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Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias., Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( n  = 82), compared to first-degree relatives (an at-risk group, n  = 37), people with schizophrenia not treated with clozapine ( n  = 13), and age- and sex-matched controls ( n  = 59)., Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r  = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia ( r  = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight ( r  = -0.305, 95% confidence interval: [-0.504, -0.076])., Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far., Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD)., Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022., Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery., Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery., Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Background: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders., Methods: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups., Results: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups., Conclusion: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC)., Method: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted., Results: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients., Conclusions: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Impaired olfactory identification has been reported as a first sign of schizophrenia during the earliest stages of illness, including before illness onset. The aim of this study was to examine the relationship between volumes of these regions (amygdala, hippocampus, gyrus rectus and orbitofrontal cortex) and olfactory ability in three groups of participants: healthy control participants (Ctls), patients with first-episode schizophrenia (FE-Scz) and chronic schizophrenia patients (Scz). Exploratory analyses were performed in a sample of individuals at ultra-high risk (UHR) for psychosis in a co-submission paper (Masaoka et al., 2020). The relationship to brain structural measures was not apparent prior to psychosis onset, but was only evident following illness onset, with a different pattern of relationships apparent across illness stages (FE-Scz vs Scz). Path analysis found that lower olfactory ability was related to larger volumes of the left hippocampus and gyrus rectus in the FE-Scz group. We speculate that larger hippocampus and rectus in early schizophrenia are indicative of swelling, potentially caused by an active neurochemical or immunological process, such as inflammation or neurotoxicity, which is associated with impaired olfactory ability. The volumetric decreases in the chronic stage of Scz may be due to degeneration resulting from an active immune process and its resolution., Competing Interests: Declaration of Competing Interest Christos Pantelis has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck and Shire., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia., Methods: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance., Results: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions., Conclusions: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.

Background: Copy number variants have made important contributions to understanding neuropsychiatric disorders, including schizophrenia. Deletions in genes encoding neuronal cell adhesion molecules have identified widely varied neurodevelopmental phenotypes., Case Summary: A 27-year old woman presented with schizophrenia, borderline intellectual functioning and shortened metacarpal bones. Subsequent electroencephalogram confirmed genetic generalised epilepsy and microarray analysis found a 0.2 megabase deletion of chromosome 3p26.3., Conclusions: We report the first case of schizophrenia in a proband with a CNTN6 deletion. Schizophrenia has been reported in relatives of probands with this deletion but not in probands themselves. This finding further contributes to the evolving literature regarding schizophrenia pathogenesis., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Background: Cognitive deficits are a core feature of schizophrenia, and impairments in most domains are thought to be stable over the course of the illness. However, cross-sectional evidence indicates that some areas of cognition, such as visuospatial associative memory, may be preserved in the early stages of psychosis, but become impaired in later established illness stages. This longitudinal study investigated change in visuospatial and verbal associative memory following psychosis onset., Methods: In total 95 first-episode psychosis (FEP) patients and 63 healthy controls (HC) were assessed on neuropsychological tests at baseline, with 38 FEP and 22 HCs returning for follow-up assessment at 5-11 years. Visuospatial associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery Visuospatial Paired-Associate Learning task, and verbal associative memory was assessed using Verbal Paired Associates subtest of the Wechsler Memory Scale - Revised., Results: Visuospatial and verbal associative memory at baseline did not differ significantly between FEP patients and HCs. However, over follow-up, visuospatial associative memory deteriorated significantly for the FEP group, relative to healthy individuals. Conversely, verbal associative memory improved to a similar degree observed in HCs. In the FEP cohort, visuospatial (but not verbal) associative memory ability at baseline was associated with functional outcome at follow-up., Conclusions: Areas of cognition that develop prior to psychosis onset, such as visuospatial and verbal associative memory, may be preserved early in the illness. Later deterioration in visuospatial memory ability may relate to progressive structural and functional brain abnormalities that occurs following psychosis onset.

Objective: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis., Methods: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years)., Results: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%)., Conclusion: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes.

