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Psychiatric and cognitive phenotypes have been associated with a range of specific, rare copy number variants (CNVs). Moreover, IQ is strongly associated with CNV risk scores that model the predicted risk of CNVs across the genome. But the utility of CNV risk scores for psychiatric phenotypes has been sparsely examined.To determine how CNV risk scores, common genetic variation indexed by polygenic scores (PGSs), and environmental factors combine to associate with cognition and psychopathology in a community sample.The Philadelphia Neurodevelopmental Cohort is a community-based study examining genetics, psychopathology, neurocognition, and neuroimaging. Participants were recruited through the Children's Hospital of Philadelphia pediatric network. Participants with stable health and fluency in English underwent genotypic and phenotypic characterization from November 5, 2009, through December 30, 2011. Data were analyzed from January 1 through July 30, 2021.The study examined (1) CNV risk scores derived from models of burden, predicted intolerance, and gene dosage sensitivity; (2) PGSs from genomewide association studies related to developmental outcomes; and (3) environmental factors, including trauma exposure and neighborhood socioeconomic status.The study examined (1) neurocognition, with the Penn Computerized Neurocognitive Battery; (2) psychopathology, with structured interviews based on the Schedule for Affective Disorders and Schizophrenia for School-Age Children; and (3) brain volume, with magnetic resonance imaging.Participants included 9498 youths aged 8 to 21 years; 4906 (51.7%) were female, and the mean (SD) age was 14.2 (3.7) years. After quality control, 18 185 total CNVs greater than 50 kilobases (10 517 deletions and 7668 duplications) were identified in 7101 unrelated participants genotyped on Illumina arrays. In these participants, elevated CNV risk scores were associated with lower overall accuracy on cognitive tests (standardized β = 0.12; 95% CI, 0.10-0.14; P = 7.41 × 10-26); lower accuracy across a range of cognitive subdomains; increased overall psychopathology; increased psychosis-spectrum symptoms; and higher deviation from a normative developmental model of brain volume. Statistical models of developmental outcomes were significantly improved when CNV risk scores were combined with PGSs and environmental factors.In this study, elevated CNV risk scores were associated with lower cognitive ability, higher psychopathology including psychosis-spectrum symptoms, and greater deviations from normative magnetic resonance imaging models of brain development. Together, these results represent a step toward synthesizing rare genetic, common genetic, and environmental factors to understand clinically relevant outcomes in youth.

Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence.To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths.A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018.United States-mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997.Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms.The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (β = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (β = -1.59 to -1.73; corrected P .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years).The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.

Importance Structural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth. Objective To investigate the presence of structural brain abnormalities in youth with PS symptoms. Design, Setting, and Participants The Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children’s hospital health care network between November 1, 2009, and November 30, 2011. Main Outcomes and Measures Measures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally. Results Following exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume ( P = 3.4 × 10 −4 ) when not accounting for intracranial volume and relatively expanded white matter volume when accounting for intracranial volume ( P = 2.2 × 10 −3 ). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score = 5.2 and cluster size of 1225 for the right and maximum z score = 4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity. Conclusions and Relevance Structural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions.

The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype.To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing.The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220).Two functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces.In the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster-corrected P .05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r = .32, P .001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P .05). The response in the amygdala correlated with positive symptom severity (r = .16, P = .01) but not with cognitive deficits.The pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help-seeking risk samples. Specific circuit dysfunction during cognitive and emotion-processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms.

Context Deficits in emotion processing are prominent in schizophrenia, and flat affect is resistant to treatment and portends poor outcome. Investigation of the underlying neural circuitry can elucidate affective dysfunction. Objective To examine the brain circuitry for facial emotion processing, dissecting response to task demands from effects of the appearance of facial expressions. Design A facial emotion identification task was presented during high-field (4-T) magnetic resonance imaging. Blood oxygenation level–dependent changes were contrasted for task compared with a scrambled face baseline (blocked analysis) and for the appearance of each of the following 4 target expressions compared with neutral faces (event related): happy, sad, anger, and fear. Setting Participants from the Schizophrenia Research Center underwent a functional magnetic resonance imaging study at the University of Pennsylvania Medical Center. Participants Patients with DSM-IV –defined schizophrenia (n = 16) and healthy controls (n = 17) were recruited from the community. Main Outcome Measures The percentage of signal change for each contrast and performance and clinical symptom severity ratings. Results Patients showed reduced limbic activation compared with controls for the emotion identification task. However, event-related analysis revealed that whereas in controls greater amygdala activation was associated with correct identifications of threat-related (anger and fear) expressions, patients showed the opposite effect of greater limbic activation, portending misidentifications. Furthermore, greater amygdala activation to the presentation of fearful faces was highly correlated with greater severity of flat affect. Conclusions Abnormal amygdala activation in schizophrenia in response to presentation of fearful faces is paradoxically associated with failure to recognize the emotion and with more severe flat affect. This finding suggests that flat affect in schizophrenia relates to overstimulation of the limbic system.

