Patterns of Gray Matter Abnormalities in Schizophrenia Based on an International Mega-analysis.

Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both source-based morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

Long-term effects of marijuana use on the brain.

Questions surrounding the effects of chronic marijuana use on brain structure continue to increase. To date, however, findings remain inconclusive. In this comprehensive study that aimed to characterize brain alterations associated with chronic marijuana use, we measured gray matter (GM) volume via structural MRI across the whole brain by using voxel-based morphology, synchrony among abnormal GM regions during resting state via functional connectivity MRI, and white matter integrity (i.e., structural connectivity) between the abnormal GM regions via diffusion tensor imaging in 48 marijuana users and 62 age- and sex-matched nonusing controls. The results showed that compared with controls, marijuana users had significantly less bilateral orbitofrontal gyri volume, higher functional connectivity in the orbitofrontal cortex (OFC) network, and higher structural connectivity in tracts that innervate the OFC (forceps minor) as measured by fractional anisotropy (FA). Increased OFC functional connectivity in marijuana users was associated with earlier age of onset. Lastly, a quadratic trend was observed suggesting that the FA of the forceps minor tract initially increased following regular marijuana use but decreased with protracted regular use. This pattern may indicate differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes in response to marijuana use. Despite the observed age of onset effects, longitudinal studies are needed to determine causality of these effects.

Function-structure associations of the brain: evidence from multimodal connectivity and covariance studies.

Despite significant advances in multimodal imaging techniques and analysis approaches, unimodal studies are still the predominant way to investigate brain changes or group differences, including structural magnetic resonance imaging (sMRI), functional MRI (fMRI), diffusion tensor imaging (DTI) and electroencephalography (EEG). Multimodal brain studies can be used to understand the complex interplay of anatomical, functional and physiological brain alterations or development, and to better comprehend the biological significance of multiple imaging measures. To examine the function-structure associations of the brain in a more comprehensive and integrated manner, we reviewed a number of multimodal studies that combined two or more functional (fMRI and/or EEG) and structural (sMRI and/or DTI) modalities. In this review paper, we specifically focused on multimodal neuroimaging studies on cognition, aging, disease and behavior. We also compared multiple analysis approaches, including univariate and multivariate methods. The possible strengths and limitations of each method are highlighted, which can guide readers when selecting a method based on a given research question. In particular, we believe that multimodal fusion approaches will shed further light on the neuronal mechanisms underlying the major structural and functional pathophysiological features of both the healthy brain (e.g. development) or the diseased brain (e.g. mental illness) and, in the latter case, may provide a more sensitive measure than unimodal imaging for disease classification, e.g. multimodal biomarkers, which potentially can be used to support clinical diagnosis based on neuroimaging techniques.

Examining the effect of psychopathic traits on gray matter volume in a community substance abuse sample.

Psychopathy is believed to be associated with brain abnormalities in both paralimbic (i.e., orbitofrontal cortex, insula, temporal pole, parahippocampal gyrus, posterior cingulate) and limbic (i.e., amygdala, hippocampus, anterior cingulate) regions. Recent structural imaging studies in both community and prison samples are beginning to support this view. Sixty-six participants, recruited from community corrections centers, were administered the Hare psychopathy checklist-revised (PCL-R), and underwent magnetic resonance imaging (MRI). Voxel-based morphometry was used to test the hypothesis that psychopathic traits would be associated with gray matter reductions in limbic and paralimbic regions. Effects of lifetime drug and alcohol use on gray matter volume were covaried. Psychopathic traits were negatively associated with gray matter volumes in right insula and right hippocampus. Additionally, psychopathic traits were positively associated with gray matter volumes in bilateral orbital frontal cortex and right anterior cingulate. Exploratory regression analyses indicated that gray matter volumes within right hippocampus and left orbital frontal cortex combined to explain 21.8% of the variance in psychopathy scores. These results support the notion that psychopathic traits are associated with abnormal limbic and paralimbic gray matter volume. Furthermore, gray matter increases in areas shown to be functionally impaired suggest that the structure-function relationship may be more nuanced than previously thought.

Heritability of multivariate gray matter measures in schizophrenia.