Abnormalities of orbitofrontal cortex (OFC) pattern type distribution have been associated with schizophrenia-spectrum disorders. We investigated OFC pattern type in a large sample of chronic schizophrenia patients and healthy controls. We found an increased frequency of Type II but no difference in Type I or III folding pattern in the schizophrenia group in comparison to controls. Further large studies are required to investigate the diagnostic specificity of altered OFC pattern type and to confirm the distribution of pattern type in the normal population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study focuses on a group of patients with chronic schizophrenia who have a more severe form of the disorder, as indicated by socio-functional decline, treatment resistance, and recurrent hospitalisation. Previous research has suggested that the pattern and severity of cognitive deficits in people with severe chronic schizophrenia is similar to that observed in behavioural variant frontotemporal dementia (bvFTD). In the current study, we compared neurocognitive performance in 16 cognitive domains in 7 inpatients with severe chronic schizophrenia, 13 community-dwelling outpatients with chronic schizophrenia, 12 patients with bvFTD, and 18 healthy controls. Our findings revealed more similar cognitive profiles between the schizophrenia inpatient and bvFTD groups compared to the schizophrenia outpatient group, who outperformed the former groups. The current results provide preliminary evidence for a distinct schizophrenia subgroup, distinguishable from other chronic schizophrenia patients by poorer clinical and functional status, who have levels of cognitive impairment comparable to those seen in bvFTD patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Whether there are differential effects of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) on the brain is currently debated. Although some studies report that FGAs reduce grey matter more than SGAs, others do not, and research to date is limited by a focus on schizophrenia spectrum disorders. To address this limitation, this study investigated the effects of medication in patients being treated for first-episode schizophrenia or affective psychoses., Method: Cortical thickness was compared between 52 first-episode psychosis patients separated into diagnostic (i.e. schizophrenia or affective psychosis) and medication (i.e. FGA and SGA) subgroups. Patients in each group were also compared to age- and sex-matched healthy controls (n = 28). A whole-brain cortical thickness interaction analysis of medication and diagnosis was then performed. Correlations between cortical thickness with antipsychotic dose and psychotic symptoms were examined., Results: The effects of medication and diagnosis did not interact, suggesting independent effects. Compared with controls, diagnostic differences were found in frontal, parietal and temporal regions. Decreased thickness in FGA-treated versus SGA-treated groups was found in a large frontoparietal region (p < 0.001, corrected). Comparisons with healthy controls revealed decreased cortical thickness in the FGA group whereas the SGA group showed increases in addition to decreases. In FGA-treated patients cortical thinning was associated with higher negative symptoms whereas increased cortical thickness in the SGA-treated group was associated with lower positive symptoms., Conclusions: Our results suggest that FGA and SGA treatments have divergent effects on cortical thickness during the first episode of psychosis that are independent from changes due to illness.

A shallow olfactory sulcus has been reported in schizophrenia, possibly reflecting abnormal forebrain development during early gestation. However, it remains unclear whether this anomaly exists prior to the onset of psychosis and/or differs according to illness stage. In the current study, magnetic resonance imaging was used to investigate the length and depth of the olfactory sulcus in 135 ultra high-risk (UHR) individuals [of whom 52 later developed psychosis (UHR-P) and 83 did not (UHR-NP)], 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, and 87 healthy controls. While there was no group difference in the length of the sulcus, UHR-P subjects had significantly shallower olfactory sulcus at baseline as compared with UHR-NP and control subjects. The depth of this sulcus became increasingly more superficial as one moved from UHR-P subjects to FEP patients to chronic schizophrenia patients. Finally, the depth of the olfactory sulcus in the UHR-P subjects was negatively correlated with the severity of negative symptoms. These findings suggest that the altered depth of the olfactory sulcus, which exists before psychosis onset, could be predictive of transition to psychosis, but also suggest ongoing changes of the sulcus morphology during the course of the illness., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Abnormalities in hippocampal morphology are characteristic of schizophrenia and have also been reported in chronic cannabis users. There is a paucity of research investigating potential additive effects of cannabis use on brain pathology associated with schizophrenia. In this study, we performed hippocampal shape analysis in cannabis-using and non-using patients with schizophrenia, healthy cannabis users and healthy non-using controls. Hippocampal shape changes were observed in each group relative to controls, with the greatest degree of alterations (i.e., deflations across the hippocampus, and with an anterior predisposition), in cannabis-using schizophrenia patients. These alterations were associated with cannabis use patterns and psychotic symptoms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

It remains unclear whether brain structural abnormalities observed before the onset of psychosis are specific to schizophrenia or are common to all psychotic disorders. This study aimed to measure regional gray matter volume prior to the onset of schizophreniform and of affective psychoses. We investigated 102 subjects at ultrahigh risk (UHR) of developing psychosis recruited from the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia. Twenty-eight of these subjects developed psychosis subsequent to scanning: 19 schizophrenia, 7 affective psychoses, and 2 other psychoses. We examined regional gray matter volume using 1.5 mm thick, coronal, 1.5 Tesla magnetic resonance imaging and voxel-based morphometry methods of image analysis. Subjects were scanned at presentation and were followed up clinically for a minimum of 12 months, to detect later transition to psychosis. We found that both groups of subjects who subsequently developed psychosis (schizophrenia and affective psychosis) showed reductions in the frontal cortex relative to UHR subjects who did not develop psychosis. The subgroup that subsequently developed schizophrenia also showed smaller volumes in the parietal cortex and, at trend level, in the temporal cortex, whereas those who developed an affective psychosis had significantly smaller subgenual cingulate volumes. These preliminary findings suggest that volumetric abnormalities in UHR individuals developing schizophrenia vs affective psychoses comprise a combination of features that predate both disorders and others that may be specific to the nature of the subsequent disorder.

