Neural correlates of stress-reactive rumination in depression - The role of childhood trauma and social anxiety.

Recent work showed an association of prefrontal dysfunctions in patients with Major Depressive Disorder (MDD) and social stress induced rumination. However, up to date it is unclear which etiological features of MDD might cause prefrontal dysfunctions. In the study at hand, we aimed to replicate recent findings, that showed prefrontal activation alterations during the Trier Social Stress Test (TSST) and subsequently increased stress-reactive rumination in MDD compared to healthy controls. Moreover, we aimed to explore the role of adverse childhood experiences and other clinical variables in this relationship. N = 55 patients currently suffering from MDD and n = 42 healthy controls (HC) underwent the TSST, while cortical activity in areas of the Cognitive Control Network (CCN) was measured via functional near-infrared spectroscopy (fNIRS). The TSST successfully induced a stress reaction (physiologically, as well as indicated by subjective stress ratings) and state rumination in all subjects with moderate to large effect sizes. In comparison to HC, MDD patients showed elevated levels of state rumination with large effect sizes, as well as a typical pattern of reduced cortical oxygenation during stress in the CCN with moderate effect sizes. Self-reported emotional abuse and social anxiety were moderately positively associated with increased stress-reactive rumination. Within the MDD sample, emotional abuse was negatively and social anxiety positively associated with cortical oxygenation within the CCN with moderate to large effect sizes. In conclusion, our results replicate previous findings on MDD-associated prefrontal hypoactivity during stress and extends the research toward specific subtypes of depression.

In situ fNIRS measurements during cognitive behavioral emotion regulation training in rumination-focused therapy: A randomized-controlled trial.

Repetitive negative thinking (RNT), including rumination, plays a key role in various psychopathologies. Although several psychotherapeutic treatments have been developed to reduce RNT, the neural correlates of those specific treatments and of psychotherapy in general are largely unknown. Functional near-infrared spectroscopy (fNIRS) offers the potential to investigate the neural correlates of psychotherapeutic techniques in situ. Therefore, in this study we investigated the efficacy and neural correlates of a fNIRS adapted Mindfulness-based Emotion Regulation Training (MBERT) for the treatment of depressive rumination in 42 subjects with major depressive disorder (MDD) in a cross-over designed randomized controlled trial. Using psychometric measures, subjective ratings and fNIRS, we analyzed in situ changes in depressive symptom severity, ruminative thoughts and cortical activity in the Cognitive Control Network (CCN). Our results show that MBERT is effective in treating depressive symptoms and rumination. On a neural level, we found consistently higher cortical activation during emotion regulation training compared to control trials in the bilateral inferior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC). Furthermore, cortical oxygenation decreased from session to session in the bilateral DLPFC. The relevance of the results for the psychotherapeutic treatment of MDD as well as further necessary investigations are discussed.

Insights from a laboratory and naturalistic investigation on stress, rumination and frontal brain functioning in MDD: An fNIRS study.

Recent research has emphasized rumination as an important maintaining factor in various mental disorders. However, operationalization and therefore induction of rumination in experimental settings poses a major challenge in terms of ecological validity. As stress seems to play a key role in everyday situations eliciting rumination, we conducted two stress paradigms while assessing behavioral and neurophysiological measures. Aiming to replicate previous findings on induced rumination by means of the Trier Social Stress Test (TSST) and comparing them to physiological (pain) stress, a clinical sample of patients with Major Depressive Disorder (MDD; n = 22) and healthy controls (HC; n = 23) was recruited. Cortical blood oxygenation was assessed during the stress paradigms using functional near-infrared spectroscopy (fNIRS). Further, we used ecological momentary assessment (EMA) of stress, rumination and mood to be able to correlate ruminative responses during induced stress and everyday rumination. Our results showed that social stress but not physiological stress induced depressive rumination in MDD but not in HC. Further, rumination reactivity in response to social stress but not to physiological stress was significantly associated with rumination reactivity in everyday life as assessed with EMA. With respect to cortical oxygenation, MDD subjects showed hypoactivity in the Cognitive Control Network during the TSST, which mediated the differences between MDD and HC in post-stress rumination. Our findings emphasize the role of negative social triggers in depressive rumination and validate the TSST as an induction method for depressive rumination. The results inform future developments in psychotherapeutic treatment for depressive rumination.

