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Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

Little is known about chromosomal loopings involving proximal promoter and distal enhancer elements regulating GABAergic gene expression, including changes in schizophrenia and other psychiatric conditions linked to altered inhibition. Here, we map in human chromosome 2q31 the 3D configuration of 200 kb of linear sequence encompassing the GAD1 GABA synthesis enzyme gene locus, and we describe a loop formation involving the GAD1 transcription start site and intergenic noncoding DNA elements facilitating reporter gene expression. The GAD1-TSS(-50kbLoop) was enriched with nucleosomes epigenetically decorated with the transcriptional mark, histone H3 trimethylated at lysine 4, and was weak or absent in skin fibroblasts and pluripotent stem cells compared with neuronal cultures differentiated from them. In the prefrontal cortex of subjects with schizophrenia, GAD1-TSS(-50kbLoop) was decreased compared with controls, in conjunction with downregulated GAD1 expression. We generated transgenic mice expressing Gad2 promoter-driven green fluorescent protein-conjugated histone H2B and confirmed that Gad1-TSS(-55kbLoop), the murine homolog to GAD1-TSS(-50kbLoop), is a chromosomal conformation specific for GABAergic neurons. In primary neuronal culture, Gad1-TSS(-55kbLoop) and Gad1 expression became upregulated when neuronal activity was increased. We conclude that 3D genome architectures, including chromosomal loopings for promoter-enhancer interactions involved in the regulation of GABAergic gene expression, are conserved between the rodent and primate brain, and subject to developmental and activity-dependent regulation, and disordered in some cases with schizophrenia. More broadly, the findings presented here draw a connection between noncoding DNA, spatial genome architecture, and neuronal plasticity in development and disease.

Objectives: Our laboratory recently identified the P85 gating ratio as a candidate biomarker for bipolar disorder. In order to evaluate the phenomenological significance of P85 gating, the current study examined reports of perceptual anomalies and their relationship to the P50 and P85 physiological measures of sensory gating., Methods: Reports of perceptual anomalies on the Structured Clinical Interview to Assess Perceptual Anomalies were compared in patients meeting DSM-IV criteria for paranoid schizophrenia (n = 66), schizoaffective disorder (n = 45), or bipolar I disorder (n = 42), and controls (n = 56), as well as their relationship with P85 and P50 gating., Results: The bipolar disorder group reported significantly more auditory, visual, and total anomalies than both the schizophrenia and control groups. The schizophrenia group also had more anomalies than the control group. Comparison of psychiatric subgroups revealed that the bipolar depressed, bipolar disorder with psychosis, and schizoaffective bipolar type groups reported the most anomalies compared to the other patient groups (bipolar disorder without psychosis, schizoaffective, bipolar manic). The total perceptual anomalies score and the P85 ratio significantly differentiated the bipolar disorder, schizoaffective, and paranoid schizophrenia groups from each other., Conclusions: These findings provide evidence of the phenomenological significance of P85. The results also yield further support not only for the P85 ratio, but also for increased reports of perceptual anomalies as possible markers for bipolar disorder., (© 2013 John Wiley and Sons A/S Published by Blackwell Publishing Ltd.)

Sleep plays an important role in the consolidation of memory. This has been most clearly shown in adults for procedural memory (i.e. skills and procedures) and declarative memory (e.g. recall of facts). The effects of sleep and memory are relatively unstudied in adolescents. Declarative memory is important in school performance and consequent social functioning in adolescents. This is the first study to specifically examine the effects of normal sleep on auditory declarative memory in an early adolescent sample. Given that the majority of adolescents do not obtain the recommended amount of sleep, it is critical to study the cognitive effects of normal sleep. Forty male and female normal, healthy adolescents between the ages of ten and fourteen years old were randomly assigned to sleep and no sleep conditions. Subjects were trained on a paired-associate declarative memory task and a control working memory task at 9 am, and tested at night (12 hours later) without sleep. The same number of subjects was trained at 9 pm and tested 9 am following sleep. An increase of 20.6% in declarative memory, as measured by the number correct in a paired-associate test, following sleep was observed compared to the group which was tested at the same time interval without sleep (p<0.03). The performance on the control working memory task that involved encoding and memoranda manipulation was not affected by time of day or relationship to sleep. Declarative memory is significantly improved by sleep in a sample of normal adolescents.

The hypothalamus regulates numerous autonomic responses and behaviors. The neuroactive substances corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), histidine decarboxylase (HDC), melanin-concentrating hormone (MCH), and orexin/hypocretins (ORX) produced in the hypothalamus mediate a subset of these processes. Although the expression patterns of these genes have been well studied in rodents, less is known about them in humans. We combined classical histological techniques with in situ hybridization histochemistry to produce both 2D and 3D images and to visually align and quantify expression of the genes for these substances in nuclei of the human hypothalamus. The hypothalamus was arbitrarily divided into rostral, intermediate, and caudal regions. The rostral region, containing the paraventricular nucleus (PVN), was defined by discrete localization of CRF- and AVP-expressing neurons, whereas distinct relationships between HDC, MCH, and ORX mRNA-expressing neurons delineated specific levels within the intermediate and caudal regions. Quantitative mRNA signal intensity measurements revealed no significant differences in overall CRF or AVP expression at any rostrocaudal level of the PVN. HDC mRNA expression was highest at the level of the premammillary area, which included the dorsomedial and tuberomammillary nuclei as well as the dorsolateral hypothalamic area. In addition, the overall intensity of hybridization signal exhibited by both MCH and ORX mRNA-expressing neurons peaked in distinct intermediate and caudal hypothalamic regions. These results suggest that human hypothalamic neurons involved in the regulation of the HPA axis display distinct neurochemical patterns that may encompass multiple local nuclei., (Copyright © 2010 Wiley-Liss, Inc.)