It has been suggested that some cases of schizophrenia may be caused by an interaction between physiological risk factors and exposure to certain neurotropic infectious agents such as Herpes Simplex Virus type 1 (HSV1). This study investigated whether HSV1 exposure was associated with structural brain abnormalities in individuals who, because of genetic or other factors, were deemed at ultra high risk (UHR) of developing psychosis. Twenty-five UHR individuals with a history of HSV1 exposure (HSV1+), 33 UHR participants without a history of HSV1 exposure (HSV1-) and 19 healthy controls participated in the study. All participants underwent a T1-weighted structural MRI scan, and HSV1 exposure was determined based on the presence of IgG class antibodies in the blood serum. Voxel based morphometry revealed that the HSV1+ participants exhibited volumetric gray matter reductions in the cuneus, relative to both the HSV1--and healthy control participants (p<0.05, small volume corrected for familywise error). The results of the study suggest that a history of HSV1 infection is associated with volumetric gray matter reductions in individuals at ultra-high risk for developing psychosis, and are consistent with previous studies that have identified structural gray matter abnormalities in HSV1-infected patients with established schizophrenia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Although historically gray matter changes have been the focus of neuropathological and neuroradiological studies in schizophrenia, in recent years an increasing body of research has implicated white matter structures and its constituent components (axons, their myelin sheaths and supporting oligodendrocytes). This article summarizes this body of literature, examining neuropathological, neurogenetic and neuroradiological evidence for white matter pathology in schizophrenia. We then look at the possible role that antipsychotic medication may play in these studies, examining both its role as a potential confounder in studies examining neuronal density and brain volume, but also the possible role that these medications may play in promoting myelination through their effects on oligodendrocytes. Finally, the role of potential novel therapies is discussed.

Despite an increasing number of published voxel based morphometry studies of schizophrenia, there has been no adequate attempt to examine gray (GM) and white matter (WM) abnormalities and the heterogeneity of published findings. In the current article, we used a coordinate based meta-analysis technique to simultaneously examine GM and WM abnormalities in schizophrenia and to assess the effects of gender, chronicity, negative symptoms and other clinical variables. 79 studies meeting our inclusion criteria were included in the meta-analysis. Schizophrenia was associated with GM reductions in the bilateral insula/inferior frontal cortex, superior temporal gyrus, anterior cingulate gyrus/medial frontal cortex, thalamus and left amygdala. In WM analyses of volumetric and diffusion-weighted images, schizophrenia was associated with decreased FA and/or WM in interhemispheric fibers, anterior thalamic radiation, inferior longitudinal fasciculi, inferior frontal occipital fasciculi, cingulum and fornix. Male gender, chronic illness and negative symptoms were associated with more severe GM abnormalities and illness chronicity was associated with more severe WM deficits. The meta-analyses revealed overlapping GM and WM structural findings in schizophrenia, characterized by bilateral anterior cortical, limbic and subcortical GM abnormalities, and WM changes in regions including tracts that connect these structures within and between hemispheres. However, the available findings are biased towards characteristics of schizophrenia samples with poor prognosis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Morphological abnormalities of the superior temporal gyrus have been consistently reported in schizophrenia, but the timing of their occurrence remains unclear., Aims: To determine whether individuals exhibit superior temporal gyral changes before the onset of psychosis., Method: We used magnetic resonance imaging to examine grey matter volumes of the superior temporal gyrus and its subregions (planum polare, Heschl's gyrus, planum temporale, and rostral and caudal regions) in 97 antipsychotic-naive individuals at ultra-high risk of psychosis, of whom 31 subsequently developed psychosis and 66 did not, and 42 controls., Results: Those at risk of psychosis had significantly smaller superior temporal gyri at baseline compared with controls bilaterally, without any prominent subregional effect; however, there was no difference between those who did and did not subsequently develop psychosis., Conclusions: Our findings indicate that grey matter reductions of the superior temporal gyrus are present before psychosis onset, and are not due to medication, but these baseline changes are not predictive of transition to psychosis.

We describe the differential presentation of schizophrenia-like psychosis in two siblings with the 'variant' biochemical presentation of adult Niemann-Pick disease type C. The male sibling presented with psychosis at age 16 years and cognitive and motor disturbance at age 25 years, whereas his elder sister, sharing the same mutation but showing less severe biochemical, neuroimaging and ocular motor parameters, presented with a similar schizophrenia-like illness with associated cognitive and motor disturbance at age 31 years. Their illness onset, course and response to treatment mirrors the sex dimorphism seen in schizophrenia, and is suggestive of an interaction between the neurobiology of their metabolic disorder and sex differences in neurodevelopment.

Spatial working memory (SWM) dysfunction has been suggested as a trait marker of schizophrenia and implicates a diffuse network involving prefrontal, temporal and parietal cortices. However, structural abnormalities in both grey and white matter in relation to SWM deficits are largely unexplored. The current magnetic resonance imaging (MRI) study examined this relationship in a sample of young first-episode schizophrenia (FES) patients using a whole-brain voxel-based method. SWM ability of 21 FES patients and 41 comparable controls was assessed by the CANTAB SWM task. Using an automated morphometric analysis of brain MRI scans, we assessed the relationship between SWM abilities and both grey matter volume and white matter density in both groups. Our findings demonstrated the different directionality of the association between SWM errors and grey matter volume in left frontal regions and white matter tracts connecting these regions with temporal and occipital areas between FES patients and controls. This suggests that the substrate underpinning the normal variability in SWM function in healthy individuals may be abnormal in FES, and that the normal neurodevelopmental processes that drive the development of SWM networks are disrupted in schizophrenia.

