Biomedical subjects

William E Bunney

Publications and source records attributed to William E Bunney.

15 recordsLinked to original sources

PubMed2006

Frontal lobe metabolic decreases with sleep deprivation not totally reversed by recovery sleep.

We studied the effects of total sleep deprivation and recovery sleep in normal subjects using position emission tomography with 18F-deoxyglycose. Sleep deprivation resulted in a significant decrease in relative metabolism of the frontal cortex, thalamus, and striatum. Recovery sleep was found to have only a partial restorative effect on frontal lobe function with minimal reversal of subcortical deficits. Sleep may be especially important for maintenance of frontal lobe activity.

Adult↗

PubMed2006

Psychological pain: a review of evidence.

This paper defines a symptom construct termed psychological pain and reviews clinical and neuroimaging evidence relevant to it. The psychological pain associated with severe depression is often perceived as worse than any physical pain that the individual has experienced and could be a critical component of suicidality that could be systematically assessed in potentially suicidal patients. Converging evidence from brain imaging studies suggests overlapping patterns of brain activation induced by both psychological pain and by physical pain. Future research on the role of psychological pain and its interaction with nociceptive pathways may provide novel clues to the understanding and treatment of depression and other psychiatric illnesses.

Brain↗

PubMed2006

SNPs on chips: the hidden genetic code in expression arrays.

Gene expression microarray analysis in postmortem brains is one of the fastest growing fields of psychiatric research. Here we show that common polymorphisms (SNPs) present on probe sets can masquerade as significant "gene expression" differences. After first observing this artifact in the Catechol-O-methyl transferase (COMT) gene, we replicate the finding in two additional genes predicted to show this artifact. Many Affymetrix chips contain thousands of SNPs that are both common and in the central probe region affecting hybridization, and thus have the potential to confound expression analysis.

Analysis of Variance↗

PubMed2006

Application of microarray technology in primate behavioral neuroscience research.

Gene expression profiling of brain tissue samples applied to DNA microarrays promises to provide novel insights into the neurobiological bases of primate behavior. The strength of the microarray technology lies in the ability to simultaneously measure the expression levels of all genes in defined brain regions that are known to mediate behavior. The application of microarrays presents, however, various limitations and challenges for primate neuroscience research. Low RNA abundance, modest changes in gene expression, heterogeneous distribution of mRNA among cell subpopulations, and individual differences in behavior all mandate great care in the collection, processing, and analysis of brain tissue. A unique problem for nonhuman primate research is the limited availability of species-specific arrays. Arrays designed for humans are often used, but expression level differences are inevitably confounded by gene sequence differences in all cross-species array applications. Tools to deal with this problem are currently being developed. Here we review these methodological issues, and provide examples from our experiences using human arrays to examine brain tissue samples from squirrel monkeys. Until species-specific microarrays become more widely available, great caution must be taken in the assessment and interpretation of microarray data from nonhuman primates. Nevertheless, the application of human microarrays in nonhuman primate neuroscience research recovers useful information from thousands of genes, and represents an important new strategy for understanding the molecular complexity of behavior and mental health.

Animals↗

PubMed2005

Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data.

Genome-wide expression profiling is a powerful tool for implicating novel gene ensembles in cellular mechanisms of health and disease. The most popular platform for genome-wide expression profiling is the Affymetrix GeneChip. However, its selection of probes relied on earlier genome and transcriptome annotation which is significantly different from current knowledge. The resultant informatics problems have a profound impact on analysis and interpretation the data. Here, we address these critical issues and offer a solution. We identified several classes of problems at the individual probe level in the existing annotation, under the assumption that current genome and transcriptome databases are more accurate than those used for GeneChip design. We then reorganized probes on more than a dozen popular GeneChips into gene-, transcript- and exon-specific probe sets in light of up-to-date genome, cDNA/EST clustering and single nucleotide polymorphism information. Comparing analysis results between the original and the redefined probe sets reveals approximately 30-50% discrepancy in the genes previously identified as differentially expressed, regardless of analysis method. Our results demonstrate that the original Affymetrix probe set definitions are inaccurate, and many conclusions derived from past GeneChip analyses may be significantly flawed. It will be beneficial to re-analyze existing GeneChip data with updated probe set definitions.

