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Auditory verbal hallucinations (AVH) are a disabling symptom for people with schizophrenia (SCZ), and do not always respond to antipsychotics. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for medication-refractory AVH, though the underlying neural mechanisms by which rTMS produces these effects remain unclear. This systematic review evaluated the structural and functional impact of rTMS for AVH in SCZ, and its association with clinical outcomes. A systematic search was conducted in Medline, PsychINFO, and PubMed using terms for four key concepts: AVH, SCZ, rTMS, neuroimaging. Using PRISMA guidelines, 18 studies were identified that collected neuroimaging data of an rTMS intervention for AVH in SCZ. Risk of bias assessments was conducted. Low frequency (<5 Hz) rTMS targeting left hemispheric language processing regions may normalize brain abnormalities in AVH patients at structural, functional, electrophysiological, and topological levels, with concurrent symptom improvement. Amelioration of aberrant neural activity in frontotemporal networks associated with speech and auditory processing was commonly observed, as well as in cerebellar and emotion regulation regions. Neuroimaging analyses identified neural substrates with direct correlations to post-rTMS AVH severity, propounding their use as therapeutic targets. Combined rTMS-neuroimaging highlights the multidimensional alterations of rTMS on brain activity and structure in treatment-resistant AVH, which may be used to develop more efficacious therapies. Larger randomized, sham-controlled studies are needed. Future studies should explore alternate stimulation targets, investigate the neural effects of high-frequency rTMS and evaluate long-term neuroimaging outcomes. [ABSTRACT FROM AUTHOR]

Objective: Earlier evidence suggested that structural-functional covariation in schizophrenia patients (SCZ) is associated with cognition, a predictor of functioning. Moreover, studies suggested that functional brain abnormalities of schizophrenia may be related with structural network features. However, only few studies have investigated the relationship between structural-functional covariation and both diagnosis and functioning in SCZ. We hypothesized that structural-functional covariation networks associated with diagnosis are related to real-world functioning in SCZ.Methods: We performed joint Independent Component Analysis on T1 images and resting-state fMRI-based Degree Centrality (DC) maps from 89 SCZ and 285 controls. Structural-functional covariation networks in which we found a main effect of diagnosis underwent correlation analysis to investigate their relationship with functioning. Covariation networks showing a significant association with both diagnosis and functioning underwent univariate analysis to better characterize group-level differences at the spatial level.Results: A structural-functional covariation network characterized by frontal, temporal, parietal and thalamic structural estimates significantly covaried with temporo-parietal resting-state DC. Compared with controls, SCZ had reduced structural-functional covariation within this network (pFDR = 0.005). The same measure correlated positively with both social and occupational functioning (both pFDR = 0.042). Univariate analyses revealed grey matter deviations in SCZ compared with controls within this structural-functional network in hippocampus, cerebellum, thalamus, orbito-frontal cortex, and insula. No group differences were found in DC.Conclusions: Findings support the existence of a phenotypical association between group-level differences and inter-individual heterogeneity of functional deficits in SCZ. Given that only the joint structural/functional analysis revealed this association, structural-functional covariation may be a potentially relevant schizophrenia phenotype. [ABSTRACT FROM AUTHOR]

Objective: This study aims to determine whether structural alterations can be used as neuroimaging markers to detect individuals with ultra-high risk (UHR) for psychosis for the diagnosis of schizophrenia and improvement of treatment outcomes.Methods: Embase and Pubmed databases were searched for related studies in July 2018. The search was performed without restriction on time and regions or languages. A total of 188 articles on voxel-based morphometry (VBM) and 96 articles on cortical thickness were obtained, and another 6 articles were included after the reference lists were checked. Our researchers assessed and extracted the data in accordance with the PRISMA guideline. The data were processed with a seed-based mapping method.Results: Fourteen VBM and nine cortical thickness studies were finally included in our study. In individuals with UHR, the gray matter volumes in the bilateral median cingulate (Z = 1.034), the right fusiform gyrus (Z = 1.051), the left superior temporal gyrus (Z = 1.048), and the right thalamus (Z = 1.039) increased relative to those of healthy controls. By contrast, the gray matter volumes in the right gyrus rectus (Z = -2.109), the right superior frontal gyrus (Z = -2.321), and the left superior frontal gyrus (Z = -2.228) decreased. The robustness of these findings was verified through Jackknife sensitivity analysis, and heterogeneity across studies was low. Typically, cortical thickness alterations were not detected in individuals with UHR.Conclusions: Structural abnormalities of the thalamocortical circuit may underpin the neurophysiology of psychosis and mark the vulnerability of transition to psychosis in UHR subjects. [ABSTRACT FROM AUTHOR]

Background: Auditory hallucinations (AH) are a core symptom of psychosis. The brain abnormalities responsible for AH remain controversial due to inconsistent and conflicting findings across studies, with substantial confounding factors, such as chronicity. Few studies have examined the pathological changes that occur in the gray matter (GM) of patients with first-episode psychosis (FEP) and AH. The present study aims to validate the presence and characteristics of these structural abnormalities in relation to the intensity of psychotic symptoms and AH in a larger homogeneous sample than those of previous studies.Methods: A magnetic resonance voxel-based morphometric analysis was applied to a group of 215 patients with FEP (93 patients with AH and 122 patients without AH) and 177 healthy controls. The patients were evaluated using the PANSS scale.Results: Patients with FEP exhibited greater reductions in GM concentrations in the temporal, frontal, cingulate and insular areas than the healthy controls did. No specific differences were found between the patients with FEP and AH and the patients without AH. In addition, total scores on the PANSS were negatively correlated with GM reductions in the FEP group. No correlations were found between the severity of the AH and the GM volumes.Conclusions: As in previous studies, reductions in the GM concentrations in patients with FEP suggest that alterations are present in the early stages of psychosis, and these alterations are correlated with the severity of the illness. The GM reductions were not found to be related to the presence or severity of AH. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We investigated IL1B genetic variation previously associated with risk for transition to psychosis for its association with gene expression in human post-mortem dorsolateral prefrontal cortex (DLPFC) from 74 (37 schizophrenia, 37 control) individuals and brain structure in 92 (44 schizophrenia, 48 control) living individuals. The IL1B A-G-T 'risk for psychosis transition' haplotype (rs16944|rs4848306|rs12621220) was associated with upregulation of IL1B mRNA expression in the DLPFC as well as reduced total grey matter and left middle frontal volumes and enlarged left lateral ventricular volume. Our results suggest IL1B genetic variation may confer psychosis risk via elevated mRNA expression and/or brain structure abnormalities. [ABSTRACT FROM AUTHOR]