Context Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia. Objective To characterize the genetic architecture of some key endophenotypic measures selected for their reported heritabilities in schizophrenia. Design Family-based heritability study. Setting Seven sites across the United States. Participants At the time of these initial data analyses, the members of 183 nuclear families ascertained through probands with schizophrenia had been assessed for these endophenotypes. Main Outcome Measures Variance component models were used to assess the heritability of and the environmental and genetic correlations among the endophenotypes. The Consortium on the Genetics of Schizophrenia assesses the neurophysiologic measures of prepulse inhibition of acoustic startle, P50 event-related potential suppression, and the antisaccade task for eye movements and the neurocognitive measures of the Continuous Performance Test (Degraded Stimulus version), the California Verbal Learning Test, the Letter-Number Sequencing test, and 6 measures from the University of Pennsylvania Computerized Neurocognitive Battery. The heritabilities of these 12 measures are the focus of this article. Results All of the endophenotypes and the University of Pennsylvania Computerized Neurocognitive Battery measures were found to be significantly heritable ( P ≤ .005), with heritabilities ranging from 24% to 55%. Significant environmental and genetic correlations were also observed between many of the endophenotypic measures. Conclusion This is the first large-scale, multisite, family-based heritability study of a collection of endophenotypes for schizophrenia and suggests that endophenotypes are important measures to consider in characterizing the genetic basis of schizophrenia.

Background Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. Objective To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patientsandthat gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Design Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Setting Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Participants Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Interventions Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Main Outcome Measures Brain volume changes assessed by MRI. Results Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. Conclusions Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Context Patients with schizophrenia exhibit olfactory deficits, but it is unclear whether these represent a specific abnormality. The link between olfactory impairments and regional brain abnormalities has yet to be established. Objectives To determine whether patients with schizophrenia exhibit volumetric deficits in the anterior ventromedial temporal lobe, the target for neuronal inputs from the olfactory bulb, and whether these are related to olfactory performance deficits. Design A cohort study of patients and healthy control subjects who underwent both 1-mm spoiled-gradient echo magnetic resonance imaging and behavioral tests of olfaction and memory. Setting Schizophrenia Research Center at the University of Pennsylvania, Philadelphia. Participants Fifty-two patients with a DSM-IV diagnosis of schizophrenia and 38 healthy control subjects. Individuals were excluded for history of head trauma, significant substance abuse, and medical conditions affecting brain function or olfactory capacity. Main Outcome Measures Gray matter volumes of the left and right temporal poles and the perirhinal and entorhinal cortexes; olfactory threshold detection sensitivity and identification test scores; composite indexes of verbal and spatial memory ability. Results Patients had reduced volumes, relative to cranial size, in left ( P = .003) and right ( P = .01) perirhinal and left ( P = .002) and right ( P = .002) entorhinal cortexes, but not in the temporal pole. Perirhinal, but not entorhinal, cortical volume decrement was associated with decreased olfactory threshold sensitivity. Neither region was associated with impaired memory performance. Conclusions Patients with schizophrenia have reduced cortical volumes in brain regions that receive afferents directly from the olfactory bulb. Behavioral olfactory deficits are related to structural brain abnormalities in these regions.

Background Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. Methods Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. Results We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. Conclusions Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.

Background There is emerging evidence that gray matter (GM) is reduced in patients with schizophrenia. Information on the extent of global differences in the 3 principal supertentorial compartments is necessary for interpretation of regional effects. The relation of GM reduction to clinical status and neurocognition also requires examination. Methods Magnetic resonance imaging, neurocognitive measures, and clinical assessment of symptoms and functioning were obtained for 130 patients (51 neuroleptic naive, 79 previously treated) and 130 healthy controls (75 men, 55 women in each group). Results Overall GM volume was reduced in patients compared with controls. This was evident in men (6% reduction) and women (2% reduction) and was already evident at the first presentation of neuroleptic-naive patients. The reduction sustained correction for age and total intracranial volume. Compartmental volumes did not correlate with the severity of positive ( r , −0.08 to 0.23) or negative ( r , −0.01 to −0.07) symptoms, but GM volume was associated with better premorbid functioning in women ( r , 0.36-0.51). Small but significant correlations ( r , 0.19-0.44) were observed between GM volume and performance in 6 neurocognitive domains. These correlations varied by diagnosis, most higher in patients, and were moderated by sex. Conclusions Gray matter volume reduction in schizophrenia is already evident in men and women at first presentation. While this reduction is not correlated with symptom severity, it is associated with cognitive performance. Since GM development accelerates in the later part of gestation, while white matter growth is primarily postnatal, the results may support the hypothesis that neurodevelopmental processes relate to GM deficit.

