isoform ,Small RNA ,RNA ,Computational biology ,Biology ,Deep sequencing ,Psychiatry and Mental health ,IsomiR ,Neurology ,microRNA ,Gene expression ,Pharmacology (medical) ,Neurology (clinical) ,Biological Psychiatry - Abstract
The nuances of small non-coding RNA biology continue to be discovered. The most characterized species of non-coding RNAs are microRNA (miRNA). miRNA largely function to modulate gene expression by repressing the translation of mRNA into protein. It is now known that miRNA participate in regulating nearly every type of cellular process and their importance in brain development, function, and disease continues to be uncovered. Recently RNA sequencing revealed that miRNA are often produced in detectable levels with slight sequence variations. Several steps are involved in the biogenesis of miRNA and slight changes in these processes can lead to a variety of extensions, deletions, or alterations in the final mature sequence. The name isomiR for these isoforms of canonically described miRNA sequences was coined in 2008. Research demonstrates that these miRNA variants have altered stability and in some cases distinct functions from their close sequence relatives. Recent findings also indicate that altered isomiR expression is associated with disease states. To date little research has characterized the expression of isomiRs in the brain, however alterations in canonical miRNA expression and miRNA biogenesis have been reproducibly associated with schizophrenia, suggesting that the biogenesis of isomiRs may also be altered. Therefore, we characterized isomiR expression in 92 postmortem dorsolateral prefrontal cortex (DLPFC) human brain samples, including 30 samples from patients with schizophrenia and 62 from healthy controls. Using small RNA sequencing, we profiled the expression of both canonical miRNAs and isomiRs. We utilized the BIOO Scientific NextFlex small RNA sequencing kit, with 500 ng of starting total RNA and ran 50 base pair sequencing on the HiSeq 3000. We achieved a sequencing depth of over 20 million reads per sample. Reads were aligned to miRNA and isomiR sequences using miRge. First, we assessed the overall magnitude and diversity of isomiR expression, however no differences were found between cases and controls. We then assessed the influence of diagnosis on the expression of individual miRNAs and isomiRs. Seven canonical miRNAs and 52 isomiRs, derived from 22 canonically described miRNA sequences, were identified to be differentially expressed between cases and controls. Importantly many of these isomiRs had alterations in the 5 prime portion of their sequence. Such alterations have been shown to shift the repertoire of binding partners to be distinct from that of the canonical sequence. Therefore, altered expression of these isomiRs may especially indicate modifications in gene expression regulation in schizophrenia. More research is necessary to decipher the role of these miRNA variants in schizophrenia and the brain. However, our study suggests that such variation should not be ignored.
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- 2019
16. Analysis of Copy Number Variations in Brain DNA from Patients with Schizophrenia and Other Psychiatric Disorders
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Kwang H. Choi, Chao Li, Liqin Wang, Daniel R. Weinberger, Richard E. Straub, Tianzhang Ye, Barbara K. Lipska, Ran Tao, Joel E. Kleinman, and Thomas M. Hyde
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Male ,medicine.medical_specialty ,DNA Copy Number Variations ,Genotype ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Autistic Disorder ,Psychiatry ,Biological Psychiatry ,Mood Disorders ,Brain ,medicine.disease ,Penetrance ,Mood disorders ,Schizophrenia ,Major depressive disorder ,Female ,Genome-Wide Association Study ,Diagnosis of schizophrenia - Abstract
Background Clinical studies have identified several regions of the genome with copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders. Methods We analyzed 1 million (M) single nucleotide polymorphism genotype arrays for evidence of previously reported recurrent CNVs and enriched genome-wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects with Illumina BeadArrays (568 subjects in total) and additionally in 66–92 subjects with quantitative real-time polymerase chain reaction. Results The CNVs in previously reported genomic regions were identified in 4 of 193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4 of 238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1 of 10 patients with autism (2p16.3). No evidence of increased genome-wide CNV burden was observed in cases with schizophrenia or mood disorders, although the study is underpowered to observe rare events. Messenger RNA expression patterns suggested incomplete molecular penetrance of observed CNVs. Conclusions Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses.
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- 2012
17. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex
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Ran Tao, Thomas M. Hyde, Tianzhang Ye, Shusuke Numata, Michael Wininger, Daniel R. Weinberger, Carlo Colantuoni, Xavier Guitart-Navarro, Barbara K. Lipska, and Joel E. Kleinman
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Genetics ,Promoter ,Methylation ,Biology ,Human genetics ,Epigenetics of physical exercise ,CpG site ,DNA methylation ,natural sciences ,Genetics(clinical) ,Epigenetics ,Erratum ,Prefrontal cortex ,Gene ,Genetics (clinical) - Abstract
The human prefrontal cortex (PFC), a mastermind of the brain, is one of the last brain regions to mature. To investigate the role of epigenetics in the development of PFC, we examined DNA methylation in ∼14,500 genes at ∼27,000 CpG loci focused on 5′ promoter regions in 108 subjects range in age from fetal to elderly. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. Additional discovery is made possible with a stand-alone application, BrainCloudMethyl.
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- 2012
18. 262. Human Dg-Seq Reveals Cell-Type-Specific Effectors of Schizophrenia Risk
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Ran Tao, Joy Ukaigwe, Mitsuyuki Matsumoto, Thomas M. Hyde, Joel E. Kleinman, Ronald D.G. McKay, Daniel J. Hoeppner, Daniel R. Weinberger, Andrew E. Jaffe, and Lou Blanpain
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Effector ,Schizophrenia (object-oriented programming) ,Cell type specific ,Computational biology ,Biology ,Biological Psychiatry - Published
- 2018
19. Expression of Kinase Interacting with Stathmin (KIS, UHMK1) in human brain and lymphoblasts: effects of schizophrenia and genotype
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M A Walker, Yoshi Sei, Li Chen, Sharon L. Eastwood, Tracy A. Lane, Joel E. Kleinman, Thomas M. Hyde, Greg C. Bristow, and Paul Harrison
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Adult ,Male ,Psychosis ,Genotype ,Blotting, Western ,Gene Expression ,Stathmin ,In situ hybridization ,Protein Serine-Threonine Kinases ,Polymorphism, Single Nucleotide ,Article ,Cell Line, Tumor ,Gene expression ,medicine ,Humans ,RNA, Messenger ,Molecular Biology ,In Situ Hybridization ,Aged ,Neurons ,Genetics ,Analysis of Variance ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Kinase ,General Neuroscience ,Lymphoblast ,Intracellular Signaling Peptides and Proteins ,Brain ,Human brain ,UHMK1 ,Middle Aged ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Schizophrenia ,biology.protein ,Autoradiography ,Female ,Neurology (clinical) ,Developmental Biology - Abstract
Single nucleotide polymorphisms (SNPs) within the gene encoding the serine/threonine kinase KIS (Kinase Interacting with Stathmin, also known as UHMK1) have recently been associated with schizophrenia. As none of the disease associated SNPs are coding, they may confer susceptibility by altering some facet of KIS expression. Here we have characterised the cellular distribution of KIS in human brain using in situ hybridisation and immunohistochemistry, and quantified KIS protein and mRNA in two large brain series to determine if KIS expression is altered in schizophrenia or bipolar disorder or in relation to a schizophrenia-associated SNP (rs7513662). Post-mortem tissue from the superior temporal gyrus of schizophrenia and control subjects, and also dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum from schizophrenia, bipolar disorder, and control subjects were used. KIS expression was measured by quantitative PCR (mRNA) and immunoautoradiography (protein), and was also quantified by immunoblot in lymphoblast cell lines derived from schizophrenia and control subjects. Our results demonstrate that KIS is expressed in neurons, and its encoded protein is localised to the nucleus and cytoplasm. No difference in KIS expression was found between diagnostic groups, or in the lymphoblast cell lines, and no effect of rs7513662 genotype on KIS expression was found. Hence, these data do not provide support for the hypothesis that altered expression is the mechanism by which genetic variation of KIS may increase susceptibility to schizophrenia, nor evidence that KIS expression is altered in the disease itself, at least in terms of the parameters studied here.