Objectives: Offspring born to patients with affective and non-affective psychoses display indicators of brain dysfunctions that affected parents carry. Such indicators may help understand the risk trajectory.Methods: We followed up the clinical/developmental trajectories of 84 young offspring born to affected parents descending from the Quebec kindreds affected by schizophrenia or bipolar disorder. We longitudinally characterized childhood trajectories using 5 established risk indicators: cognitive impairments, psychotic-like experiences, non-psychotic DSM diagnosis and episodes of poor functioning, trauma and drug use.Results: Overall, offspring individually presented a high rate of risk indicators with 39% having 3 or more indicators. Thirty-three offspring progressed to an axis 1 DSM-IV disorder, 15 of whom transitioned to a major affective or non-affective disorder. The relative risks for each risk indicator were low in these vulnerable offspring (RR = 1.92 to 2.99). Remarkably, transitioners accumulated more risk indicators in childhood-adolescence than non-transitioners (Wilcoxon rank test; Z = 2.64, p = 0.008). Heterogeneity in the risk trajectories was observed. Outcome was not specific to parent's diagnosis.Conclusion: Young offspring descending from kindreds affected by major psychoses would accumulate risk indicators many years before transition. A clustering of risk factors has also been observed in children at risk of metabolic-cardiovascular disorders and influences practice guidelines in this field. Our findings may be significant for the primary care surveillance of millions of children born to affected parents in the G7 nations. Future longitudinal risk research of children at genetic risk should explore concurrently several intrinsic and environmental risk modalities to increase predictivity. [ABSTRACT FROM AUTHOR]

Schizophrenia is associated with structural brain abnormalities that are likely to be present before disease onset. It remains unclear to what extent these represent general vulnerability indicators or are associated with the developing clinical state itself. It also remains unclear whether such state or trait alterations may be evident at any given time-point, or whether they progress over time. To investigate this, structural brain scans were acquired at two time-points (mean scan-interval 1.87years) in a cohort of young unaffected individuals at high familial risk of schizophrenia (baseline, n=142; follow-up, n=64) and healthy controls (baseline, n=36; follow-up, n=18). Sub-cortical reconstructions of the hippocampus and amygdala were generated using the longitudinal pipeline available with Freesurfer. The high risk cohort was subdivided into individuals that remained well during the study (HR[well], baseline, n=68; follow-up, n=30), transient and/or partial symptoms that were insufficient to support a formal diagnosis (HR[symp], baseline, n=57; follow-up, n=26) and individuals that subsequently developed schizophrenia according to ICD-10 criteria (HR[ill], baseline, n=17; follow-up, n=8). Longitudinal change in the hippocampus and amygdala was compared, focusing first on overall differences between high-risk individuals and controls and then on sub-group differences within the high-risk cohort. We found a significantly altered developmental trajectory for all high risk individuals compared to controls, with controls showing a significant increase in hippocampal volume over time compared to those at high risk. We did not find evidence of altered longitudinal trajectories based on clinical outcome within the high risk cohort. These results suggest that an altered developmental trajectory of hippocampal volume is associated with a general familial predisposition to develop schizophrenia, as this alteration was not related to subsequent clinical outcome. [ABSTRACT FROM AUTHOR]

Background Apathy is an enduring and debilitating feature related to poor outcome in patients with first-episode psychosis (FEP). The biological underpinnings of apathy are unknown. We tested if FEP patients with persistent apathy (PA) differed from FEP patients without persistent apathy (NPA) in specific brain structure measures in the early phase of illness. Methods A total of 70 Norwegian FEP patients were recruited within 1 year of first adequate treatment. They were defined as having PA ( N = 18) or NPA ( N = 52) based on Apathy Evaluation Scale score at baseline and 1 year later. MRI measures of cortical thickness and subcortical structure volumes were compared between the PA and NPA groups. Results The PA group had significantly thinner left orbitofrontal cortex and left anterior cingulate cortex. The results remained significant after controlling for depressive symptoms and antipsychotic medication. Discussion FEP patients with persistent apathy in the early phase of their illness show brain structural changes compared to FEP patients without persistent apathy. The changes are confined to regions associated with motivation, occur early in the disease course and appear selectively in PA patients when both groups are compared to healthy controls. [ABSTRACT FROM AUTHOR]

Introduction Diffusion tensor imaging (DTI) studies in patients with schizophrenia have shown abnormalities in the microstructure of white matter tracts. Specifically, reduced fractional anisotropy (FA) has been described across multiple white matter tracts, in studies that have mainly included patients treated with antipsychotic medications. Objective To compare FA in antipsychotic-naïve patients experiencing a first episode of psychosis (FEP) to FA in healthy controls to demonstrate that the variance of FA can be grouped, in a coincidental manner, in four predetermined factors in accordance with a theoretical partition of the white matter tracts, using a principal components analysis (PCA). Methods Thirty-five antipsychotic-naïve FEP patients and 35 age- and gender-matched healthy controls underwent DTI at 3 T. Analysis was performed using a tract-based spatial statistics (TBSS) method and exploratory PCA. Results DTI analysis showed extensive FA reduction in white matter tracts in FEP patients compared with the control group. The PCA grouped the white matter tracts into four factors explaining 66% of the total variance. Comparison of the FA values within each factor highlighted the differences between FEP patients and controls. Discussion Our study confirms extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients. [ABSTRACT FROM AUTHOR]

Introduction A longer duration of untreated psychosis (DUP) is associated with poor outcomes in first-episode psychosis (FEP); however, it is unclear whether this is due to the effects of psychosis on brain structure. We systematically reviewed the literature on the association between the length of untreated psychosis and brain structure in first-episode psychosis. Methods We searched three electronic databases and conducted forward and backward citation searching to identify relevant papers. Studies were included if they: (1) included patients with a psychotic disorder who were treatment naïve or minimally treated; and (2) had correlated measures of DUP or duration of untreated illness (DUI) with structural measures. Results We identified 48 studies that met the inclusion criteria. Forty-three examined the correlation between DUP and brain structure, and 19 examined the correlation between DUI and brain structure. There was evidence of significant associations in brain regions considered important in psychosis; however, the proportion of significant associations was low and the findings were inconsistent across studies. The majority of included studies were not primarily designed to examine whether DUP/DUI is correlated with brain structure, and there were methodological limitations in many studies that prevent drawing a strong conclusion. Conclusion To date, there is minimal evidence of an association between untreated psychosis and brain structure in FEP. Although the body of literature is substantial, there are few hypothesis-driven studies with a primary objective to answer this question. Future studies should be specifically designed to examine whether untreated psychosis has a deleterious effect on brain structure. [ABSTRACT FROM AUTHOR]

Schizophrenia has long been hypothesized to result from a disconnection syndrome due to a disruption of the association fibers of the brain. However, only with the advent of in vivo neuroimaging, a formal disconnectivity hypothesis for schizophrenia has been developed. Diffusion tensor MRI, a non-invasive technique which is sensitive to features of tissue microstructure and to the anatomy of the white matter fibers, has gained a crucial role in the field. Here, we provide a state-of-the-art review of structural connectivity abnormalities detected in schizophrenia and discuss the most relevant findings at preclinical, first episode drug-naïve, and chronic stages. Imaging studies showed white matter alterations from the preclinical to the chronic stage of the disease, which involve the corticospinal tracts, interhemispheric connections, long association white matter tracts, cerebello-thalamo-cortical circuit, and limbic system. Such abnormalities were found to be associated with the psychiatric and cognitive manifestations of the disease and to predict, at least partially, the patient clinical evolution and response to treatment. [ABSTRACT FROM AUTHOR]