Background The cognitive and functional deterioration that is observed in many "poor-outcome" patients with schizophrenia suggests a neurodegenerative process extending into late life. Previous diagnostic studies have excluded known neurodegenerative diseases as explanations for this dementia. However, we hypothesized that relatively small accumulations of age- or disease-related neurodegenerative lesions occurring in an otherwise abnormal brain could result in deterioration in schizophrenia. Methods Postmortem studies were conducted using 23 prospectively accrued elderly persons with chronic schizophrenia for whom clinical ratings had been determined before death, 14 elderly control patients with no neuropsychiatric disease, and 10 control patients with Alzheimer disease. Immunohistochemistry and unbiased stereological counting methods were used to quantify common neurodegenerative lesions (ie, neurofibrillary tangles, amyloid plaques, and Lewy bodies) and cellular reactions to a variety of noxious stimuli (ubiquitinated dystrophic neurites, astrocytosis, and microglial infiltrates) in the ventromedial temporal lobe and the frontal and the calcarine (primary visual) cortices. Results No statistically significant differences were found between the patients with schizophrenia and the control patients without neuropsychiatric disease for the densities of any of the markers, while both groups exhibited fewer lesions than did the control group with Alzheimer disease. Correlation analyses in the schizophrenia sample failed to identify significant correlations between cognitive and psychiatric ratings and densities of any of the neuropathologic markers. Conclusions No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia. Furthermore, the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena.

Background: Quantitative magnetic resonance imaging (MRI) studies demonstrate reduced brain volumes in schizophrenics, but specific structural abnormalities have not been clearly delineated. The structural abnormalities of this disorder are likely to be heterogeneous, consistent with its diverse clinical presentation. To investigate the relationship between structural abnormality and clinical symptoms, we examined regional brain and cerebral spinal fluid (CSF) volumes in a large sample of schizophrenic patients and controls, with patients aggregated into clinical subtypes. Methods: Right and left hemisphere frontal and temporal lobe brain and CSF volumes were quantified from 5-mm axial spin-echo MRIs for 71 schizophrenic patients and 77 age- and sex-matched controls. The following four standardized rating scales were used to assess symptom severity: Negative Symptoms, Disorganization, Schneiderian Delusions and Hallucinations, and Suspicion-Hostility. Patients were also subtyped as either deficit or nondeficit on the basis of enduring negative symptoms. Results: Schizophrenic patients overall exhibited ab-a normal brain asymmetry, with selective decrease in brain volume in the left temporal and right frontal regions. Left temporal lobe parenchymal volume reduction and CSF volume increase were correlated with the severity of negative symptoms. Consistent with this, the subtype analysis revealed abnormal temporal lobe asymmetry for the deficit subgroup only. Right frontal lobe volume reduction correlated with the duration of illness, independent of symptom severity or schizophrenic subtype. Conclusions: Abnormal lateral asymmetry suggests selective structural deficits in schizophrenia, rather than diffusely undifferentiated CNS abnormalities. The pattern of regional abnormalities is related to clinical symptoms, with negative symptoms being associated with left temporal lobe rather than frontal lobe abnormality. This is consistent with suggestions of a temporolimbic prefrontal network abnormality in schizophrenia. Further longitudinal studies are warranted, using higherresolution MRI technology and gray matter—white matter segmentation to confirm and extend these findings.

Background: Medication and chronicity have complicated past attempts to characterize the neuropsychological performance of patients with schizophrenia. There have been inconsistencies regarding the pattern, selectivity, and sources of observed deficits. Our objective was to comprehensively examine neuropsychological function in patients with schizophrenia who had never been exposed to neuroleptic medication, and who were experiencing their first episode (FE) of psychosis. Methods: Subjects were consecutive recruitments that included 37 patients with FE schizophrenia who were never exposed to neuroleptics. These subjects were compared with 65 unmedicated, previously treated (PT) patients and 131 healthy controls. Results: The patient groups had nearly identical profiles showing generalized impairment, particularly in verbal memory and learning, attention-vigilance, and speeded visual-motor processing and attention. Verbal memory and learning accounted for most of the variance between patients and controls and removing this effect substantially attenuated all other differences. By contrast, both the FE group and PT group continued to show highly significant deficits in verbal memory and learning after controlling for attention, abstraction, and all other functions. Some functions not typically implicated in schizophrenia (spatial cognition, fine motor speed, and visual memory) were more impaired in the PT group than in the FE group. Conclusions: Verbal memory, as a primary neuropsychological deficit present early in the course of schizophrenia, implicates the left temporal-hippocampal system. Neuropsychological evaluations before treatment permit differentiation of primary deficits from changes secondary to medication or chronicity. This is essential for developing a neurobehavioral perspective on schizophrenia.