Objectives: Progress toward understanding the neurobiological and genetic underpinnings of bipolar disorder has been limited by the scarcity of potential biological markers that predict its occurrence. A measure of the integrity of brain inhibitory function, sensory gating, measured using the amplitude of the evoked potential at 50 ms to the first of two paired clicks divided by the response to the second, has been characterized as a biological marker for schizophrenia. Currently, no such biological marker exists for bipolar disorder. The goal of this research was to determine how gating of an auditory brain potential at 85 ms (P85), not previously examined in sensory gating studies, differentiated control and patient groups., Methods: P50 and P85 auditory evoked potentials were collected from individuals diagnosed with schizoaffective disorder (n = 45), paranoid schizophrenia (n = 66), and bipolar I disorder (n = 42) using DSM-IV criteria and the Structured Clinical Interview for DSM-IV; and from 56 healthy controls., Results: The P85 gating ratio was significantly larger in the bipolar disorder group compared to each of the other groups (F(3,204) = 5.47, p = 0.001, and post-hoc tests). The P50 gating ratio was significantly larger for the schizoaffective group than for the control group (F(3,204) = 2.81, p = 0.040), but did not differ from the ratio for the schizophrenia, paranoid type (p = 0.08) and bipolar groups., Conclusions: The previously unstudied P85 gating ratio may provide a new marker specific to bipolar disorder. The findings will promote further studies to investigate the unique contribution of this measure as an endophenotype.

Many studies have found that the P50 sensory gating ratio in a paired click task is smaller in normal control subjects than in patients with schizophrenia, indicating more effective sensory gating. However, a wide range of gating ratios has been reported in the literature for both groups. The purpose of this study was to compile these findings and to compare reported P50 gating ratios in controls and patients with schizophrenia. Current data collected from individual controls in eight studies from the University of California, Irvine (UCI), Indiana University (IU), and Yale University also are reported. The IU, UCI, and Yale data showed that approximately 40% of controls had P50 ratios within 1 S.D. below the mean of means for patients with schizophrenia. The meta-analysis rejected the null hypothesis that all studies showed no effect. The meta-analysis also showed that the differences were not the same across all studies. The mean ratios in 45 of the 46 group comparisons were smaller for controls than for patients, and the observed difference in means was significant for 35 of those studies. Reported gating ratios for controls from two laboratories whose findings were reported in the literature differed from all the other control groups. Variables affecting the gating ratio included band pass filter setting, rules regarding the inclusion of P30, sex, and age. Standards of P50 collection and measurement would help determine whether the gating ratio can be sufficiently reliable to be labeled an endophenotype, and suggestions are made toward this goal.

Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.

Gene expression profiles of postmortem brain tissue represent important resources for understanding neuropsychiatric illnesses. The impact(s) of quality covariables on the analysis and results of gene expression studies are important questions. This paper addressed critical variables which might affect gene expression in two brain regions. Four broad groups of quality indicators in gene expression profiling studies (clinical, tissue, RNA, and microarray quality) were identified. These quality control indicators were significantly correlated, however one quality variable did not account for the total variance in microarray gene expression. The data showed that agonal factors and low pH correlated with decreased integrity of extracted RNA in two brain regions. These three parameters also modulated the significance of alterations in mitochondrial-related genes. The average F-ratio summaries across all transcripts showed that RNA degradation from the AffyRNAdeg program accounted for higher variation than all other quality factors. Taken together, these findings confirmed prior studies, which indicated that quality parameters including RNA integrity, agonal factors, and pH are related to differences in gene expression profiles in postmortem brain. Individual candidate genes can be evaluated with these quality parameters in post hoc analysis to help strengthen the relevance to psychiatric disorders. We find that clinical, tissue, RNA, and microarray quality are all useful variables for collection and consideration in study design, analysis, and interpretation of gene expression results in human postmortem studies.

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.

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.