It has long been debated whether a progressive process is involved in schizophrenia. The aim of the current study was to determine whether a progressive process was involved in patients with early schizophrenia, who were drug naive or had received short-term minimal antipsychotic treatment to avoid the distortion through medication effects. Twenty-eight patients with schizophrenia with illness-duration of up to 3 years and twenty-six matched healthy controls were recruited. Structural and functional brain networks were examined based on diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI). The intergroup differences and correlation with illness duration in the patient group were surveyed. The schizophrenic patients showed lower fractional anisotropy (FA) values in the corpus callosum and corona radiata. Negative correlations of illness duration with FA values were observed in similar regions. During functional analysis, reduced functional connectivity between bilateral temporoparietal-junction (TPJ) and the posterior cingulate cortex (PCC) were found in the default mode network (DMN) in schizophrenic patients. In addition, the left TPJ showed gradually weaker functional connectivity with PCC and the medial prefrontal cortex (MPFC) in DMN as the duration of schizophrenia increased. The results suggested that early in the disease process patients have decreased connectivity in both structural and functional networks and that the weaker structural and functional connectivity negatively correlated with illness duration, which provided evidence for progressive brain abnormalities in early schizophrenia. [ABSTRACT FROM AUTHOR]

First episode psychosis (FEP) has been associated with structural brain changes, largely identified by volumetric analyses. Advances in neuroimaging processing have made it possible to measure geometric properties that may identify subtle structural changes not appreciated by a measure of volume alone. In this study we adopt complementary methods of assessing the structural integrity of grey matter in FEP patients and assess whether these relate to patient clinical and functional outcome at 3 year follow-up. 1.5 Tesla T1-weighted Magnetic Resonance (MR) images were acquired for 46 patients experiencing their first episode of psychosis and 46 healthy controls. Cerebral cortical thickness and local gyrification index (LGI) were investigated using FreeSurfer software. Volume and shape of the hippocampus, caudate and lateral ventricles were assessed using manual tracing and spherical harmonics applied for shape description. A cluster of cortical thinning was identified in FEP compared to controls; this was located in the right superior temporal gyrus, sulcus, extended into the middle temporal gyrus (lateral temporal cortex — LTC). Bilateral caudate volumes were significantly lower in FEP relative to controls and the right caudate also displayed regions of shape deflation in the FEP group. No significant structural abnormalities were identified in cortical LGI or hippocampal or lateral ventricle volume/shape. Neither LTC nor caudate abnormalities were related to change in symptom severity or global functioning 3 years later. LTC and caudate abnormalities are present at the first episode of psychosis but do not appear to directly affect clinical or functional outcome. [ABSTRACT FROM AUTHOR]

Abstract: We tested the hypothesis that family risk for psychosis (FR) and clinical risk for psychosis (CR) are associated with structural brain abnormalities, with increased deficits in those at both family risk and clinical risk for psychosis (FRCR). The study setting was the Oulu Brain and Mind Study, with subjects drawn from the Northern Finland 1986 Birth Cohort (n=9479) using register and questionnaire based screening, and interviews using the Structured Interview for Prodromal Symptoms. After this procedure, 172 subjects were included in the study, classified as controls (n=73) and three risk groups: FR excluding CR (FR, n=60), CR without FR (CR, n=26), and individuals at both FR and CR (FRCR, n=13). T1-weighted brain scans were acquired and processed in a voxel-based analysis using permutation-based statistics. In the comparison between FRCR versus controls, we found lower grey matter volume (GMV) in a cluster (1689 voxels at −4.00, −72.00, −18.00mm) covering both cerebellar hemispheres and the vermis. This cluster was subsequently used as a mask to extract mean GMV in all four groups: FR had a volume intermediate between controls and FRCR. Within FRCR there was an association between cerebellar cluster brain volume and motor function. These findings are consistent with an evolving pattern of cerebellar deficits in psychosis risk with the most pronounced deficits in those at highest risk of psychosis. [Copyright &y& Elsevier]

Abstract: Siblings of patients diagnosed with schizophrenia are at elevated risk for developing this disorder. The nature of such risk associated with brain abnormalities, and whether such abnormalities are similar to those observed in schizophrenia, remain unclear. Deficits in language processing are frequently reported in increased risk populations. Interestingly, white matter pathology involving fronto-temporal language pathways, including arcuate fasciculus (AF), uncinate fasciculus (UF), and inferior occipitofrontal fasciculus (IOFF), are frequently reported in schizophrenia. In this study, high spatial and directional resolution diffusion MRI data was obtained on a 3T magnet from 33 subjects with increased familial risk for developing schizophrenia, and 28 control subjects. Diffusion tractography was performed to measure white matter integrity within AF, UF, and IOFF. To understand these abnormalities, Fractional Anisotropy (FA, a measure of tract integrity) and Trace (a measure of overall diffusion), were combined with more specific measures of axial diffusivity (AX, a putative measure of axonal integrity) and radial diffusivity (RD, a putative measure of myelin integrity). Results revealed a significant decrease in Trace within IOFF, and a significant decrease in AX in all tracts. FA and RD anomalies, frequently reported in schizophrenia, were not observed. Moreover, AX group effect was modulated by age, with increased risk subjects demonstrating a deviation from normal maturation trajectory. Findings suggest that familial risk for schizophrenia may be associated with abnormalities in axonal rather than myelin integrity, and possibly associated with disruptions in normal brain maturation. AX should be considered a possible biomarker of risk for developing schizophrenia. [Copyright &y& Elsevier]

Abstract: The default-mode network (DMN) of the brain shows highly coherent intrinsic activity in healthy subjects and is implicated in self-referential processing important for social cognitive functioning. Schizophrenia patients show abnormal resting-state connectivity within the DMN and this aberrant connectivity is thought to contribute to difficulties in self-referential and introspective processing. Subjects at increased genetic risk of developing schizophrenia, including unaffected siblings of patients, also exhibit brain abnormalities and impaired social cognitive processing. However, it is unclear whether resting-state connectivity within the DMN is abnormal in these subjects. Here, we investigate resting-state DMN connectivity in siblings and whether this is related to the functioning of the network during self-referential processing. Brain activity was measured using functional MRI in 25 unaffected siblings of patients with schizophrenia and 25 healthy controls during an 8-minute resting-state period and during a self-referential processing task in which the subjects had to indicate whether a trait adjective (e.g. “lazy”) described their personality (self-referential condition) or whether the trait was socially desirable (non-referential condition). Compared with controls, siblings showed exaggerated connectivity during resting-state between the midline areas of the DMN. Moreover, they failed to adequately modulate connectivity between these areas during self-referential processing. No abnormalities in activation during self-referential processing were observed. These findings suggest that subjects at increased genetic risk of developing schizophrenia exhibit abnormal intrinsic connectivity within the midline DMN and that this is associated with aberrant interactions between these regions during self-referential processing. [Copyright &y& Elsevier]

Abstract: 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 &y& Elsevier]

Abstract: Mounting evidence suggests that white matter abnormalities and altered subcortical–cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age- and sex-matched individuals with SPD (n=33) and healthy controls (HCs; n=38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant''s MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC–DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia. [Copyright &y& Elsevier]

