Structural Brain Abnormalities In Schizophrenia Research Articles

White matter impairments in patients with schizophrenia: A multisite diffusion MRI study

There is a lack of convincing and replicative findings regarding white matter abnormalities in schizophrenia. Several multisite diffusion magnetic resonance imaging (dMRI) studies have been conducted to increase statistical power and reveal subtle white matter changes. Data pooling methods are crucial in joint analysis to compensate for the use of different scanners and image acquisition parameters. A harmonization method using raw dMRI data was developed to overcome the limited generalizability of previous data pooling methods. We obtained dMRI data of 242 healthy controls and 190 patients with schizophrenia from four different study sites. After applying the harmonization method to the raw dMRI data, a two-tensor whole-brain tractography was performed, and diffusion measures were compared between the two groups. The correlation of fractional anisotropy (FA) with the positive and negative symptoms was evaluated, and the interaction effect of diagnosis-by-age, age-squared, and sex was examined. The following white matter tracts showed significant group differences in the FA: the right superior longitudinal fascicle (SLF), the left-to-right lateral orbitofrontal commissural tract, pars orbitalis (pOr-pOr) commissural tract, and pars triangularis (pTr-pTr) commissural tract. The FA of the right SLF and pTr-pTr commissural tract were significantly associated with the Positive and Negative Syndrome Scale (PANSS) positive and negative scores. No significant interaction effect was observed. These findings add to the evidence on structural brain abnormalities in schizophrenia and can aid in obtaining a better understanding of the biological foundations of schizophrenia.

Functional and Structural Brain Abnormalities in Schizophrenia: A Multimodal Meta-Analysis of Neuroimaging Studies

Functional and Structural Brain Abnormalities in Schizophrenia: A Multimodal Meta-Analysis of Neuroimaging Studies

Structural brain abnormalities in schizophrenia in adverse environments: examining the effect of poverty and violence in six Latin American cities.

Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear. We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed. This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model. A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = -0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure. Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.

A Systematic Characterization of Structural Brain Changes in Schizophrenia.

A systematic characterization of the similarities and differences among different methods for detecting structural brain abnormalities in schizophrenia, such as voxel-based morphometry (VBM), tensor-based morphometry (TBM), and projection-based thickness (PBT), is important for understanding the brain pathology in schizophrenia and for developing effective biomarkers for a diagnosis of schizophrenia. However, such studies are still lacking. Here, we performed VBM, TBM, and PBT analyses on T1-weighted brain MR images acquired from 116 patients with schizophrenia and 116 healthy controls. We found that, although all methods detected wide-spread structural changes, different methods captured different information - only 10.35% of the grey matter changes in cortex were detected by all three methods, and VBM only detected 11.36% of the white matter changes detected by TBM. Further, pattern classification between patients and controls revealed that combining different measures improved the classification accuracy (81.9%), indicating that fusion of different structural measures serves as a better neuroimaging marker for the objective diagnosis of schizophrenia.

Gray matter volume changes following antipsychotic therapy in first-episode schizophrenia patients: A longitudinal voxel-based morphometric study

Despite evidence of structural brain abnormalities in schizophrenia, the current study aimed to explore the effects of antipsychotic treatment on gray matter (GM) volume using structural magnetic resonance imaging (MRI) and investigate the relationship between brain structure and treatment response. The GM volumes of 33 patients with first-episode schizophrenia were calculated with voxel-based morphometry (VBM), with 33 matched healthy controls. Longitudinal volume changes within subjects after 4-month antipsychotic treatment were also evaluated. Correlation between volumetric changes and clinical symptoms derived from the Positive and Negative Syndrome Scale (PANSS) were further investigated. Compared with healthy controls, decreased GM volumes in the frontal gyrus were observed in schizophrenia patients. After 4-month treatment, patients showed significantly decreased GM volume primarily in the bilateral frontal, temporal and left parietal brain regions. In addition, the GM volume changes of the left postcentral gyrus was positively correlated with negative symptoms improvement, and the correlation analysis revealed the total PANSS scores changes were associated with GM volume changes in the right inferior frontal gyrus and the right superior temporal gyrus. Besides, non-responders had reduced GM volume in the bilateral middle frontal gyrus and the right superior frontal gyrus compared with responders and healthy controls. Our results suggest that the abnormality in the right frontal gyrus exists in the early stage of schizophrenia. Moreover, the relationship between antipsychotics and structural changes was identified. The GM volume might have the potential to reflect the symptom improvement in schizophrenia patients. And MRI may assist in predicting the antipsychotic treatment response in first-episode schizophrenia patients.