Abnormalities in L-glutamic acid (glutamate) and GABA signal transmission have been postulated to play a role in depression, but little is known about the underlying molecular determinants and neural mechanisms. Microarray analysis of specific areas of cerebral cortex from individuals who had suffered from major depressive disorder demonstrated significant down-regulation of SLC1A2 and SLC1A3, two key members of the glutamate/neutral amino acid transporter protein family, SLC1. Similarly, expression of L-glutamate-ammonia ligase, the enzyme that converts glutamate to nontoxic glutamine was significantly decreased. Together, these changes could elevate levels of extracellular glutamate considerably, which is potentially neurotoxic and can affect the efficiency of glutamate signaling. The astroglial distribution of the two glutamate transporters and L-glutamate-ammonia ligase strongly links glia to the pathophysiology of depression and challenges the conventional notion that depression is solely a neuronal disorder. The same cortical areas displayed concomitant up-regulation of several glutamate and GABA(A) receptor subunits, of which GABA(A)alpha1 and GABA(A)beta3 showed selectivity for individuals who had died by suicide, indicating their potential utility as biomarkers of suicidality. These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression.

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.

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.

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.

A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P < 0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT(2A), and 5HT(2C) polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P < 0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype.

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.

The antidepressant and cerebral metabolic effects of total sleep deprivation (TSD) or partial sleep deprivation (PSD) for one night has been studied with functional neuroimaging in seven publications from five different groups. Despite the variations in methods and techniques, the over-all findings were relatively consistent. First, before sleep deprivation, responders have significantly elevated metabolism compared with non-responders and normal controls, in the orbital medial prefrontal cortex, and especially the ventral portions of the anterior cingulate cortex. Second, after sleep deprivation, these hyperactive areas normalize in the responders. One functional imaging study suggested that synaptic dopamine release was associated with the antidepressant effects of TSD. The neurochemical implications of these findings are explored. Possible dopaminergic and serotonergic mechanisms are discussed.

Positron emission tomography with deoxyglucose-F18 was obtained during nighttime sleep in 36 normal volunteers, 12 studied in rapid eye movement sleep (REM period 2), 12 in nonREM sleep, and 12 while awake with eyes closed. Metabolic rate was higher throughout the cortex in REM than nonREM sleep, with differences most marked in the cingulate and frontal cortex, thalamus, and visual association areas. Whole-brain metabolic rates in the waking condition were intermediate between those in REM and nonREM sleep. Metabolism in the primary visual cortex and parts of the lateral temporal lobe was relatively constant in the REM/nonREM conditions. REM sleep did not differ from either the nonREM or waking conditions in hemispheric lateralization of metabolic activity. Compared with REM sleep, nonREM sleep was associated with significantly lower metabolic rates in the temporal and occipital regions, as well as the thalamus.

The hypoactivity of dorsolateral prefrontal cortex in schizophrenics is well known. One cause of this hypoactivity may be defective corticocortical or thalamocortical connections. Recent imaging studies of the thalamus suggest reductions in volume of the whole thalamus and reduced activity in the medial group of thalamic nuclei, which may indicate loss of functional input to the cortex. Using stereological techniques in six pairs of individually matched brains from schizophrenics and controls, we measured the volumes and obtained estimates of the number of neurons in the three subnuclei (parvocellular, pc; densocellular, dc; magnocellular, mc) of the mediodorsal nucleus (MD) and from the ventral posterior medial nucleus. There was a significant reduction in total neuron number in MD as a whole but this neuron loss was largely restricted to MDpc and MDdc [-30.9 and -24.5%, respectively (P

Background: Deficits in attention and cognition are common in schizophrenia. Using an auditory dual-click paradigm, a number of studies have found that, compared with normal controls, patients with schizophrenia show impaired inhibition, or gating, of repeated stimulation as measured by the average P50 evoked response to the second click. Since responses to many trials are collected to study the average response, fluctuations in the timing of the P50 response from trial to trial may influence the differences observed. We present a computerized, objective procedure that evaluates temporal variability in brain responses of patients with schizophrenia., Methods: Ten normal controls and 10 patients diagnosed with schizophrenia were studied using the dual-click procedure. For each single trial, the temporal shift in P50 that yielded the best alignment with the average P50 response was used to derive a measure of P50 temporal variability from trial to trial and to form P50 averages corrected for temporal variability., Results: Patients with schizophrenia had significantly more temporal variability than normal controls. Correction for temporal variability in the P50 responses increased the size of P50 for both patients with schizophrenia and normal controls. Patients with schizophrenia had smaller P50 responses to the first click than controls and less inhibition to the second click before, but not after, correction for temporal variability., Conclusions: These findings suggest that temporal variability contributes significantly to the P50 response as measured using the gating procedure. The measure of temporal variability may provide a new index of inhibitory and attentional function in schizophrenia.

Objective: Sleep deprivation has been shown to have an antidepressant benefit in a subgroup of depressed patients. Functional imaging studies by the authors and others have suggested that patients with elevated metabolic rates in the anterior cingulate gyrus at baseline are more likely to respond to either sleep deprivation or antidepressant medications than patients with normal metabolic rates. The authors extend their earlier work in a larger group of patients and explore additional brain areas with statistical probability mapping., Method: Thirty-six patients with unipolar depression and 26 normal volunteers were studied with positron emission tomography before and after sleep deprivation. Response to sleep deprivation was defined as a 40% or larger decrease in total scores on the Hamilton Depression Rating Scale., Results: One-third of the depressed patients had a significant response to sleep deprivation. Responders had higher relative metabolic rates in the medial prefrontal cortex, ventral anterior cingulate, and posterior subcallosal gyrus at baseline than depressed patients who did not respond to sleep deprivation and normal volunteers. Lower Hamilton depression scores correlated significantly with lower metabolic rates in the left medial prefrontal cortex. After sleep deprivation, significant decreases in metabolic rates occurred in the medial prefrontal cortex and frontal pole in the patients who responded positively to sleep deprivation., Conclusions: High pretreatment metabolic rates and decreases in metabolic rates after treatment in the medial prefrontal cortex may characterize a subgroup of depressed patients who improve following sleep deprivation and, perhaps, other antidepressant treatments.

