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Background Research has implicated IQ and executive function (EF) as contributors to episodic memory impairments in schizophrenia. However, it has been difficult to quantitatively apportion the respective contributions of these factors . We conducted a series of analyses to objectively parse the associated variance and to determine to what extent episodic memory impairment in schizophrenia is independent of IQ and EF. Methods Participants included 323 schizophrenia patients and 327 healthy controls from the National Insitute of Mental Health Sibling Study. Neurocognitive tests assessing IQ, EF, and episodic memory were administered. We examined group differences while controlling for IQ or EF in analyses of covariance, we used linear regression to quantify the amount of variance not explained by IQ or EF, and we matched control and patient subgroups on IQ or EF to determine if memory measures remained different. Results Analyses of covariance revealed significant group differences between schizophrenia individuals and healthy control subjects across multiple episodic memory measures after controlling for IQ or EF. Furthermore, regressions with IQ and/or EF factors entered left more than 50% of variance in memory unaccounted. Follow-up true score variance analyses indicated that the majority of this variance was directly related to memory function. Matched subgroups also yielded subgroup differences on all memory measures. Conclusions Findings across the multiple statistical strategies suggested that the mechanisms underlying the memory impairment in schizophrenia are fully attributable neither to IQ nor EF. Rather, they most likely reflect compromises in episodic memory processing itself and, by inference, the medial temporal system.

Background Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. Methods We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. Results Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. Conclusions Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.

Background Catechol-O-methyltransferase (COMT) val 108/158 met ( rs4680 ) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865 , rs165599 , and rs2097603 . In a large sample, we examined whether these SNPs affect WM. Methods Schizophrenic probands ( n = 325), their nonpsychotic siblings ( n = 359), and normal control subjects ( n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val 108/158 met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val 108/158 met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. Conclusions We extended earlier findings of a val 108/158 met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val 108/158 met effect in a nonlinear manner.

Background Increased variability of stimulus-induced prefrontal electromagnetic activity ("noise") has been associated with genetic risk for schizophrenia. On the basis of animal experiments and computational models, we have predicted that this prefrontal "noise" phenotype would be related to variation in prefrontal dopamine (DA) signaling, which itself might be abnormal in schizophrenia. In the present study, the effect of a functional single nucleotide polymorphism (val 108/158 met) within the catechol- O -methyltransferase (COMT) gene on prefrontal "noise" was examined, because the COMT enzyme is involved in cortical synaptic dopamine metabolism and weakly predictive of risk for schizophrenia. Methods A Caucasian sample comprising 112 unrelated normal subjects, 83 schizophrenic probands, and 87 of their unaffected siblings was investigated, all of whom had measures of prefrontal "noise" estimated from event-related electroencephalogram during an auditory oddball task. Results The val 108/158 met genotype was significantly associated with prefrontal "noise"; homozygous Val-carriers had greatest prefrontal "noise" values; odds ratio (OR) = 2.37 (95% confidence interval [CI] 1.37–4.10), p = 003. The genotype-phenotype association was stronger when only considering male subjects with an OR=3.37 (95% CI: 1.63–6.98), p = 002. Conclusions The results suggest that COMT genotype impacts the level of prefrontal physiologic "noise."

Background The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism ( val 108/158 met ) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val 108/158 met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. Methods Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. Results Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. Conclusions These results support other data suggesting that the COMT val 108/158 met polymorphism might be an important factor in the cognitive response to antipsychotic medication.

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.

This article reviews prefrontal cortical biology as it relates to pathophysiology and genetic risk for schizophrenia. Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the catechol-o-methyl transferase (COMT) gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. The COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. Functional magnetic resonance imaging confirms that COMT genotype affects prefrontal physiology during working memory. Family-based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing-the first plausible mechanism for a genetic effect on normal human cognition and risk for mental illness.

Background: Event-related potentials (ERPs) during an auditory oddball task were investigated in patients with schizophrenia and in their healthy siblings to explore the question of whether abnormalities of two-dimensional topographic scalp-distribution of P300 amplitude and latency relate to genetic risk for schizophrenia. We also examined the P50, N100, and P200-waves, elicited during the same task. Methods: We investigated 42 schizophrenic patients, 62 of their healthy siblings, and 34 unrelated normal control subjects with a standard auditory oddball paradigm and 16 electroencephalogram electrodes. Amplitudes and latencies of the ERPs P50, N100, P200, and P300 were topographically analyzed. Results: In the patients, P300 amplitude was significantly decreased in the range of 54%–58% over the left parietotemporal area. Siblings did not show decreased P300 amplitudes when compared with normal subjects. P300 latencies were unchanged in both groups. No significant group differences were observed for the other event-related potentials. Conclusions: In line with previous studies, the P300 amplitude in schizophrenic patients was decreased over the left temporoparietal area; however, we found no evidence for a genetic trait effect in the event-related potential abnormality. Possible reasons for these largely negative findings are discussed.