Abstract: Fibers connecting fronto-temporal and fronto-medial structures that pass through the anterior limb of the internal capsule (ALIC) subserve executive and psychomotor functioning. Both of these functions are adversely affected in schizophrenia, and may be abnormal at illness onset. In a study of first-episode psychosis, we used diffusion tensor imaging (DTI) and cognitive testing to examine ALIC integrity. Fourteen early psychosis patients and 29 healthy volunteers were included. Symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). All structural and diffusion scans were acquired on a GE Signa 1.5T scanner. A T1-weighted 3D FSPGR Inversion Recovery imaging series was acquired for manual seeding in structural space. Diffusion tensor imaging (DTI) was performed, and all DTI images were co-registered to structural space. Seeds were manually drawn bilaterally on the coronal plane at a specified location. Diffusion images were post-processed for subsequent Tract-based Spatial Statistics (TBSS) analysis. First-episode psychosis patients had significantly smaller fronto-medial and fronto-temporal AIC tract volumes compared to healthy volunteers on the left and the right (p-values<0.04). No differences in mean fractional anisotropy (FA) were seen within either left or right tracts (p-values>0.05), nor did TBSS reveal any other differences in FA values between groups in other regions. Relationships between tract volumes and symptom severity were not observed in this study. [Copyright &y& Elsevier]

Abstract: There is growing evidence that schizophrenia (SZ) and bipolar disorder (BD) overlap significantly in risk factors, neurobiological features, clinical presentations, and outcomes. SZ is characterized by well documented gray matter (GM) abnormalities in multiple frontal, temporal and subcortical structures. Recent voxel-based morphometry (VBM) studies and meta-analyses in BD also report GM reductions in overlapping, albeit less widespread, brain regions. Psychosis, a hallmark of SZ, is also experienced by a significant proportion of BD patients and there is evidence that psychotic BD may be characterized by specific clinical and pathophysiological features. However, there are few studies comparing GM between SZ and psychotic BD. In this study we compared GM volumes in a sample of 58 SZ patients, 28 BD patients experiencing psychotic symptoms and 43 healthy controls using whole-brain voxel-based morphometry. SZ patients had GM reductions in multiple frontal and temporal regions compared to healthy controls and in the subgenual cortex compared to psychotic BD patients. GM volume was increased in the right posterior cerebellum in SZ patients compared to controls. However, psychotic BD patients did not show significant GM deficits compared to healthy controls or SZ patients. We conclude that GM abnormality as measured by VBM analysis is less pronounced in psychotic BD compared to SZ. This may be due to disease-specific factors or medications used more commonly in BD. [Copyright &y& Elsevier]

Abstract: Alterations in gray matter density as well as cognitive impairments are commonly described in patients with schizophrenia (SCH patients). Both gray matter deficits and cognitive impairments have recently been discussed to represent vulnerability markers of schizophrenia. The counterintuitive finding of better cognitive performance in patients with schizophrenia and cannabis use (SCH+CAN patients) compared to cannabis naïve patients is discussed as a reflection of lower vulnerability for schizophrenia in at least one subgroup of SCH+CAN patients. We hypothesized that SCH+CAN patients would display fewer gray matter deficits compared to SCH patients reflecting their presumed lower vulnerability. We therefore compared gray matter density in 30 first episode SCH+CAN and 24 first episode SCH patients using a fast diffeomorphic registration algorithm (DARTEL) and voxel-based morphometry (VBM). We found less severe cognitive impairments and middle frontal gray matter deficits in the SCH+CAN patients. In the pooled sample gray matter density was positively associated with cognitive functioning. Results may support the hypothesis of a lower biological vulnerability in at least one subgroup of SCH+CAN patients. [Copyright &y& Elsevier]

Abstract: We examined hippocampal activation in schizophrenia (SZ) with fMRI BOLD in response to the presentation of novel and familiar scenes. Voxel-wise analysis showed no group differences. However, anatomical region-of-interest analyses contrasting normal (NL), SZ-on-medication (SZ-ON), SZ-off-medication (SZ-OFF) showed substantial differences in MTL-based novelty responding, accounted for by the reduction in novelty responses in the SZ-OFF predominantly in the anterior hippocampus and parahippocampal cortex. These differences in novelty-based activation in the SZ-OFF group represent disease characteristics of schizophrenia without confounding effects of antipsychotic medication and illustrate the tendency of antipsychotic drug treatment to improve memory functions in schizophrenia. [Copyright &y& Elsevier]

Abstract: Alterations in brain function in schizophrenia and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Here we apply probabilistic independent component analysis (pICA) to resting state fMRI series in 25 schizophrenia patients and 25 matched healthy controls. We use an automated algorithm to extract the ICA component representing the default mode network (DMN) as defined by a DMN-specific set of 14 brain regions, resulting in z-scores for each voxel of the (whole-brain) statistical map. While goodness of fit was found to be similar between the groups, the region of interest (ROI) as well as voxel-wise analysis of the DMN showed significant differences between groups. Healthy controls revealed stronger effects of pICA-derived connectivity measures in right and left dorsolateral prefrontal cortices, bilateral medial frontal cortex, left precuneus and left posterior lateral parietal cortex, while stronger effects in schizophrenia patients were found in the right amygdala, left orbitofrontal cortex, right anterior cingulate and bilateral inferior temporal cortices. In patients, we also found an inverse correlation of negative symptoms with right anterior prefrontal cortex activity at rest and negative symptoms. These findings suggest that aberrant default mode network connectivity contributes to regional functional pathology in schizophrenia and bears significance for core symptoms. [Copyright &y& Elsevier]

Abstract: Background: Dysconnectivity between brain regions is thought to underlie the cognitive abnormalities that characterise schizophrenia (SZ). Consistent with this notion functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) studies in SZ have reliably provided evidence of abnormalities in functional integration and in white matter connectivity. Yet little is known about how alterations at the functional level related to abnormalities in anatomical connectivity. Methods: We obtained fMRI data during the 2-back working memory task from 25 patients with SZ and 19 healthy controls matched for age, sex and IQ. DTI data were also acquired in the same session. In addition to conventional unimodal analyses we extracted “features” [contrast maps for fMRI and fractional anisotropy (FA) for DTI] that were subjected to joint independent component analysis (JICA) in order to examine interactions between fMRI and DTI data sources. Results: Conventional unimodal analyses revealed both functional and structural deficits in patients with SZ. The JICA identified regions of joint, multimodal brain sources that differed in patients and controls. The fMRI source implicated regions within the anterior cingulate and ventrolateral prefrontal cortex and in the cuneus where patients showed relative hypoactivation and within the frontopolar cortex where patients showed relative hyperactivation. The DTI source localised reduced FA in patients in the splenium and posterior cingulum. Conclusions: This study promotes our understanding of structure–function relationships in SZ by characterising linked functional and white matter changes that contribute to working memory dysfunction in this disorder. [Copyright &y& Elsevier]

