Brain Volumes in Schizophrenia: A Meta-Analysis in Over 18 000 Subjects
TL;DR: Brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.
Abstract: Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.
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University of California, Irvine1, University of Southern California2, Yale University3, Oslo University Hospital4, Karolinska Institutet5, University of Oslo6, University of California, San Diego7, University of Göttingen8, Trinity College, Dublin9, National University of Ireland, Galway10, University of Amsterdam11, VU University Amsterdam12, University of Pennsylvania13, San Francisco VA Medical Center14, University of California, San Francisco15, University of Minnesota16, Harvard University17, Dresden University of Technology18, University of New Mexico19, University of Iowa20, Utrecht University21, University of California, Los Angeles22, University of Cantabria23, Northwestern University24, University of Edinburgh25, Osaka University26, Georgia State University27
TL;DR: Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches, and validates that collaborative data analyses can readily be used across brain phenotypes and disorders.
Abstract: The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.
919 citations
TL;DR: It is proposed that mind-wandering is best understood as a member of a family of spontaneous-thought phenomena that also includes creative thought and dreaming, and can shed new light on mental disorders that are marked by alterations in spontaneous thought, including depression, anxiety and attention deficit hyperactivity disorder.
Abstract: Mind-wandering is often defined as task-unrelated or stimulus-unrelated thought. In this Review, Christoff and colleagues present a definition for mind-wandering that places more emphasis on the dynamic nature of this process. They also examine the brain networks underlying mind-wandering and its involvement in various brain disorders. Most research on mind-wandering has characterized it as a mental state with contents that are task unrelated or stimulus independent. However, the dynamics of mind-wandering — how mental states change over time — have remained largely neglected. Here, we introduce a dynamic framework for understanding mind-wandering and its relationship to the recruitment of large-scale brain networks. We propose that mind-wandering is best understood as a member of a family of spontaneous-thought phenomena that also includes creative thought and dreaming. This dynamic framework can shed new light on mental disorders that are marked by alterations in spontaneous thought, including depression, anxiety and attention deficit hyperactivity disorder.
807 citations
TL;DR: Genome-wide association studies of brain imaging data from 8,428 individuals in UK Biobank show that many of the 3,144 traits studied are heritable, and genes associated with individual phenotypes are identified.
Abstract: The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.
504 citations
TL;DR: Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases, and some of these neuroanatomical alterations may be associated with antipsychotic treatment.
431 citations
University of Tokyo1, Iwate Medical University2, Osaka University3, National Institute of Radiological Sciences4, University of Tsukuba5, University of Southern California6, University of California, Irvine7, Kyoto University8, Kyushu University9, Hokkaido University10, University of Toyama11, Yamaguchi University12, Nagoya University13, Kanazawa Medical University14, University of Occupational and Environmental Health Japan15, Georgia State University16
TL;DR: The findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia, and replicate the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium.
Abstract: Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.
291 citations
References
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01 Dec 1969TL;DR: The concepts of power analysis are discussed in this paper, where Chi-square Tests for Goodness of Fit and Contingency Tables, t-Test for Means, and Sign Test are used.
Abstract: Contents: Prefaces. The Concepts of Power Analysis. The t-Test for Means. The Significance of a Product Moment rs (subscript s). Differences Between Correlation Coefficients. The Test That a Proportion is .50 and the Sign Test. Differences Between Proportions. Chi-Square Tests for Goodness of Fit and Contingency Tables. The Analysis of Variance and Covariance. Multiple Regression and Correlation Analysis. Set Correlation and Multivariate Methods. Some Issues in Power Analysis. Computational Procedures.
115,069 citations
TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
TL;DR: In this article, the authors conducted a systematic search for structural magnetic resonance imaging (MRI) studies of patients with schizophrenia that reported volume measurements of selected cortical, subcortical, and ventricular regions in relation to comparison groups.