Clinical descriptions of perceptual and attentional anomalies in schizophrenia emphasize phenomena such as flooding, or inundation, by sensory stimuli. A failure of sensory "gating" mechanisms in the brain is hypothesized to account for these symptoms, and this hypothesis has led to a marked interest in their putative psychophysiological substrates. However, there are no systematic analyses of the phenomenology of these perceptual experiences, nor has the hypothesized connection between the clinical phenomena and their reported psychophysiological substrates been tested. In this investigation, a structured interview instrument was developed to measure perceptual anomalies as distinct from hallucinations and to determine their prevalence across sensory modalities in schizophrenia in 67 schizophrenia subjects and 98 normal controls. The instrument includes Likert ratings of hypersensitivity, inundation, and selective attention to external sensory stimuli. Good interrater agreement, determined from interviews, was obtained. Schizophrenia subjects had significantly higher auditory, visual, and combined scores (i.e., across all modalities) than normal controls did, indicating significantly more perceptual anomalies. For the schizophrenia group, the prevalence of auditory and visual anomalies was significantly greater than the other sensory modalities. The data indicate that the putative phenomenological correlates of sensory gating may be reliably measured and tested with the Structured Interview for Assessing Perceptual Anomalies.

The relative abundance of alternatively spliced long (gamma2L) and short (gamma2S) mRNAs of the gamma2 subunit of the gamma-amino butyrate type A (GABAA) receptor was examined in dorsolateral prefrontal cortex of schizophrenics and matched controls by using in situ hybridization histochemistry and semiquantitative reverse transcription-PCR (RT-PCR) amplification. A cRNA probe identifying both mRNAs showed that the transcripts are normally expressed at moderately high levels in the prefrontal cortex. Consistent with previous studies, overall levels of gamma2 transcripts in prefrontal cortex of brains from schizophrenics were reduced by 28.0%, although this reduction did not reach statistical significance. RT-PCR, performed under nonsaturating conditions on total RNA from the same blocks of tissue used for in situ hybridization histochemistry, revealed a marked reduction in the relative proportion of gamma2S transcripts in schizophrenic brains compared with controls. In schizophrenics, gamma2S transcripts had fallen to 51.7% (+/-7.9% SE; P < 0.0001) relative to control levels. Levels of gamma2L transcripts showed only a small and nonsignificant reduction of 16. 9% (+/-12.0% SE, P > 0.05). These findings indicate differential transcriptional regulation of two functionally distinct isoforms of one of the major GABAA receptor subunits in the prefrontal cortex of schizophrenics. The specific reduction in relative abundance of gamma2S mRNAs and the associated relative increase in gamma2L mRNAs should result in functionally less active GABAA receptors and have severe consequences for cortical integrative function.

Background: Abnormal P50 response has been hypothesized to reflect the sensory gating deficit in schizophrenia. Despite the extensive literature concerning the sensory filtering or gating deficit in schizophrenia, no evidence has been provided to test the relationship of the P50 phenomenon with patients' experiences of perceptual anomalies., Methods: Sixteen drug-free DSM-IV diagnosed schizophrenic patients who reported moderate to severe perceptual anomalies in the auditory or visual modality were examined as compared to 16 schizophrenic patients who did not report perceptual anomalies, and 16 normal subjects. Both control groups were age- and gender-matched with the study group., Results: Patients reporting perceptual anomalies exhibited P50 patterns that did not differ from normal subjects. In contrast, patients who did not report perceptual anomalies showed the abnormal P50 ratios previously found to be associated with schizophrenia., Conclusions: These paradoxical findings do not support the hypothetical relationship between the P50 and behavioral measures of sensory gating, suggesting that additional studies are needed to further explore the clinical correlates of the P50.

Reduced EEG photic driving has been found to be diagnostically sensitive and specific for schizophrenia. Thirty-one patients with schizophrenia were tested in this study to identify the typical and atypical neuroleptic effects on the photic driving. Compared with the placebo, clozapine significantly enhanced the photically driven EEG in theta and low alpha frequency band, while haloperidol did not have the same effect. These changes with clozapine appeared to be symmetrical and located primarily in the frontal, central and mid-parietal areas but not in the lateral parietal, temporal and occipital regions. Results were consistent with previous findings and suggested that the atypical EEG profile of clozapine might be associated with 5-HT2 antagonistic property.