Structural brain measures are employed as endophenotypes in the search for schizophrenia susceptibility genes. We analyzed two independent structural imaging datasets with voxel-based morphometry and with source-based morphometry, a multivariate, independent components analysis, to determine the stability and heritability of regional gray matter concentration abnormalities in schizophrenia. The samples comprised 209 and 102 patients with schizophrenia and 208 and 96 healthy volunteers, respectively. The second sample additionally included non-ill siblings of participants with and without schizophrenia. A standard voxel-based analysis showed reproducible regional gray matter deficits in the affected participants compared with unrelated, unaffected controls in both datasets: patients showed significant gray matter concentration deficits in cortical frontal, temporal, and insular lobes. Source-based morphometry (SBM) was applied to the gray matter images of the entire sample to determine the effects of diagnosis on networks of covarying structures. The SBM analysis extracted 24 significant sets of covarying regions (components). Four of these components showed significantly lower gray matter concentrations in patients (p < .05). We determined the familiality of the observed SBM components based on 66 sibling pairs (25 discordant for schizophrenia). Two components, one including the medial frontal, insular, inferior frontal, and temporal lobes, and the other including the posterior occipital lobe, showed significant familiality (p < .05). We conclude that structural brain deficits in schizophrenia are replicable, and that SBM can extract unique familial and likely heritable components. SBM provides a useful data reduction technique that can provide measures that may serve as endophenotypes for schizophrenia.

Correspondence between structure and function in the human brain at rest.

To further understanding of basic and complex cognitive functions, previous connectome research has identified functional and structural connections of the human brain. Functional connectivity is often measured by using resting-state functional magnetic resonance imaging (rs-fMRI) and is generally interpreted as an indirect measure of neuronal activity. Gray matter (GM) primarily consists of neuronal and glia cell bodies; therefore, it is surprising that the majority of connectome research has excluded GM measures. Therefore, we propose that by exploring where GM corresponds to function would aid in the understanding of both structural and functional connectivity and in turn the human connectome. A cohort of 603 healthy participants underwent structural and functional scanning on the same 3 T scanner at the Mind Research Network. To investigate the spatial correspondence between structure and function, spatial independent component analysis (ICA) was applied separately to both GM density (GMD) maps and to rs-fMRI data. ICA of GM delineates structural components based on the covariation of GMD regions among subjects. For the rs-fMRI data, ICA identified spatial patterns with common temporal features. These decomposed structural and functional components were then compared by spatial correlation. Basal ganglia components exhibited the highest structural to resting-state functional spatial correlation (r = 0.59). Cortical components generally show correspondence between a single structural component and several resting-state functional components. We also studied relationships between the weights of different structural components and identified the precuneus as a hub in GMD structural network correlations. In addition, we analyzed relationships between component weights, age, and gender; concluding that age has a significant effect on structural components.

A baseline for the multivariate comparison of resting-state networks.

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12-71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

WITHDRAWN: Erratum to "Does function follow form?: Methods to fuse structural and functional brain images show decreased linkage in schizophrenia" [NeuroImage 49 (2010) 2626-2637].

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Mining the mind research network: a novel framework for exploring large scale, heterogeneous translational neuroscience research data sources.

A neuroinformatics (NI) system is critical to brain imaging research in order to shorten the time between study conception and results. Such a NI system is required to scale well when large numbers of subjects are studied. Further, when multiple sites participate in research projects organizational issues become increasingly difficult. Optimized NI applications mitigate these problems. Additionally, NI software enables coordination across multiple studies, leveraging advantages potentially leading to exponential research discoveries. The web-based, Mind Research Network (MRN), database system has been designed and improved through our experience with 200 research studies and 250 researchers from seven different institutions. The MRN tools permit the collection, management, reporting and efficient use of large scale, heterogeneous data sources, e.g., multiple institutions, multiple principal investigators, multiple research programs and studies, and multimodal acquisitions. We have collected and analyzed data sets on thousands of research participants and have set up a framework to automatically analyze the data, thereby making efficient, practical data mining of this vast resource possible. This paper presents a comprehensive framework for capturing and analyzing heterogeneous neuroscience research data sources that has been fully optimized for end-users to perform novel data mining.

Cortical thickness and subcortical gray matter reductions in neuropsychiatric systemic lupus erythematosus.

