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Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as “disconnection syndromes,” with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from postmortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labeling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal, and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory, and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.

Background Combining increased dietary protein intake and resistance exercise training for elderly people is a promising strategy to prevent or counteract the loss of muscle mass and decrease the risk of disabilities. Using findings from controlled interventions in a real-life setting requires adaptations to the intervention and working procedures of healthcare professionals (HCPs). The aim of this study is to adapt an efficacious intervention for elderly people to a real-life setting (phase one) and test the feasibility and potential impact of this prototype intervention in practice in a pilot study (phase two). Methods The Intervention Mapping approach was used to guide the adaptation in phase one. Qualitative data were collected from the original researchers, target group, and HCPs, and information was used to decide whether and how specified intervention elements needed to be adapted. In phase two, a one-group pre-test post-test pilot study was conducted ( n  = 25 community-dwelling elderly), to elicit further improvements to the prototype intervention. The evaluation included participant questionnaires and measurements at baseline (T0) and follow-up (T1), registration forms, interviews, and focus group discussions (T1). Qualitative data for both phases were analysed using an inductive approach. Outcome measures included physical functioning, strength, body composition, and dietary intake. Change in outcomes was assessed using Wilcoxon signed-rank tests. Results The most important adaptations to the original intervention were the design of HCP training and extending the original protein supplementation with a broader nutrition programme aimed at increasing protein intake, facilitated by a dietician. Although the prototype intervention was appreciated by participants and professionals, and perceived applicable for implementation, the pilot study process evaluation resulted in further adaptations, mostly concerning recruitment, training session guidance, and the nutrition programme. Pilot study outcome measures showed significant improvements in muscle strength and functioning, but no change in lean body mass. Conclusion The combined nutrition and exercise intervention was successfully adapted to the real-life setting and seems to have included the most important effective intervention elements. After adaptation of the intervention using insights from the pilot study, a larger, controlled trial should be conducted to assess cost-effectiveness. Trial registration Trial registration number: ClinicalTrials.gov NL51834.081.14 (April 22, 2015).

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Abstract Background and Hypotheses Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Study Design Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. Study Results We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. Conclusions The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

BackgroundSchizophrenia (SZ) and bipolar disorder (BD) have been increasingly viewed as psychotic mood disorders along a shared spectrum. Long-range and short-range structural connectivity have been implicated in both disorders, conceptualising them as “disconnection syndromes”. There has been a rise in neuroimaging tools to understand the overlap and boundaries between the two disorders, which has shifted our focus towards appreciating traits in addition to diagnosis. Our recent pilot study examining short-range U-fibers found in superficial white matter (SWM) found shared and distinct traits among people with SZ and BD and we aimed to investigate SWM further using data from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium.MethodsUsing diffusion weighted imaging (DWI), we performed whole brain tractography in 113 people with SZ, 69 people with SA disorder, 49 people with psychotic BD and 77 healthy controls using BrainVISA and Connectomist 2.0. Segmentation and labelling of SWM tracts were performed using a comprehensive U-fiber atlas. ComBat was applied to remove site effects and principle components analysis was performed to identity networks of bundles used for comparative analyses.ResultsPrinciple component analysis revealed a network comprised of 8 short tracts in frontal, parietal, and temporal regions that had decreased anatomical connectivity in patients, regardless of diagnosis, relative to healthy controls. This network overlaps, in part, regions that differed between patients (SZ and BD) and healthy controls in our recent pilot study. However, we were unable to detect differences between people with SZ, SA disorder and psychotic BD.DiscussionWe demonstrate that short U-fibers are likely vulnerable to pathological processes in psychotic illnesses, encouraging further understanding of their anatomy and function. Our lack of findings between patient groups may reflect a more homogeneous population (three subgroups of psychosis) and may suggest that abnormalities in SWM are less likely due to mood disturbances.