Alleles↗

PubMed2005

Therapeutic effects of individualized alpha frequency transcranial magnetic stimulation (alphaTMS) on the negative symptoms of schizophrenia.

Previous research in clinical electroencephalography (EEG) has demonstrated that reduction of alpha frequency (8-13 Hz) EEG activity may have particular relevance to the negative symptoms of schizophrenia. Repetitive Transcranial Magnetic Stimulation (rTMS) was utilized to investigate this relationship by assessing the therapeutic effects of stimulation set individually at each subject's peak alpha frequency (alphaTMS). Twenty-seven subjects, with predominantly negative symptom schizophrenia, received 2 weeks of daily treatment with either alphaTMS, 3 Hz, 20 Hz, or sham stimulation bilaterally over the dorsolateral prefrontal cortex. Individualized alphaTMS demonstrated a significantly larger (F (3,33) = 4.7, p = .007) therapeutic effect (29.6% reduction in negative symptoms) than the other 3 conditions (< 9%). Furthermore, these clinical improvements were found to be highly correlated (r = 0.86, p = .001) with increases (34%) in frontal alpha amplitude following alphaTMS. These results affirm that the resonant features of alpha frequency EEG play an important role in the pathophysiology of schizophrenia and merit further investigation as a particularly efficacious frequency for rTMS treatments.

Alpha Rhythm↗

PubMed2005

Chromatin alterations associated with down-regulated metabolic gene expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Schizophrenia is frequently accompanied by hypometabolism and altered gene expression in the prefrontal cortex. Cellular metabolism regulates chromatin structure, including covalent histone modifications, which are epigenetic regulators of gene expression. OBJECTIVE: To test the hypothesis that down-regulated metabolic gene expression is associated with histone modification changes in the prefrontal cortex of subjects with schizophrenia. DESIGN AND SUBJECTS: Histones and gene transcripts were profiled in the postmortem prefrontal cortex of 41 subjects with schizophrenia and 41 matched controls. The phosphorylation, acetylation, and methylation of 6 lysine, serine, and arginine residues of histones H3 and H4 were examined together with 16 metabolic gene transcripts using serial immunoblotting, immunohistochemical analysis, custom-made complementary DNA arrays, and quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Subjects with schizophrenia, as a group, showed no significant alterations in histone profiles or gene expression. In a subgroup of 8 patients with schizophrenia, levels of H3-(methyl)arginine 17, H3meR17, exceeded control values by 30%, and this was associated with the decreased expression of 4 metabolic transcripts. CONCLUSIONS: High levels of H3-(methyl)arginine 17 are associated with down-regulated metabolic gene expression in the prefrontal cortex of a subset of subjects with schizophrenia. Histone modifications may contribute to the pathogenesis of prefrontal dysfunction in schizophrenia.

Chromatin↗

PubMed2004

Microarray screening of lymphocyte gene expression differences in a multiplex schizophrenia pedigree.

In order to help prioritize the selection of candidate genes and to study possible trait and not state related changes in gene expression, we compared lymphocytic gene expression patterns of five individual family members with schizophrenia and nine unaffected individuals from a large multiplex high density pedigree. We screened gene expression by microarray consisting of 1128 brain focused genes. Three criteria for selection of microarray gene differences between schizophrenia and unaffected family members were employed: a significant t-test, expression in a majority of subjects, and fold change magnitude. Gene expression levels were significantly different for nine genes between individuals with schizophrenia compared to unaffected controls, and two genes were validated by real-time PCR. The expression of the neuropeptide Y receptor Y1 gene (NPY1R localized at 4q31.3-q32) and the human guanine nucleotide-binding regulatory protein Go-alpha (GNAO1 localized at 16q13) was significantly decreased in individuals with schizophrenia compared to unaffected family controls by microarray and real-time PCR. The cytosolic malate dehydrogenase gene (MDH1 localized at 2p13.3) was also significantly increased by microarray analysis and showed a trend for increase by real-time PCR. The significant genes are discussed in terms of proximity to linkage regions, prior association studies of schizophrenia, and other reports of microarray screening of schizophrenia tissue. Evidence from these studies taken together with the present study suggests critical pathways in schizophrenia may be studied in peripheral tissue as part of the strategy in functional genomic convergence. This preliminary study needs to be repeated by screening a larger set of genes in additional families with schizophrenia. The present study offers support for examination of gene expression patterns using lymphocytic RNA for complex neuropsychiatric disorders from large cohorts of patients.