Abstract: Background: There is considerable variation in progressive brain volume changes in schizophrenia. Whether this is related to the clinical heterogeneity that characterizes the illness remains to be determined. This study examines the relationship between change in brain volume over time and individual variation in psychopathology, as measured by five continuous symptom dimensions (i.e. negative, positive, disorganization, mania and depression). Methods: Global brain volume measurements from 105 schizophrenia patients and 100 healthy comparison subjects, obtained at inclusion and 5-year follow-up, were used in this study. Symptom dimension scores were calculated by factor analysis of clinical symptoms. Using linear regression analyses and independent-samples t-tests, the relationship between symptom dimensions and progressive brain volume changes, corrected for age, gender and intracranial volume, was examined. Antipsychotic medication, outcome and IQ were investigated as potential confounders. Results: In patients, the disorganization dimension was associated with change in total brain (β=−0.295, p=0.003) and cerebellar (β=−0.349, p<0.001) volume. Furthermore, higher levels of disorganization were associated with lower IQ, irrespective of psychiatric status (i.e. patient or control). In healthy comparison subjects, disorganization score was not associated with progressive brain volume changes. Conclusion: Heterogeneity in progressive brain volume changes in schizophrenia is particularly associated with variation in disorganization. Schizophrenia patients with high levels of disorganization exhibit more progressive decrease of global brain volumes and have lower total IQ. We propose that these patients form a phenotypically and biologically homogenous subgroup that may be useful for etiological (e.g., genetic) studies. [Copyright &y& Elsevier]

Abstract: Background: The heterogeneity of symptoms and cognitive deficits in schizophrenia can be explained by abnormal connectivity between brain regions. Childhood-onset schizophrenia (COS) is a particularly severe form of schizophrenia, with an onset during a key time period for both cerebral pruning and myelination. Methods: Diffusion tensor images were acquired from 18 children and adolescents with COS and 25 controls. The COS group was divided into two sub-groups—one with linguistic impairment (LI) and the other without (NLI). The fractional anisotropy (FA), axial (AD), and radial diffusivity (RD) data from the two COS sub-groups were compared to each other and to the controls using tract-based spatial statistics (TBSS) analyses, which is a voxel-based method used to identify regions of white matter abnormalities. Results: TBSS identified several regions in the left hemisphere where the LI group had increased AD and RD relative to the NLI and the control groups. These areas primarily localized to linguistic tracts: left superior longitudinal fasciculus and left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus. Regions of increased RD overlapped regions of increased AD, with the former showing more pronounced effects. Conclusions: Studies of adult-onset schizophrenia typically identify areas of higher RD but unchanged AD; however, normal development studies have shown that while RD decreases are pronounced over this age range, smaller decreases in AD can also be detected. The observed increases in both RD and AD suggest that developmental disturbances affecting the structural connectivity of these pathways are more severe in COS accompanied by severe linguistic impairments. [Copyright &y& Elsevier]

Abstract: Objective: Previous research has linked maternal anemia during pregnancy with increased risk for schizophrenia in offspring. However, no study has sought to determine whether this early insult leads to a more severe form of the disorder, characterized by worsened motor and neurocognitive functioning. Method: Subjects were 24 cases diagnosed with schizophrenia and 22 controls from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Hemoglobin values were measured throughout pregnancy. Among offspring, psychiatric diagnoses were determined through semi-structured interviews and medical records review and comprehensive neurocognitive assessment batteries were conducted in adulthood. Results: Results indicated that among cases decreases in maternal hemoglobin led to significant decreases in scores on the Grooved Pegboard test, the Finger Tapping test and the Wechsler Adult Intelligent Scales (WAIS) information subtest. In contrast, controls only exhibited decreases in performance on the California Verbal Learning Test (CVLT) long-delay recall after fetal exposure to lower hemoglobin. There were also significant interactions between hemoglobin and case status for all of the motor tasks. Conclusions: These findings support the hypothesis that fetal exposure to decreases in maternal hemoglobin is related to preferentially poorer neuromotor function among cases compared to controls, as well as general intellectual difficulties among cases. Controls were relatively unaffected by decreased maternal hemoglobin, which suggests that liability to schizophrenia renders cases susceptible to the deleterious influences of in utero exposure to decreases in maternal hemoglobin. [Copyright &y& Elsevier]

Abstract: Background: Previous studies have shown that patients with schizophrenia show abnormalities in brain activation when processing emotional faces. However, very few studies have examined if such abnormalities are also found in non-western patient samples and in at-risk individuals. The current study explored whether patients with schizophrenia and siblings of patients in China would show abnormal brain activation during processing of emotional faces. Methods: Thirty-six participants (three groups of twelve each of patients with schizophrenia, nonpsychotic siblings, and healthy controls) took part in the study. They were administered a task to judge emotional valence of three types of faces (viz., happy, fearful, and neutral), during fMRI scanning. Results: Results of this study demonstrated that patients with schizophrenia showed abnormalities in the social brain neural circuit during facial emotion processing, in comparison with nonpsychotic siblings and healthy controls. Patients with schizophrenia demonstrated lower activation right superior and middle frontal gyrus, left precentral gyrus, left middle temporal gyrus and left insula in comparison with healthy controls; and showed abnormal activation in bilateral inferior and middle frontal gyri, right orbital frontal gyrus, left superior and middle temporal gyrus, bilateral insula, and right superior parietal gyrus/postcentral gyrus when compared with their nonpyschotic siblings. Meanwhile, patients with schizophrenia showed greater activation in left middle frontal gyrus than healthy controls, and overactivation in bilateral middle frontal gyri, right orbital frontal gyrus and left middle temporal gyrus than their nonpsychotic siblings during processing of fearful faces. Moreover, nonpsychotic siblings seemed to share some similar dysfunctions in processing facial expressions as their psychotic probands, the two groups both showed abnormal activation in precentral and superior frontal gyri, and such abnormal activation lied between patients with schizophrenia and healthy controls. Conclusions: The current findings support the universality of emotion perception impairments in schizophrenia, and also suggest that facial emotion perception might be a potential endophenotype of schizophrenia. [Copyright &y& Elsevier]

Abstract: Dysfunction of cerebral white matter (WM) is a potential factor underlying the neurobiology of schizophrenia. People with 22q11 deletion syndrome have altered brain morphology and increased risk for schizophrenia, therefore decreased WM integrity may be related to schizophrenia in 22q11DS. We measured fractional anisotropy (FA) and WM volume in 27 adults with 22q11DS with schizophrenia (n=12, 22q11DS SCZ+) and without schizophrenia (n=15, 22q11DS SCZ−), 12 individuals with idiopathic schizophrenia and 31 age-matched healthy controls. We found widespread decreased WM volume in posterior and temporal brain areas and decreased FA in areas of the frontal cortex in the whole 22q11DS group compared to healthy controls. In 22q11DS SCZ+ compromised WM integrity included inferior frontal areas of parietal and occipital lobe. Idiopathic schizophrenia patients showed decreased FA in inferior frontal and insular regions compared to healthy controls. We found no WM alterations in 22q11DS SCZ+ vs. 22q11DS SCZ−. However, there was a negative correlation between FA and PANSS scores (Positive and Negative Symptom Scale) in the whole 22q11DS group in the inferior frontal, cingulate, insular and temporal areas. This is the first study to investigate WM integrity in adults with 22q11DS. Our results suggest that pervasive WM dysfunction is intrinsic to 22q11DS and that psychotic development in adults with 22q11DS involves similar brain areas as seen in schizophrenia in the general population. [Copyright &y& Elsevier]

