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Aim: Increased oxidative stress in cerebral mitochondria may follow exposure to the systemic hypobaric hypoxia associated with residing at higher altitudes. Because mitochondrial dysfunction is implicated in bipolar disorder (BD) pathophysiology, this may impact the cerebral bioenergetics in BD. In this study, we evaluated the cerebral bioenergetics of BD and healthy control (HC) subjects at two sites, located at sea level and at moderate altitude., Methods: Forty-three veterans with BD and 33 HC veterans were recruited in Boston (n = 22) and Salt Lake City (SLC; n = 54). Levels of phosphocreatine, β nucleoside triphosphate (βNTP), inorganic phosphate, and pH over total phosphate (TP) were measured using phosphorus-31 magnetic resonance spectroscopy in the following brain regions: anterior cingulate cortex and posterior occipital cortex, as well as bilateral prefrontal and occipitoparietal (OP) white matter (WM)., Results: A significant main effect of site was found in βNTP/TP (Boston > SLC) and phosphocreatine/TP (Boston < SLC) in most cortical and WM regions, and inorganic phosphate/TP (Boston < SLC) in OP regions. A main effect analysis of BD diagnosis demonstrated a lower pH in posterior occipital cortex and right OP WM and a lower βNTP/TP in right prefrontal WM in BD subjects, compared to HC subjects., Conclusion: The study showed that there were cerebral bioenergetic differences in both BD and HC veteran participants at two different sites, which may be partly explained by altitude difference. Future studies are needed to replicate these results in order to elucidate the dysfunctional mitochondrial changes that occur in response to hypobaric hypoxia., (© 2019 The Authors. Psychiatry and Clinical Neurosciences © 2019 Japanese Society of Psychiatry and Neurology.)