Within systemic lupus erythematosus (SLE) patients can be divided into groups with and without central nervous system involvement, the latter being subcategorized as neuropsychiatric systemic lupus erythematosus (NPSLE). While a number of research groups have investigated NPSLE, there remains a lack of consistent application of this diagnostic criteria within neuroimaging studies. Previous neuroimaging research suggests that SLE patients have reduced subcortical and regional gray matter volumes when compared to controls, and that these group differences may be driven by SLE patients with neuropsychiatric symptoms. The current study sought to compare measures of cortical thickness and subcortical structure volume between NPSLE, SLE, and healthy controls. We hypothesized that patients with NPSLE (N = 21) would have thinner cortex and reduced subcortical gray matter volumes when compared to SLE (N = 16) and control subjects (N = 21). All subjects underwent MRI examinations on a 1.5 Tesla Siemens Sonata scanner. Anatomical reconstruction and segmentation were performed using the FreeSurfer image analysis suite. Cortical and subcortical volumes were extracted from FreeSurfer and analyzed for group differences, controlling for age. The NPSLE group exhibited decreased cortical thickness in clusters of the left frontal and parietal lobes as well as in the right parietal and occipital lobes compared to control subjects. Compared to the SLE group, the NPSLE group exhibited comparable thinning in clusters of the frontal and temporal lobes. Controlling for age, we found that between group effects for subcortical gray matter structures were significant for the thalamus (F = 3.06, p = .04), caudate nucleus (F = 3.19, p = .03), and putamen (F = 4.82, p = .005). These results clarify previous imaging work identifying cortical atrophy in a mixed SLE and NPSLE group, and suggest that neuroanatomical abnormalities are specific to SLE patients diagnosed with neuropsychiatric symptoms. Future work should help elucidate the underlying mechanisms underlying the emerging neurobiological profile seen in NPSLE, as well as clarify the apparent lack of overlap between cortical thinning and functional activation results and other findings pointing to increased functional activation during cognitive tasks.

Does function follow form?: methods to fuse structural and functional brain images show decreased linkage in schizophrenia.

When both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) data are collected they are typically analyzed separately and the joint information is not examined. Techniques that examine joint information can help to find hidden traits in complex disorders such as schizophrenia. The brain is vastly interconnected, and local brain morphology may influence functional activity at distant regions. In this paper we introduce three methods to identify inter-correlations among sMRI and fMRI voxels within the whole brain. We apply these methods to examine sMRI gray matter data and fMRI data derived from an auditory sensorimotor task from a large study of schizophrenia. In Method 1 the sMRI-fMRI cross-correlation matrix is reduced to a histogram and results show that healthy controls (HC) have stronger correlations than do patients with schizophrenia (SZ). In Method 2 the spatial information of sMRI-fMRI correlations is retained. Structural regions in the cerebellum and frontal regions show more positive and more negative correlations, respectively, with functional regions in HC than in SZ. In Method 3 significant sMRI-fMRI inter-regional links are detected, with regions in the cerebellum showing more significant positive correlations with functional regions in HC relative to SZ. Results from all three methods indicate that the linkage between gray matter and functional activation is stronger in HC than SZ. The methods introduced can be easily extended to comprehensively correlate large data sets.

Neuroanatomy of creativity.

Creativity has long been a construct of interest to philosophers, psychologists and, more recently, neuroscientists. Recent efforts have focused on cognitive processes likely to be important to the manifestation of novelty and usefulness within a given social context. One such cognitive process - divergent thinking - is the process by which one extrapolates many possible answers to an initial stimulus or target data set. We sought to link well established measures of divergent thinking and creative achievement (Creative Achievement Questionnaire - CAQ) to cortical thickness in a cohort of young (23.7 +/- 4.2 years), healthy subjects. Three independent judges ranked the creative products of each subject using the consensual assessment technique (Amabile, 1982) from which a "composite creativity index" (CCI) was derived. Structural magnetic resonance imaging was obtained at 1.5 Tesla Siemens scanner. Cortical reconstruction and volumetric segmentation were performed with the FreeSurfer image analysis suite. A region within the lingual gyrus was negatively correlated with CCI; the right posterior cingulate correlated positively with the CCI. For the CAQ, lower left lateral orbitofrontal volume correlated with higher creative achievement; higher cortical thickness was related to higher scores on the CAQ in the right angular gyrus. This is the first study to link cortical thickness measures to psychometric measures of creativity. The distribution of brain regions, associated with both divergent thinking and creative achievement, suggests that cognitive control of information flow among brain areas may be critical to understanding creative cognition.

Voxel-based morphometric multisite collaborative study on schizophrenia.

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.

Multinuclear NMR investigations of the oxygen, water, and hydroxyl environments in sodium hexaniobate.