Recognition of Schizophrenia with Regularized Support Vector Machine and Sequential Region of Interest Selection using Structural Magnetic Resonance Imaging

Structural brain abnormalities in schizophrenia have been well characterized with the application of univariate methods to magnetic resonance imaging (MRI) data. However, these traditional techniques lack sensitivity and predictive value at the individual level. Machine-learning approaches have emerged as potential diagnostic and prognostic tools. We used an anatomically and spatially regularized support vector machine (SVM) framework to categorize schizophrenia and healthy individuals based on whole-brain gray matter densities estimated using voxel-based morphometry from structural MRI scans. The regularized SVM model yielded recognition accuracy of 86.6% in the training set of 127 individuals and validation accuracy of 83.5% in an independent set of 85 individuals. A sequential region-of-interest (ROI) selection step was adopted for feature selection, improving recognition accuracy to 92.0% in the training set and 89.4% in the validation set. The combined model achieved 96.6% sensitivity and 74.1% specificity. Seven ROIs were identified as the optimal discriminatory subset: the occipital fusiform gyrus, middle frontal gyrus, pars opercularis of the inferior frontal gyrus, anterior superior temporal gyrus, superior frontal gyrus, left thalamus and left lateral ventricle. These findings demonstrate the utility of spatial and anatomical priors in SVM for neuroimaging analyses in conjunction with sequential ROI selection in the recognition of schizophrenia.

TSPO expression and brain structure in the psychosis spectrum

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Brain anatomy of symptom stratification in schizophrenia: A voxel based morphometry study

IntroductionAlthough some magnetic resonance imaging (MRI) studies have investigated the existence of a relationship between clinical severity and neuroanatomical alterations in patients with schizophrenia (SCZ), the biological signature associated with illness severity in schizophrenia is still uncertain.ObjectivesThis study aims to investigate structural brain abnormalities in SCZ with particular regards to the identification of potential deficits associated to the severity of illness.Methods1.5 T MRI data were acquired for 61 subjects with SCZ and 59 matched healthy controls (HC). The patient group was divided in two subgroups based on clinical severity, one composed by 34 mild-to-moderately ill patients and the other one by 27 severely ill patients, and compared with matched HC.ResultsThe whole group of patients with SCZ had significantly reduced gray matter (GM) volumes in left inferior and middle temporal gyrus compared to HC (P < 0.05, pFWE corrected). Furthermore, compared to HC, patients with mild-to-moderate illness showed decreased GM volumes in inferior temporal gyrus (P < 0.05, pFWE corrected) whereas those with severe illness had reduced right cerebellum (P < 0.05, cFWE corrected). No differences were observed between the two subgroups of patients.ConclusionsOur results showed significant GM volume reductions in left inferior and middle temporal gyrus in patients with SCZ compared to matched HC, confirming the role of this region in the pathophysiology of SCZ. Furthermore, we identified specific cerebellar gray matter volume reductions in patients with severe illness, which may contribute to stratify patients with SCZ according to their clinical phenotype expression, ultimately helping in guiding targeted therapeutic/rehabilitation interventions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Brain anatomy of symptom stratification in schizophrenia: a voxel-based morphometry study