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- 2009
20. Reduced DTNBP1 (dysbindin-1) mRNA in the hippocampal formation of schizophrenia patients
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Richard E. Straub, Thomas M. Hyde, Joel E. Kleinman, Debora A. Rothmond, and Cynthia Shannon Weickert
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Psychosis ,medicine.medical_specialty ,Synaptophysin ,Gene Expression ,Nerve Tissue Proteins ,In situ hybridization ,Hippocampal formation ,Hippocampus ,Article ,Synapse ,Internal medicine ,mental disorders ,Gene expression ,medicine ,Humans ,RNA, Messenger ,In Situ Hybridization ,Biological Psychiatry ,biology ,Dentate gyrus ,Dysbindin ,Microfilament Proteins ,Genetic Variation ,Middle Aged ,medicine.disease ,Control Groups ,Psychiatry and Mental health ,Endocrinology ,Dentate Gyrus ,Dystrophin-Associated Proteins ,Synapses ,Schizophrenia ,biology.protein ,Autoradiography ,Carrier Proteins ,Neuroscience - Abstract
Genetic and molecular studies indicate that dysbindin-1 plays a role in the pathophysiology of schizophrenia. We examined dysbindin-1 mRNA in the hippocampal formation of patients with schizophrenia and found reduced expression in dentate granule and polymorph cells and in hippocampal field CA3, but not in CA1. Furthermore, there were positive correlations between dysbindin-1 mRNA and expression of synaptic markers known to be reduced in schizophrenia. Our results indicate that previously reported dysbindin-1 protein reductions may be due in part to decreased dysbindin-1 mRNA and that reduced dysbindin-1 may contribute to hippocampal formation synaptic pathology in schizophrenia.
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- 2008
21. Critical Factors in Gene Expression in Postmortem Human Brain: Focus on Studies in Schizophrenia
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Barbara K. Lipska, Catherine E. Martin, Cynthia Shannon Weickert, Joel E. Kleinman, Thomas M. Hyde, Amy Deep-Soboslay, and Mary M. Herman
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Adult ,Male ,Postmortem studies ,Pathology ,medicine.medical_specialty ,Time Factors ,Gene Expression ,Grey matter ,Bioinformatics ,Gene expression ,medicine ,Humans ,RNA, Messenger ,Gene ,Biological Psychiatry ,Aged ,Messenger RNA ,Chi-Square Distribution ,Reverse Transcriptase Polymerase Chain Reaction ,Age Factors ,Brain ,Human brain ,Middle Aged ,Housekeeping gene ,Dorsolateral prefrontal cortex ,medicine.anatomical_structure ,Gene Expression Regulation ,Case-Control Studies ,Postmortem Changes ,Schizophrenia ,Female ,Psychology - Abstract
Background Studies of postmortem human brain are important for investigating underlying pathogenic molecular mechanisms of neuropsychiatric disorders. They are, however, confounded by pre- and postmortem factors. The purpose of this study was to identify sources of variation that will enable a better design of gene expression studies and higher reliability of gene expression data. Methods We assessed the contribution of multiple variables to messenger RNA (mRNA) expression of reference (housekeeping) genes measured by reverse transcriptase–polymerase chain reaction (RT-PCR) by multiple regression analysis in a large number ( N = 143) of autopsy samples from the hippocampus and white and grey matter of the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia and normal control subjects. Results The strongest predictor of gene expression was total RNA quality. Other significant factors included pH, postmortem interval, age and the duration of the agonal state, but the importance of these factors depended on transcript measured, brain region analyzed, and diagnosis. The quality of RNA obtained from the DLPFC white matter was also adversely affected by smoking. Conclusions Our results show that normalization of expression data of target genes with a geometric mean of multiple housekeeping genes should be used to control for differences in RNA quality between samples. The results also suggest that accurate assessment of other confounding factors and their inclusion as regressors in the analysis is critical for obtaining reliable and accurate quantification of mRNA expression.
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- 2006
22. Reduced Density of Cholinergic Interneurons in the Ventral Striatum in Schizophrenia: An In Situ Hybridization Study
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Joel E. Kleinman, Susan E. Bachus, Clifford B. Saper, Thomas M. Hyde, Mary M. Herman, Daphne J. Holt, Mark Vangel, and Michael Wittie
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Adult ,Male ,Interneuron ,education ,Caudate nucleus ,Cell Count ,Striatum ,Biology ,Basal Ganglia ,Choline O-Acetyltransferase ,Interneurons ,mental disorders ,Basal ganglia ,medicine ,Humans ,In Situ Hybridization ,health care economics and organizations ,Biological Psychiatry ,Aged ,Putamen ,Ventral striatum ,Middle Aged ,Choline acetyltransferase ,medicine.anatomical_structure ,nervous system ,Postmortem Changes ,Schizophrenia ,Female ,Neuron ,Neuroscience - Abstract
Background The role of the striatum in the pathophysiology of schizophrenia is not understood. In a previous postmortem study, we found a reduction in the density of striatal interneurons that stain immunohistochemically for choline acetyltransferase (ChAT) in schizophrenia. Methods To determine whether this finding represents a specific alteration in ChAT gene expression, we used in situ hybridization to study the striatum of 11 control and 9 schizophrenic subjects with oligonucleotide probes complementary to human ChAT mRNA, preprosomatostatin (PPS) mRNA, and β-actin mRNA. Densities of ChAT mRNA-positive neurons, ChAT mRNA expression per neuron, PPS mRNA-positive neurons, and β-actin mRNA expression levels were measured. Results There were no significant differences between the two groups in densities of PPS mRNA-positive neurons and levels of β-actin mRNA expression throughout the striatum, or in densities of ChAT mRNA-positive neurons in the caudate nucleus or putamen. However, in the ventral striatum, the mean density of ChAT mRNA-positive neurons was reduced to 26% of control levels in the schizophrenic group. Conclusions There is a reduction in number or function of the cholinergic interneurons of the ventral striatum in schizophrenia.