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness.

Morphologic abnormalities of the superior temporal gyrus (STG) have been reported in schizophrenia, but have not been extensively studied in other psychotic disorders such as affective psychosis. In the present study, magnetic resonance imaging was used to examine the volumes of the STG and its subregions [planum polare (PP), Heschl gyrus (HG), planum temporale (PT), rostral STG, and caudal STG] in 162 first-episode patients with various psychotic disorders [46 schizophrenia (31 schizophrenia and 15 schizoaffective disorder), 57 schizophreniform disorder, 34 affective psychosis, and 25 other psychoses] and 62 age- and sex-matched healthy controls. The first-episode schizophrenia patients had significantly less gray matter in HG, PT, and caudal STG bilaterally compared with all other groups, but there was no difference between the controls and affective psychosis, schizophreniform disorder, or other psychoses for any STG subregion. The STG white matter volume did not differ between groups. Our findings indicate that morphologic abnormalities of the STG gray matter are specific to schizophrenia among various psychotic disorders, implicating its role in the underlying pathophysiology of schizophrenia.

In this review, we describe neuropsychological and brain imaging findings in the early stages of psychosis and schizophrenia. We focus on recent clinical high-risk studies and consider whether the evidence supports these as 'endophenotypes' of a vulnerability to the illness or as 'biomarkers' of illness onset and transition. The findings suggest that there are a number of processes at psychosis onset that may represent biomarkers of incipient illness. These neurobiological indices particularly implicate the integrity of frontal and temporal cortices, which may or may not be related to the genetics of psychosis (i.e. potential 'endophenotypes'). However, these brain regions are dynamically changing during normal maturation, meaning that any putative neurobiological markers identified at the earliest stages of illness may be relatively unstable.We suggest that, while such measures maybe readily identified as potential neurobiological markers of established illness, they are inconsistent at (or around) the time of illness onset when assessed cross-sectionally. Instead,identification of more valid risk markers may require longitudinal assessment to ascertain normal or abnormal trajectories of neurodevelopment. Accordingly, we assert that the current conceptualisations of potential biomarkers and/or 'endophenotypes' for schizophrenia may need to be reconsidered in the context of normal and abnormal brain maturational processes at the time of onset of psychotic disorders.

Objective: Young patients with frontotemporal dementia (FTD) may present with schizophrenia-like psychosis. Few studies have investigated whether FTD-like neuropathological changes are present in schizophrenia. The purpose of the present study was therefore to determine whether FTD-like abnormalities in TARDNA binding protein (TDP-43) and ubiquitin are detectable in hippocampal dentate gyrus of patients with schizophrenia and bipolar disorder. A secondary objective was to identify clinicopathological relationships of any such abnormalities., Methods: Hippocampal sections from 12 patients (nine with schizophrenia and three with bipolar disorder) and 11 control subjects Facility from the National Neural Tissue Resource Centre, Melbourne were blindly rated for the presence or absence of normal TDP-43 staining or ubiquitin-positive neuronal inclusions within the dentate gyrus. The clinical files of all subjects were reviewed for demographic and clinical information., Results: In three patients the normal expression of nuclear TDP-43 staining was not detected. Significantly, all three subjects presented after the age of 50 and had an adult child diagnosed with the same psychiatric disorder., Conclusion: Abnormalities in TDP-43 nuclear expression were identified in patients with late-onset psychosis and a positive family history.

Reductions in the size of the anterior callosum have been described for both first-episode and established schizophrenia and bipolar affective disorder, but never in individuals with psychotic bipolar disorder. We recruited 110 first-episode psychosis subjects (74 schizophrenia spectrum and 36 affective psychosis) and 36 age- and gender-matched controls. The callosum was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum were compared. The schizophrenia-spectrum group showed reductions in thickness of the genu across schizophreniform and schizoaffective disorder and schizophrenia, and the schizoaffective disorder group also showed an increase in thickness in the splenium and isthmus. None of these changes were seen in the affective disorder group, although a non-significant increase in the region of the isthmus and splenium was seen, particularly in the depressed group. Psychotic affective disorders do not show the anterior callosal reductions that are seen in the schizophrenia-spectrum group at first episode. The schizoaffective patients show additional posterior callosal expansions that may be a marker of an affective diathesis. This suggests that schizoaffective disorder may represent two interacting illness processes or be mid-way along a continuum of these two broad categories of illness at first psychosis.