Background: Although some Magnetic Resonance Imaging (MRI) studies have investigated the relationship between clinical severity and neuroanatomical alterations in patients with schizophrenia (SCZ), the biological signature associated with illness severity in schizophrenia is still uncertain. Therefore, this study aims to investigate structural brain abnormalities in SCZ, with particular regards to the identification of potential deficits associated with the severity of illness.Methods: In total, 1.5T MRI data were acquired for 61 subjects with SCZ and 59 matched healthy controls (HC). The patient group was divided in two sub-groups based on clinical severity, one composed of 34 mild-to-moderately ill patients, and the other of 27 severely ill patients, and compared with matched HC.Results: The whole group of patients with SCZ had significantly reduced grey matter (GM) volumes in the left inferior and middle temporal gyrus compared to HC (p < 0.05, pFWE corrected). Furthermore, compared to HC, patients with mild-to-moderate illness showed decreased GM volumes in the inferior and middle temporal gyrus, whereas those with severe illness had reduced GM volumes in the middle temporal gyrus and cerebellum bilaterally (all p < 0.001 uncorrected). No differences were observed between the two sub-groups of patients.Conclusion: The results showed significant GM volume reductions in temporal regions in patients with SCZ compared to matched HC, confirming the role of these regions in the pathophysiology of SCZ. Furthermore, specific cerebellar grey matter volume reductions were identified in patients with severe illness, which may contribute to stratifying patients with SCZ according to their clinical phenotype expression, ultimately helping in guiding targeted therapeutic/rehabilitation interventions.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness.

Background: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinal MRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-based morphometry (VBM) study was carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertain which (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity.Methods: We gathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) from four previous morphometric MRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General Linear Model Analysis of Co-variance (ANCOVA), always including total GM volume, scan protocol, age and gender as nuisance variables. Finally, correlation analyses were performed between the aforementioned clinical moderators and regional and global brain volumes.Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regions were directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region.Conclusion: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Antipsychotics Linked to Cortical Loss in Patients With Schizophrenia

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessAntipsychotics Linked to Cortical Loss in Patients With SchizophreniaVabren WattsVabren WattsSearch for more papers by this authorPublished Online:28 Sep 2015https://doi.org/10.1176/appi.pn.2015.10a14AbstractThough antipsychotic use in patients with schizophrenia was found to be associated with reduction in cortical gray matter volume, first-generation antipsychotics may cause greater reduction than second-generation antipsychotics.Although it is well established that patients with schizophrenia have deficits in cortical gray matter, a meta-analysis published in the September issue of Biological Psychiatry suggests that cumulative antipsychotic intake and the type of antipsychotic a patient with schizophrenia takes may influence the degree of gray matter loss over time.Triff/ShutterstockResearchers from the Department of Mental Health at the University of Brescia School of Medicine in Italy led a retrospective study to determine whether changes in cortical gray matter differ between patients with schizophrenia who take first-generation antipsychotics and those who take second-generation antipsychotics.“The role played by antipsychotic treatment on the pathophysiologic trajectory of brain abnormalities in schizophrenia is currently a matter of lively debate,” explained the study’s lead author, Antonio Vita, M.D., Ph.D., a professor of psychiatry at the University of Brescia, in an interview with Psychiatric News. As Vita and his colleagues noted in the paper, qualitative reviews and independent studies addressing the topic of structural brain changes in schizophrenia in relation to antipsychotic treatment have yielded inconclusive results, with few looking at whether a patient was prescribed first-generation or second-generation antipsychotics.To evaluate the influence of antipsychotic treatment on cortical gray matter volume in patients with schizophrenia, the researchers compiled data from 18 longitudinal magnetic resonance imaging studies, published from January 1, 1983, to March 31, 2014, totaling 1,155 patients with schizophrenia and 911 healthy controls. The results showed that patients with schizophrenia showed significantly greater loss of total cortical gray matter volume than healthy controls, which was related to cumulative antipsychotic intake during the interval between imaging scans among the longitudinal studies. When comparing changes in cortical gray matter volumes in patients who were treated with first-generation antipsychotics (FGAs) with those who were treated with second-generation antipsychotics (SGAs), the researchers found that greater gray matter loss was correlated with higher mean daily dose in studies including patients treated with FGAs, whereas less progressive loss was observed in studies including only patients treated with SGAs. “On the whole, our results indicate that the putative contributory role of antipsychotic treatment in reducing the volume of cortical [gray matter] in schizophrenia cannot be generalized and appears to be less evident for SGAs, which seem to be associated with less loss of brain tissue,” the study authors wrote.Vita told Psychiatric News that many issues remain to be clarified. “We still do not know whether the effects on the brain of antipsychotics vary as a function of age and stage of illness, or whether they may occur only when a certain threshold of exposure [daily dose or cumulative dose] is reached,” said Vita. He concluded that “clarification of these issues will have crucial importance in the clinical management of schizophrenia and will allow a better understanding of the mechanisms underlying the progression of structural brain abnormalities in schizophrenia.”The study was funded by a grant from the Lombardia Region. ■“The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies” can be accessed here. ISSUES NewArchived