The conditioning-testing (S1-S2) P50 auditory evoked potential (EP) has been well-documented and accepted as an important tool for measuring sensory gating in schizophrenia research. However, the physiological mechanism of the phenomenon is not known. In this study a single-trial analysis was used to determine the influence of the latency variability of the responses in the formation of the averaged P50. Ten schizophrenic patients and 10 normal controls were tested in the dual-click EP paradigm. Using ensemble averaging analysis, we replicated the previous finding of a lower S1 P50 amplitude and higher S2/S1 ratio in schizophrenics compared with normal controls. The single-trial analysis revealed that patients had significantly higher trial-to-trial latency variability in S1 responses than normal subjects, while the S2 showed the same variability as in controls. Measured by the single-trial procedure, the arithmetic mean amplitudes of P50 responses to S1 and S2 were similar between normal and schizophrenic subjects. The same measure also eliminated the difference in averaged P50 amplitude between S1 and S2 for both groups. Temporal variability appears to be an important factor in the assessment of averaged EPs and thus contribute to the change of P50 amplitude observed in schizophrenia.

Objective: This study examined glucose metabolism in the anterior and posterior cingulate cortex in schizophrenia., Method: Fifty unmedicated male schizophrenic patients and 24 normal men were studied with positron emission tomography., Results: Compared with the normal men, the schizophrenic patients had lower relative metabolic rates in the anterior cingulate and higher rates in the posterior cingulate., Conclusions: The findings suggest hypofunction in the anterior cingulate cortex in schizophrenia.

[3H]Nemonapride differentially defines sigma and dopamine receptor sites depending upon assay conditions. In post-mortem schizophrenic brain tissues, [3H]nemonapride-labeled sigma receptor binding is decreased compared to match normal controls. No striatal dopamine D4/D4-like receptor differential was observed between the schizophrenic or control tissues, using the [3H]nemonapride minus [3H]raclopride subtraction method.

Background: Depression is characterized by several sleep-related abnormalities shortly before and after sleep onset, such as prolonged sleep latency, loss of stage 3-4 sleep, reduced rapid eye movement (REM) latency, increased nocturnal core body temperature, and abnormal hormone secretion patterns. Sleep deprivation is associated with a temporary improvement in depression. We hypothesized that depressed patients may be "overaroused" and that absolute cerebral glucose metabolism would be elevated during the first nocturnal non-REM sleep period in depressed patients compared with normal controls. In addition, since hypofrontality (greater metabolic activity in occipital compared with frontal cortical activity) has been reported in waking positron emission tomographic studies of depressed patients compared with controls, we predicted significant hypofrontality in depressed patients during the first non-REM period., Methods: Positron emission tomography with fludeoxy-glucose F 18 was used to compare 10 unmedicated men with unipolar depression with 12 normal men during the first non-REM sleep period at normal bedtime., Results: Whole-brain absolute metabolic rate during non-REM sleep was significantly elevated (+47%) in patients compared with controls. Mean absolute cerebral glucose metabolic rate was also higher in every area of the brain in patients compared with normal controls. The greatest significant mean increases were in the posterior cingulate and amygdala (+44%), hippocampus (+37% to +43%), occipital and temporal cortex (+33% to +34%), and pons (+33%). Relative metabolic rates in specific neroanatomical areas, however, varied considerably both within the patient group and between patients and controls. Patients showed significant hypofrontality, particularly in the medio-orbital frontal cortex, compared with controls. Patients also showed significant reductions of relative metabolic rate in the anterior cingulate, caudate, and medial thalamus compared with controls., Conclusions: These findings provide further support for the hyperarousal hypothesis of some types of major depressive disorder. Abnormal patterns of cerebral metabolism during non-REM sleep in depressed patients confirmed earlier waking findings of decreased relative frontal and abnormal limbic metabolic activity and striatal metabolism in association with posterior cortical increases.

Background: The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development., Methods: Three histochemically or immunocytochemically defined neuronal populations were studied in WM beneath the middle frontal gyrus of 20 schizophrenic patients and 20 matched control subjects., Results: Brains of schizophrenic patients showed significant changes in the distribution of the three neuronal populations: microtubule-associated protein 2 and nonphosphorylated neurofilament-immunoreactive neurons showed a decreased density in superficial WM and an increased density in deeper WM. Nicotinamide adenine dinucleotide phosphate-diaphorase neurons were reduced in superficial WM and showed variable densities in deeper WM. Thirty-five percent of the brains of schizophrenic patients but no brains of the control subjects showed a maldistribution of neurons toward deeper WM with at least two of the three markers. Changes in neuronal distribution were not linked to age, gender, autolysis time, or subtype of schizophrenia., Conclusions: Selective displacement of interstitial WM neurons in the frontal lobe of brains of schizophrenic patients may indicate alteration in the migration of subplate neurons or in the pattern of programmed cell death. Both could lead to defective cortical circuitry in the brains of schizophrenic patients.