Risk stratification for short-term mortality at hospital admission for acute exacerbations of COPD.

BACKGROUND AND OBJECTIVE: Exacerbations of chronic obstructive pulmonary disease (ECOPD) are associated with increased in-hospital and short-term mortality. Developing an easy-to-use model to predict adverse outcomes will be useful in daily clinical practice and will facilitate management decisions. We aimed to assess mortality rates and potential predictors for short-term mortality after severe ECOPD. Classification and Regression Tree (CART) model was used to identify predictors of adverse outcome. METHODS: A retrospective observational cohort study, including all patients admitted to Maastricht University Medical Center with ECOPD between June 2011 and December 2014 was performed. The last admission was taken into account, and its demographic, clinical and biochemical data were recorded. RESULTS: A total of 364 hospitalized patients were enrolled. Mean (SD) age was 70.5 (10.2) years, 54.4% were male and mean FEV1 45.2% (17.7) of predicted. The in-hospital and 90-day mortality were, respectively, 8.5 and 16.2%. Independent risk factors for 90-day mortality were: PaC02 (odds ratio (OR): 1.31; 95% confidence interval (CI): 1.00-0.35), age (OR: 1.09; CI: 0.06-0.11), body mass index (BMI) < 18.5 kg/m2 (OR: 2.72; 95% CI: 0.53-1.47) and previous admission for ECOPD in last 2 years (OR: 1.29; 95% CI: -0.14, -0.65). The CART model selected PaCO2 ≥ 9.1 kPa, age > 80 years, BMI < 18.5 kg/m2 and previous admission for ECOPD as the most discriminatory factors. CONCLUSION: According CART analysis, high PaCO2 and age, low BMI and previous admission for ECOPD in last 2 years were the strongest predictors of 90-day mortality in patients with severe ECOPD. In absence of any of these factors, no patients died, suggesting that this model indeed enables risk stratification.

Exploring the idiographic dynamics of mood and anxiety via network analysis.

Individual variation is increasingly recognized as important to psychopathology research. Concurrently, new methods of analysis based on network models are bringing new perspectives on mental (dys)function. This current work analyzed idiographic multivariate time series data using a novel network methodology that incorporates contemporaneous and lagged associations in mood and anxiety symptomatology. Data were taken from 40 individuals with generalized anxiety disorder (GAD), major depressive disorder (MDD), or comorbid GAD and MDD, who answered questions about 21 descriptors of mood and anxiety symptomatology 4 times a day over a period of approximately 30 days. The model provided an excellent fit to the intraindividual symptom dynamics of all 40 individuals. The most central symptoms in contemporaneous systems were those related to positive and negative mood. The temporal networks highlighted the importance of anger to symptomatology, while also finding that depressed mood and worry-the principal diagnostic criteria for GAD and MDD-were the least influential nodes across the sample. The method's potential for analysis of individual symptom patterns is demonstrated by 3 exemplar participants. Idiographic network-based analysis may fundamentally alter the way psychopathology is assessed, classified, and treated, allowing researchers and clinicians to better understand individual symptom dynamics. (PsycINFO Database Record

The global spread of HIV-1 subtype B epidemic.

Human immunodeficiency virus type 1 (HIV-1) was discovered in the early 1980s when the virus had already established a pandemic. For at least three decades the epidemic in the Western World has been dominated by subtype B infections, as part of a sub-epidemic that traveled from Africa through Haiti to United States. However, the pattern of the subsequent spread still remains poorly understood. Here we analyze a large dataset of globally representative HIV-1 subtype B strains to map their spread around the world over the last 50years and describe significant spread patterns. We show that subtype B travelled from North America to Western Europe in different occasions, while Central/Eastern Europe remained isolated for the most part of the early epidemic. Looking with more detail in European countries we see that the United Kingdom, France and Switzerland exchanged viral isolates with non-European countries than with European ones. The observed pattern is likely to mirror geopolitical landmarks in the post-World War II era, namely the rise and the fall of the Iron Curtain and the European colonialism. In conclusion, HIV-1 spread through specific migration routes which are consistent with geopolitical factors that affected human activities during the last 50years, such as migration, tourism and trade. Our findings support the argument that epidemic control policies should be global and incorporate political and socioeconomic factors.