Abstract: Background: Structural abnormalities in the callosal fibers connecting the heteromodal association areas of the prefrontal and temporoparietal cortices bilaterally have been suggested to play a role in the etiology of schizophrenia. Aims: To investigate for geometric abnormalities in these callosal fibers in schizophrenia patients by using a novel Diffusion-Tensor Imaging (DTI) metric of fiber geometry named Shape-Normalized Dispersion (SHD). Methods: DTIs (3T, 51 gradient directions, 1.7mm isotropic voxels) were acquired from 26 schizophrenia patients and 23 matched healthy controls. The prefrontal and temporoparietal fibers of the corpus callosum were extracted by means of whole-brain tractography, and their mean SHD calculated. Results: The schizophrenia patients exhibited subnormal levels of SHD in the prefrontal callosal fibers when controlling for between-group differences in Fractional Anisotropy. Reduced SHD could reflect either irregularly turbulent or inhomogeneously distributed fiber trajectories in the corpus callosum. Conclusions: The results suggest that the transcallosal misconnectivity thought to be associated with schizophrenia could reflect abnormalities in fiber geometry. These abnormalities in fiber geometry could potentially be underpinned by neurodevelopmental irregularities. [Copyright &y& Elsevier]

Abstract: Deficit schizophrenia (D-SZ) has been proposed as a putative disease subtype defined by prominent, primary negative symptoms that endure as trait-like features during periods of clinical stability. In this study, we acquired magnetic resonance images of the whole brain using a 1.5T scanner in 19 outpatients with D-SZ, 31 with non-deficit schizophrenia (ND-SZ), and 90 healthy adults. Voxel-based morphometry was used to investigate differences in regional gray-matter volume (GMV) between outpatients with D-SZ and ND-SZ, and between the combined patient subgroups and healthy adults. Compared to healthy adults outpatients with schizophrenia showed GMV reductions, especially in left frontal and temporal cortices and in the left insula. The D-SZ subgroup showed reduced GMV in the insula bilaterally and in the left superior frontal, middle temporal and occipital gyri. Regions in which GMV reductions best distinguished D-SZ from ND-SZ patients included the superior frontal gyrus (Brodmann area 8) and superior temporal gyrus (Brodmann areas 22, 38) bilaterally, the left supplementary motor area (Brodmann area 6), left anterior cingulate, left cuneus and right putamen. These results suggest that patients with deficit schizophrenia have brain abnormalities that differ from those of patients with non-deficit schizophrenia. Further, the neuroanatomic differences between these two putative subtypes of schizophrenia involve brain regions that appear to be associated with the negative symptoms that define the deficit syndrome of schizophrenia. [Copyright &y& Elsevier]

Abstract: Background: Recent genetic results have indicated that the two major, classically distinct forms of psychosis – schizophrenia and bipolar disorder – may share causative factors in common. However it is not clear to what extent they may also have similar profiles of brain abnormality. We used meta-analytic techniques to generate and compare maps of brain structural abnormality in the large samples of patients with both disorders that have been studied using magnetic resonance imaging. Method: A systematic search was conducted for voxel-based morphometry studies examining gray matter in patients with schizophrenia or bipolar disorder. The anatomical distribution of the co-ordinates of gray matter differences was meta-analysed using Anatomical Likelihood Estimation. Results: Forty-two schizophrenia studies including 2058 patients with schizophrenia and 2131 comparison subjects were compared with fourteen bipolar studies including 366 patients with bipolar disorder and 497 comparison subjects. In schizophrenia, there were extensive gray matter deficits in frontal, temporal, cingulate and insular cortex and thalamus, and increased gray matter in the basal ganglia. In bipolar disorder, gray matter reductions were present in the anterior cingulate and bilateral insula. These substantially overlapped with areas of gray matter reduction in schizophrenia, except for a region of anterior cingulate where gray matter reduction was specific to bipolar disorder. Implications: In bipolar disorder studies there were consistent regional gray matter reductions in paralimbic regions (anterior cingulate and insula) implicated in emotional processing. Gray matter reductions in schizophrenia studies were more extensive and involved limbic and neocortical structures as well as the paralimbic regions affected in bipolar disorder. [Copyright &y& Elsevier]

Abstract: Alterations of verbal fluency may correlate with deficits of gray matter volume and hemispheric lateralization of language brain regions like the pars triangularis (PT) in schizophrenia. Examining non-psychotic individuals at high genetic risk (HR) for schizophrenia may clarify if these deficits represent heritable trait markers or state dependent phenomena. We assessed adolescent and young adult HR subjects (N =60) and healthy controls (HC; N =42) using verbal fluency tests and Freesurfer to process T1-MRI scans. We hypothesized volumetric and lateralization alterations of the PT and their correlation with verbal fluency deficits. HR subjects had letter verbal fluency deficits (controlling for IQ), left PT deficits (p =.00), (controlling ICV) and reversal of the L>R PT asymmetry noted in HC. Right Heschl''s (p =.00), left supramarginal (p =.00) and right angular gyrii (p =.02) were also reduced in HR subjects. The L>R asymmetry of the Heschl''s gyrus seen in HC was exaggerated and asymmetries of L>R of supramarginal and R>L of angular gyri, seen in HC were attenuated in HR subjects. L>R asymmetry of the PT predicted better verbal fluency across the pooled HR and HC groups. Young relatives of schizophrenia patients have verbal fluency deficits, gray matter volume deficits and reversed asymmetry of the pars triangularis. A reversed structural asymmetry of the PT in HR subjects may impair expressive language abilities leading to verbal fluency deficits. Volumetric deficits and altered asymmetry in inferior parietal and Heschl''s gyrii may accompany genetic liability to schizophrenia. [Copyright &y& Elsevier]

Abstract: Evidence so far indicates the consistent association between brain structural abnormalities and schizophrenia already present at the early phases of the illness. This study investigates the specificity of brain structural abnormalities in schizophrenia by using region-of-interest method of volumetric analysis in a heterogeneous sample of schizophrenia spectrum patients at their first break of the illness. 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with non-schizophrenic non-affective psychoses, and 83 healthy individuals underwent a magnetic resonance imaging brain scan. Quantitative brain morphometric variables were assessed: cortical CSF, lateral ventricle, total brain tissue, white matter and cortical and subcortical gray matter volumes. The contribution of sociodemographic, cognitive and clinical characterictics was controlled. Compared with controls, schizophrenia (P =0.017) and schizophreniform disorder (P =0.023) patients showed an increase in cortical CSF volume. Schizophrenia patients had also markedly enlarged lateral ventricle volume compared to controls (P =0.026). The patients with non-schizophrenic non-affective psychoses did not significantly differ in lateral ventricle and cortical CSF volumes from controls. Compared with controls, schizophrenia and schizophreniform disorder patients demonstrated a significant decrease in total brain tissue (−1.30% and −1.12% respectively). Thalamic volume was reduced (−3.84%) in schizophrenia patients compared to controls (P =0.040). Clinical and cognitive variables were not significantly related with morphological changes. The brain changes found in patients with a first episode of schizophrenia spectrum disorders are robustly associated with the diagnoses of schizophrenia and schizophreniform disorder and are independent of relevant intervening variables. [Copyright &y& Elsevier]

