MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Cost-effectiveness of early intervention in psychosis in low- and middle-income countries: economic evaluation from São Paulo, Brazil.

AIMS: The effectiveness and cost-effectiveness of early intervention for psychosis (EIP) services are well established in high-income countries but not in low- and middle-income countries (LMICs). Despite the scarcity of local evidence, several EIP services have been implemented in LMICs. Local evaluations are warranted before adopting speciality models of care in LMICs. We aimed to estimate the cost-effectiveness of implementing EIP services in Brazil. METHODS: A model-based economic evaluation of EIP services was conducted from the Brazilian healthcare system perspective. A Markov model was developed using a cohort study conducted in São Paulo. Cost data were retrieved from local sources. The outcome of interest was the incremental cost-effectiveness ratio (ICER) measured as the incremental costs over the incremental quality-adjusted life-years (QALYs). Sensitivity analyses were performed to test the robustness of the results. RESULTS: The study included 357 participants (38% female), with a mean (SD) age of 26 (7.38) years. According to the model, implementing EIP services in Brazil would result in a mean incremental cost of 4,478 Brazilian reals (R$) and a mean incremental benefit of 0.29 QALYs. The resulting ICER of R$ 15,495 (US dollar [USD] 7,640 adjusted for purchase power parity [PPP]) per QALY can be considered cost-effective at a willingness-to-pay threshold of 1 Gross domestic product (GDP) per capita (R$ 18,254; USD 9,000 PPP adjusted). The model results were robust to sensitivity analyses. CONCLUSIONS: This study supports the economic advantages of implementing EIP services in Brazil. Although cultural adaptations are required, these data suggest EIP services might be cost-effective even in less-resourced countries.

Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Pupil Size Tracks Attentional Performance In Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) diagnosis is based on reported symptoms, which carries the potential risk of over- or under-diagnosis. A biological marker that helps to objectively define the disorder, providing information about its pathophysiology, is needed. A promising marker of cognitive states in humans is pupil size, which reflects the activity of an 'arousal' network, related to the norepinephrine system. We monitored pupil size from ADHD and control subjects, during a visuo-spatial working memory task. A sub group of ADHD children performed the task twice, with and without methylphenidate, a norepinephrine-dopamine reuptake inhibitor. Off-medication patients showed a decreased pupil diameter during the task. This difference was no longer present when patients were on-medication. Pupil size correlated with the subjects' performance and reaction time variability, two vastly studied indicators of attention. Furthermore, this effect was modulated by medication. Through pupil size, we provide evidence of an involvement of the noradrenergic system during an attentional task. Our results suggest that pupil size could serve as a biomarker in ADHD.

Coordinated brain development: exploring the synchrony between changes in grey and white matter during childhood maturation.

Brain development during childhood and early adolescence is characterized by global changes in brain architecture. Neuroimaging studies have revealed overall decreases in cortical thickness (CT) and increases in fractional anisotropy (FA). Furthermore, previous studies have shown that certain cortical regions display coordinated growth during development. However, there is significant heterogeneity in the timing and speed of these developmental transformations, and it is still unclear whether white and grey matter changes are co-localized. In this multimodal neuroimaging study, we investigated the relationship between grey and white matter developmental changes and asynchronous maturation within brain regions in 249 normally developing children between the ages 7-14. We used structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to analyze CT and FA, respectively, as well as their covariance across development. Consistent with previous studies, we observed overall cortical thinning with age, which was accompanied by increased FA. We then compared the coordinated development of grey and white matter as indexed by covariance measures. Covariance between grey matter regions and the microstructure of white matter tracts connecting those regions were highly similar, suggesting that coordinated changes in the cortex were mirrored by coordinated changes in their respective tracts. Examining within-brain divergent trajectories, we found significant structural decoupling (decreased covariance) between several brain regions and tracts in the 9- to 11-year-old group, particularly involving the forceps minor and the regions that it connects to. We argue that this decoupling could reflect a developmental pattern within the prefrontal region in 9- and 11-year-old children, possibly related to the significant changes in cognitive control observed at this age.

HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

Whole-Brain Atrophy Rate in Idiopathic Parkinson's Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy.

In multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), the absence of surrogate endpoints makes clinical trials long and expensive. We aim to determine annualized whole-brain atrophy rates (a-WBAR) in idiopathic Parkinson's disease (IPD), MSA, and PSP. Ten healthy controls, 20 IPD, 12 PSP, and 8 MSA patients were studied using a volumetric MRI technique (SIENA). In controls, the a-WBAR was 0.37% ± 0.28 (CI 95% 0.17-0.57), while in IPD a-WBAR was 0.54% ± 0.38 (CI 95% 0.32-0.68). The IPD patients did not differ from the controls. In PSP, the a-WBAR was 1.26% ± 0.51 (CI 95%: 0.95-1.58). In MSA, a-WBAR was 1.65% ± 1.12 (CI 95%: 0.71-2.59). MSA did not differ from PSP. The a-WBAR in PSP and MSA were significantly higher than in the IPD group (p = 0.004 and p < 0.001, resp.). In PSP, the use of a-WBAR required one-half of the patients needed for clinical scales to detect a 50% reduction in their progression. In MSA, one-quarter of the patients would be needed to detect the same effect. a-WBAR is a reasonable candidate to consider as a surrogate endpoint in short clinical trials using smaller sample sizes. The confidence intervals for a-WBAR may add a potential retrospective application for a-WBAR to improve the diagnostic accuracy of MSA and PSP versus IPD.