Patients with established schizophrenia perform poorly on attentional set-shifting tasks, due to a failure of inhibitory control and/or perseverative errors. However, attentional set-shifting is also dependent on working memory capacity, which is additionally impaired in schizophrenia. No studies in first-episode psychosis have specifically examined the contribution of working memory to set-shifting ability in schizophrenia. We investigated 48 first-episode schizophreniform psychosis/schizophrenia (FE) and 40 chronic schizophrenia (CHR) patients, compared to 67 comparable healthy subjects (CTL). All subjects were assessed using the CANTAB 'attentional set-shifting (IDED)' and 'spatial working memory (SWM)' tasks. Both FE and CHR made significantly greater errors on the SWM task (p< or =0.001). Compared with CTL, CHR was more likely to fail at intra-dimensional (p<0.05) and extra-dimensional (p<0.01) shifting and reversal stages of IDED; CHR required significantly greater trials to reach criterion, which was not explained by deficits in SWM (p<0.001). FE did not differ from CTL on IDED level reached. However, FE required significantly more trials (p=0.001); this was no longer significant after controlling for SWM deficits (p>0.05). Given that the capacity to be flexible and shift attentional set is intact only at the early stages of illness, 'neurodegenerative' processes may explain the more severe deficits in chronic schizophrenia. In contrast, deficits in SWM identified at all stages of schizophrenia may reflect incomplete maturation prior to illness onset ('neurodevelopmental arrest'). Longitudinal studies assessing these cognitive functions from illness onset or in prepsychotic individuals are required.

Context: Longitudinal magnetic resonance imaging studies have shown progressive gray matter reduction in the superior temporal gyrus during the earliest phases of schizophrenia. It is unknown whether these progressive processes predate the onset of psychosis., Objective: To examine gray matter reduction of the superior temporal gyrus over time in individuals at risk for psychosis and in patients with first-episode psychosis., Design: Cross-sectional and longitudinal comparisons., Setting: Personal Assessment and Crisis Evaluation Clinic and Early Psychosis Preventions and Intervention Centre., Participants: Thirty-five ultrahigh-risk individuals (of whom 12 later developed psychosis [UHRP] and 23 did not [UHRNP]), 23 patients with first-episode psychosis (FEP), and 22 control subjects recruited from the community., Main Outcome Measures: Volumes of superior temporal subregions (planum polare, Heschl gyrus, planum temporale, and rostral and caudal regions) were measured at baseline and follow-up (mean, 1.8 years) and were compared across groups., Results: In cross-sectional comparisons, only the FEP group had significantly smaller planum temporale and caudal superior temporal gyrus than other groups at baseline, whereas male UHRP subjects also had a smaller planum temporale than controls at follow-up. In longitudinal comparison, UHRP and FEP patients showed significant gray matter reduction (approximately 2%-6% per year) in the planum polare, planum temporale, and caudal region compared with controls and/or UHRNP subjects. The FEP patients also exhibited progressive gray matter loss in the left Heschl gyrus (3.0% per year) and rostral region (3.8% per year), which were correlated with the severity of delusions at follow-up., Conclusions: A progressive process in the superior temporal gyrus precedes the first expression of florid psychosis. These findings have important implications for underlying neurobiologic features of emerging psychotic disorders and emphasize the importance of early intervention during or before the first episode of psychosis.

Background: Few studies have investigated the relationship between schizophrenia and frontotemporal dementia., Aims: To investigate this relationship through a clinicopathological investigation of young-onset frontotemporal dementia and a review of the case literature., Method: Cases of young-onset frontotemporal dementia were identified within the local brain bank. The clinical course and pathological findings were collated. For the literature review, cases of frontotemporal dementia identified through Medline were selected according to defined criteria. The demographic, clinical, pathological and genetic characteristics of cases presenting with a psychotic illness were identified., Results: In the case series, 5 of 17 patients with frontotemporal dementia had presented with a psychotic illness (schizophrenia/schizoaffective disorder n=4, bipolar disorder n=1) an average of 5 years prior to the dementia diagnosis. Patients with schizophrenia exhibited changes consistent with TDP-43 and ubiquitin-positive frontotemporal dementia. In the cases review, a third of patients aged 30 years or under and a quarter of those aged 40 years or under had been diagnosed with psychosis at presentation., Conclusions: Patients with young-onset frontotemporal dementia may be diagnosed with a psychotic illness years before the dementia diagnosis is made. These findings have implications for clinicians and for our further understanding of the neurobiology of psychotic illness.

Morphologic abnormalities of the insular cortex have been described in psychotic disorders such as schizophrenia, but it remains unknown whether these abnormalities develop progressively over the course of the illness. In the current study, longitudinal magnetic resonance imaging data were obtained from 23 patients with first-episode psychosis (FEP), 11 patients with chronic schizophrenia, and 26 healthy controls. The volumes of the short (anterior) and long (posterior) insular cortices were measured on baseline and follow-up (between 1 and 4 years later) scans and were compared across groups. In cross-sectional comparison at baseline, the FEP and chronic schizophrenia patients had significantly smaller short insular cortex than did controls. In longitudinal comparison, the FEP patients showed significant gray matter reduction of the insular cortex over time (-4.3%/2.0 years) compared with controls (0.3%/2.2 years) without significant subregional effects, but there was no difference between chronic schizophrenia patients (-1.7%/2.4 years) and controls. The gray matter loss of the left insular cortex over time in FEP patients was correlated with the severity of positive and negative symptoms at follow-up. These findings indicate that patients with psychotic disorders have smaller gray matter volume of the insular cortex especially for its anterior portion (short insula) at first expression of overt psychosis, but also exhibit a regional progressive pathological process of the insular cortex during the early phase after the onset, which seems to reflect the subsequent symptomatology.

While hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been implicated in psychotic disorders, previous magnetic resonance imaging (MRI) studies of the pituitary gland volume in schizophrenia have yielded controversial results. It is also unknown whether patients with schizophrenia spectrum such as schizotypal disorder exhibit pituitary volume changes. In this study, we investigated the pituitary volume using MRI in 47 schizotypal disorder patients (29 males, mean age=25.0 years), 72 schizophrenia patients (38 males, mean age=26.2 years), and 81 age and gender matched healthy controls (46 males, mean age=24.5 years). Both patient groups had a larger pituitary volume compared with controls, but no difference was found between the schizophrenia and schizotypal patients. The pituitary volume was larger in females than in males for all diagnostic groups. There was no association between the pituitary volume and type (typical versus atypical), daily dosage, or duration of antipsychotic medication in either patient group. These findings are consistent with a stress-diathesis model of schizophrenia and further suggest that the schizotypal patients share HPA axis hyperactivity with young established schizophrenia patients reflecting a common vulnerability to stress within the schizophrenia spectrum.

Neuroimaging studies of individuals at risk of psychosis have the potential to identify markers predictive of illness onset and features that progress with transition. To date, reduced brain volumes have shown weak predictive value for onset of psychotic illness. All published longitudinal studies of the transition to psychosis show progressive brain changes that are not seen in at-risk individuals who do not develop the disorder. Although the cause of these changes is unclear, they challenge the conventional neurodevelopmental model of schizophrenia.

Abnormal neurodevelopment in midline structures such as the adhesio interthalamica (AI) has been reported in psychotic disorders, but it is unknown whether individuals at risk for the disorder share the AI findings observed in patients with florid psychosis. Magnetic resonance imaging of 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 individuals at ultra high-risk (UHR) of psychosis (of whom 39 later developed psychosis), and 87 healthy controls were used to investigate the length and prevalence of the AI. The relation of the AI length to lateral ventricular enlargement was also explored. The patients with FEP and chronic schizophrenia as well as UHR individuals had a shorter AI than the controls, but there was no difference in the AI findings between the UHR individuals who did and did not subsequently develop psychosis. There was a negative correlation between the AI length and lateral ventricular volume in all the diagnostic groups. The absence of the AI was more common in the chronic schizophrenia patients when compared with all other groups. These results support the notion that the AI absence or shorter length could be a neurodevelopmental marker related to vulnerability to psychopathology, but also suggest that schizophrenia patients may manifest progressive brain changes related to ongoing atrophy of the AI after the onset.

An increased prevalence of large cavum septum pellucidum (CSP), a marker of midline neurodevelopmental abnormality, has been reported in schizophrenia. However, not all studies have been able to replicate this finding and very few studies have been conducted in large samples. In the current study, magnetic resonance imaging was used to assess the presence of an abnormal CSP in 162 patients with first-episode psychosis (FEP), 89 patients with chronic schizophrenia, 135 ultra high-risk (UHR) individuals, and 87 controls. The prevalence of a large CSP (>5.6 mm) did not differ between the groups (9.3% of the FEP patients, 11.2% of the chronic schizophrenia patients, 11.1% of the UHR individuals, and 11.5% of the controls). The length of the CSP was not associated with sulcal morphology of the anterior cingulate cortex (ACC), suggesting different biological processes responsible for the CSP enlargement versus ACC folding. These findings suggest that the CSP is not a neurodevelopmental marker of psychosis and cast doubt over the notion that it plays a major role in the neurobiology of psychosis.

Reductions in the size of the anterior callosum have been described for both first-episode schizophrenia-spectrum psychosis and established schizophrenia, but have not been examined in individuals at ultra-high risk for psychosis (UHR). We compared 100 UHR individuals (27 of whom later developed psychosis) with 38 age-matched control subjects on measures of size and shape of the corpus callosum to determine if changes previously demonstrated in first-episode and established schizophrenia are present in the pre-psychotic phase. Each individual's callosum was extracted from the mid-sagittal slice from T1-weighted magnetic resonance images, and total area, length and curvature of the callosum was compared using one-way ANOVA, and 39 regional thicknesses via a non-parametric permutation method to account for non-independence of adjacent measures. Total area, length and curvature did not differ between the groups. Compared to both the UHR-NP group and controls, the UHR-P group showed significant regional reductions in the region of the anterior genu of the callosum. The UHR-NP group did not differ from controls. Positive and negative symptoms did not affect regional thickness in either of the patient groups. Cox regression showed that mean anterior genu thickness was highly predictive of a transition to psychosis. Reductions in the thickness of the anterior callosum differentiate between high-risk individuals who transition to psychosis and those who do not, and is highly predictive of transition. These changes may reflect primary pathology of orbitofrontal and medial frontal cortex, or deficits in anterior interhemispheric myelination.