Abstract Background Alterations in brain connectivity are strongly implicated in the pathophysiology of schizophrenia (SZ). Very recently, evidence is mounting to suggest that changes in superficial white matter (SWM) U-shaped short range fibers are integral components of disease neuropathology, a theory that is supported by findings from postmortem studies and less often in vivo in patients with SZ. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in the frontal cortex in people with SZ. Methods Whole brain tractography was performed in 31 people with SZ and 54 healthy controls using BrainVISA and Connectomist 2.0 software. Segmentation and labelling of superficial white matter tracts were performed using a novel atlas characterizing 100 bundles. Principal Components Analysis (PCA) using a varimax orthogonal rotation was performed on mean generalised fractional anisotropy (gFA) of bundles located in the frontal cortex. Composites scores were computed for each subject, reflecting a linear combination of mean gFA values. Results PCA revealed three components explaining 19.7 %, 5.8 %, and 5.4 % of the total variance. The mean score of the second component was significantly lower in the people with SZ compared with controls (p = 0.01) and included 13 bundles connecting regions in the pars orbitalis, insula, pars triangularis, pars opercularis, orbitofrontal cortex, anterior cingulate, superior frontal cortex and middle frontal cortex. Discussion Our results support findings of reduced white matter integrity in the frontal cortex in people with SZ. Moreover, PCA may be helpful in identifying specific networks as the deficits do not appear to be widespread. Identifying patterns of superficial white matter dysconnectivity may be helpful in understanding the prominent symptoms and cognitive deficits and observed in SZ.

To investigate (i) how the SLIMMER intervention was delivered and received in Dutch primary health care and (ii) how this could explain intervention effectiveness. A randomised controlled trial was conducted and subjects were randomly allocated to the intervention (10-month combined dietary and physical activity intervention) or the control group. A process evaluation including quantitative and qualitative methods was conducted. Data on process indicators (recruitment, reach, dose received, acceptability, implementation integrity and applicability) were collected via semi-structured interviews with health-care professionals (n 45) and intervention participant questionnaires (n 155). SLIMMER was implemented in Dutch primary health care in twenty-five general practices, eleven dietitians, nine physiotherapist practices and fifteen sports clubs. Subjects at increased risk of developing type 2 diabetes were included. It was possible to recruit the intended high-risk population (response rate 54 %) and the SLIMMER intervention was very well received by both participants and health-care professionals (mean acceptability rating of 82 and 80, respectively). The intervention programme was to a large extent implemented as planned and was applicable in Dutch primary health care. Higher dose received and participant acceptability were related to improved health outcomes and dietary behaviour, but not to physical activity behaviour. The present study showed that it is feasible to implement a diabetes prevention intervention in Dutch primary health care. Higher dose received and participant acceptability were associated with improved health outcomes and dietary behaviour. Using an extensive process evaluation plan to gain insight into how an intervention is delivered and received is a valuable way of identifying intervention components that contribute to implementation integrity and effective prevention of type 2 diabetes in primary health care.

No abstract available Copyright © 2012 S. Karger AG, Basel

Objective: Schizophrenia is associated with widespread brain-morphological alterations, believed to be shaped by the underlying connectome architecture. This study tests whether large-scale structural reorganization in schizophrenia relates to normative network architecture, in particular regional centrality/hubness and connectivity patterns. We examine network effects in schizophrenia across different disease stages, and transdiagnostically explore consistency of such relationships in patients with bipolar and major depressive disorder. Methods: We studied anatomical MRI scans from 2,439 adults with schizophrenia and 2,867 healthy controls from 26 ENIGMA sites. Case-control patterns of structural alterations were evaluated against two network susceptibility models: 1) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; 2) epicenter models, which identify regions whose typical connectivity profile most closely resembles the disease-related morphological alteration patterns. Both susceptibility models were tested across schizophrenia disease stages and compared to meta-analytic bipolar and major depressive disorder case-control maps. Results: In schizophrenia, regional gray matter reductions co-localized with interconnected hubs, in both the functional (r=0.58, pspin<0.0001) and structural connectome (r=0.32, pspin=0.01). Epicenters were identified in temporo-paralimbic regions, extending to frontal areas. We found unique epicenters for first-episode and early stages, and a shift from occipital to temporal-frontal epicenters in chronic stages. Transdiagnostic comparisons revealed shared epicenters in schizophrenia and bipolar, but not major depressive disorders. Conclusions: Cortical reorganization over the course of schizophrenia closely reflects brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters. The observed overlapping epicenters for schizophrenia and bipolar disorder furthermore suggest shared pathophysiological processes within the schizophrenia-bipolar-spectrum.Competing Interest StatementThe authors have declared no competing interest.