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- 2005
23. Reliability of psychiatric diagnosis in postmortem research
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Catherine E. Martin, Thomas M. Hyde, Amy Deep-Soboslay, Mary M. Herman, L.B. Bigelow, Joel E. Kleinman, and Mayada Akil
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Adult ,Male ,medicine.medical_specialty ,Psychosis ,medicine ,Humans ,Bipolar disorder ,Medical diagnosis ,Psychiatry ,Biological Psychiatry ,Psychiatric Status Rating Scales ,Postmortem Diagnosis ,Mental Disorders ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Diagnostic and Statistical Manual of Mental Disorders ,Mood disorders ,Schizophrenia ,Postmortem Changes ,Cohort ,Major depressive disorder ,Female ,Autopsy ,Psychology ,Clinical psychology - Abstract
Background Postmortem human brain research is an important approach for identifying the cellular, molecular, and genetic pathways involved in the pathophysiology of psychiatric disorders. One critical component in postmortem research is the reliability of psychiatric diagnoses used to define study cohorts. Finding reliable methods for assessing lifetime psychiatric diagnoses in subjects after death is extremely challenging. Methods Two commonly used approaches were compared: psychiatric record reviews and postmortem family interviews. We hypothesized that these two methods would lead to more diagnostic agreement for subjects with schizophrenia than those with mood disorders. For 37 cases, psychiatric records were reviewed retrospectively using the Diagnostic Evaluation After Death, and family members were interviewed using the Structured Clinical Interview for DSM-IV. Results Comparison of diagnoses derived from these two approaches generated an overall kappa coefficient of .67. Kappa coefficients for the schizophrenia cohort were .94, .68 for the major depressive disorder cohort, and .58 for the bipolar disorder cohort. Conclusions Thus, although it may be sufficient to establish the postmortem diagnosis of schizophrenia using one of the two methods, the best method for reaching an accurate postmortem diagnosis for mood disorders is more difficult to determine and requires further study.
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- 2005
24. Basic fibroblast growth factor and fibroblast growth factor receptor-1 in the human hippocampal formation
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R.A. Horlick, Thomas M. Hyde, Joel E. Kleinman, Cynthia Shannon Weickert, D.A. Kittell, Richard C. Saunders, and Mary M. Herman
- Subjects
Adult ,Male ,medicine.medical_specialty ,Basic fibroblast growth factor ,Black People ,Biology ,Hippocampal formation ,Fibroblast growth factor ,Hippocampus ,White People ,Subgranular zone ,chemistry.chemical_compound ,Reference Values ,Internal medicine ,medicine ,Humans ,RNA, Messenger ,Receptor, Fibroblast Growth Factor, Type 1 ,In Situ Hybridization ,General Neuroscience ,Fibroblast growth factor receptor 1 ,Dentate gyrus ,Neurogenesis ,Receptor Protein-Tyrosine Kinases ,Middle Aged ,Receptors, Fibroblast Growth Factor ,United States ,stomatognathic diseases ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,nervous system ,chemistry ,Fibroblast growth factor receptor ,Mesothelin ,Female ,Fibroblast Growth Factor 2 ,Autopsy - Abstract
Basic fibroblast growth factor (bFGF) is an important mitogen and neurotrophic factor that binds and signals through the high-affinity receptor, fibroblast growth factor receptor 1 (FGFR1). However, only a limited amount of information is available concerning the molecular forms and anatomical distribution of fibroblast growth factors (FGFs) in the normal human brain. We found multiple bFGF and FGFR1 mRNA transcripts which vary in expression pattern across human brain regions. Using in situ hybridization and immunohistochemistry, we localized bFGF and FGFR1 mRNA and protein to cells in the normal adult human hippocampus and caudal entorhinal cortex (ERC). The majority of pyramidal neurons contained FGFR1 mRNA and protein in the mesial temporal lobe, with neurons in the CA2/CA3 region demonstrating the highest levels of FGFR1 mRNA. In contrast to FGFR1, bFGF mRNA expression was detected at very low levels in a small fraction of the neurons in the human hippocampus and caudal ERC. While bFGF mRNA may be expressed at low levels in neurons, bFGF-immunopositive cells with astrocytic features were detected throughout the mesial temporal lobe in rats, monkeys and humans. bFGF immunoreactive processes are found traversing the dentate gyrus, and bFGF immunoreactive cells are found in the neurogenic subgranular zone in all three mammalian species studied. The anatomical distribution of these two FGF family members suggests that bFGF is endogenously positioned to be involved in ongoing neurogenesis in the adult hippocampus, and that FGF trophic signaling to differentiated neurons could involve the release of astrocytic bFGF acting on neuronal FGFR1 in the normal adult human hippocampus.