Neuroimaging studies of social cognition in schizophrenia.

Impaired social cognition is considered a core contributor to unfavorable psychosocial functioning in schizophrenia. Rather than being a unitary process, social cognition is a collection of multifaceted processes that recruit multiple brain structures, thus structural and functional neuroimaging techniques are ideal methodologies for revealing the underlying pathophysiology of impaired social cognition. Many neuroimaging studies have suggested that in addition to white-matter deficits, schizophrenia is associated with decreased gray-matter volume in multiple brain areas, especially fronto-temporal and limbic regions. However, few schizophrenia studies have examined associations between brain abnormalities and social cognitive disabilities. During the last decade, we have investigated structural brain abnormalities in schizophrenia using high-resolution magnetic resonance imaging, and our findings have been confirmed by us and others. By assessing different types of social cognitive abilities, structural abnormalities in multiple brain regions have been found to be associated with disabilities in social cognition, such as recognition of facial emotion, theory of mind, and empathy. These structural deficits have also been associated with alexithymia and quality of life in ways that are closely related to the social cognitive disabilities found in schizophrenia. Here, we overview a series of neuroimaging studies from our laboratory that exemplify current research into this topic, and discuss how it can be further tackled using recent advances in neuroimaging technology.

Poster #T182 CLINICAL PREDICTORS OF THE DIAGNOSTIC STABILITY OF BRIEF PSYCHOTIC DISORDER

There is a lack of convincing and replicative findings regarding white matter abnormalities in schizophrenia. Several multisite diffusion magnetic resonance imaging (dMRI) studies have been conducted to increase statistical power and reveal subtle white matter changes. Data pooling methods are crucial in joint analysis to compensate for the use of different scanners and image acquisition parameters. A harmonization method using raw dMRI data was developed to overcome the limited generalizability of previous data pooling methods. We obtained dMRI data of 242 healthy controls and 190 patients with schizophrenia from four different study sites. After applying the harmonization method to the raw dMRI data, a two-tensor whole-brain tractography was performed, and diffusion measures were compared between the two groups. The correlation of fractional anisotropy (FA) with the positive and negative symptoms was evaluated, and the interaction effect of diagnosis-by-age, age-squared, and sex was examined. The following white matter tracts showed significant group differences in the FA: the right superior longitudinal fascicle (SLF), the left-to-right lateral orbitofrontal commissural tract, pars orbitalis (pOr-pOr) commissural tract, and pars triangularis (pTr-pTr) commissural tract. The FA of the right SLF and pTr-pTr commissural tract were significantly associated with the Positive and Negative Syndrome Scale (PANSS) positive and negative scores. No significant interaction effect was observed. These findings add to the evidence on structural brain abnormalities in schizophrenia and can aid in obtaining a better understanding of the biological foundations of schizophrenia.

Focal and global brain measurements in siblings of patients with schizophrenia.