Measuring the potential of individual airports for pandemic spread over the world airline network.

BACKGROUND: Massive growth in human mobility has dramatically increased the risk and rate of pandemic spread. Macro-level descriptors of the topology of the World Airline Network (WAN) explains middle and late stage dynamics of pandemic spread mediated by this network, but necessarily regard early stage variation as stochastic. We propose that much of this early stage variation can be explained by appropriately characterizing the local network topology surrounding an outbreak's debut location. METHODS: Based on a model of the WAN derived from public data, we measure for each airport the expected force of infection (AEF) which a pandemic originating at that airport would generate, assuming an epidemic process which transmits from airport to airport via scheduled commercial flights. We observe, for a subset of world airports, the minimum transmission rate at which a disease becomes pandemically competent at each airport. We also observe, for a larger subset, the time until a pandemically competent outbreak achieves pandemic status given its debut location. Observations are generated using a highly sophisticated metapopulation reaction-diffusion simulator under a disease model known to well replicate the 2009 influenza pandemic. The robustness of the AEF measure to model misspecification is examined by degrading the underlying model WAN. RESULTS: AEF powerfully explains pandemic risk, showing correlation of 0.90 to the transmission level needed to give a disease pandemic competence, and correlation of 0.85 to the delay until an outbreak becomes a pandemic. The AEF is robust to model misspecification. For 97 % of airports, removing 15 % of airports from the model changes their AEF metric by less than 1 %. CONCLUSIONS: Appropriately summarizing the size, shape, and diversity of an airport's local neighborhood in the WAN accurately explains much of the macro-level stochasticity in pandemic outcomes.

Understanding the influence of all nodes in a network.

Centrality measures such as the degree, k-shell, or eigenvalue centrality can identify a network's most influential nodes, but are rarely usefully accurate in quantifying the spreading power of the vast majority of nodes which are not highly influential. The spreading power of all network nodes is better explained by considering, from a continuous-time epidemiological perspective, the distribution of the force of infection each node generates. The resulting metric, the expected force, accurately quantifies node spreading power under all primary epidemiological models across a wide range of archetypical human contact networks. When node power is low, influence is a function of neighbor degree. As power increases, a node's own degree becomes more important. The strength of this relationship is modulated by network structure, being more pronounced in narrow, dense networks typical of social networking and weakening in broader, looser association networks such as the Internet. The expected force can be computed independently for individual nodes, making it applicable for networks whose adjacency matrix is dynamic, not well specified, or overwhelmingly large.

Evolution of hepatitis C virus quasispecies during repeated treatment with the NS3/4A protease inhibitor telaprevir.