- Published
- 2005
25. Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain
- Author
-
Mitsuyuki Matsumoto, Thomas M. Hyde, Jose A. Apud, Samer Melhem, Barbara K. Lipska, Quang D. Ma, Jingshan Chen, Mary M. Herman, Daniel R. Weinberger, Bhaskar Kolachana, Joel E. Kleinman, Nader D. Halim, and Michael F. Egan
- Subjects
Methyltransferase ,Genotype ,Blotting, Western ,Prefrontal Cortex ,Single-nucleotide polymorphism ,Biology ,Catechol O-Methyltransferase ,Methylation ,Polymorphism, Single Nucleotide ,Gene Expression Regulation, Enzymologic ,Mice ,Sex Factors ,Gene expression ,Genetics ,medicine ,Animals ,Humans ,Genetics(clinical) ,Lymphocytes ,RNA, Messenger ,Prefrontal cortex ,Genetics (clinical) ,DNA Primers ,Analysis of Variance ,Catechol-O-methyl transferase ,Reverse Transcriptase Polymerase Chain Reaction ,Genetic Variation ,Proteins ,Articles ,Human brain ,Molecular biology ,Enzyme assay ,medicine.anatomical_structure ,Mutagenesis, Site-Directed ,biology.protein ,rs4680 - Abstract
Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
- Published
- 2004
26. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function
- Author
-
Mitsuyuki Matsumoto, Thomas M. Hyde, C. Shannon Weickert, Daniel R. Weinberger, Mary M. Herman, Mayada Akil, Barbara K. Lipska, and Joel E. Kleinman
- Subjects
Male ,Prefrontal Cortex ,Striatum ,Catechol O-Methyltransferase ,behavioral disciplines and activities ,Rats, Sprague-Dawley ,Prosencephalon ,Mesencephalon ,Dopamine ,Cortex (anatomy) ,mental disorders ,medicine ,Animals ,Humans ,RNA, Messenger ,Prefrontal cortex ,In Situ Hybridization ,Brain Chemistry ,Neurons ,Catechol-O-methyl transferase ,Chemistry ,Pyramidal Cells ,General Neuroscience ,Dentate gyrus ,fungi ,Dopaminergic ,Blotting, Northern ,Corpus Striatum ,Rats ,medicine.anatomical_structure ,nervous system ,Forebrain ,Neuroscience ,medicine.drug - Abstract
Catechol O-methyltransferase (COMT) is involved in the inactivation of catecholamines, including the neurotransmitter dopamine. A Val108/158 Met functional polymorphism of the COMT gene has been shown to affect working memory-associated frontal lobe function in humans. In the present study, in situ hybridization histochemistry was employed to determine the mRNA expression profile of COMT in the human prefrontal cortex, striatum and midbrain and in the rat forebrain. In both species, COMT mRNA signals were observed in large pyramidal and smaller neurons in all cortical layers of the prefrontal cortex as well as in medium and large neurons in the striatum. Levels of COMT mRNA were obviously higher in neurons than in glia. The striatum, which receives a dense dopaminergic input, expressed lower levels of COMT mRNA as compared with the prefrontal cortex. Consistent with previous protein expression data, COMT mRNA was abundant in ependymal cells lining the cerebral ventricles. In the midbrain, COMT mRNA was detected in dopaminergic neurons in both species, albeit at low levels. In the rat forebrain, dense labeling was also detected in choroid plexus and hippocampal dentate gyrus and Ammon’s horn neurons. Contrary to expectations that COMT would be expressed predominantly in non-neuronal cells, the present study shows that neurons are the main cell populations expressing COMT mRNA in the prefrontal cortex and striatum. Combined with previous data about protein localization, the present results suggest that the membrane-bound isoform of COMT having a high affinity for dopamine is expressed at neuronal dendritic processes in human cortex, consistent with functional evidence that it plays an important role in dopaminergic neurotransmission. Published by Elsevier Science Ltd on behalf of IBRO.
- Published
- 2003
27. Neurotensin receptor binding abnormalities in the entorhinal cortex in schizophrenia and affective disorders
- Author
-
Emad H. Hamid, Charles B. Nemeroff, Mary M. Herman, Steve S Wolf, Thomas M. Hyde, Joel E. Kleinman, and Michael F. Egan
- Subjects
Adult ,Male ,Psychosis ,Cell Culture Techniques ,Hippocampus ,Cell Count ,Binding, Competitive ,chemistry.chemical_compound ,Image Processing, Computer-Assisted ,medicine ,Entorhinal Cortex ,Humans ,Receptors, Neurotensin ,Neurotensin receptor ,Biological Psychiatry ,Aged ,Neurotensin receptor binding ,Aged, 80 and over ,Mood Disorders ,Human brain ,Middle Aged ,medicine.disease ,Entorhinal cortex ,medicine.anatomical_structure ,chemistry ,Schizophrenia ,Female ,Psychology ,Neuroscience ,Neurotensin - Abstract
Background: Convergent evidence from in vivo and in vitro studies of schizophrenia have implicated the mesial temporal lobe as a primary site of pathological change in this disorder. We have previously reported decreased neurotensin receptor density in layer II of the intermediate entorhinal cortex (ERC) in schizophrenia, a finding seen elsewhere but not seen in more caudal ERC. Methods: To study neuroanatomic and diagnostic specificity, we measured the density of neurotensin receptors in the intermediate and caudal ERC and hippocampal formation of schizophrenic, affective disorder control subjects, and normal control subjects. Slide-based radioligand binding was used to perform these studies. Results: Not only schizophrenic but also affective disorder subjects had decreased neurotensin receptor density in layer II of the intermediate ERC. Affective disorder subjects had significantly decreased neurotensin receptor density in layers V/VI of the intermediate ERC, and schizophrenic subjects trended in the same direction. Conclusions: These findings demonstrate region-specific changes in neurotensin receptor binding levels in the mesial temporal lobe; however, there is no clear diagnostic specificity for these changes, because they were seen to varying degrees in both schizophrenia and affective disorders.
- Published
- 2002
28. Cholinergic systems and schizophrenia: primary pathology or epiphenomena?
- Author
-
Thomas M. Hyde and Jeremy M. Crook
- Subjects
Pathology ,medicine.medical_specialty ,Cellular and Molecular Neuroscience ,Neurochemical ,Dopamine ,Neural Pathways ,medicine ,Animals ,Humans ,Receptors, Cholinergic ,Prefrontal cortex ,Dopamine hypothesis of schizophrenia ,Brain Chemistry ,Neurons ,business.industry ,Glutamate receptor ,Brain ,Human brain ,medicine.disease ,Acetylcholine ,medicine.anatomical_structure ,Cholinergic Fibers ,Schizophrenia ,Cholinergic ,business ,Neuroscience ,medicine.drug - Abstract
Post mortem schizophrenia research has been driven first by the dopamine and then the glutamate hypotheses. These hypotheses posit primary pathology in pathways dependent upon dopamine or glutamate neurotransmission. Although the dopamine and glutamate hypotheses retain considerable theoretical strength, neurobiological findings of altered dopamine or glutamate activity in schizophrenia do not explain all features of this disorder. A more synthetic approach would suggest that focal pathological change in either the prefrontal cortex or mesial temporal lobe leads to neurochemical changes in multiple neurotransmitter systems. Despite the limited experimental evidence for abnormal cholinergic neurotransmission in psychiatric disorders, increased understanding of the role of acetylcholine in the human brain and its relationship to other neurotransmitter systems has led to a rapidly growing interest in the cholinergic system in schizophrenia. This review focuses on the basic anatomy of the mammalian cholinergic system, and its possible involvement in the neurobiology of schizophrenia. Summaries of cholinergic cell groups, projection pathways, and receptor systems, in the primate and human brain, are followed by a brief discussion of the functional correlations between aberrant cholinergic neurotransmission and the signs and symptoms of schizophrenia.