Objective: Evidence suggests relationships between abnormalities in various cortical and subcortical brain structures and language dysfunction in individuals with schizophrenia, and to some extent in those with increased genetic risk for this diagnosis. The topological features of the structural brain network at the systems-level and their impact on language function in schizophrenia and in those at high genetic risk has been less well studied., Method: Single-subject morphological brain network was constructed in a total of 71 subjects (20 patients with schizophrenia, 19 individuals at high genetic risk for schizophrenia, and 32 controls). Among these 71 subjects, 56 were involved in our previous neuroimaging studies. Graphic Theoretical Techniques was applied to calculate the global and nodal topological characteristics of the morphological brain network of each participant. Index scores for five language-related cognitive tests were also attained from each participant., Results: Significantly smaller nodal degree in bilateral superior occipital gyri (SOG) were observed in individuals with schizophrenia, as compared to the controls and those at high risk; while significantly reduced nodal betweenness centrality (quantifying the level of a node in connecting other nodes in the network) in right middle frontal gyrus (MFG) was found in the high-risk group, relative to controls. The right MFG nodal efficiency and hub capacity (represented by both nodal degree and betweenness centrality) of the morphological brain network were negatively associated with the wide range achievement test (WRAT) standard performance score; while the right SOG nodal degree was positively associated with the WRAT standard performance score, in the entire study sample., Conclusions: These findings enhance the understanding of structural brain abnormalities at the systems-level in individuals with schizophrenia and those at high genetic risk, which may serve as critical neural substrates for the origin of the language-related impairments and symptom manifestations of schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Working memory impairment (especially in verbal and spatial domains) is the core neurocognitive impairment in schizophrenia and the familial high-risk (FHR) population. Inconsistent results have been reported in clinical and neuroimaging studies examining the verbal- and spatial-memory deficits in the FHR subjects, due to sample differences and lack of understanding on interactions of the brain regions for processing verbal- and spatial-working memory., Methods: Functional MRI data acquired during a verbal- vs. spatial-memory task were included from 51 young adults [26 FHR and 25 controls]. Group comparisons were conducted in brain activation patterns responding to 1) verbal-memory condition (A), 2) spatial-memory condition (B), 3) verbal higher than spatial (A-B), 4) spatial higher than verbal (B-A), 5) conjunction of brain regions that were activated during both A and B (A∧B). Group difference of the laterality index (LI) in inferior frontal lobe for condition A was also assessed., Results: Compared to controls, the FHR group exhibited significantly decreased brain activity in left inferior frontal during A, and significantly stronger involvement of ACC, PCC, paracentral gyrus for the contrast of A-B. The LI showed a trend of reduced left-higher-than-right pattern for verbal-memory processing in the HR group., Conclusions: Our findings suggest that in the entire functional brain network for working-memory processing, verbal information processing associated brain pathways are significantly altered in people at familial high risk for developing schizophrenia. Future studies will need to examine whether these alterations may indicate vulnerability for predicting the onset of Schizophrenia., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Cortical structural and functional anomalies have been found to associate with language impairments in both schizophrenia patients and genetic high risk individuals for developing schizophrenia. However, subcortical structures that contribute to language processing haven't been well studied in this population, and thus became the main objective of this study., Method: We examined structural MRI data from 20 patients with schizophrenia, 21 individuals at genetic high risk, and 48 controls. Surface shape and volume differences of 6 subcortical structures that are involved in language processing, including nuclei pallidum, putamen, caudate, amygdala, thalamus, and hippocampus from both hemispheres, were compared between groups. Performance scores of language-associated cognitive tests were obtained to identify relationships of subcortical structures to language-related behaviors., Results: Significantly reduced volumes of both the left and right side caudate nuclei, thalami and right side amygdala were shown in patients when compared with controls. Very interestingly, the high risk group demonstrated significantly increased correlations between volumes of left side pallidum nucleus and bilateral thalami and language-related cognitive test scores when compared to controls., Conclusions: This study furthers our understanding of subcortical structural alterations in schizophrenia and high risk individuals, and suggests the contribution of subcortical structures to the language impairments that may serve as an early sign for impending development of schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Theory-of-mind (ToM) ability is foundational for successful social relationships, and dependent on a neurocognitive system, which includes temporoparietal junction and medial prefrontal cortex. Schizophrenia is associated with ToM impairments, and initial studies demonstrate similar, though more subtle deficits, in unaffected first-degree relatives, indicating that ToM deficits are a potential biomarker for the disorder. Importantly, the social consequences of ToM deficits could create an additional vulnerability factor for individuals at familial high risk (FHR). However, behavioral studies of ToM are inconsistent and virtually nothing is known about the neural basis of ToM in FHR or the relationship between ToM and social functioning. Here, FHR and non-FHR control participants underwent functional MRI scanning while reasoning about a story character's thoughts, emotions or physical appearance. Afterwards, participants completed a 28-day online 'daily-diary' questionnaire in which they reported daily social interactions and degree of ToM reasoning. FHR participants demonstrated less neural activity in bilateral temporoparietal junction when reasoning about thoughts and emotions. Moreover, across all participants, the degree of neural activity during ToM reasoning predicted several aspects of daily social behavior. Results suggest that vulnerability for schizophrenia is associated with neurocognitive deficits in ToM and the degree of deficit is related to day-to-day social functioning., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Background: Abnormalities in language and language neural circuitry are observed in schizophrenia (SZ). Similar, but less pronounced language deficits are also seen in young first-degree relatives of people with SZ, who are at higher familial risk (FHR) for the disorder than the general population. The neural underpinnings of these deficits in people with FHR are unclear., Methods: Participants were 43 people with FHR and 32 comparable controls. fMRI scans were collected while participants viewed associated and unrelated word pairs, and performed a lexical decision task. fMRI analyses conducted in SPM8 examined group differences in the modulation of hemodynamic activity by semantic association., Results: There were no group differences in demographics, IQ or behavioral semantic priming, but FHR participants had more schizotypal traits than controls. Controls exhibited the expected suppression of hemodynamic activity to associated versus unrelated word pairs. Compared to controls, FHR participants showed an opposite pattern of hemodynamic modulation to associated versus unrelated word pairs, in the left inferior frontal gyrus (IFG), right superior and middle temporal gyrus (STG) and the left cerebellum. Group differences in activation were significant, FWE-corrected for multiple comparisons (p<0.05). Activity within the IFG during the unrelated condition predicted schizotypal symptoms in FHR participants., Conclusions: FHR for SZ is associated with abnormally increased neural activity to semantic associates within an inferior frontal/temporal network. This might increase the risk of developing unusual ideas, perceptions and disorganized language that characterize schizotypal traits, potentially predicting which individuals are at greater risk to develop a psychotic disorder., (© 2013.)