In treating hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections, the rapid reselection of resistance-associated variants (RAVs) is well known in patients with repeated exposure to the same class of antiviral agents. For chronic hepatitis C patients who have experienced virologic failure with direct-acting antiviral drugs, the potential for the reselection of persistent RAVs is unknown. Nine patients who received 14 days of telaprevir monotherapy were retreated with telaprevir-based triple therapy 4.3 to 5.7 years later. In four patients with virologic failure with both telaprevir-containing regimens, population-based and deep sequencing (454 GS-FLX) of the NS3 protease gene were performed before and at treatment failure (median coverage, 4,651 reads). Using deep sequencing, with a threshold of 1.0% for variant calling, no isolates were found harboring RAVs at the baseline time points. While population-based sequencing uncovered similar resistance patterns (V36M plus R155K for subtype 1a and V36A for subtype 1b) in all four patients after the first and second telaprevir treatments, deep sequencing analysis revealed a median of 7 (range, 4 to 23) nucleotide substitutions on the NS3 backbone of the resistant strains, together with large phylogenetic differences between viral quasispecies, making the survival of resistant isolates highly unlikely. In contrast, in a comparison of the two baseline time points, the median number of nucleotide exchanges in the wild-type isolates was only 3 (range, 2 to 8), reflecting the natural evolution of the NS3 gene. In patients with repeated direct antiviral treatment, a continuous evolution of HCV quasispecies was observed, with no clear evidence of persistence and reselection but strong signs of independent de novo generation of resistance. Antiviral therapy for chronic viral infections, like HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV), faces several challenges. These viruses have evolved survival strategies and proliferate by escaping the host's immune system. The development of direct-acting antiviral agents is an important achievement in fighting these infections. Viral variants conferring resistance to direct antiviral drugs lead to treatment failure. For HIV/HBV, it is well known that viral variants associated with treatment failure will be archived and reselected rapidly during retreatment with the same drug/class of drugs. We explored the mechanisms and rules of how resistant variants are selected and potentially reselected during repeated direct antiviral therapies in chronically HCV-infected patients. Interestingly, in contrast to HIV and HBV, we could not prove long-term persistence and reselection of resistant variants in HCV patients who failed protease inhibitor-based therapy. This may have important implications for the potential to reuse direct-acting antivirals in patients who failed the initial direct antiviral treatment. (The phase IIIb study described in this paper is registered at ClinicalTrials.gov under registration number NCT01054573.).

COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification.

Viral sequence classification has wide applications in clinical, epidemiological, structural and functional categorization studies. Most existing approaches rely on an initial alignment step followed by classification based on phylogenetic or statistical algorithms. Here we present an ultrafast alignment-free subtyping tool for human immunodeficiency virus type one (HIV-1) adapted from Prediction by Partial Matching compression. This tool, named COMET, was compared to the widely used phylogeny-based REGA and SCUEAL tools using synthetic and clinical HIV data sets (1,090,698 and 10,625 sequences, respectively). COMET's sensitivity and specificity were comparable to or higher than the two other subtyping tools on both data sets for known subtypes. COMET also excelled in detecting and identifying new recombinant forms, a frequent feature of the HIV epidemic. Runtime comparisons showed that COMET was almost as fast as USEARCH. This study demonstrates the advantages of alignment-free classification of viral sequences, which feature high rates of variation, recombination and insertions/deletions. COMET is free to use via an online interface.

Genotyping hepatitis B virus dual infections using population-based sequence data.

The hepatitis B virus (HBV) is classified into distinct genotypes A-H that are characterized by different progression of hepatitis B and sensitivity to interferon treatment. Previous computational genotyping methods are not robust enough regarding HBV dual infections with different genotypes. The correct classification of HBV sequences into the present genotypes is impaired due to multiple ambiguous sequence positions. We present a computational model that is able to identify and genotype inter- and intragenotype dual infections using population-based sequencing data. Model verification on synthetic data showed 100 % accuracy for intergenotype dual infections and 36.4 % sensitivity in intragenotype dual infections. Screening patient sera (n = 241) revealed eight putative cases of intergenotype dual infection (one A-D, six A-G and one D-G) and four putative cases of intragenotype dual infection (one A-A, two D-D and one E-E). Clonal experiments from the original patient material confirmed three out of three of our predictions. The method has been integrated into geno2pheno([hbv]), an established web-service in clinical use for analysing HBV sequence data. It offers exact and detailed identification of HBV genotypes in patients with dual infections that helps to optimize antiviral therapy regimens. geno2pheno([hbv]) is available under http://www.genafor.org/g2p_hbv/index.php.

Endogenous or exogenous spreading of HIV-1 in Nordrhein-Westfalen, Germany, investigated by phylodynamic analysis of the RESINA Study cohort.