- Published
- 2001
29. Relative risk for cognitive impairments in siblings of patients with schizophrenia
- Author
-
Daniel R. Weinberger, Terry E. Goldberg, Tonya Gscheidle, Robert R. Rawlings, Mary Weirich, Michael F. Egan, Llewellyn B. Bigelow, and Thomas M. Hyde
- Subjects
Adult ,Male ,Wechsler Memory Scale ,medicine.medical_specialty ,Neuropsychological Tests ,Audiology ,behavioral disciplines and activities ,Nuclear Family ,Developmental psychology ,Wisconsin Card Sorting Test ,Memory ,Risk Factors ,medicine ,Humans ,Biological Psychiatry ,medicine.diagnostic_test ,Intelligence quotient ,Cognitive disorder ,Neuropsychological test ,medicine.disease ,Phenotype ,Schizophrenia ,Wide Range Achievement Test ,Female ,Schizophrenic Psychology ,Verbal memory ,Cognition Disorders ,Psychology - Abstract
Background: Patients with schizophrenia have impairments in several domains of cognition, including working memory/executive function, verbal memory, language, oculomotor scanning/psychomotor speed, and general intelligence. Impairments have also been found in unaffected siblings, suggesting they could be heritable. To assess the suitability of cognitive dysfunction for use in genetic studies, we estimated relative risk (λ) in a large cohort of siblings. Methods: One hundred forty-seven patients with schizophrenia, 193 of their siblings, and 47 control subjects were studied using a neuropsychological test battery, which included intelligence quotient (IQ), Wide Range Achievement Test, Wisconsin Card Sort, Wechsler Memory Scale (revised), California Verbal List Test, Trails A and B, and Letter and Category Fluency. Relative risk was estimated using a cutoff score of 1 SD below the control mean. Results: As expected, patients performed markedly worse than control subjects on all tests except the Wide Range Achievement Test. Siblings had impaired performance on the Wisconsin Card Sort and Trails B, with trends for reduction ( p = .01–.05) on the California Verbal List Test and Letter Fluency. Relative risk to siblings was elevated on the Trails B (λ = 4.0) and California Verbal List Test (λ = 2.8). Trends ( p = .01–.05) for increased λ were also seen for Wisconsin Card Sort, Letter Fluency, Wechsler Memory Scale and decline in IQ (λ = 1.74–2.4). Correlations between tests of different cognitive functions were weak, indicating they measure relatively independent processes. Conclusion: Unselected siblings of patients with schizophrenia have impairments in several cognitive domains. Relative risk scores were in the moderate range, suggesting a significant genetic component. Impairments on one test only weakly predicted impairments on other tests. Thus, cognitive phenotypes identify distinct, familial traits associated with schizophrenia. Using this dimensional approach to subdividing schizophrenia may reduce the clinical and genetic heterogeneity of schizophrenia and improve the power of genetic studies.
- Published
- 2001
30. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia
- Author
-
Joel E. Kleinman, Mary M. Herman, Maree J. Webster, Thomas M. Hyde, and Cynthia Shannon Weickert
- Subjects
Adult ,Male ,Psychosis ,Presynaptic Terminals ,Synaptophysin ,Hippocampus ,Neurotransmission ,Hippocampal formation ,GAP-43 Protein ,Culture Techniques ,mental disorders ,medicine ,Humans ,RNA, Messenger ,Gap-43 protein ,In Situ Hybridization ,Biological Psychiatry ,Aged ,biology ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Temporal Lobe ,Psychiatry and Mental health ,nervous system ,Schizophrenia ,Synaptic plasticity ,biology.protein ,Female ,Psychology ,Neuroscience ,Antipsychotic Agents - Abstract
Synaptophysin and growth associated protein-43 (GAP-43) are synaptic proteins colocalized to the presynaptic terminal, and involved in regulating transmitter release and synaptic plasticity. Recent studies have proposed an alteration in the number of synapses in the brains of individuals with schizophrenia. As a corollary, we hypothesized that there may be an alteration in the level of mRNAs that code for synaptic proteins in brains of patients with schizophrenia. Using in situ hybridization, we investigated the levels of synaptophysin and GAP-43 mRNA in the medial temporal lobe of 10 normal subjects, 11 subjects with schizophrenia and 10 psychiatric control subjects. Synaptophysin mRNA levels were significantly reduced in several hippocampal subfields in both the schizophrenic and psychiatric control groups. GAP-43 mRNA levels were not significantly reduced in either group. The implications of these findings are discussed in relation to neuroleptic treatment and the pathophysiology of mental illness.
- Published
- 2001
31. A comparison of human brain dissection by drill versus saw on nucleic acid quality
- Author
-
Anchal Khosla, Wilton E. Robinson, Joel E. Kleinman, Thomas M. Hyde, Ross C. Buerlein, and Barbara K. Lipska
- Subjects
Pathology ,medicine.medical_specialty ,Drill ,General Neuroscience ,Dental drill ,Dna concentration ,RNA ,Human brain ,Dissection (medical) ,Biology ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Nucleic acid ,medicine ,DNA - Abstract
This study examined the effect of two dissection techniques on the quality of human brain specimens. Frozen cerebellar samples were obtained from postmortem brains of 10 subjects free from neurological and psychiatric disease. These tissues were tested for RNA and DNA concentration and quality after being dissected with either an electric dental drill or a small handsaw. RNA and DNA were extracted separately from each sample, and the concentrations and quality of each were measured. We found that dissection technique does not significantly affect RNA or DNA quality/yield. RNA and DNA yields, as well as RNA integrity showed no significant differences between the two dissection techniques. Therefore, these results support the use of a high-speed hand-held electric dental drill as an efficient and anatomically precise means of human brain dissection without compromising tissue quality.
- Published
- 2009
32. Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia
- Author
-
Dwight C. German, Daphne J. Holt, Christopher M. Sinton, Joel E. Kleinman, Louis B. Hersh, Clifford B. Saper, Thomas M. Hyde, Mary M. Herman, and Ann M. Graybiel
- Subjects
Adult ,Caudate nucleus ,Cell Count ,Striatum ,Nucleus accumbens ,Biology ,Choline O-Acetyltransferase ,S100 Calcium Binding Protein G ,Interneurons ,Basal ganglia ,medicine ,Humans ,Cholinergic neuron ,Aged ,Aged, 80 and over ,Brain Chemistry ,General Neuroscience ,Ventral striatum ,Middle Aged ,Choline acetyltransferase ,Corpus Striatum ,medicine.anatomical_structure ,Cholinergic Fibers ,nervous system ,Calbindin 2 ,Schizophrenia ,Cholinergic ,Neuroscience - Abstract
Neurochemical and functional abnormalities of the striatum have been reported in schizophrenic brains, but the cellular substrates of these changes are not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuron. We measured the densities of cholinergic neurons in the striatum in schizophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthetic enzyme of acetylcholine. As an independent marker, we used immunoreactivity for calretinin, a protein which is co-localized with choline acetyltransferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin-positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-positive cells: controls: 3.21 +/- 0.48 cells/mm2 (mean +/- S.D.), schizophrenics: 2.43 +/- 0.68 cells(mm2; P < 0.02]. The decrease was patchy in nature and most prominent in the ventral striatum (for the choline acetyltransferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/ mm2; P < 0.005) which included the ventral caudate nucleus and nucleus accumbens region. Three of the schizophrenic cases with the lowest densities of cholinergic neurons had not been treated with neuroleptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-prefrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia.