Objective: This study reports the first paired measurements of glucose metabolism and size of thalamic regions in never-medicated schizophrenic patients using coregistered magnetic resonance imaging (MRI) templates., Method: Positron emission tomography with [18F]fluorodeoxyglucose and matching MRI scans were obtained in 20 never-medicated patients with schizophrenia and 15 normal volunteers. Methods for thalamic edge finding, statistical testing of shape differences with chi-square maps, and MRI localization of major thalamic subregions were developed., Results: Patients with schizophrenia showed a diminished metabolic rate in the right thalamus, with a loss of the normal pattern of right greater than left asymmetry. Division into anterior/posterior segments revealed that the left anterior and right posterior showed the decrease. Differences were greater for metabolism in the weighted thalamic area (ratexarea) than for rate per unit area, a finding consistent with reported greater decreases in total neuron number than of neuron density in the thalami of schizophrenic patients. The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region., Conclusions: The reduced thalamic activity observed in this study lends further support to the concept of deficits in sensory filtering in schizophrenia.

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.

Central nervous system (CNS) inhibitory mechanisms hypothesized to "gate" repetitive sensory inputs have been implicated in the pathology of schizophrenia. The present study investigated gender differences in inhibitory gating of evoked brain responses to repeated stimuli in normal subjects (30 women and 30 men) using an auditory conditioning-testing paradigm. Pairs of click stimuli (S1 and S2) were presented with a 0.5 s intrapair and a 10 s interpair interval. The amplitudes and latencies of the P50, N100, P180 components of the auditory evoked response to the conditioning (S1) and test response (S2) were measured, and the gating ratios were computed (T/C ratio = S2/S1 * 100). The amplitudes to S1 were not significantly different between men and women at P50, N100, or P180. However, women had significantly higher amplitudes to S2 at P50 (p = 0.03) and N100 (p = 0.04). The T/C ratios for women were higher (i.e., less suppression of response to S2) for P50 (p = 0.08) and N100 (p = 0.04) compared to men. The results suggested that differences in auditory gating between men and women were not due to biological differences in the P50 and N100 generators but possibly to differential influence of inhibitory mechanisms acting on the generator substrates of these evoked responses.

We studied 18 never-mediated schizophrenic patients and 22 normal control subjects with 18F-deoxyglucose (FDG) positron emission tomography. Patients and controls performed the continuous performance test during FDG uptake. Cortical and subcortical structures comprising two circuits selected on the basis of several theoretical models of schizophrenia were examined. The correlation of glucose metabolic rate (GMR) for each structure in each circuit with connected structures was calculated and tested for two-tailed significance. Schizophrenics showed significantly different patterns of intercorrelations for both circuits. The largest difference was in the correlation of GMR in the anterior thalamus with the frontal cortex, a key element in the thalamo-cortical-striatal circuit suggested to be abnormal in some models of schizophrenia. Correlations of the frontal lobe with other regions were also more positive in normal controls than schizophrenics; controls had three correlational paths from the frontal cortex (to temporal cortex, ventral anterior thalamus, and dorsal medial thalamus) with significantly more positive correlations than schizophrenics perhaps consistent with other findings of frontal cortical dysfunction in schizophrenia. Normal controls also had both more significant positive and more significant negative correlations between the occipital cortex and other brain areas than schizophrenics. Correlations between homologous areas in the right and left hemispheres were prominent in both groups.

The prefrontal cortex of schizophrenics is hypoactive and displays changes related to inhibitory, GABAergic neurons, and GABAergic synapses. These changes include decreased levels of glutamic acid decarboxylase (GAD), the enzyme for GABA synthesis, upregulation of muscimol binding, and downregulation of benzodiazepine binding to GABAA receptors. Studies in the visual cortex of nonhuman primates have demonstrated that gene expression for GAD and for several GABAA receptor subunit polypeptides is under control of neuronal activity, raising the possibility that similar mechanisms in the hypoactive prefrontal cortex of schizophrenics may explain the abnormalities in GAD and in GABAA receptor regulation. In the present study, which is the first of its type on human cerebral cortex, levels of mRNAs for six GABAA receptor subunits (alpha 1, alpha 2, alpha 5, beta 1, beta 2, gamma 2) and their laminar expression patterns were analyzed in the prefrontal cortex of schizophrenics and matched controls, using in situ hybridization histochemistry and densitometry. Three types of laminar expression pattern were observed: mRNAs for the alpha 1, beta 2, and gamma 2 subunits, which are the predominant receptor subunits expressed in the mature cortex, were expressed at comparatively high levels by cells of all six cortical layers, but most intensely by cells in lower layer III and layer IV. mRNAs for the alpha 2, alpha 5, and beta 1 subunits were expressed at lower levels; alpha 2 and beta 1 were expressed predominantly by cells in layers II, III, and IV; alpha 5 was expressed predominantly in layers IV, V, and VI. There were no significant changes in overall mRNA levels for any of the receptor subunits in the prefrontal cortex of schizophrenics, and the laminar expression pattern of all six receptor subunit mRNAs did not differ between schizophrenics and controls. Because gene expression for GABAA receptor subunits is not consistently altered in the prefrontal cortex of schizophrenics, the previously reported upregulation of muscimol binding sites and downregulation of benzodiazepine binding sites in the prefrontal and adjacent cingulate cortex of schizophrenics are possibly due to posttranscriptional modifications of mRNAs and their translated polypeptides.