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.

Background: The specific intracellular effects of antipsychotic drugs are largely unknown. Studies in animals have suggested that antipsychotics modify the expression of various intraneuronal proteins, but no analogous in vivo data in humans are available. The objective of the present study was to assess whether antipsychotics modify N -acetylaspartate (an intraneuronal marker of neuronal functional integrity) measures in brains of patients with schizophrenia. Methods: We used proton magnetic resonance spectroscopic imaging to study 23 patients with schizophrenia (DSM-IV diagnosis) using a within-subject design. Patients were studied twice: once while on a stable regimen of antipsychotic drug treatment (for at least 4 weeks) and once while off medication for at least 2 weeks. Several cortical and subcortical regions were assessed, including the dorsolateral prefrontal cortex and the hippocampal area. Results: Analysis of variance showed that, while on antipsychotics, patients had significantly higher N -acetylaspartate measures in the dorsolateral prefrontal cortex ( p = .002). No other region showed any significant effect of treatment. Conclusions: These results indicate that antipsychotic drugs increase N -acetylaspartate measures selectively in the dorsolateral prefrontal cortices of patients with schizophrenia, suggesting that these drugs modify in a regionally specific manner the function of a population of cortical neurons. N -Acetylaspartate measures may provide a useful tool to further investigate the effects of antipsychotics at the intracellular level.

Background: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. Methods: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. Results: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (λ S ) of between 3.8 and 8.8, suggesting this characteristic is heritable. Conclusions: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.

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.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23 cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of “organicity.” Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.

Background Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative (“inhibitory”) frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed.

Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady-state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relationship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophrenia and in a nonhuman primate model of abnormal prefrontal cortical development.In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic imaging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis.Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D2 receptor availability in the striatum (n = 14, rho = -.64, p.01), suggesting that the greater the apparent dorsolateral prefrontal cortex pathology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA measures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p.05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infusion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release.These data demonstrate direct relationships between putative neuronal pathology in dorsolateral prefrontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopamine dysregulation in schizophrenia.

Alterations in brain iron could play an important role in the development of tardive dyskinesia in patients receiving neuroleptic medication. To test this hypothesis, magnetic resonance imaging scans of the brain were performed on 21 chronic schizophrenic patients. Ten patients met research diagnostic criteria for persistent tardive dyskinesia, and 11 were free of tardive dyskinesia. All patients had received long-term neuroleptic treatment and were on a stable neuroleptic dose for at least 3 months before scanning. The signal intensity of basal ganglia structures was obtained as a quantitative estimate of brain iron content. No difference was found in the signal intensity ratios between the two groups. This suggests that iron deposition in the basal ganglia, at least as assessed by this measure, does not play a role in the pathophysiology of tardive dyskinesia.

Diminished evoked response to repeated auditory stimuli, an example of sensory gating normally present in human subjects, is often absent in schizophrenics. To examine the mechanism of the normal response and to delineate possible sites of its abnormality in psychosis, it would be desirable to reproduce the phenomenon in laboratory animals. In this study, we show that the pattern of diminished response to the second of paired auditory stimuli is found in activity recorded from the CA3 region of the hippocampus of anesthetized rats. The evoked potential recorded from this area is predominantly an N40 wave, at identical latency to the prominent negative wave recorded from the skull surface of unanesthetized rats. Similar responses were not found in other areas, including the auditory neocortex and the medial geniculate nucleus. Amphetamine, which diminished sensory gating in both animals and humans, diminished the gating of the evoked potential recorded in the hippocampus. The effect of amphetamine was reversed by haloperidol. The rat hippocampus may therefore contain neurons that can be used to study the neurobiology of sensory gating.

patients are usually unable to perform as well as normal, healthy subjects (NV). In order to better characterize and represent this cognitivemaladaptationwe have studiedNV and SZ subjectsfollowing extensive(3 -5 thousandtrials) tonerecognitiontraining.The task consistedof a tone presentedevery 2 seconds;the subjectrecognized the tone as relativelyhighor lowin frequency.Thereferencestimulus was fixed but the test stimulusvariedduringthe trainingphase of the study. Sufficient disparity between the tones was used in order to generate an 80%accuracy score. A subgroupof SZ (n=12) was able to perform as well as the NV (n= 12) with respect to accuracy and response time (RT). Using positronemissiontomography(PET) and 15-Oxygen,water, blood flow methodology,we studied subjects recognizinglow disparity tones. The contrasting conditions showed similar shifts in brain activity when switchingfrom one conditionto another for NV and SZ. The correlationmaps for blood flow (rCBF) and RT, accurate trials only, differed significantlybetween groups. WhereasNVexhibitedgreaterrCBFfor faster RT in auditorycortices and cerebellum,SZ subjectsexhibitedrobustcorrelationsfor fast RT in frontal, cuneus and occipital regions. Multiple scan conditions permit analyses of brain changes between and within conditions, between and within groups.