- Published
- 1999
33. Failure to down regulate NMDA receptors in the striatum and nucleus accumbens associated with neuroleptic-induced dyskinesia
- Author
-
Thomas M. Hyde, Michael F. Egan, Emad H. Hamid, and Serapio M. Baca
- Subjects
Male ,Dyskinesia, Drug-Induced ,medicine.medical_specialty ,Haloperidol Decanoate ,Down-Regulation ,Striatum ,Nucleus accumbens ,Tardive dyskinesia ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,Nucleus Accumbens ,Rats, Sprague-Dawley ,Internal medicine ,Basal ganglia ,medicine ,Haloperidol ,Animals ,Molecular Biology ,business.industry ,General Neuroscience ,medicine.disease ,Corpus Striatum ,Rats ,Endocrinology ,Dyskinesia ,Mastication ,NMDA receptor ,Neurology (clinical) ,Dizocilpine Maleate ,medicine.symptom ,business ,Excitatory Amino Acid Antagonists ,Antipsychotic Agents ,Developmental Biology ,medicine.drug - Abstract
The syndrome of vacuous chewing movements (VCMs) in rats is similar in many respects to tardive dyskinesia (TD) in humans. Both syndromes are characterized by delayed onset of persistent orofacial dyskinesias in a sub-group of subjects chronically treated with neuroleptics. Using the rat model, we examined the role of NMDA receptor-mediated corticostriatal neurotransmission in the expression of VCMs. Rats were treated for 36 weeks with haloperidol decanoate or vehicle and then withdrawn for an additional 28 weeks. Chronic persistent VCMs were induced in one subgroup of treated animals (+VCM), but not in another group (−VCM). Rats from +VCM, −VCM groups and vehicle-treated controls were selected for post mortem studies (n=12 to 14 per group). NMDA receptor levels were assessed using [ 3 H ]-MK-801 binding in sections from the mid-striatum and nucleus accumbens. Chronic haloperidol treatment produced a marked reduction of NMDA receptor binding levels throughout the striatum and nucleus accumbens. Post hoc comparisons demonstrated that −VCM rats had lower NMDA receptor binding levels than +VCM and vehicle-treated controls. Ventromedial striatum and nucleus accumbens core were the most affected areas. These findings suggest that down-regulation of striatal NMDA receptor binding levels may protect against the expression of neuroleptic-induced dyskinesia.
- Published
- 1998
34. Abnormal Expression of Cell Recognition Molecules in Schizophrenia
- Author
-
Dale M. VanderPutten, Marquis P. Vawter, Joel E. Kleinman, John J. Hemperly, H. Eleanor Cannon-Spoor, William J. Freed, and Thomas M. Hyde
- Subjects
Gene isoform ,Psychosis ,Bipolar Disorder ,animal structures ,Cell Adhesion Molecules, Neuronal ,Prefrontal Cortex ,Hippocampus ,Developmental Neuroscience ,Reference Values ,mental disorders ,Gene expression ,medicine ,Humans ,Prefrontal cortex ,Neural Cell Adhesion Molecules ,Membrane Glycoproteins ,Brain morphometry ,Middle Aged ,medicine.disease ,Suicide ,Neurology ,Schizophrenia ,Neural cell adhesion molecule ,Psychology ,Leukocyte L1 Antigen Complex ,Neuroscience - Abstract
Schizophrenia is a neuropsychiatric disorder of unknown etiology associated with subtle changes in brain morphology. The cell recognition molecules (CRMs) neural cell adhesion molecule (N-CAM) and L1 are involved in morphoregulatory events and numerous neurodevelopmental processes. We found a selective increase of 105- to 115-kDa N-CAM in the hippocampus and prefrontal cortex of patients with schizophrenia while other N-CAM isoforms and L1 proteins were not altered. There was also evidence for an abnormality in CRM expression in schizophrenic patients: concentrations of 200-kDa L1 were strongly correlated with expression of N-CAM isoforms and cleaved L1 proteins in controls, whereas these correlations were absent in patients with schizophrenia. The increase of the 105- to 115-kDa N-CAM isoform in the brains of patients with schizophrenia confirms previous cerebrospinal fluid findings. Increased N-CAM in schizophrenia may result from structural brain abnormalities, from glial processing of N-CAM, or from an aberration in the regulation of N-CAM expression.
- Published
- 1998
35. Simultaneous measurement of water and polymer concentration profiles during swelling of poly(ethylene oxide) using magnetic resonance imaging
- Author
-
Lynn F. Gladden and Thomas M. Hyde
- Subjects
chemistry.chemical_classification ,Absorption of water ,Polymers and Plastics ,Ethylene oxide ,Organic Chemistry ,Kinetics ,Oxide ,Analytical chemistry ,Polymer ,Penetration (firestop) ,Condensed Matter::Soft Condensed Matter ,chemistry.chemical_compound ,Penetrant (mechanical, electrical, or structural) ,chemistry ,Materials Chemistry ,medicine ,Swelling ,medicine.symptom - Abstract
A one-dimensional, slice-selective magnetic resonance imaging (MRI) technique is used to image in situ the penetration of water into poly(ethylene oxide) (PEO). Spin-lattice relaxation time ( T 1 )-weighted imaging experiments provide simultaneous, quantitative measurements of polymer and water concentration profiles, penetrant front motion kinetics and swelling kinetics. The propagation of the penetrant front is observed to be a diffusion-controlled process, with no volume change on mixing during swelling. Excellent agreement is observed when comparing the polymer concentration profiles obtained from the T 1 analysis with those measured by 1 H imaging of PEO during penetration by D 2 O, under which conditions only the polymer response is imaged.
- Published
- 1998
36. Effects of rating parameters on assessment of neuroleptic-induced vacuous chewing movements
- Author
-
Jennifer N. Ferguson, Thomas M. Hyde, and Michael F. Egan
- Subjects
Male ,Restraint, Physical ,medicine.medical_specialty ,Psychometrics ,Clinical Biochemistry ,Motor Activity ,Audiology ,Toxicology ,Tardive dyskinesia ,Biochemistry ,Locomotor activity ,Rats, Sprague-Dawley ,Behavioral Neuroscience ,medicine ,Haloperidol ,Animals ,Habituation ,Habituation, Psychophysiologic ,Biological Psychiatry ,Pharmacology ,Body movement ,medicine.disease ,Rats ,Dyskinesia ,Anesthesia ,Exploratory Behavior ,Mastication ,Female ,Stereotyped Behavior ,medicine.symptom ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Long-term administration of neuroleptics to rats produces a syndrome of vacuous chewing movements (VCMs). The validity of the VCM syndrome as a model for tardive dyskinesia (TD) in humans is unclear. This is due, in part, to inconsistencies between studies. Methods for rating VCMs have varied markedly and could account for the inconsistencies. The purpose of this study was to evaluate the importance of the different methods on VCM scores. The effects of habituation and length of rating sessions were examined in rats habituated for 2 min, 1 h, or several hours over 4 days, compared to unhabituated rats. Ratings with and without habituation were highly correlated, as were ratings from 2- and 5-min observation periods. Ratings from neuroleptic-treated rats in restraining tubes, however, were significantly correlated with unrestrained ratings only following several hours of habituation. Locomotor activity was not correlated with VCM scores. These results suggest that habituation to open cages is not an important factor in assessing VCMs. Use of restraining tubes, however, may alter scores. The lack of an habituation effect or of a relationship between activity and VCMs suggests that locomotor and oral behaviors are not necessarily in competition. Restraining rats to rate VCMs does not appear to be necessary and could alter the neurobiology of VCMs.