Abstract: Objective: The authors’ goal was to determine whether patients with schizophrenia differ from comparison subjects in regional brain volumes and whether these differences are similar in male and female subjects. Method: They conducted a systematic search for structural magnetic resonance imaging (MRI) studies of patients with schizophrenia that reported volume measurements of selected cortical, subcortical, and ventricular regions in relation to comparison groups. They carried out a meta-analysis of the volumes of these regions in the patients with schizophrenia and the comparison subjects using a random effects model; they also used random effects regression analysis to examine the influence of gender on effect sizes. Results: Fifty-eight studies were identified as suitable for analysis; these studies included 1,588 independent patients with schizophrenia. Assuming a volume of 100% in the comparison group, they found that the mean cerebral volume of the subjects with schizophrenia was smaller (98%), but the mean total ventricular volume of the subjects with schizophrenia was greater (126%). Relative to the cerebral volume differences, the regional volumes of the subjects with schizophrenia were 94% in the left and right amygdala, 94% in the left and 95% in the right hippocampus/amygdala, and 93% in the left and 95% in the right parahippocampus. Relative to the global ventricular system differences, the largest differences in ventricular subdivisions were in the right and left body of the lateral ventricle, where the volumes of schizophrenic subjects were 116% and 116%, respectively. For most regions, effect size was not significantly related to gender. Conclusions: Regional structural differences in patients with schizophrenia include bilaterally reduced volume of medial temporal lobe structures. There is a need for greater integration of results from structural MRI studies to avoid redundant research activity. (Am J Psychiatry 2000; 157:16‐25)
1,644 citations
"Brain Volumes in Schizophrenia: A M..." refers methods in this paper
...Studies that applied MRI to compare brain volumes between patients with schizophrenia and healthy controls were included if they fulfilled all following criteria: (1) the study was written in the English language, (2) the study was published in print between August 1998 and January 2012, (3) patient samples contained at least 10 individuals, (4) diagnosis was established according to the Diagnostic and Statistical Manual of Mental Disorders (version III-R or IV) or International Classification of Diseases (version 9 or 10) criteria, (5) patient and control samples were matched with regard to age and sex, (6) patients with other illnesses than schizophrenia (ie, schizophreniform disorder, schizoaffective disorder or psychosis not otherwise specified) did not account for more than 50% of patient samples, (7) reported volumes represented volumes instead of an area or a volume estimation by means of an inadequate number of slices, and (8) sufficient data were available in order to calculate effect sizes....
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TL;DR: By comparison with age-matched controls in employment, 17 institutionalised schizophrenic patients were shown by computerised axial tomography of the brain to have increased cerebral ventricular size.
1,153 citations
"Brain Volumes in Schizophrenia: A M..." refers methods in this paper
...Studies that applied MRI to compare brain volumes between patients with schizophrenia and healthy controls were included if they fulfilled all following criteria: (1) the study was written in the English language, (2) the study was published in print between August 1998 and January 2012, (3) patient samples contained at least 10 individuals, (4) diagnosis was established according to the Diagnostic and Statistical Manual of Mental Disorders (version III-R or IV) or International Classification of Diseases (version 9 or 10) criteria, (5) patient and control samples were matched with regard to age and sex, (6) patients with other illnesses than schizophrenia (ie, schizophreniform disorder, schizoaffective disorder or psychosis not otherwise specified) did not account for more than 50% of patient samples, (7) reported volumes represented volumes instead of an area or a volume estimation by means of an inadequate number of slices, and (8) sufficient data were available in order to calculate effect sizes....
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...The same approach was applied to the meta-analysis on antipsychotic-naive patients, with 2 additional inclusion criteria: (1) patients were never exposed to antipsychotic medication before being scanned, (2) articles published before September 1998 were included as well....
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TL;DR: In this article, the authors quantitatively quantitate neuroanatomic parameters in healthy volunteers and compare the values with normative values from postmortem studies, using MRI images of 116 volunteers aged 19 months to 80 years.
Abstract: PURPOSE: To quantitate neuroanatomic parameters in healthy volunteers and to compare the values with normative values from postmortem studies. MATERIALS AND METHODS: Magnetic resonance (MR) images of 116 volunteers aged 19 months to 80 years were analyzed with semiautomated procedures validated by means of comparison with manual tracings. Volumes measured included intracranial space, whole brain, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Results were compared with values from previous postmortem studies. RESULTS: Whole brain and intracranial space grew by 25%–27% between early childhood (mean age, 26 months; age range, 19–33 months) and adolescence (mean age, 14 years; age range, 12–15 years); thereafter, whole-brain volume decreased such that volunteers (age range, 71–80 years) had volumes similar to those of young children. GM increased 13% from early to later (6–9 years) childhood. Thereafter, GM increased more slowly and reached a plateau in the 4th decade; it decreased by 13...
932 citations