Objective: Schizophrenia is a severe and heritable brain disorder. Language impairment has been hypothesized to spur its onset and underlie the characteristic symptoms. In this study, we investigate whether altered topological pattern of the language processing brain network exists and could be a potential biomarker of schizophrenia. We hypothesized that both patients with schizophrenia and the genetic high risk population would show significantly weakened efficiencies of the network hubs for normal language processing, especially at left inferior frontal and bilateral temporal lobes., Method: Language task-based fMRI data from 21 patients with schizophrenia, 22 genetic high risk subjects and 36 controls were analyzed. Graph theoretic and post hoc analyses of the fMRI data, and correlations between the functional network features and scores of language tests were carried out., Results: Compared to controls, patients with schizophrenia and the high risk subjects showed significantly weakened network hubs in left inferior frontal and right fusiform gyri. A unique topology of super active and intercommunicating network hubs at left fusiform gyrus and right inferior/middle frontal gyri, which were associated with the behavioral language impairment was found in the patient group, compared to the high risk and control groups., Conclusions: Aberrant systems-level topology of language processing network, especially significantly weakened network hubs in left inferior frontal and right fusiform gyri, may serve as a candidate biomarker of schizophrenia. Supported by existing findings, the hyperactive left fusiform gyrus communicating with right frontal lobe might be the key neurophysiological component causing hallucinations in schizophrenia. These findings provided a new systems-level diagnostic target for the disorder., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: Neuroanatomical and cognitive alterations typical of schizophrenia (SZ) patients are observed to a lesser extent in their adolescent and adult first-degree relatives, likely reflecting neurodevelopmental abnormalities associated with genetic risk for the illness. The anatomical pathways for language are hypothesized to be abnormal and to underlie the positive symptoms of schizophrenia. Examining non-psychotic relatives at high familial risk (FHR) for schizophrenia may clarify if these deficits represent trait markers associated with genetic vulnerability, rather than specific markers resulting from the pathological process underlying schizophrenia., Methods: T1 MRI scans from a 3T Siemens scanner of young adult FHR subjects (N=46) and controls with no family history of illness (i.e. at low genetic risk LRC; N=31) were processed using FreeSurfer 5.0. We explored volumetric and lateralization alterations in regions associated with language processing. An extensive neuropsychological battery of language measures was administered., Results: No significant differences were observed between groups on any language measures. Controlling intracranial volume, significantly smaller left pars triangularis (PT) (p<0.01) and right pars orbitalis (PO) (p<0.01) volumes and reversal of the L>R pars orbitalis (p<0.001) lateralization were observed in FHR subjects. In addition, the L pars triangularis and R pars orbitalis correlated with performance on tests of linguistic function in the FHR group., Conclusions: Reduced volume and reversed structural asymmetry in language-related regions hypothesized to be altered in SZ are also found in first degree relatives at FHR, despite normal language performance. To clarify if these findings are endophenotypes for Sz, future studies would need to be performed of ill and well family members no longer within the age range of risk for illness to show these deficits segregate with schizophrenia within families. Moreover, measures of complex language need to be studied to determine if FHR individuals manifest impairments in some aspects of language function., (Published by Elsevier B.V.)

Recent genetics research focusing on schizophrenia has led to candidate cognitive and neuroimaging variables as intermediate phenotypes or "endophenotype" markers for the illness. Among other stringent criteria, to be an endophenotype, a marker must demonstrate heritability. In an effort to explore the validity of a selection of cognitive and neuroimaging endophenotypes, the present study was designed to determine estimates of their heritability. One hundred fourteen subjects, including 27 with schizophrenia and 39 unaffected relatives from 23 multiplex schizophrenia families, participated in a comprehensive neuropsychological test battery and structural brain imaging with diffusion tensor imaging (DTI). Variables were selected if they previously have been demonstrated to show differences between people with schizophrenia and normal controls. Significant evidence of heritability was confirmed for overall cognitive function ("g"), as well as expressive and receptive language, verbal and visual memory, processing speed and cognitive inhibition. In addition, significant heritability estimates were determined for specific regions in the frontal, central, parietal, and occipital areas. These results suggest that the variables chosen may be useful endophenotypes for genetic and early detection studies, although further work with larger cohorts should be conducted to show that deficits in these functions and structures also segregate with schizophrenia within families and thus fully satisfy the definition of an endophenotype. In addition, other cognitive and neuroimaging variables that were not studied here may be candidates for schizophrenia endophenotypes.

Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca's area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca's area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca's area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.

In 1990 a satellite session of the American College of Neuropsychopharmacology (ACNP) Annual Meeting was held that focused on the question of whether progressive changes in brain structure occur in schizophrenia and this session raised considerable controversy. Eighteen years later, on December 12, 2008, after much data have since accumulated on this topic, a group of approximately 45 researchers gathered after the annual ACNP meeting to participate in a similar workshop on several unresolved questions still remaining: (1) How strong and consistent is the evidence? (2) Is there anatomic specificity to changes and is it disease specific or subject specific? (3) What is the time course? (4) What is the underlying pathophysiology (i.e. is it central to the disease process or is it due to neuroleptic treatment or other epiphenomena? (5) What is its clinical significance? and (6) Are there treatment implications? The day was chaired by Lynn E. DeLisi and co-chaired by Stephen J. Wood. Christos Pantelis and Jeffrey A. Lieberman extensively helped with its planning. The ACNP assisted in its organization as an official satellite of its annual meeting and several pharmaceutical companies provided support with unrestricted educational grants. The following is a summary of the sessions as recounted by rapporteurs whose job was to record as closely as possible the outcome of discussions on the above outlined questions.