Schizophrenia is associated with significant brain abnormalities, including changes in brain metabolites as measured by proton magnetic resonance spectroscopy (MRS). What remains unclear is the extent to which these changes are a consequence of the emergence of psychotic disorders or the result of treatment with antipsychotic medication. We assessed 34 patients with first episode psychosis (15 antipsychotic naïve) and 19 age- and gender-matched controls using short-echo MRS in the medial temporal lobe bilaterally. Overall, there were no differences in any metabolite, regardless of treatment status. However, when the analysis was limited to patients with a diagnosis of schizophrenia, schizophreniform or schizoaffective disorder, significant elevations of creatine/phosphocreatine (Cr/PCr) and myo-inositol (mI) were found in the treated group. These data indicate a relative absence of temporal lobe metabolic abnormalities in first episode psychosis, but suggest that some treatment-related changes in mI might be apparent in patients with schizophrenia-spectrum diagnoses. Seemingly illness-related Cr/PCr elevations were also specific to the diagnosis of schizophrenia-spectrum disorder and seem worthy of future study.

Background: The shape of the corpus callosum may differ in schizophrenia, although no study has compared first-episode with established illness., Aims: To investigate the size and shape of the corpus callosum in a large sample of people with first-episode and established schizophrenia., Method: Callosal size and shape were determined using high-resolution magnetic resonance imaging on 76 patients with first-episode schizophrenia-spectrum disorders, 86 patients with established schizophrenia and 55 healthy participants., Results: There were no significant differences in total area across groups. Reductions in callosal width were seen in the region of the anterior genu in first-episode disorder (P<0.005). Similar reductions were seen in the chronic schizophrenia group in the anterior genu, but also in the posterior genu and isthmus (P=0.0005)., Conclusions: Reductions in anterior callosal regions connecting frontal cortex are present at the onset of schizophrenia, and in established illness are accompanied by changes in other regions of the callosum connecting cingulate, temporal and parietal cortices.

The anterior cingulate cortex (ACC) appears to be critically involved in the pathophysiology of schizophrenia, but past attempts at characterizing pathological changes in the region using magnetic resonance imaging have been restricted by a limited appreciation of its functional and anatomical diversity and a reliance on relatively coarse metrics (e.g., volume) to index anatomical change. In this study, we applied a novel, surface-based protocol to T1-weighted scans acquired from 40 first episode schizophrenia patients and 40 healthy controls individually matched for age, sex, and morphology of the paracingulate sulcus, a major anatomical variation that has been shown to affect morphometric estimates in the region. The surface-based approach enabled calculation of regional grey matter volume, surface area and curvature, cortical thickness, and depth of the cingulate sulcus, with sub-millimeter precision. Relative to controls, schizophrenia patients displayed a bilateral reduction in thickness of paralimbic regions of the ACC, along with a concomitant increase in surface area of both the limbic and paralimbic ACC. No differences were identified for regional grey matter volume, surface curvature, or CS depth. These findings illustrate the advantages of moving beyond traditional volume-based approaches when investigating cortical morphometry, and indicate that the early stages of schizophrenia are associated with a specific pattern of ACC abnormalities that cannot be attributed to variations in sulcal and gyral morphology., ((c) 2007 Wiley-Liss, Inc.)

Although the underlying neurobiology of emerging psychotic disorders is not well understood, there is a growing conviction that the study of patients at clinical high risk for the illness will provide important insights. Further, a better understanding of the transition period may help the development of novel therapies. In this review, we summarize the extant neuroimaging and neuropsychological studies of people at clinical high risk for psychosis. By and large, there are few definitive markers that distinguish those who go on to develop the illness from those who do not. The 2 most consistently abnormal brain regions in schizophrenia research, the hippocampi and the lateral ventricles, are not significantly different from healthy controls prior to psychosis onset. However, frontal lobe measures (eg, cortical thickness in the anterior cingulate) do show promise, as do cognitive measures sensitive to prefrontal cortex dysfunction. Further, longitudinal magnetic resonance imaging findings in individuals at ultrahigh risk for developing a psychotic illness show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal cortical regions. While the pathological processes underlying such changes remain unclear, speculatively they may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. Active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.

We describe the case of a 23-year-old Caucasian woman who presented with alien hand syndrome and a first episode of the coenesthetic subtype of schizophrenia. 'Alienness' of her non-dominant hand was intimately phenomenologically associated with the onset of first-psychosis. Cerebral MRI revealed a partial agenesis of the corpus callosum with a complete absence of the rostrum, hypoplastic anterior and inferior genu, and a hypoplastic splenium. This case suggests that this syndrome can occur with the development of a functional disconnection syndrome involving the anterior callosum, and in this case the 'second hit' proposed to occur in early adulthood in schizophrenia may have interacted with her earlier neurodevelopmental lesion to result in a combination of psychosis and alien hand syndrome., (2008 S. Karger AG, Basel.)

Objectives: The characterization, aetiology, and course of verbal memory deficits in schizophrenia remain ill defined. The impact of antipsychotic medications is also unclear. The purpose of the present paper was to investigate verbal memory performance in established schizophrenia (SZ) and first-episode schizophreniform psychosis (FE)., Method: Performances of 32 SZ and 33 FE patients were compared to those of 47 healthy volunteers on measures of verbal working memory, verbal associative learning and story recall., Results: Story recall deficits, but not deficits in working memory or paired associate learning, were demonstrated by both patient groups. Patients treated with typical neuroleptics had more impairment in associative learning with arbitrary word pairings than those treated with atypicals, regardless of patient group., Conclusions: The results are consistent with the notion that some neuropsychological impairment is present at the time of psychosis onset and that this impairment is non-progressive. However, deficits may be specific to subclasses of memory function.