- Published
- 1996
37. The subnuclear distribution of 5-HT3 receptors in the human nucleus of the solitary tract and other structures of the caudal medulla
- Author
-
Michael B. Knable, Joel E. Kleinman, Donald C. Ohuoha, Thomas M. Hyde, and Steven S. Wolf
- Subjects
Adult ,Indazoles ,Adolescent ,Solitary Nucleus ,medicine ,Humans ,Molecular Biology ,Medulla ,Aged ,Analgesics ,Medulla Oblongata ,Chemistry ,General Neuroscience ,Solitary nucleus ,Area postrema ,Spinal trigeminal nucleus ,Solitary tract ,Middle Aged ,medicine.anatomical_structure ,Receptors, Serotonin ,Substantia Gelatinosa ,Medulla oblongata ,Antiemetics ,Autoradiography ,Serotonin Antagonists ,Neurology (clinical) ,Brainstem ,Neuroscience ,Nucleus ,Brain Stem ,Tropanes ,Developmental Biology - Abstract
The distribution of 5-HT 3 receptors was examined in the human medulla using [ 3 H]LY278584, a highly selective 5-HT 3 receptor antagonist. The highest density of 5-HT 3 receptors was found in the substantia gelatinosus subnucleus of nucleus of the solitary tract (NTS) throughout its rostrocaudal extent, followed by the dorsal subnucleus, the area postrema (AP), the commissural sub nucleus, the medial subnucleus, and in an arc correspondingto the gelatinosus of the spinal trigeminal nucleus (nSp5). The distribution of 5-HT 3 receptors in the brain may help explain some of the reported CNS activities of 5-HT 3 -selective drugs. The anti-emetic and antinociceptive activities of 5-HT 3 antagonists may be mediated by receptors in sensory areas of the brainstem.
- Published
- 1994
38. Subnuclear organization of the human caudal nucleus of the solitary tract
- Author
-
Thomas M. Hyde and Richard R. Miselis
- Subjects
Adult ,Dorsum ,Adolescent ,Central nervous system ,Biology ,Dogs ,Species Specificity ,medicine ,Animals ,Humans ,Aged ,Aged, 80 and over ,Medulla Oblongata ,General Neuroscience ,Solitary nucleus ,Area postrema ,Solitary tract ,Anatomy ,Middle Aged ,Commissure ,Rats ,Dorsal motor nucleus ,medicine.anatomical_structure ,nervous system ,Acetylcholinesterase ,Cats ,Nucleus - Abstract
The caudal human nucleus of the solitary tract (NTS) is composed of 10 subnuclei. The commissural subnucleus spans the midline below the obex, merging rostrally into the medial subnucleus. The other subnuclei of the NTS are best seen just above the obex. The ventrolateral subnucleus contains large, darkly staining neurons. The interstitial subnucleus consists of neurons lying in groups intermingled with the fibers of the tract. The lateral subnucleus is small at caudal levels, merging with the interstitial subnucleus more rostrally. The dorsal subnucleus contains large melanotic neurons and encircles the substantia gelatinosus, a round, cell-poor subnucleus. The ventromedial subnucleus curls around the medial and ventral edge of the tract. The intermediate subnucleus, laying ventrolateral to the dorsal motor nucleus of the vagus, also contains melanotic neurons. The subpostremal subnucleus separates the area postrema from the NTS proper. The medial subnucleus is the largest subnucleus in the caudal NTS, containing medium-sized fusiform neurons. Adoption of a uniform cytoarchitectural map of the caudal NTS will permit more accurate comparisons between human and nonhuman studies.
- Published
- 1992
39. Laterality of appendicular tardive dyskinesia in chronic schizophrenia
- Author
-
Thomas M. Hyde, David L. Tirschwell, Daniel R. Weinberger, Joel E. Kleinman, and Michael F. Egan
- Subjects
Adult ,Male ,Dyskinesia, Drug-Induced ,Psychosis ,medicine.medical_specialty ,Neuropathology ,Audiology ,Tardive dyskinesia ,Functional Laterality ,Lateralization of brain function ,medicine ,Humans ,Psychiatry ,Biological Psychiatry ,Aged ,Retrospective Studies ,Chi-Square Distribution ,Middle Aged ,medicine.disease ,Dyskinesia ,Schizophrenia ,Laterality ,Female ,Chronic schizophrenia ,medicine.symptom ,Psychology - Abstract
The notion that the neuropathology of schizophrenia is lateralized is supported, in part, by findings of asymmetries in tardive dyskinesia (TD). To verify the existence of asymmetric TD, this study used the AIMS examination to look for lateralization of limb movements in a sample of 58 patients with TD. Patients with schizophrenia were compared with patients with affective and schizoaffective disorders. Asymmetry was seen in the majority of patients, regardless of psychiatric diagnosis. There was no preference for one side over the other. In a subgroup of 16 patients rated repeatedly over 13 weeks, the presence and sidedness of asymmetry fluctuated. At least four ratings were needed to accurately predict the presence and sidedness of “persistent” asymmetry. This study does not support the notion that there is a consistent, lateralized asymmetry of TD in patients with schizophrenia. Moreover, it raises questions about the reliability of assessment of persistent laterality in TD using a single exam.