The cognitive deficits present in individuals with sex chromosome aneuploidies suggest that hemispheric differentiation of function is determined by an X-Y homologous gene [Crow (1993); Lancet 342:594-598]. In particular, females with Turner's syndrome (TS) who have only one X-chromosome exhibit deficits of spatial ability whereas males with Klinefelter's syndrome (KS) who possess a supernumerary X-chromosome are delayed in acquiring words. Since spatial and verbal abilities are generally associated with right and left hemispheric function, such deficits may relate to anomalies of cerebral asymmetry. We therefore applied a novel image analysis technique to investigate the relationship between sex chromosome dosage and structural brain asymmetry. Specifically, we tested Crow's prediction that the magnitude of the brain torque (i.e., a combination of rightward frontal and leftward occipital asymmetry) would, as a function of sex chromosome dosage, be respectively decreased in TS women and increased in KS men, relative to genotypically normal controls. We found that brain torque was not significantly different in TS women and KS men, in comparison to controls. However, TS women exhibited significantly increased leftward brain asymmetry, restricted to the posterior of the brain and focused on the superior temporal and parietal-occipital association cortex, while KS men showed a trend for decreased brain asymmetry throughout the frontal lobes. The findings suggest that the number of sex chromosomes influences the development of brain asymmetry not simply to modify the torque but in a complex pattern along the antero-posterior axis., (2008 Wiley-Liss, Inc.)

Structural brain developmental anomalies, particularly those in frontotemporal white matter pathways, may have a genetic component and place people at increased risk for schizophrenia. The current study employed Diffusion Tensor Imaging (DTI) to measure fractional anisotropy (FA) as a quantitative indicator of white matter integrity. We examined twenty-two participants at high genetic risk for schizophrenia (HR), 23 people with schizophrenia (most of whom were family members of those at HR) and 37 non-psychiatric controls for comparison. In those at HR, reduced FA was observed in the cingulate and angular gyri bilaterally. In a few regions, FA was higher in HR participants than in comparison participants. These regional variations in FA might reflect differences in white matter development from comparison participants. Our data provide some evidence that abnormal white matter integrity may be detectable before the onset of a psychotic illness, although longitudinal studies are necessary to determine whether these individuals at genetic risk with abnormal FA will develop illness and whether these changes are associated with the genetic risk for the disorder.

Kraepelin originally defined dementia praecox as a progressive brain disease, although this concept has received various degrees of acceptance and rejection over the years since his famous published textbooks appeared. This article places an historical perspective on the current renewal of Kraepelin's concept in brain imaging literature that supports progressive brain change in schizophrenia from its earliest stages through its chronic course. It is concluded that a great deal of future research is needed focusing on the longitudinal course of change, the extent to the regions of change within each individual and the underlying mechanism and implications of brain change through functional and neurochemical imaging, combined with structural studies in the same individuals.

Purpose of Review: This review explores what is known about the association of cannabis with schizophrenia, its effects on the brain, and whether the brain changes known to be present in schizophrenia could be caused by cannabis and thus lead to a psychosis., Recent Findings: The heavy use of cannabis is known to be associated with some adverse consequences, such as the occurrence of acute psychotic episodes and the development of chronic schizophrenia in some people even after its use has terminated. Recent studies have produced controversy about whether cannabis in heavy use can cause irreversible brain damage, particularly to adolescents, and thus whether a chronic psychosis could be a result of brain changes caused by cannabis., Summary: From the evidence that exists, it appears that the above view is unlikely and that cannabis may even have benign effects on brain structure, not producing deleterious damage. Its neurochemical interactions with the dopaminergic pathway, however, may, particularly in genetically vulnerable individuals, have adverse consequences.

Background: Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals., Method: A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning., Results: Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group., Conclusions: This study reinforces previous language related imaging studies in high-risk subjects and patients with schizophrenia suggesting that reduced functional lateralization in language related frontal cortex may be a vulnerability marker for schizophrenia. Future studies will determine whether it is predictive of who develops illness.