Solid-state (1)H, (17)O MAS NMR, (1)H-(93)Nb TRAPDOR NMR, and (1)H double quantum 2D MAS NMR experiments were used to characterize the oxygen, water, and hydroxyl environments in the monoprotonated hexaniobate material, Na(7)[HNb(6)O(19)].15H(2)O. These solid-state NMR experiments demonstrate that the proton is located on the bridging oxygen of the [Nb(6)O(19)](8-) cluster. The solid-state NMR results also show that the NbOH protons are spatially isolated from similar protons, but undergo proton exchange with the water species located in the crystal lattice. On the basis of double quantum (1)H MAS NMR measurements, it was determined that the water species in the crystal lattice have restricted motional dynamics. Two-dimensional (1)H-(17)O MAS NMR correlation experiments show that these restricted waters are preferentially associated with the bridging oxygen. Solution (17)O NMR experiments show that the hydroxyl proton is also attached to the bridging oxygen for the compound in solution. In addition, solution (17)O NMR kinetic studies for the hexaniobate allowed the measurement of relative oxygen exchange rates between the bridging, terminal, and hydroxyl oxygen and the oxygen of the solvent as a function of pH and temperature. These NMR experiments are some of the first investigations into the proton location, oxygen and proton exchange processes, and water dynamics for a base stable polyoxoniobate material, and they provide insight into the chemistry and reactivity of these materials.

Resuscitating hypothermic dogs after 2 hours of circulatory arrest below 6 degrees C.

BACKGROUND: Ultraprofound hypothermia may have a place in trauma rescue and resuscitation. We describe resuscitation of dogs after asanguineous perfusion and circulatory arrest of 2 hours at 2 degrees to 4 degrees C. METHODS: Nine dogs were cooled using a bypass apparatus and their circulating blood replaced with bicarbonated Hextend (Abbott, North Chicago, IL). Perfusion was continued to 2 degrees to 4 degrees C, and 60 mL of 2 mol/L KCl and 20 mL of 50% MgSO(4).7H(2)O were infused intra-arterially, and circulation was arrested for 2 hours. The dogs were then rewarmed, transfused, defibrillated, weaned from bypass, and allowed to awaken. Preoperative and postoperative biochemistry and hematology were compared. RESULTS: Six dogs recovered fully. One of these dogs died of an infection 2 weeks later. Three other dogs never recovered because of technical or procedural difficulties. Biochemical and hematologic parameters were normal by 3 weeks. CONCLUSION: Hypothermic blood substitution with Hextend allows resuscitation after 2 hours of ice-cold circulatory arrest in dogs.

Chemistry of a novel family of tridentate alkoxy tin(II) clusters.

The chemical interconversions observed for a novel family of trihydroxymethyl ethane (THME-H(3)) ligated Sn(II) compounds have been determined using single-crystal X-ray and (119)Sn NMR experiments. (mu-THME)(2)Sn(3) (1) was isolated from the reaction of 3 equiv of [Sn(NR(2))(2)](2) (R = SiMe(3)) with 4 equiv of THME as a unique trinuclear species capped above and below the plane of Sn atoms by two THME ligands. Upon reaction with "Sn(NR(2))(2)", compound 1 rearranged to yield another novel molecule [(mu-THME)Sn(2)(NR(2))](2) (2). Compound 2 could also be formed directly from the stoichiometric mixture of THME-H(3) and [Sn(NR(2))(2)](2). Further studies revealed that 1 would also rearrange in the presence of Sn(OR)(2) to form [(mu-THME)Sn(2)(mu-OR)](2) [OR = OMe (3), OCH(2)Me (4), OCH(2)CH(Me)CH(2)CH(3) (5), OCH(2)CMe(3) (6, ONep), OC(6)H(5) (7, not structurally characterized), OC(6)H(4)Me-3 (8), OC(6)H(4)Me-2 (9), OC(6)H(3)(Me)(2)-2,6 (10), OC(6)H(3)(CHMe(2))(2)-2,6 (11). Additionally, 3-11 could by synthesized from the reaction of 2 and the appropriate H-OR. (119)Sn solution NMR studies of 2-11, in THF-d(8), indicate that an equilibrium between the parent complex and its disassociation products (1 and the free parent Sn alkoxy or amide precursor) exists at room temperature. This is a likely reason behind the ease of interconversion observed for 1. The generality of this exchange was further verified through the reaction of 1 with [Ti(mu-ONep)(ONep)(3)](2), which led to the isolation of (mu-ONep)(2)Sn(3)(mu-THME)(2)Ti(ONep)(2) (12). For 12, the solid-state structure was maintained in solution with no indication of an equilibrium.