HIV's genetic instability means that sequence similarity can illuminate the underlying transmission network. Previous application of such methods to samples from the United Kingdom has suggested that as many as 86% of UK infections arose outside of the country, a conclusion contrary to usual patterns of disease spread. We investigated transmission networks in the Resina cohort, a 2,747 member sample from Nordrhein-Westfalen, Germany, sequenced at therapy start. Transmission networks were determined by thresholding the pairwise genetic distance in the pol gene at 96.8% identity. At first blush the results concurred with the UK studies. Closer examination revealed four large and growing transmission networks that encompassed all major transmission groups. One of these formed a supercluster containing 71% of the sex with men (MSM) subjects when the network was thresholded at levels roughly equivalent to those used in the UK studies, though methodological differences suggest that this threshold may be too generous in the current data. Examination of the endo- versus exogenesis hypothesis by testing whether infections that were exogenous to Cologne or to Dusseldorf were endogenous to the greater region supported endogenous spread in MSM subjects and exogenous spread in the endemic transmission group. In intravenous drug using group subjects, it depended on viral strain, with subtype B sequences appearing to have origin exogenous to the Resina data, while non-B sequences (primarily subtype A) were almost completely endogenous to their local community. These results suggest that, at least in Germany, the question of endogenous versus exogenous linkages depends on subject group.

Novel search method for the discovery of functional relationships.

MOTIVATION: Numerous annotations are available that functionally characterize genes and proteins with regard to molecular process, cellular localization, tissue expression, protein domain composition, protein interaction, disease association and other properties. Searching this steadily growing amount of information can lead to the discovery of new biological relationships between genes and proteins. To facilitate the searches, methods are required that measure the annotation similarity of genes and proteins. However, most current similarity methods are focused only on annotations from the Gene Ontology (GO) and do not take other annotation sources into account. RESULTS: We introduce the new method BioSim that incorporates multiple sources of annotations to quantify the functional similarity of genes and proteins. We compared the performance of our method with four other well-known methods adapted to use multiple annotation sources. We evaluated the methods by searching for known functional relationships using annotations based only on GO or on our large data warehouse BioMyn. This warehouse integrates many diverse annotation sources of human genes and proteins. We observed that the search performance improved substantially for almost all methods when multiple annotation sources were included. In particular, our method outperformed the other methods in terms of recall and average precision.

HIV-1 mutational pathways under multidrug therapy.

BACKGROUND: Genotype-derived drug resistance profiles are a valuable asset in HIV-1 therapy decisions. Therapy decisions could be further improved, both in terms of predicting length of current therapy success and in preserving followup therapy options, through better knowledge of mutational pathways- here defined as specific locations on the viral genome which, when mutant, alter the risk that additional specific mutations arise. We limit the search to locations in the reverse transcriptase region of the HIV-1 genome which host resistance mutations to nucleoside (NRTI) and non-nucleoside (NNRTI) reverse transcriptase inhibitors (as listed in the 2008 International AIDS Society report), or which were mutant at therapy start in 5% or more of the therapies studied. METHODS: A Cox proportional hazards model was fit to each location with the hazard of a mutation at that location during therapy proportional to the presence/absence of mutations at the remaining locations at therapy start. A pathway from preexisting to occurring mutation was indicated if the covariate was both selected as important via smoothly clipped absolute deviation (a form of regularized regression) and had a small p-value. The Cox model also allowed controlling for non-genetic parameters and potential nuisance factors such as viral resistance and number of previous therapies. Results were based on 1981 therapies given to 1495 distinct patients drawn from the EuResist database. RESULTS: The strongest influence on the hazard of developing NRTI resistance was having more than four previous therapies, not any one existing resistance mutation. Known NRTI resistance pathways were shown, and previously speculated inhibition between the thymidine analog pathways was evidenced. Evidence was found for a number of specific pathways between NRTI and NNRTI resistance sites. A number of common mutations were shown to increase the hazard of developing both NRTI and NNRTI resistance. Viral resistance to the therapy compounds did not materially effect the hazard of mutation in our model. CONCLUSIONS: The accuracy of therapy outcome prediction tools may be increased by including the number of previous treatments, and by considering locations in the HIV genome which increase the hazard of developing resistance mutations.