Abstract: 22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Objectives: 22q11.2 deletion syndrome (22q11.2DS), also known as velocardiofacial syndrome (VCFS) or DiGeorge Syndrome, is a genetic disorder due to a micro deletion on chromosome 22q11.2. VCFS is associated with abnormalities in brain structure and with an increased risk of psychiatric disorders, particularly schizophrenia. The aim of this review was to statistically summarize the structural imaging literature on VCFS which due to the relatively rarity of the disorder tends to consider small sample sizes. Method: A systematic review and meta-analysis of region of interest (ROI) studies comparing VCFS with healthy controls was carried out. Significant heterogeneity was explored using meta-regression. Results: Subjects with VCFS were characterised by global brain volumetric reduction including several cortical regions, cerebellum and hippocampus. The area of the corpus callosum was increased. Conclusions: Many regions extensively studied in schizophrenia were not covered in the existing VCFS literature. However, the studies considered support volumetric abnormalities which may help explain why VCFS is associated with a greatly increased risk of psychosis and other psychiatric disorders. [Copyright &y& Elsevier]

Abstract: Previous diffusion tensor imaging (DTI) studies have shown structural abnormalities of the cingulum bundle (CB) in patients with schizophrenia. However, regional specificity and functional relevance of the pregenual and dorsal CB subdivisions has not been fully studied. In the current study, 31 patients with schizophrenia and 65 age- and gender-matched healthy subjects underwent DTI to measure fractional anisotropy (FA) and mean diffusivity (MD) in cross sections of dorsal and pregenual CB tractography. To test the hypothesis of region-specific association with neurocognition, all of the patients and 31 controls performed the Stroop task, which is assumed to mainly involve dorsal cingulate function. The verbal memory subscale of Wechsler Memory Scale-Revised and premorbid IQs estimated from the Japanese version of the National Adult Reading Test, which were non-specific to dorsal cingulate function, were also employed as control neurocognitive indices. Significant bilateral FA reductions in the pregenual and dorsal CB, and bilateral MD increases in the dorsal CB were observed in the patients compared with the controls. As predicted, significant associations between DTI measures and neurocognition were found in the schizophrenia group only: double-dissociable correlation between higher MD in the dorsal, not in the pregenual CB, and a longer reaction time in the Stroop task, not verbal memory or premorbid IQs. The current DTI study suggests that structural disruption of the dorsal CB has region-specific functional relevance to selective attention deficits, although structural disruption also exists in the pregenual CB in patients with schizophrenia. [Copyright &y& Elsevier]

Abstract: Objective: Numerous studies have implicated the hippocampus and prefrontal cortex in schizophrenia. However, precisely which subregions of the hippocampus and prefrontal cortex are abnormal remain unknown. Our study goal was to investigate the structure of the anterior hippocampus, posterior hippocampus, dorsolateral prefrontal cortex (DLPFC), and orbitofrontal cortex (OFC) simultaneously in thirty-eight patients with schizophrenia and twenty-nine controls to determine which of these subregions are abnormal in schizophrenia. As an exploratory study goal, we investigated the relation of neurocognition to brain structure in schizophrenia patients. Method: We generated detailed structural magnetic resonance imaging data and compared hippocampal and prefrontal subregional structural brain volumes between schizophrenia and control groups. We obtained a neurocognitive test battery in schizophrenia patients and studied the association of abnormal brain structures to neurocognition. Results: Structural brain abnormalities were pinpointed to the left anterior hippocampus and left OFC in schizophrenia patients, which were both significantly reduced in volume. The DLPFC and posterior hippocampus, though numerically decreased in volume, were not significantly decreased. Anterior hippocampal volumes were more strongly associated with OFC volumes in schizophrenia patients compared to controls. By contrast, DLPFC volume was unrelated to anterior or posterior hippocampal volume. Both the anterior hippocampus and OFC were independently related to cognitive abnormalities common in schizophrenia, including indices of verbal, language, and executive functions. The DLPFC and posterior hippocampal volumes were unrelated to cognitive measures. Conclusions: These findings highlight related abnormalities of the anterior hippocampus and OFC in schizophrenia, which may shed light on the pathophysiology of the disorder. [Copyright &y& Elsevier]

Abstract: Maternal infection during pregnancy has been associated with an increased risk for the development of schizophrenia, a disorder characterized by abnormalities in hippocampal morphology and function. Neurogenesis occurs in the hippocampus throughout development into adulthood and is believed to modulate hippocampal function. This study used a rat model in which bacterial endotoxin, lipopolysaccharide (LPS), is administered to pregnant dams, to test if prenatal immune activation has acute and/or long term effects on various phases of neurogenesis (proliferation, survival, differentiation) in the hippocampal dentate gyrus of offspring. When LPS was administered to dams on gestation days (GD) 15 and 16, there was decreased proliferation of dentate cells at postnatal day (PD) 14 and decreased survival of cells generated at PD14 in offspring. When prenatal exposure to LPS was later in pregnancy (GD 18 and 19), offspring showed decreased survival of cells generated both at the time of LPS exposure and at PD14. There was no change in cell proliferation or survival in adult offspring at PD60, with prenatal LPS exposure. Co-administration of the cyclo-oxygenase inhibitor, ibuprofen (IBU), together with prenatal LPS on GD 15 and 16, was unable to prevent the deficit in neuronal survival at PD14. IBU blocked LPS-induced fever but did not block LPS-induced increases in plasma cytokines and corticosterone in the pregnant dam. This indicates that deficits in neurogenesis caused by prenatal LPS are not mediated by LPS-induced fever or eicosanoid induction, but could be mediated by LPS-induced increases in maternal cytokines or corticosterone. [Copyright &y& Elsevier]

Abstract: Abnormalities of brain white matter and oligodendroglia are among the most consistent findings in schizophrenia (Sz) research. Various gene expression microarray studies of post-mortem Sz brains showed a downregulation of myelin transcripts, while imaging and microscopy studies demonstrated decreases in prefrontal cortical (PFC) white matter volume and oligodendroglia density. Currently, the extent to which reduced oligodendrocyte markers contribute to pathophysiological domains of Sz is unknown. We exposed adolescent rats to cuprizone (CPZ), a copper chelator known to cause demyelination in mice, and examined expression of oligodendrocyte mRNA transcripts and PFC-mediated behavior. Rats on the CPZ diet showed decreased expression of mRNA transcripts encoding oligodendroglial proteins within the medial PFC, but not in the hippocampus or the striatum. These rats also displayed a specific deficit in the ability to shift between perceptual dimensions in the attentional set-shifting task, a PFC-mediated behavioral paradigm modeled after the Wisconsin Card Sorting Test (WCST). The inability to shift strategies corresponds to the deficits exhibited by Sz patients in the WCST. The results demonstrate that a reduction in oligodendrocyte markers is associated with impaired PFC-mediated behaviors. Thus, CPZ exposure of rats can serve as a model to examine the contribution of oligodendrocyte perturbation to cognitive deficits observed in Sz. [Copyright &y& Elsevier]