It remains unclear whether structural brain abnormalities in schizophrenia are caused by genetic and/or disease-related factors. Structural brain abnormalities have been found in nonpsychotic first-degree relatives of patients with schizophrenia, but results are inconclusive. This large magnetic resonance imaging study examined brain structures in patients with schizophrenia, their nonpsychotic siblings, and healthy control subjects using global and focal brain measurements. From 155 patients with schizophrenia, their 186 nonpsychotic siblings, and 122 healthy controls (including 25 sibling pairs), whole-brain scans were obtained. Segmentations of total brain, gray matter (GM), and white matter of the cerebrum, lateral and third ventricle, and cerebellum volumes were obtained. For each subject, measures of cortical thickness and GM density maps were estimated. Group differences in volumes, cortical thickness, and GM density were analyzed using Structural Equation Modeling, hence controlling for familial dependency of the data. Patients with schizophrenia, but not their nonpsychotic siblings, showed volumetric differences, cortical thinning, and reduced GM density as compared with control subjects. This study did not reveal structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects using multiple imaging methods. Therefore, the structural brain abnormalities observed in patients with schizophrenia are for the largest part explained by disease-related factors.

S12-5 Mismatch negativity: a physiological index of functional and structural brain abnormalities in schizophrenia

S12-5 Mismatch negativity: a physiological index of functional and structural brain abnormalities in schizophrenia

Genetic Associations of Brain Structural Networks in Schizophrenia: A Preliminary Study

Schizophrenia is a complex genetic disorder, with multiple putative risk genes and many reports of reduced cortical gray matter. Identifying the genetic loci contributing to these structural alterations in schizophrenia (and likely also to normal structural gray matter patterns) could aid understanding of schizophrenia's pathophysiology. We used structural parameters as potential intermediate illness markers to investigate genomic factors derived from single nucleotide polymorphism (SNP) arrays. We used research quality structural magnetic resonance imaging (sMRI) scans from European American subjects including 33 healthy control subjects and 18 schizophrenia patients. All subjects were genotyped for 367 SNPs. Linked sMRI and genetic (SNP) components were extracted to reveal relationships between brain structure and SNPs, using parallel independent component analysis, a novel multivariate approach that operates effectively in small sample sizes. We identified an sMRI component that significantly correlated with a genetic component (r = -.536, p < .00005); components also distinguished groups. In the sMRI component, schizophrenia gray matter deficits were in brain regions consistently implicated in previous reports, including frontal and temporal lobes and thalamus (p < .01). These deficits were related to SNPs from 16 genes, several previously associated with schizophrenia risk and/or involved in normal central nervous system development, including AKT, PI3K, SLC6A4, DRD2, CHRM2, and ADORA2A. Despite the small sample size, this novel analysis method identified an sMRI component including brain areas previously reported to be abnormal in schizophrenia and an associated genetic component containing several putative schizophrenia risk genes. Thus, we identified multiple genes potentially underlying specific structural brain abnormalities in schizophrenia.

Morphometric Brain Abnormalities in Schizophrenia in a Population-Based Sample: Relationship to Duration of Illness

Biased recruitment and sample selection may cause variability in neuroimaging studies. Epidemiologically principled population-based magnetic resonance imaging (MRI) studies of schizophrenia are very rare. We gathered structural MRI data on 154 subjects from the Northern Finland 1966 Birth Cohort, aged 33-35 (100 controls, 54 schizophrenia patients). Regional differences in density of gray matter, white matter, and cerebrospinal fluid (CSF) were identified between groups using nonparametric statistical analysis, and the relationship of the regional differences to duration of illness was explored. Gray matter reductions were found bilaterally in the cerebellum, thalamus, basal ganglia, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, insula, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, cuneus, and lingual gyrus; in the left posterior cingulate, superior frontal gyrus, transverse temporal gyrus, and precuneus; and in the right postcentral gyrus. Gray matter excesses were observed bilaterally in the basal ganglia, anterior cingulate, and medial orbitofrontal cortices. There were white matter deficits in an extensive network including inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal, and occipital lobes, subcortical structures, cerebellum, and brain stem. CSF excesses were found bilaterally in the lateral ventricles, third ventricle, interhemispheric, and left Sylvian fissure. We replicated the previous findings of structural brain abnormalities in schizophrenia on a general population level. Gray and white matter deficits were associated with duration of illness suggesting either that developmental brain deficits relate to an earlier age of onset or that brain abnormalities in schizophrenia are progressive in nature.