Adult↗

PubMed2004

Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain.

There are major concerns that specific agonal conditions, including coma and hypoxia, might affect ribonucleic acid (RNA) integrity in postmortem brain studies. We report that agonal factors significantly affect RNA integrity and have a major impact on gene expression profiles in microarrays. In contrast to agonal factors, gender, age, and postmortem factors have less effect on gene expression profiles. The Average Correlation Index is proposed as a method for evaluating RNA integrity on the basis of similarity of microarray profiles. Reducing the variance due to agonal factors is critical in investigating small but validated gene expression differences in messenger RNA levels between psychiatric patients and control subjects.

Adult↗

PubMed2004

Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions.

Studies of gene expression abnormalities in psychiatric or neurological disorders often involve the use of postmortem brain tissue. Compared with single-cell organisms or clonal cell lines, the biological environment and medical history of human subjects cannot be controlled, and are often difficult to document fully. The chance of finding significant and replicable changes depends on the nature and magnitude of the observed variations among the studied subjects. During an analysis of gene expression changes in mood disorders, we observed a remarkable degree of natural variation among 120 samples, which represented three brain regions in 40 subjects. Most of such diversity can be accounted for by two distinct expression patterns, which in turn are strongly correlated with tissue pH. Individuals who suffered prolonged agonal states, such as with respiratory arrest, multi-organ failure or coma, tended to have lower pH in the brain; whereas those who experienced brief deaths, associated with accidents, cardiac events or asphyxia, generally had normal pH. The lower pH samples exhibited a systematic decrease in expression of genes involved in energy metabolism and proteolytic activities, and a consistent increase of genes encoding stress-response proteins and transcription factors. This functional specificity of changed genes suggests that the difference is not merely due to random RNA degradation in low pH samples; rather it reflects a broad and actively coordinated biological response in living cells. These findings shed light on critical molecular mechanisms that are engaged during different forms of terminal stress, and may suggest clinical targets of protection or restoration.

Adult↗

PubMed2004

Gene expression of metabolic enzymes and a protease inhibitor in the prefrontal cortex are decreased in schizophrenia.

Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8- to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P = 0.006), HINT1 (P = 0.050), and neuroserpin (P = 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

Adult↗

PubMed2004

Gender-specific gene expression in post-mortem human brain: localization to sex chromosomes.

Gender differences in brain development and in the prevalence of neuropsychiatric disorders such as depression have been reported. Gender differences in human brain might be related to patterns of gene expression. Microarray technology is one useful method for investigation of gene expression in brain. We investigated gene expression, cell types, and regional expression patterns of differentially expressed sex chromosome genes in brain. We profiled gene expression in male and female dorsolateral prefrontal cortex, anterior cingulate cortex, and cerebellum using the Affymetrix oligonucleotide microarray platform. Differentially expressed genes between males and females on the Y chromosome (DBY, SMCY, UTY, RPS4Y, and USP9Y) and X chromosome (XIST) were confirmed using real-time PCR measurements. In situ hybridization confirmed the differential expression of gender-specific genes and neuronal expression of XIST, RPS4Y, SMCY, and UTY in three brain regions examined. The XIST gene, which silences gene expression on regions of the X chromosome, is expressed in a subset of neurons. Since a subset of neurons express gender-specific genes, neural subpopulations may exhibit a subtle sexual dimorphism at the level of differences in gene regulation and function. The distinctive pattern of neuronal expression of XIST, RPS4Y, SMCY, and UTY and other sex chromosome genes in neuronal subpopulations may possibly contribute to gender differences in prevalence noted for some neuropsychiatric disorders. Studies of the protein expression of these sex-chromosome-linked genes in brain tissue are required to address the functional consequences of the observed gene expression differences.