Abstract: Background: We have previously demonstrated that putaminal but not caudate volumes are associated with poor outcome in patients with chronic schizophrenia. Present longitudinal study was designed to investigate progressive differences in striatal volumes among chronic schizophrenia patients with different outcomes and healthy subjects. Methods: Structural MRI scans were acquired at baseline and at follow-up four years later to evaluate volumetric changes in 26 poor-outcome schizophrenia patients, 23 good-outcome patients and 16 healthy subjects. Results: Schizophrenia patients with different outcomes entered the study with similar volumes of the caudate nucleus and putamen. The rate of decline in volumes of the putamen was greater in patients with poor outcome than in the good-outcome group, so that their putaminal but not caudate volumes were significantly smaller at the time of follow-up. There were no differences in baseline and follow-up volumes of the putamen or in the rate of their progression among patients with schizophrenia and healthy comparison subjects. The caudate volumes were lower in schizophrenia patients than healthy subjects at baseline and follow-up, but showed no differential patterns of progression between the groups. Conclusions: Volumes of the putamen may represent a longitudinal marker of treatment responsiveness and outcome in patients with chronic schizophrenia. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Two of the most frequently investigated regions in diffusion tensor imaging studies in chronic schizophrenia are the uncinate fasciculus (UF) and cingulum bundle (CB). The purpose of the present study was to determine whether UF and CB white matter integrity were altered at the early stage of illness and specific to schizophrenia. Fifteen schizophrenia subjects and 15 affective psychosis within 4 years of first hospitalization (12 patients with schizophrenia and 12 patients with affective psychosis during their first hospitalization), and 15 psychiatrically healthy controls underwent line-scan diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (D m) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Bilaterally reduced FA, but not D m, was present in the UF of schizophrenia compared with healthy controls. Affective psychosis was intermediate between schizophrenia subjects and healthy controls, but not significantly different from either. For CB, there was no significant group difference for FA or D m. These findings suggest that UF, but not CB, white matter integrity is altered at the early stage of illness in schizophrenia although it may not be specific to schizophrenia. The CB abnormalities reported in chronic schizophrenia may develop during the later course of the disease. [Copyright &y& Elsevier]

Abstract: Background: Contemporary theories and evidence implicate defective emotion regulation in violent behaviour. The two psychiatric illnesses most implicated in violence are schizophrenia and antisocial personality disorder (APD). This study examined behavioural and brain abnormalities in violent men with schizophrenia or APD during anticipatory fear. Method: Fifty-three men [14 non-violent healthy controls, 13 with schizophrenia and a history of serious violence (VSZ), 13 with schizophrenia without a history of violence (SZ), 13 with APD and a history of serious violence] underwent blood-oxygenation-level-dependent fMRI during an experiment involving repeated presentations of ‘safe’ and ‘threat of electric shock’ conditions and provided ratings of shock anticipation and fear. Schizophrenia patients did not have co-morbid APD. Results: VSZ participants reported the highest, and APD participants the lowest, level of shock anticipation and fear, with intermediate ratings by SZ and healthy participants. The violent, relative to non-violent, groups showed altered activity modulation in occipital and temporal regions, from early to latter parts of threat periods. Additionally, VSZ patients displayed exaggerated whereas APD patients showed attenuated thalamic-striatal activity during latter threat periods. Conclusions: Aberrant activity in occipital and temporal regions when exposed to sustained visual threat cues is associated with a predisposition to violence in both schizophrenia and APD. This common biological deficit, however, appears to arise from dissimilar behavioural mechanisms related to differences in the strength of aversive conditioning and behavioural response to sustained threat cues (enhanced in VSZ; attenuated in APD), also reflected in opposite patterns of alternations in thalamic-striatal activity, in these two disorders. [Copyright &y& Elsevier]

Abstract: Objective: Tardive dyskinesia (TD) is a severe side effect of antipsychotics. While increasing evidence suggests that damaged brain microcircuitry of white matter (WM) is responsible for the clinical symptoms in schizophrenia, no reports of WM abnormality associated with TD were noted. Method: Brain white matter abnormalities were investigated among 20 schizophrenia patients with TD (Schizophrenia with TD group), 20 age-, gender-, and handedness-matched schizophrenic patients without TD (Schizophrenia without TD group), and 20 matched healthy subjects with magnetic resonance imaging and diffusion tensor imaging analysis. Voxel-wise analysis was used to compare fractional anisotropy (FA) maps of the white matter following intersubject registration to Talairach space. Clinical ratings included the Positive and Negative Symptoms Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS). Results: The study subjects were 75% female with average of 40.1±9. 8 years. The Schizophrenia with TD group had significantly higher PANSS total scores (p =0.024), PANSS negative score (p =0.001), SAS (p <0.001) and AIMS (p <0.001) scores; and demonstrated more widespread FA decreases than the Schizophrenia without TD group, especially over the inferior frontal gyrus, temporal sublobar extranuclear WM (around the basal ganglion), parietal precuneus gyrus WM (around somatosensory cortex), and medial frontal gyrus WM (around dorsolateral prefrontal cortex). The AIMS (p <0.01) and SAS (p <0.01) score positively correlated with decreased FA over these areas, and PANSS negative score positively correlated with FA decrease over medial frontal gyrus WM (p <0.01). Conclusions: More widespread abnormality of white matter was noted among schizophrenia patients than those without, especially involved cortico-basal ganglion circuits with clinical symptom correlation of involuntary movements and negative symptoms. Further studies with larger sample size are required to validate the findings. [Copyright &y& Elsevier]

Abstract: The search for genes conferring liability for schizophrenia may be aided by the identification of endophenotypes. Response selection is a heritable cognitive function that is impaired in patients with schizophrenia and their unaffected siblings. The abnormalities in cerebral function that presumably underlie the deficit in patients and unaffected siblings remain to be elucidated. Cerebral neurophysiology during performance of a 4-choice reaction time (CRT) task in 25 patients with schizophrenia (15 medication free first episode (FEP) and 10 chronic patients), 32 controls, and 12 unaffected siblings of individuals with schizophrenia was investigated using fMRI. CRT was impaired in both medication free FEP and chronic patients with schizophrenia, and unaffected siblings. FEP patients, chronic patients, and unaffected siblings demonstrated greater BOLD response in the right dorsolateral prefrontal cortex (dlPFC) during CRT task blocks. The nature of the altered activation in the dlPFC was further examined using functional connectivity analysis. This revealed marked reductions in connectivity between the right dlPFC and multiple brain regions in both patient groups and, to a lesser degree, unaffected siblings. The magnitude of connectivity between right dlPFC and inferior parietal lobule correlated with task performance in the combined patient/unaffected siblings group, but not controls suggesting that the network of brain regions recruited to perform the task differed as a function of genetic liability for schizophrenia. The findings suggest that altered activity and connectivity of the right dlPFC appears to be related to genetic vulnerability for schizophrenia and may represent a potential endophenotype of the disorder. [Copyright &y& Elsevier]