Gray matter abnormalities in paranoid schizophrenia and their clinical correlations

Numerous imaging studies have shown structural brain abnormalities in schizophrenia. Recently, voxel-based morphometry enabled whole brain analysis beyond the regions of interest (ROI). Regional gray matter concentrations of magnetic resonance (MR) images from 35 patients with paranoid schizophrenia were compared with those from 35 age- and sex-matched controls, and their clinical correlations were explored using voxel-based morphometry. Gray matter concentrations in the patients were significantly reduced in the left insular and dorsolateral prefrontal regions, and bilaterally in the medial frontal, anterior cingulate, inferior frontal and superior temporal regions. On the other hand, gray matter concentrations in the bilateral cerebellum and right striatum were significantly increased in the patients compared with controls. A negative correlation between the score for the severity of ‘lack of insight and judgment’ and gray matter concentrations in the left posterior and right anterior cingulate and bilateral inferior temporal regions including the lateral fusiform gyri was found. These results suggest the important roles of the paralimbic structures in the pathophysiology of schizophrenia and the involvement of the perceptual and monitoring systems in the mechanism of insight.

Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives

Structural brain abnormalities in schizophrenia are well replicated; many emerge before the onset of illness and are present in relatives who remain well. Structural changes in bipolar disorder are less clearly established. The possibility that structural abnormalities might provide a means by which the disorders might be separated is one that has attracted limited research effort. This study sought to examine these issues and clarify the associations of phenotypic expression and genetic liability. Forty-nine control subjects, 71 patients, and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone, and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives were recruited from the families of the three patient groups. Subjects underwent a magnetic resonance imaging scan of the brain, which was analyzed with a grey-matter-optimized, voxel-based morphometry technique. Compared with control subjects, all patient and relative groups showed evidence of reduced anterior thalamic gray matter. Reductions in middle prefrontal gyrus and dorsomedial thalamus were specific to participants with schizophrenia. Whereas prefrontal and dorsomedial thalamic gray matter reductions seem to be specific to schizophrenia, anterior thalamic reductions seem to be a marker of liability to psychosis in general. These results are discussed in the context of their functional role and in terms of their connections with other cortical and subcortical structures.

Progressive Structural Brain Abnormalities and Their Relationship to Clinical Outcome

Many studies have shown that structural brain abnormalities in schizophrenia are already present by the time of index evaluation of first-episode patients. However, whether these abnormalities progressively worsen during the subsequent course of the disorder remains unresolved. To study the longitudinal progression of structural brain abnormalities, high-resolution multispectral magnetic resonance images obtained on 73 recent-onset schizophrenic patients and 23 controls were analyzed using state-of-the-art, well-validated, and highly reliable neuroimaging tools. The mean duration between initial and follow-up MRIs was 3 years. Repeated-measures analysis of covariance was carried out to determine (1) whether brain volume changes differed between patients and controls and (2) the significance of regional brain changes on functional outcome in schizophrenia. We found accelerated enlargement in cortical sulcal cerebrospinal fluid spaces early in the course of schizophrenia. Instead of the usual trajectory of volume enlargement, patients showed progressive reduction in frontal lobe white matter volume. A reciprocal increase in frontal lobe cerebrospinal fluid volume also occurred at a more rapid rate in patients than in controls. In keeping with most of our a priori hypotheses, patients with poor outcome had greater lateral ventricular enlargement over time than patients with good outcome. Progressive decrement in frontal lobe white matter volume and enlargement in frontal lobe cerebrospinal fluid volume were associated with greater negative symptom severity. Reductions in frontal lobe gray and white matter volumes correlated with poorer executive functioning. There are ongoing changes in the brains of schizophrenic patients during the initial years after diagnosis despite ongoing antipsychotic drug treatment. These progressive changes seem to be most evident in the frontal lobes and to correlate with functional impairment. Disruptions in neurodevelopment or neural plasticity may act alone or in combination to bring about these progressive brain deficits in schizophrenia.