Background: Abnormalities in language processing and the related brain structures have been reported in people with schizophrenia. It has been proposed that the brain pathways for language processing are anomalous in these individuals and form the underlying basis for the positive symptoms of the illness. If language pathway abnormalities can be detected early in people at high-risk for schizophrenia prior to the onset of symptoms, early treatment can ensue., Methods: Fifteen young adults at high genetic risk for developing schizophrenia were compared with 15 of their siblings with schizophrenia or schizoaffective disorder and 15 age and sex matched individuals at low risk for schizophrenia using a visual lexical decision task during fMRI. The data were analyzed by contrasting activation obtained during a real word-pseudoword discrimination task to activation obtained during a nonlinguistic discrimination task, and the differential activations were examined., Results: Patterns of brain activation while reading and discriminating between real and pseudowords differed across groups, with more bilateral activation in schizophrenia patients and their high-risk siblings than controls. In control subjects discrimination of words from psuedowords significantly activated Brodmann's area 44 more strongly than when non-linguistic symbols were discriminated. However, high-risk subjects and their siblings with schizophrenia activated this region similarly for both language and non-language tasks., Conclusions: Normal individuals can be distinguished from subjects at high genetic risk for schizophrenia and patients with schizophrenia by their more lateralized and stronger activation of Brodmann's area 44 to word compared with symbol discrimination tasks. Thus, evaluation of language processing by fMRI may be a valuable tool for use in the prediction of individual risk for developing schizophrenia.

Schizophrenia is a chronic progressive disorder that has at its origin structural brain changes in both white and gray matter. It is likely that these changes begin prior to the onset of clinical symptoms in cortical regions, particularly those concerned with language processing. Later, they can be detected by progressive ventricular enlargement. Current magnetic resonance imaging (MRI) technology can provide a valuable tool for detecting early changes in cortical atrophy and anomalous language processing, which may be predictive of who will develop schizophrenia.

Alterations, sometimes sex-dependent, in volumes and gyral structure of areas of cerebral cortex have been reported in schizophrenia. Such changes imply an anomaly of connectivity. The gyrification, percentage of tissue volume attributed to white matter, cortical volume and white matter volume were measured from magnetic resonance images in males and females with (n = 61) and without (n = 42) schizophrenia. The frontal, temporal and an amalgam of occipital and parietal lobes were examined in both hemispheres. There was no effect of schizophrenia on the gyrification of the brain. For the volume of occipito-parietal white matter, females with schizophrenia had bilaterally lower volumes, while males with schizophrenia had greater volumes than controls. It is concluded that the changes in connectivity underlying the pathogenesis of schizophrenia are sex-specific and expressed in occipito-parietal white matter.

The hypothesis that normal brain torque (i.e. rightward frontal and leftward occipital asymmetry) is anomalous in schizophrenia (Crow, 1997. Trends in Neuroscience, 20, 339-343) was tested by application of a novel image analysis technique on three-dimensional magnetic resonance images obtained in 26 adult patients with chronic schizophrenia (18 males, 8 females) and 24 controls (14 males, 10 females). Right and left cerebral hemisphere tissue was extracted via non-linear co-registration with a mask image, and maps were computed of inter-hemispheric differences in tissue volume in an array of columns of voxels orthogonal to the mid-plane (2D), and profiles of coronal slice volumes (1D). Furthermore, integration of two-dimensional column maps gave approximate lobar asymmetries, and occipital and frontal asymmetries were combined to give a volumetric measure of brain torque. Significant brain torque was revealed in male and female control and patient groups, and did not correlate with brain size. Frontal and occipital asymmetries were significantly correlated in all groups. Both frontal and occipital components of torque were significantly increased in males than females. Patients tended to have reduced torque, particularly the leftward occipital component. Furthermore, 3/26 patients (but no controls) had reversed torque (leftward frontal and rightward occipital asymmetry). Contrary to Crow's hypothesis, brain torque was not significantly reduced in patients with schizophrenia relative to controls, although reversal of torque was found in three cases. Future studies with larger sample sizes should consider sexual dimorphism and specific symptoms in relation to asymmetry.

Objective: The purpose of the study was to determine whether the duration of illness before antipsychotic drug treatment for schizophrenia was associated with the severity of cognitive deficits and volumetric brain structure anomalies observed in some patients with a first episode of schizophrenia., Method: Duration of psychotic symptoms and of other symptoms marking a behavioral change was estimated from structured interviews with 50 patients who had a first episode of schizophrenia and their family members. Interviews were conducted within a month of the patients' hospitalization. Duration of untreated psychotic symptoms and of behavioral change was correlated with neuropsychological summary scores from a comprehensive cognitive battery and with measurements of lateral ventricular, temporal lobe, and cerebral hemispheric volumes., Results: No significant correlations were observed between measures of untreated illness and the severity of either cognitive or structural brain deficits at baseline., Conclusions: The duration of untreated symptoms of schizophrenia, for which an association with an uncontrolled toxic brain process has been proposed, is unlikely to explain why first-episode patients with schizophrenia have widespread deficits in cognitive functioning and have detectable ventricular enlargement and some loss of cortical mass.