- Published
- 1992
40. Magnetic resonance imaging evaluation of brain iron levels
- Author
-
Bobbie K. Lewis, Joseph A. Frank, Ahmed M. Elkashef, Thomas M. Hyde, Richard J. Wyatt, Michael F. Egan, Stephen R. Marder, and George Bartzokis
- Subjects
Physics of magnetic resonance imaging ,Nuclear magnetic resonance ,medicine.diagnostic_test ,business.industry ,Iron levels ,Medicine ,Magnetic resonance imaging ,business ,Biological Psychiatry - Published
- 1995
41. ALLELIC VARIATION IN NKCC1 IS ASSOCIATED WITH HIPPOCAMPAL AND DORSOLATERAL PREFRONTAL CORTEX ACTIVATION DURING WORKING MEMORY
- Author
-
Yukitaka Morita, Lauren R. Testa, Richard E. Struab, Daniel R. Weinberger, Joseph H. Callicott, Bhaskar Kolachana, and Thomas M. Hyde
- Subjects
Working memory ,Long-term memory ,Interference theory ,Hippocampal formation ,Biology ,Dorsolateral prefrontal cortex ,Psychiatry and Mental health ,Variation (linguistics) ,medicine.anatomical_structure ,medicine ,Allele ,Consumer neuroscience ,Neuroscience ,Biological Psychiatry - Published
- 2010
42. Identification of cytosolic human N-CAM. An isoform of N-CAM which is increased in schizophrenia
- Author
-
Marquis P. Vawter, L. Thatcher, C. Conant, William J. Freed, Mary M. Herman, D.M. Vander Putten, Thomas M. Hyde, P. Zhang, and Nsima Usen
- Subjects
Gene isoform ,Psychiatry and Mental health ,Cytosol ,Schizophrenia (object-oriented programming) ,Identification (biology) ,Biology ,Molecular biology ,Biological Psychiatry - Published
- 2000
43. 127. Entorhinal cortical preprosomatostatin mRNA in psychiatric disorders
- Author
-
Thomas M. Hyde, S.L. Rubinstein, Mary M. Herman, Susan E. Bachus, and Joel E. Kleinman
- Subjects
medicine.medical_specialty ,Endocrinology ,Internal medicine ,medicine ,Biological Psychiatry - Published
- 1998
44. Abnormalities in neurotensin gene expression levels in the hippocampus of schizophrenics
- Author
-
Susan E. Bachus, Mary M. Herman, Joel E. Kleinman, Michael F. Egan, Thomas M. Hyde, Steven S. Wolf, Charles B. Nemeroff, Emad H. Hamid, and B.L. Kinkead
- Subjects
Psychiatry and Mental health ,medicine.medical_specialty ,Endocrinology ,Neurotensin Gene ,Internal medicine ,medicine ,Hippocampus ,Biology ,Biological Psychiatry - Published
- 1998
45. Limbic cortical serotonin 1A receptor mRNA in schizophrenia
- Author
-
Susan E. Bachus, Thomas M. Hyde, Mary M. Herman, and Joel E. Kleinman
- Subjects
medicine.medical_specialty ,Messenger RNA ,Endocrinology ,Schizophrenia ,business.industry ,Internal medicine ,Serotonin 1A Receptor ,medicine ,5-HT6 receptor ,medicine.disease ,business ,Biological Psychiatry - Published
- 1995
46. Neuronal gene expression is decreased in prefrontal cortex in schizophrenia
- Author
-
Thomas M. Hyde, D.R. Weinberger, William J. Freed, Erick Ferran, Marquis P. Vawter, Cynthia Shannon Weickert, William E. Bunney, M. Matsuymoto, and Joel E. Kleinman
- Subjects
Psychiatry and Mental health ,Schizophrenia (object-oriented programming) ,Gene expression ,Biology ,Prefrontal cortex ,Neuroscience ,Biological Psychiatry - Published
- 2003
47. Languages system abnormalities in patients with schizophrenia: Syntactic deficits are related to prefrontal function, thought disorder, and abnormal movement
- Author
-
D.R. Weinberger, Michael F. Egan, Thomas M. Hyde, T.E. Goldberg, Thomas W. Weickert, and L.B. Bigelow
- Subjects
Movement (music) ,media_common.quotation_subject ,Thought disorder ,medicine.disease ,Psychiatry and Mental health ,Schizophrenia ,medicine ,In patient ,medicine.symptom ,Function (engineering) ,Psychology ,Biological Psychiatry ,Cognitive psychology ,media_common - Published
- 2003
48. An unusual presentation of tardive dyskinesia with prominent involvement of the pectoral musculature
- Author
-
Michael F. Egan, Thomas M. Hyde, and Sanjay Gupta
- Subjects
Adult ,Male ,Involuntary movement ,Dyskinesia, Drug-Induced ,Mouth ,medicine.medical_specialty ,business.industry ,Pectoral musculature ,Pectoral muscle ,Anatomy ,Tardive dyskinesia ,medicine.disease ,Pectoralis Muscles ,Surgery ,medicine.anatomical_structure ,Dyskinesia ,Tongue ,Arm ,medicine ,Humans ,medicine.symptom ,Presentation (obstetrics) ,business ,Biological Psychiatry ,Antipsychotic Agents - Published
- 1993
49. Erratum to: 'An association between reduced interhemispheric EEG coherence in the temporal lobe and genetic risk for schizophrenia' [Schizophr. Res. 49 (2001) 129–143]
- Author
-
Thomas Rädler, Michael F. Egan, Thomas M. Hyde, Richard Coppola, Georg Winterer, and Daniel R. Weinberger
- Subjects
medicine.medical_specialty ,medicine.diagnostic_test ,Coherence (statistics) ,Heritability ,Audiology ,Electroencephalography ,medicine.disease ,Temporal lobe ,Developmental psychology ,Psychiatry and Mental health ,Schizophrenia ,Relative risk ,medicine ,Genetic risk ,Association (psychology) ,Psychology ,Biological Psychiatry - Abstract
Previous studies have suggested that schizophrenic patients show resting EEG changes such as frequency-slowing and decreased coherence in the frontal and temporal area. We sought to determine whether these findings are also found in clinically unaffected siblings of schizophrenics and estimate heritability by calculating relative risk. We investigated two independent data sets: (1) from the NIMH St. Elisabeths campus (59 schizophrenics, 76 unaffected siblings and 32 unrelated normal controls) and (2) from the NIH-campus (Bethesda) (59 schizophrenics, 90 unaffected siblings and 26 unrelated normal controls). We computed power spectra and coherence on the first data set and then tried to replicate the results on the second data set. Power spectrum analysis suggested that schizophrenics are cortically hypoactivated, whereas in unaffected siblings, a tendency for hyperactivation was found. In contrast, spectral coherences (0.5–5 Hz) were reduced in both data sets in the temporal lobe areas in schizophrenics and in their unaffected siblings. Changes were most pronounced for the interhemispheric coherence linking both posterior temporal lobe areas. Relative risk calculations ( λ s ) ranged between 3.7 and 9.8, depending on phenotype definition. Thus, while power spectrum EEG abnormalities may be state-dependent, reduced coherence as a possible measure of neuronal synchronization is familial and potentially a heritable trait related to genetic risk for schizophrenia.
- Published
- 2001
50. Introduction
- Author
-
Rémi Quirion and Thomas M. Hyde
- Subjects
Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,medicine ,Psychology ,Neuroscience ,Neuroanatomy - Published
- 2000
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