Amphetamine dependence and co-morbid alcohol abuse: associations to brain cortical thickness.

BACKGROUND: Long-term amphetamine and methamphetamine dependence has been linked to cerebral blood perfusion, metabolic, and white matter abnormalities. Several studies have linked methamphetamine abuse to cortical grey matter reduction, though with divergent findings. Few publications investigate unmethylated amphetamine's potential effects on cortical grey matter. This work investigated if amphetamine dependent patients showed reduced cortical grey matter thickness. Subjects were 40 amphetamine dependent subjects and 40 healthy controls. While all subjects were recruited to be free of alcohol dependence, structured clinical interviews revealed significant patterns of alcohol use in the patients. Structural magnetic resonance brain images were obtained from the subjects using a 1.5 Tesla GE Signa machine. Brain cortical thickness was measured with submillimeter precision at multiple finely spaced cortical locations using semi-automated post-processing (FreeSurfer). Contrast analysis of a general linear model was used to test for differences between the two groups at each cortical location. In addition to contrasting patients with controls, a number of analyses sought to identify possible confounding effects from alcohol. RESULTS: No significant cortical thickness differences were observed between the full patient group and controls, nor between non-drinking patients and controls. Patients with a history of co-morbid heavy alcohol use (n = 29) showed reductions in the superior-frontal right hemisphere and pre-central left hemisphere when compared to healthy controls (n = 40). CONCLUSIONS: Amphetamine usage was associated with reduced cortical thickness only in patients co-morbid for heavy alcohol use. Since cortical thickness is but one measure of brain structure and does not capture brain function, further studies of brain structure and function in amphetamine dependence are warranted.

Investigating relationships between cortical thickness and cognitive performance in patients with schizophrenia and healthy adults.

Relationships between prefrontal and temporal lobe grey matter volumes as assessed by magnetic resonance imaging and neurocognitive test results have been reported in schizophrenia. This investigation aimed to localize brain regions where cortical thickness and neurocognitive performance were related, and investigate if such relationships might differ in schizophrenia patients and healthy controls. Sixty-seven patients with schizophrenia and 69 healthy controls were characterized by neurocognitive testing and by brain cortical thickness maps. Putative cortical thickness/cognitive score relationships were investigated with contrast analyses of general linear models for the combined sample. Regions in which relationships were present were further investigated for diagnostic interaction. In the combined sample, significant positive relationships were found between frontal, temporal and occipital regions and tests for verbal IQ, verbal learning and executive functions. Diagnostic interaction was found for the relationships between verbal IQ and the right temporo-occipital junction and the left middle occipital gyrus. In conclusion, the significant relationships between cortical thickness and neurocognitive performances were localized in brain areas known to be involved in cognition. The relationships were similar in patients and controls, except for the right temporo-occipital and left occipital cortical areas, indicating a disrupted structure-function relationship in patients with schizophrenia compared to healthy control subjects.

Cerebral cortical thickness and a history of obstetric complications in schizophrenia.

INTRODUCTION: Magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have thinner brain cortices compared with healthy control subjects. Neurodevelopment is vulnerable to obstetric complications (OCs) such as hypoxia and birth trauma, factors that are also related to increased risk of developing schizophrenia. With the hypothesis that OCs might explain the thinner cortices found in schizophrenia, we studied patients with schizophrenia and healthy controls subjects for association between number and severity of OCs and variation in cortical thickness. METHODS: MRI scans of 54 adults with schizophrenia or schizoaffective disorder and 54 healthy controls were acquired at Karolinska Institutet, Stockholm, Sweden. Measures of brain cortical thickness were obtained using automated computer processing (FreeSurfer). OCs were assessed from obstetric records and scored blindly according to the McNeil-Sjöström scale. At numerous cortical locations, putative effects of OCs on cortical thickness variation were tested for each trimester, for labour, for composite OC scores, severe OC scores, and hypoxia scores among patients and controls separately. RESULTS: Number and severity of OCs varied among both patient and control subjects but were not associated with cortical thickness in either of the groups. Patients demonstrated thinner brain cortices but there were no significant differences in number and severity of OC scores across groups. CONCLUSION: In the present study, number and severity of obstetric complications were not associated with brain cortical thickness, in patients with schizophrenia or in healthy control subjects. The thinner brain cortices found in patients with schizophrenia were not explained by a history of OCs.