Recent evidence from controlled CT and MRI longitudinal studies suggests that some cerebral ventricular enlargement and hemispheric volumetric reductions (e.g. cerebral atrophy) may have a progressive component in patients with schizophrenia. These studies vary in cohort composition, stage of illness examined, duration of follow-up interval, imaging techniques used, and specific brain regions with findings. They also conflict with earlier evidence suggesting that schizophrenia is a neurodevelopmental disorder with brain pathological deviance occurring prior to the illness onset. The newer brain imaging reports may be detecting subtle brain plasticity that results from a continuing cortical disruptive process, may be epi-phenomena caused by scanning and image analysis artifacts or may possibly reflect systemic physiological fluctuations. Future longitudinal studies of subjects at all stages of illness using a variety of new technologies are needed to clarify these findings.

The concept that schizophrenia has its antecedents in neurodevelopment has long been debated and has been at the forefront of research on this disorder over the last decade. However new recent evidence from controlled longitudinal studies indicates that some of the structural brain anomalies observed in schizophrenia may continue to progress sporadically after the onset of clinical illness. The studies vary in cohort composition, stage of illness studied, duration of follow-up interval, and specific brain regions with findings. Nevertheless, the findings as a whole suggest that the brain changes in size throughout the lifespan of an individual and to a greater extent in schizophrenia. While the detected abnormalities could be explained by various technical artifacts, or physiological epi-phenomena, that they result from an ongoing neurochemical, physiological or morphological process characteristic of the underlying basis for the disorder is an intriguing possibility that lends itself to possible future intervention.

Fifty first-episode patients with schizophrenia were followed for 5 years subsequent to their first hospitalization. The course of illness was charted prospectively and premorbid childhood histories were obtained retrospectively at the initial evaluation, and MRI scans were obtained initially and at each follow-up. Fifteen different life-time patterns of illness course emerged, although none were specifically associated with structural brain change. A deterioration in premorbid scores was positively correlated with larger ventricular volume at the first hospitalization, and the larger the ventricles, the less the subsequent change in ventricular size thereafter. An analysis to see whether initial hemispheric and ventricular size could predict different course types only revealed that patients with an acute onset and complete recovery had significantly smaller ventricles than all others. No differences emerged for initial hemispheric size. Thirty-four percent of patients individually showed some association of brain ventricular size and 28% hemisphere volume reductions with fluctuation in psychotic symptoms. Paradoxically, most showed larger ventricles and smaller hemispheres to be associated with clinical improvement, rather than the predicted reverse. These latter data question the notion that the structural brain changes seen over time in some patients are related to poor outcome, although small ventricular size in those patients with acute onset may be predictive of recovery. Thus, brain structural change is occurring early in the course of illness and may be a consequence of the process leading to resolution.

Brain structural deviation is known to be present in chronic patients with schizophrenia when compared with normal age-matched individuals. While the assumption is that these differences are based on a neurodevelopmental disturbance, whether they are static or continue to change throughout the disease process remains unknown. The following report describes a prospective follow-up study of first episode cases of schizophrenic illness. Analyses of MRI evaluations on an approximate annual basis for a minimum of four years are presented on 50 patients and 20 controls. Computer-assisted image analysis measuring the volume of several brain regions, using the program ANALYZE (Mayo Clinic), was performed on all scans. Patients were compared with controls for the rate of change over time in size of structures. No differences were found for the volumes of the caudate nucleus, temporal lobes, or hippocampus; and no changes in the degree of cerebral laterality were detected. However, there was a significant difference in the rate of change in the overall volumes of left and right hemispheres (P < 0.0004 and 0.001, respectively), right cerebellum (P < 0.02) and area of the isthmus of the corpus callosum (P < 0.05). The left cerebral ventricle had significantly greater enlargement over time when measured on coronal slice sequences (P < 0.02), but was not detected by axial views. These findings suggest that a subtle active brain process may be continuing through the first few years of a schizophrenic illness causing greater than the normal adult cortical deterioration. Further studies using other methods of image analysis and over a longer period of time are needed to determine the course and nature of this biologic process.