• Unmedicated schizophrenic patients (according to DSM-III-R criteria) (n = 36) and age-matched normal controls (n = 36), balanced for parental socioeconomic status, were administered a battery of standardized neuropsychological tests. Patients showed generalized impairment relative to controls and a selective deficit in memory and learning compared with other functions. Selective impairment was not found on tests related to frontal system function (abstraction, verbal fluency, and motor). The observed pattern is consistent with greater involvement of the temporal-hippocampal system, against the background of diffuse dysfunction. Although impairment in memory and learning has been reported, the selectivity and relative severity compared with other behavioral functions have not been recognized. The specificity of this profile merits further examination. These findings lend support to the hypothesized importance of the temporal-hippocampal region in understanding the pathophysiology of schizophrenia.

In Reply.— We completely agree with Dr Levick and Dr Voneida that alternative explanations should be sought out whenever behavioral aspects, such as eye movements, are believed to indicate a physiological substrate. We believe that this is particularly true when an attempt is made to implicate, on that basis, neurophysiological involvement in psychopathology. However, we fail to see how the data reported by Dr Levick and Dr Voneida, or our findings as cited by them, suggest an alternative interpretation to the results of Schweitzer et al. 1 What Schweitzer et al found was a preponderance of rightward eye movements among schizophrenics as compared to control subjects. Their finding is congruent with some of our own work. 2 To the extent that eye movements are indicative of cerebral activation in the hemisphere contralateral to the direction of movement, these findings suggest that schizophrenia is associated with an overactivation of the left hemisphere. Clearly

• Forty-eight schizophrenics (24 paranoids, 24 nonparanoids) and 24 matched controls (12 men and 12 women in each group) were asked to detect the differences between 30 pairs of altered pictures presented successively (15 pairs) and simultaneously (15 pairs) in a counterbalanced order. Overall performance, as measured by reaction time and response quality, was better for controls than for schizophrenics. However, schizophrenics, like right hemisphere brain-damaged patients who presumably rely on their left hemisphere, reacted faster in the successive presentation procedure while the controls reacted equally fast in both conditions. These results support the hypothesis that schizophrenics tend to overactivate their left dysfunctional hemisphere. Twenty-four depressed patients, tested in the same procedure, showed a pattern of results similar to that of controls, suggesting that the results obtained for schizophrenics are not a general characteristic of psychosis.

In Reply.— In a multivariate study, particularly one that explores new methods for understanding psychopathology, the investigator treads on a tightrope between two pitfalls. On the one hand is the temptation to draw as many conclusions as possible from every study, even when the data are from a limited sample. The risk, of course, is capitalizing on chance. On the other hand, it may be dangerous to confine data analysis to the testing of specific hypotheses, as one may lose sight of effects that have not been hypothesized. In our first study of a series designed to examine systematically the relationship between psychopathology and regional brain function, 1 we followed conservative statistical procedures to minimize the risk of the first pitfall. The hypothesis that has motivated the study was of left hemispheric dysfunction and overactivation in schizophrenia. 2 We interpreted the predicted diagnosis X task X hemisphere interaction as supporting the hypothesis.

• Two hundred schizophrenics were compared to 200 normal controls on a measure of laterality that included handedness, footedness, and eye dominance scales. Schizophrenics showed more left-sidedness on the laterality score. The established relationship between motoric and cognitive aspects of functional brain asymmetry, found in neurological and normal populations, suggests that the leftward tendency of schizophrenics may be manifested in cognitive and conative functions as well. These results seem to corroborate previous findings indicating that schizophrenia might be related to left hemisphere dysfunction. No relationship was found between handedness and eye dominance either in the schizophrenic or the normal groups. This finding questions the assumption that eyedness-handedness nonconcordance is a pathological sign.

• Local cerebral glucose metabolism was determined with 18-F-fluorodeoxyglucose using positron emission tomography in a sample of 12 unmedicated schizophrenics and 12 matched normal controls. The data were analyzed for absolute metabolic rates and region/whole-brain ratios using the cortical-subcortical, antero-posterior, and laterality dimensions. Lobar areas within cortical regions were also compared. Across groups, subcortical metabolism was higher than cortical metabolism. Patients had lower metabolism, cortically and subcortically, and a steeper subcortical to cortical gradient. Patients with higher scores on the Brief Psychiatric Rating Scale had higher absolute metabolism and higher left relative to right hemispheric metabolism than did patients with lesser severity. The results did not show "hypofrontality" in schizophrenia. These findings provide some support for cerebral dysfunction in schizophrenia and indicate the need for further examination of the cortical-subcortical dimension.