The anterior cingulate region is thought to be dysfunctional in schizophrenia, but whether this is the result of reduced neuronal integrity or changes in neurotransmitter systems remains an issue of debate. Fifteen male patients with schizophrenia and 14 male controls were assessed using proton magnetic resonance spectroscopy, with regions of interest placed in the right and left dorsal and rostral cingulate. The metabolites of interest were N-acetylaspartate (NAA), a putative neuronal marker, and glutamate + glutamine (Glx), which may index synapse number. Schizophrenia patients had lower NAA concentrations throughout the dorsal and rostral portions of the anterior cingulate and in both hemispheres, but showed no changes in Glx. Anterior cingulate involvement in schizophrenia is likely to be a result of neuronal loss or dysfunction.

Although the underlying neurobiology of emerging psychotic disorders is not well understood, evidence from structural imaging and other studies support the notion that schizophrenia arises as a consequence of both an 'early neurodevelopmental' disturbance, as well as 'late neurodevelopmental' changes occurring during the initial stages of a psychotic illness, including around the time of transition to illness. In line with this, our longitudinal MRI findings in individuals at ultra-high risk for developing a psychotic illness show that there are excessive neuroanatomical changes in those who convert to psychosis. These aberrant changes are observed most prominently in medial temporal and prefrontal lobe regions. In a further series of longitudinal studies in first-episode psychosis, we have identified changes in prefrontal regions that indicate an accelerated loss of grey matter in patients compared to healthy control subjects. We suggest that the available evidence is consistent with the presence of subtle regionally and temporally specific neurobiological changes through the course of psychosis (Pantelis et al., 2005), including: (1) evidence for early (pre- and peri-natal) neurodevelopmental anomalies, (2) evidence for progressive grey matter loss involving medial temporal and orbital prefrontal regions around the time of transition to illness, and (3) evidence of late (post-pubertal) neurodevelopmental changes soon after the onset of psychosis, involving an acceleration of normal brain maturational processes, associated with significant loss of grey matter in dorsal prefrontal regions. The pathological processes underlying such changes remain unclear and may reflect anomalies in genetic and/or other endogenous mechanisms responsible for brain maturation, the adverse effects of intense or prolonged stress, or other environmental factors. These findings suggest that early markers of impending illness may prove difficult to define, and that brain changes in psychosis may better be conceptualized as anomalous trajectories of brain development. Further, active changes during transition to illness may present the potential to intervene and ameliorate these changes with potential benefit clinically.

Unlabelled: Anterior cingulate (ACC) hypo-activity is commonly observed in chronically ill schizophrenia patients. However, it is unclear whether this is secondary to persistent illness and/or medication., Method: We examined eight antipsychotic-naïve first-episode patients and matched healthy controls undergoing PET scanning while performing the Stroop task., Results: Group-averaged and single-subject analyses showed ACC activation in both controls and patients, albeit in different sub-regions (paracingulate and cingulate respectively). A direct comparison revealed relative under-activity of the left paracingulate cortex in patients., Conclusion: These findings suggest that the more pervasive hypo-activation observed in chronic patients may be secondary to persistent illness and/or medication.

Objective: Cognitive deficits, particularly those related to executive function and behavioural control, are a core feature of patients with schizophrenia and implicate disturbances of the prefrontal cortex (PFC). Consistent with this, functional imaging studies have identified abnormalities of PFC activity in chronically affected patients. The objective of the current study was to investigate executive-control related neural activity from first onset of the illness through to symptom stabilization., Method: The authors examined eight neuroleptic-naïve first-episode psychosis (FEP) patients within 3 days of first presentation and eight healthy age- premorbid-IQ, and gender-matched controls (CTL). All FEP patients were later confirmed with a diagnosis of schizophrenia. Subjects underwent H2-15O positron emission tomography (PET) while performing the Stroop interference task that has previously been shown to engage the PFC in healthy samples. In a double-blind paradigm, FEP patients were randomly treated with either haloperidol or risperidone for 8 weeks, after which CTLs and all but one of the FEP patients were re-scanned., Results: Behaviorally, there was no change in task performance from baseline to follow up for either the FEPs or CTLs. However, there were significant changes in functional activation in both groups across the same period. For CTLs, task-performance was associated with greater recruitment of posterior brain regions at follow up compared to baseline, while for FEP this involved greater recruitment frontal regions. Concurrently, FEP also showed significant improvement in positive symptomatology., Conclusions: These findings suggest that disturbances of the PFC often seen in FEP may be, at least partially, associated with acute symptom expression. However, it is still unclear whether this increase in frontal activity is due to symptom stabilization per se, the effects of medication, a lack of neurophysiological 'learning' with experience/practice, or a combination of these factors. In the context of the CTLs performance, we interpret the patient findings as reflective of greater neurophysiological effort required for task accomplishment relative to the learned, more automated, processing apparent in the CTLs.