The relationship between symptom severity and regional cortical and grey matter volumes in schizophrenia.

OBJECTIVE: To investigate the relationship between symptom severity and cortical and grey matter volumes in schizophrenia. METHOD: Fifty-three outpatients with schizophrenia were assessed by the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. Symptoms were grouped into five factors (negative, relational, inattention, disorganization, and reality distortion). Cortical and lobar grey matter volumes within all regions of the brain were obtained from magnetic resonance images using two independent software tools. The relationships between brain volumes and symptom factors were analyzed by partial correlations controlling for age, gender, dose and type of antipsychotic medication, and intracranial volume. RESULTS: Negative symptoms were generally associated with larger cortical volumes in all regions of the brain, and the relational and inattention factors were associated with larger frontal grey matter volumes. The reality distortion factor was associated with smaller cortical volumes throughout the brain and with smaller frontal and temporal grey matter volumes. CONCLUSION: Differential contribution of positive and negative symptoms to variation in cortical and grey matter volumes indicates separate neurobiological mechanisms underlying the two major symptom domains in schizophrenia.

Local and covariate-modulated false discovery rates applied in neuroimaging.

False discovery rate (FDR) control has become a standard technique in neuroimaging. Recent work has shown that a finer grained estimate of the FDR is obtained by estimating, at a specific value of the test statistic, the scaled ratio of the null density to the observed density of the test statistic. The method can be extended by allowing an external covariate, also measured on the points where the hypothesis was tested, to modulate estimation of this local FDR. The current work, in addition to demonstrating these methods by re-analyzing results from two previously published investigations of cortical thickness, presents a method to test if the covariate modulation differs significantly from chance. The first study compared schizophrenia patients to healthy controls and the second compared genotypes of the -633 T/A polymorphism of the gene coding the brain derived neurotrophic factor (BDNF) protein in a subset of the subjects from the case/control study. Local FDR estimates increased findings over FDR in both studies. Using p-values from the case/control study to modulate local FDR estimation in the BDNF study further increased findings. The relationship between case/control related and BDNF related cortical thickness variation was found to be highly significant, providing support for this gene's involvement in the etiology of the disease. The increased statistical precision from more accurate models of the distribution of the test statistic demonstrates the potential of these methods for neuroimaging and suggests the possibility to test novel hypothesis.

Grey and white matter proportional relationships in the cerebellar vermis altered in schizophrenia.

Magnetic resonance imaging studies frequently report abnormalities of the cerebellar vermis in schizophrenia, though with some discrepancies as to the nature and location of such abnormalities. Imaging studies typically investigate volumetric differences between groups. Yet substantial evidence supports the hypothesis that grey and white matter proportions in the mammalian brain are controlled by scaling relationships. If strong proportional relationships between grey and white matter tissue volumes are observed in the healthy vermis, then disturbances to these proportions might characterize vermian dysmorphology in schizophrenia. Measures of grey and white matter tissue volumes from three anatomical divisions of the vermis were obtained from 52 patients with chronic schizophrenia and 55 healthy controls. Cross-correlations of the tissue class volumes were computed for each subject group, controlling for age. The number of significant correlations in each group were compared. In addition, the grey/white matter ratio was computed within and across each vermian division. Differences in mean and variance were assessed using t and F tests. A false discovery rate of 0.05 controlled for multiple comparisons. Among controls, 11 of 15 correlations were significant. Among patients, eight of 15 correlations were significant. Five of the nine grey/white matter ratios had an increased mean in the patient group, and all of the variances were trend level or significantly increased in the patients. Tissue class volumes in the cerebellar vermis were strongly interrelated in controls. These relationships were disturbed in patients with schizophrenia.