Background: Up-regulation of gamma-aminobutyric acidA (GABAA) receptors and decreased GABA uptake in the cerebral cortex of schizophrenics suggest altered GABAergic transmission, which could be caused by primary disturbance of GABA synapses or by decreased production of the transmitter. Decreased production could be due to a shutdown in GABA production or to loss of GABA neurons caused by cell death or their failure to migrate to the cortex during brain development., Methods: To discriminate between these possibilities, we quantified levels of messenger RNA (mRNA) for the 67-kd isoform of glutamic acid decarboxylase (GAD), the key enzyme in GABA synthesis, and the number and laminar distribution of GAD mRNA--expressing neurons in the dorsolateral prefrontal cortex (DLPFC) of schizophrenics and matched controls, using in situ hybridization-histochemistry, densitometry, and cell-counting methods. These data were compared with the total number of neurons, the number of small, round or ovoid neurons 8 to 15 microns in diameter, and overall frontal lobe volume. As a control, mRNA levels for type II calcium-calmodulin-dependent protein kinase (CamIIK) were quantified., Results: Schizophrenics showed a pronounced decrease in GAD mRNA levels in neurons of layer I (40%) and layer II (48%) and an overall 30% decrease in layers III to VI. There were also strong overall reductions in GAD mRNA levels. The CamIIK mRNA levels showed no significant differences between samples. No differences were found in the total number of neurons nor in small, round or ovoid neurons, which should include a majority of the GABA cells. Prefrontal gray and white matter volume did not differ significantly between controls and schizophrenics., Conclusions: The prefrontal cortex of schizophrenics shows reduced expression for GAD in the absence of significant cell loss. This may be brought about by an activity-dependent down-regulation associated with the functional hypoactivity of the DLPFC. The lack of significant alterations in cell numbers in the DLPFC and frontal lobe volume in schizophrenics also implies that overall cortical neuronal migration had not been compromised in development. Previous reports of altered neuronal distribution in the subcortical white matter of schizophrenic brains in comparison with that of controls may indicate disturbances of migration or programmed cell death in the cortical subplate, leading to altered connection formation in the overlying cortex of schizophrenics and activity-dependent down-regulation of neurotransmitter-related gene expression.

This article reviews evidence for morphological abnormalities in schizophrenia as assessed by brain imaging and neurohistochemical techniques including immunohistochemistry and in situ hybridization. Localized deficits in schizophrenic brain appear in many regions including frontal and temporal lobes, anterior cingulate, mediodorsal thalamic nucleus, and corpus callosum. These areas are interconnected and may provide the basis for a "psychosis circuitry." Neuronal disruption of elements in this circuitry may result in a hypothesized dysconnection syndrome. Evidence suggests an alteration in neuronal development related to either genetic and/or environmental factors. Primary and secondary anterograde and retrograde effects may accompany this neurodevelopmental defect and may further alter intrinsic and extrinsic neuronal communications. A number of studies are consistent with the second trimester of gestation being a critical period for fetal brain development, especially for neuronal migration. Fetal trauma due to environmental insults (e.g., influenza) during this trimester may increase the incidence of schizophrenia. Recent advances in the identification of factors that modulate neuronal development including axon guidance molecules, neurotrophins, and programmed cell death genes provide intriguing new areas for potential investigation. Future research may focus on the factors controlling neuronal migration and programmed cell death in the schizophrenic brain.

The effect of a 90-min nap period on mood was studied in 22 sleep-deprived patients with a diagnosis of major depression. All patients remained awake from 7 AM until 12 noon the following day at which time they were permitted to nap while being monitored by sleep encephalography. Fifteen subjects showed a significant response to sleep deprivation as defined by a 35% improvement on the Hamilton Rating Scale for Depression. After the nap a relapse of depressive symptoms occurred which was significantly related to the amount of non-rapid eye movement sleep time.

Objective: The cortical-striatal-thalamic circuit modulates cognitive processing and thus may be involved in the cognitive dysfunction in schizophrenia. The imaging of metabolic rate in the structures making up this circuit could reveal the correlates of schizophrenia and its main symptoms., Method: Seventy male schizophrenic patients underwent [18F]-fluorodeoxyglucose positron emission tomography after a period of at least 4 weeks during which they had not received neuroleptic medication and were compared to 30 age-matched male normal comparison subjects., Results: Analyses revealed decreased metabolism in medial frontal cortex, cingulate gyrus, medial temporal lobe, corpus callosum, and ventral caudate and increased metabolism in the left lateral temporal and occipital cortices in the schizophrenic cohort. Consistent with previous studies, the schizophrenic group had lower hypofrontality scores (ratios of lateral frontal to occipital metabolism) than did comparison subjects. The lateral frontal cortical metabolism of schizophrenic patients did not differ from that of comparison subjects, while occipital cortical metabolism was high, suggesting that lateral hypofrontality is due to abnormalities in occipital rather than lateral frontal activity. Hypofrontality was more prominent in medial than lateral frontal cortex. Brief Psychiatric Rating Scale (BPRS) scores, obtained for each schizophrenic patient on the scan day, were correlated with regional brain glucose metabolic rate. Medial frontal cortical and thalamic activity correlated negatively with total BPRS score and with positive and negative symptom scores. Lateral frontal cortical metabolism and hypofrontality scores did not significantly correlate with negative symptoms. Analyses of variance demonstrated a reduced right greater than left asymmetry in the schizophrenic patients for the lateral cortex as a whole, with simple interactions showing this effect specifically in temporal and frontal cortical regions., Conclusions: Low metabolic rates were confirmed in medial frontal cortical regions as well as in the basal ganglia, consistent with the importance of the cortical-striatal-thalamic pathways in schizophrenia. Loss of normal lateralization patterns was also observed on an exploratory basis. Correlations with negative symptoms and group differences were more prominent in medial than lateral frontal cortex, suggesting that medial regions may be more important in schizophrenic pathology.