Previous accounts of cerebral dominance in schizophrenic patients have been conflicting. While many studies report decreased patterns of functional laterality in schizophrenic subjects, others report increases or no differences. Conceptual differences in the definition of laterality and its effects on behavior may be a reason for the poor concordance among studies. The present report addresses some of these problems and examines the hypothesis that schizophrenia may be associated with an alteration in normal patterns of functional laterality. In addition, the relationship between patterns of laterality and cognitive functioning was assessed. Twenty-one schizophrenic patients and 24 control subjects, all right-handed, were compared on two neuropsychological batteries, one designed to test cerebral dominance and the other, cognitive performance. Cerebral dominance was measured by two dichotic listening tests (verbal and nonverbal) and three motoric tests. Cognitive ability was assessed with a comprehensive neuropsychological battery. Schizophrenic and control subjects differed significantly in performance on laterality measures, but they did not differ in patterns of functional laterality when performance was taken into account. In addition, it was shown that the relationship between cognitive ability and laterality is complex, with some aspects of laterality appearing to be beneficial to cognitive ability.

Brain morphological abnormalities have been reported in several independent investigations of chronic schizophrenic patients. The present study is a prospective 4-year follow-up of first-episode schizophrenic patients to determine whether some of these abnormalities may be a consequence of regional brain structural change over time after the onset of a first psychotic episode. Whole hemisphere, temporal lobes, superior temporal gyrus, hippocampus, caudate, corpus callosum, and lateral ventricles were measured in a series of MRI scans taken over a 4-year period in 20 patients and five controls. Total volume reduction was noted in both hemispheres to a greater degree in patients than controls. When adjusted for total brain size, left ventricular enlargement occurred in patients, but not controls, over time. These preliminary data suggest that subtle cortical atrophy may be occurring over time after the onset of illness.

The present study is an examination of ventricular and temporal lobe size in 50 DSM-III-R first-episode schizophreniform or schizoaffective patients who were ill for less than 6 months. Two-year clinical follow-up and magnetic resonance imaging (MRI) scan analyses are also reported from data collected on an initial group of 30 first-episode schizophrenic patients and controls. Left ventricular enlargement, which was present in our previously published report of first-episode cases of schizophrenia, is not present to the same extent in this larger group of schizophreniform patients closer to the onset of their illness, and no temporal lobe volume reduction was detected. However, lateral ventricular size at the time of the first-episode was generally correlated with outcome--the larger the ventricles, the poorer the outcome. No mean change in ventricular or temporal lobe size was found at rescanning 2 years later, but the degree of ventricular change was inversely correlated with the number of hospitalizations and the amount of time spent in hospital; it did not correlate with temporal lobe size. When rescanned, some patients showed change greater than 20% in ventricular size and 10% in temporal lobe size. Thus, these findings need further evaluation by serial scans over a longer time period before it can be determined that no progression of brain structural abnormalities is occurring as part of the pathology of schizophrenia, even in a subgroup of patients.

This study examines the cognitive functioning of first-episode schizophreniform patients within several weeks of hospitalization and at 2 years into the illness. Differences between patients and controls are also reported for measurements of the length of the lateral sulcus, which borders the planum temporal, an area of the brain integral to language function. Neuropsychological test results are also correlated to magnetic resonance imaging structural variables at the time of first hospitalization. Findings on neuropsychological summary scales reveal a diffuse pattern of cognitive impairment in schizophreniform patients compared to controls, which appears to improve over time. An atypical pattern of anatomic lateral symmetry is found in female schizophreniform patients, with female appearing to have a reduction in the normally occurring left greater than right length of the lateral sulcus. Such atypical asymmetry of the lateral sulcus is also associated with better cognitive function, particularly in schizophreniform patients. These findings suggest that atypical lateralization in an area critical to language function may be related to cognitive function in schizophreniform illness.

Brain morphology was examined using magnetic resonance imaging in 30 first-episode patients with a schizophreniclike psychosis, 15 chronic schizophrenics, and 20 neurological controls. Statistical analyses of computer-generated measurements of regions of interest were controlled for gender, age, social class, and total brain volume. Lateral ventricular size was increased in both first-episode and chronic schizophrenic patients, with greater significance on the left than on the right side. Only the chronic patients, however, had reduced temporal lobe size, which also was greater on the left side. No major correlations of regional brain morphological measurements with cognitive functioning were found, although some measurements of verbal memory were correlated with parahippocampal size. This is a report of a preliminary study that suggests that some morphological brain changes may be present at the time of first treatment for a psychotic illness, whereas others may occur later in the course of illness. Future prospective studies may determine the clinical significance of these changes and whether they progress with the development of illness chronicity.