Actins↗

PubMed2003

MRNA expression patterns and distribution of white matter neurons in dorsolateral prefrontal cortex of depressed patients differ from those in schizophrenia patients.

BACKGROUND: Schizophrenia, bipolar illness, and major depressive disorder have distinct presentations, but share some common symptoms. Hence, some common cellular and molecular abnormalities may be identifiable in these disorders. METHODS: We examined cell-specific markers in the dorsolateral prefrontal cortex of brains from 18 patients with bipolar or major depressive disorder, and 18 matched controls, using in situ hybridization histochemistry and staining for nicotinamide-dinucleotide phosphate-diaphorase (NADPH). The distribution of NADPH-positive interstitial cells of the white matter and the expression of the mRNA for the 67 KD form of glutamic acid decarboxylase (GAD(67)) had previously been shown to be altered in prefrontal cortex of schizophrenics. Other markers identifying glutamatergic neuronal populations were alpha-type II calcium/calmodulin dependent protein kinase (CAMKII-alpha), brain derived neurotrophic factor, (BDNF) and the putative transcription factor, T-brain-1 (TBR1). RESULTS: Expression of GAD67 and the distribution of NADPH-positive cells in the white matter were not significantly altered in the dorsolateral prefrontal cortex of depressed subjects. Expression of CAMKII-alpha and TBR1 mRNAs was significantly increased in bipolar patients but not in major depressed patients, and there was a trend toward reduced BDNF expression in both groups. Abnormal patterns of gene expression and neuronal distribution in schizophrenics are markedly different from those in depressed patients. CONCLUSIONS: The findings that TBR1 and CAMKII-alpha expression is increased only in bipolar patients suggests abnormalities of specific genes related to a major cortical cell type and its connectivity.

Adult↗

PubMed2003

Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders.

OBJECTIVE: An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology-microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once. METHOD: This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed. RESULTS: New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies. CONCLUSIONS: Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.

Brain Chemistry↗

PubMed2002

Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia.

BACKGROUND: The neurotransmitters dopamine and glutamate have been implicated in the prefrontal dysfunction associated with schizophrenic illness. Studies suggest that the D1 subclass of dopamine receptor and the N-methyl-D-aspartate subclass of glutamate receptor are involved in this prefrontal dysfunction. These 2 receptors regulate, in opposing directions, the amount of phosphorylated activated DARPP-32, a potent inhibitor of protein phosphatase 1 that modulates the activity of several classes of receptors and ion channels. Thus, DARPP-32 occupies a key regulatory position, and may play an important role in the pathophysiological changes in dopamine and glutamate function reported in patients with schizophrenia. METHODS: The amounts of DARPP-32, synapsin I, and the alpha subunit of calcium/calmodulin-dependent protein kinase II were measured by immunoblotting in postmortem samples from 14 schizophrenic subjects and their age-, gender-, and autolysis time-matched control subjects. Possible confounding influences of neuroleptic treatment were analyzed by comparing subjects with Alzheimer disease who were and were not treated with neuroleptic agents. RESULTS: DARPP-32 was significantly reduced in the dorsolateral prefrontal cortex in more schizophrenic subjects relative to matched controls. The ratios of 2 other synaptic phosphoproteins, synapsin I and the alpha subunit of calcium/calmodulin-dependent protein kinase II, did not differ between schizophrenic and control subjects, nor between subjects with Alzheimer disease who were and were not treated with neuroleptic agents. CONCLUSIONS: Our findings are consistent with a selective reduction in DARPP-32 levels in schizophrenic subjects. This may be involved in the prefrontal dysfunction associated with schizophrenia.

Adult↗