The distribution of neurons expressing the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) in the lateral and medial temporal lobes of schizophrenic and matched control brains was investigated in a systematic blind analysis. Schizophrenics had significantly lower numbers of NADPH-d neurons in the hippocampal formation and in the neocortex of the lateral temporal lobe but significantly greater numbers of NADPH-d neurons in the white matter of the lateral temporal lobe and a tendency toward greater numbers in parts of the parahippocampal white matter. The distorted distribution of NADPH-d neurons in the lateral temporal lobe, which may be explained by developmental disturbances, such as impaired neuronal migration or an alteration in the death cycle of transitory subcortical neurons, is similar to that found in the prefrontal cortex of schizophrenics. Alterations of cortical ontogenesis, as reflected in the distribution of NADPH-d neurons, appear to be widespread among neocortical association fields in schizophrenics and may provide a clue to the cause of the disease.

Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.

Objective: Sleep deprivation is a rapid, nonpharmacologic antidepressant intervention that is effective for a subset of depressed patients. The objective of this study was to identify which brain structures' activity differentiates responders from nonresponders and to study how metabolism in these brain regions changes with mood., Method: Regional cerebral glucose metabolism was assessed by positron emission tomography (PET) with [18F]deoxyglucose (FDG) before and after total sleep deprivation in 15 unmedicated awake patients with unipolar major depression and 15 normal control subjects, who did the continuous performance test during FDG uptake., Results: After sleep deprivation, four patients showed a 40% or more improvement on the Hamilton Rating Scale for Depression. Before sleep deprivation the depressed responders had a significantly higher cingulate cortex metabolic rate than the depressed nonresponders, and this normalized after sleep deprivation. The normal control subjects and nonresponding depressed patients showed no change in cingulate metabolic rate after sleep deprivation., Conclusions: Overactivation of the limbic system as assessed by PET scans may characterize a subset of depressed patients. Normalization of activity with sleep deprivation is associated with a decrease in depression.

This study is the first report on the effects of total sleep deprivation (about 32 h) on regional cerebral glucose metabolism during wakefulness in man, using positron emission tomography (PET) with F-18 deoxyglucose (FDG). Sleep deprivation leads to a significant reorganization of regional cerebral metabolic activity, with relative decreases in the temporal lobes and increases in visual cortex. Absolute glucose metabolic measurements indicate a decrease in thalamus, basal ganglia, white matter, and cerebellum. No overall decrease in whole brain metabolism was noted after sleep deprivation. As expected, sleep deprivation significantly reduced visual vigilance as assessed by the continuous performance test and this decrease was correlated significantly with reduced metabolic rate in thalamic, basal ganglia, and limbic regions.

This study explored the relationship between rapid eye movement (REM) sleep and schizophrenia using positron emission tomography. Glucose use was compared between 49 schizophrenics, 30 awake controls and 12 controls in REM sleep. Assessment of the frequency and locations of brain areas showing significant differences suggested that REM did not resemble schizophrenia. Schizophrenics were between the higher awake controls and lower REM controls in corpus callosum glucose use. Hallucinating schizophrenics showed lower left caudate glucose use.

Carbamazepine was administered to nine patients with manic-depressive illness at doses ranging from 600 to 1600 mg per day, achieving blood levels between 6 and 11 microgram per milliliter. Compared to medication-free values, GABA levels in the cerebrospinal fluid (CSF) were not significantly altered by an average of 30 days' treatment with carbamazepine. These preliminary data do not support a major effect of carbamazepine on brain GABA as reflected in CSF as a mechanism for its anticonvulsant or psychotropic effects.

The catecholamine hypothesis proposed an increase in functional brain norepinephrine in the manic phase of manic-depressive illness. This paper reviews a secondary hypothesis suggesting that dopamine may be involved in the manic process. Increases in functional dopamine may result from the release of dopamine which is amplified by a supersensitive dopamine receptor that has developed during the depressive phase prior to the onset of mania. Lithium may act, in part, by blocking the development of supersensitive dopamine receptors. Evidence compatible with this hypothesis is reviewed.