To assess whether computed tomographic findings are present at the onset of schizophrenia, we evaluated CT scans of 35 patients with first-episode schizophreniform disorder, 17 with chronic schizophrenia, 23 with affective disorders, 27 with other psychiatric disorders, and 26 controls. Both the schizophreniform and the chronic schizophrenic patients had significantly larger cerebral ventricles than did the other psychiatric or control subjects. Ventricular size in the patients with affective disorder was not significantly different than in any of the other groups. Twenty percent of the schizophreniform patients had enlarged ventricles, (ventricular-brain ratio, greater than 10). The only other subjects outside this limit were four chronic schizophrenic patients (24%). Five schizophreniform patients and three with affective disorder had evidence of mild cortical atrophy. The results suggest that, in some schizophrenic patients, ventricular enlargement and less frequently cortical atrophy predate the onset of psychoses and are not a result of psychiatric treatment.

Although a familial component to schizophrenia has been established through several family, twin and adoption studies, an inherited biological factor has yet to be established. Efforts to define clinical familial subtypes of schizophrenia have generally been unsuccessful, although recent data from our study population of pairs of siblings with schizophrenia suggests that schizophrenia with recurrent episodes of major depression may define one such group. There have only been a few biological traits consistently found to be associated with schizophrenia and also found to be heritable. These findings (e.g. measures of monoamine metabolism, brain structural morphology, neurophysiological markers, and protein polymorphisms) are reviewed in the present chapter. The proportion of patients with any of the noted abnormalities never approaches 100%, nor have any been found to be specific to schizophrenia. Research into the biogenetics of schizophrenia is clearly just beginning.

The finding in schizophrenic patients of a reversal of the normal frontal to posterior pattern of brain metabolic activity with positron emission tomography (PET) is of interest, but its relevance to psychopathology is unknown. Using PET, the authors studied 21 patients with chronic schizophrenia and 21 age- and sex-matched control subjects. Although eight of the 21 patients and only one of the control subjects showed a relatively lower anteroposterior metabolic gradient, no clinical correlates of this finding were noted. In addition, cerebral atrophy, as determined by CAT scan, was not associated with this aberrant metabolic pattern.

Gender differences are present in the clinical expression of schizophrenia, age of onset, course of illness, and response to pharmacologic treatment. These differences are not surprising in view of the normal gender differences in brain growth, differentiation, adult brain structure, and neurochemistry. The present review examines what is presently known about brain gender differences, and whether this information is consistent with the published reports of brain functional and morphological abnormalities in schizophrenia. Whether gender differences in the brain can explain the gender differences in clinical aspects of the disorder remains unknown.

Local cerebral uptake of deoxyglucose labeled with fluorine 18 was measured by positron emission tomography in 16 patients with schizophrenia and 11 patients with affective disorder. Patients received no medication a minimum of 14 days and an average of 39.8 days. The subjects were administered the deoxyglucose 18F just before receiving a 34-minute 1/s series of unpleasant electrical stimuli to the right forearm while resting with eyes closed in a darkened, acoustically attenuated psychophysiologic testing chamber. Following monitored stimulation in the controlled environment, subjects were scanned and images converted to values of glucose use in micromoles per 100 g per minute according to Sokoloff's model. Data were analyzed with a four-way analysis of variance (ANOVA) with independent groups (normals, schizophrenics, and affectives) and repeated measures for slice level (supraventricular, midventricular, and infraventricular), hemisphere (right, left), and anteroposterior position (four sectors). Both normal subjects and patients showed a significant anteroposterior gradient in glucose use with highest values in the frontmost sector. Patients both with schizophrenia and with affective illness showed less of an anteroposterior gradient especially at superior levels, which was statistically confirmed by ANOVA. Absolute glucose levels in patients, which were actually higher in posterior regions rather than lower in frontal regions, were the largest contributors to the effect. Neither group differences in whole brain glucose use nor left-right asymmetries reached statistical significance. These results are consistent with our earlier reports of a relative hypofrontal function in schizophrenia compared with controls. This report extends this finding to affective illness, sharing a lack of diagnostic specificity with many biologic measures.

Four 51-year-old monozygotic quadruplets concordant for schizophrenia, originally studied at the National Institute of Mental Health 25 years ago, were restudied with topographic electroencephalography (EEG), evoked potentials (EPs), computed tomography (CT scans), polysomnographic sleep recordings, and positron emission tomography (PET) with 18F-2-deoxyglucose. EEG and EP findings were consistent with those from other groups of patients with schizophrenia and showed great similarity within the quadruplets. CT scans revealed uniformly small lateral ventricles. PET scans replicated earlier findings of relatively low glucose use in the frontal lobes but did not show strong familial concordance.