Meta-connectomics: human brain network and connectivity meta-analyses.

Abnormal brain connectivity or network dysfunction has been suggested as a paradigm to understand several psychiatric disorders. We here review the use of novel meta-analytic approaches in neuroscience that go beyond a summary description of existing results by applying network analysis methods to previously published studies and/or publicly accessible databases. We define this strategy of combining connectivity with other brain characteristics as 'meta-connectomics'. For example, we show how network analysis of task-based neuroimaging studies has been used to infer functional co-activation from primary data on regional activations. This approach has been able to relate cognition to functional network topology, demonstrating that the brain is composed of cognitively specialized functional subnetworks or modules, linked by a rich club of cognitively generalized regions that mediate many inter-modular connections. Another major application of meta-connectomics has been efforts to link meta-analytic maps of disorder-related abnormalities or MRI 'lesions' to the complex topology of the normative connectome. This work has highlighted the general importance of network hubs as hotspots for concentration of cortical grey-matter deficits in schizophrenia, Alzheimer's disease and other disorders. Finally, we show how by incorporating cellular and transcriptional data on individual nodes with network models of the connectome, studies have begun to elucidate the microscopic mechanisms underpinning the macroscopic organization of whole-brain networks. We argue that meta-connectomics is an exciting field, providing robust and integrative insights into brain organization that will likely play an important future role in consolidating network models of psychiatric disorders.

Renal transplants with delayed graft function show decreased renal function despite monitoring with postabsorptive levels.

Cyclosporine (CyA) monitoring with postabsorptive levels can predict the risk of an acute rejection episode (ARE). Large doses of CyA are needed to obtain adequate drug exposure. The impact of this strategy on renal function, especially in patients with delayed graft function (DGF), is unknown. We report our experience comparing C3 (3-hour postdose) monitoring with a historical series of cadaveric renal transplants. Sixty-three consecutive patients who received cadaveric renal transplants were followed for 1 year. Group A (historical n = 31) patients received 6 mg/kg/d CyA with the dose adjusted according to the trough level (target, 250-350 ng/mL), group B (study n = 32) received 10 mg/kg/d CyA with dose adjustments based upon C3 (target, 1100-1500 ng/mL). All patients received cyclosporine prednisone and a third agents. The general characteristics of the donors and recipients were comparable. The incidence of biopsy-proven ARE at 1 year in group A was 42% and 19% in group B (P <.05). Patients achieving C3 levels >1000 ng/mL at 1 week displayed significantly lower ARE rates (8% vs 50%; P <.05). The rate of DGF was similar in both groups, but the duration was longer in group B (15 vs 21 days, P <.05). The serum creatinine (SCr) level was significantly higher in group B at 3 months (1.47 mg/dL group A vs 1.76 mg/dL group B; P <.05). Patients in group B with DGF showed significantly higher SCr values at 1 year (1.18mg% vs 2.03 mg%; P <.05). C3 level monitoring of CyA yields excellent results in terms of decreased ARE, but an increased SCR was observed among patients with DGF.

Análisis critico de un artículo. Heparina no-fraccionada subcutánea versus heparina de bajo peso molecular en el tratamiento inicial de la enfermedad tromboembólica. Prandoni P, Carnovali M, Marchiori A, Galilei investigators. Arch Intern Med 2004; 164: 1077-83 / Critical appraisal: Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni P, Carnovali M, Marchiori A, Galilei investigators. Arch Intern Med 2004; 164: 1077-83

BACKGROUND: Few reports have addressed the value of unfractionated heparin (UFH) or low-molecular-weight heparin in treating the fill spectrum of patients with venous thromboembolism (VTE), including recurrent VTE and pulmonary embolism. METHODS: In an open, multicenter clinical trial, 720 consecutive patients with acute symptomatic VTE, including 119 noncritically ill patients (16.5%) with pulmonary embolism and 102 (14.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy was started concomitantly and continued for at least 3 months. We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up. RESULTS: Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as compared with 14 (3.9%) of the 360 patients assigned to nadroparin (absolute difference between rates, 0.3%; 95% confidence interval, -2.5% to 3.1%). Four patients assigned to UFH (1.1%) and 3 patients assigned to nadroparin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence interval, -1.2% to 1.7%). Overall mortality was 3.3% in each group. CONCLUSIONS: Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE, including those with pulmonary embolism and recurrent VTE.

'Patient' voices, social movements and the habitus; how psychiatric survivors 'speak out'.

What is the 'voice' of the mental health 'user'? This paper seeks to address this question through the presentation of a detailed comparative analysis of two anthologies written by people living with mental 'illness' in the 1950s and 1990s. Using a narrative-style qualitative analysis, the structure and content of the two anthologies is explored. The analysis illustrates the way in which the 'voice' of the mental patient in the 1950s was very different to that of today. The paper then aims to provide a theoretical explanation that accounts for this transformation of voice. Appropriating theoretical concepts from phenomenology and sociology, in particular, Bourdieu's concept of 'habitus', the paper explores the way in which the 'personal' voice of the mental patient is formulated in dialogical relation to wider public and collective movements. These, in turn, connect to broader transformations in the social, economic and health 'fields'.

Fish, field, habitus and madness: the first wave mental health users movement in Great Britain.

This paper traces and explains the emergence of the mental health users movement in Great Britain, focusing specifically upon the formation of the Mental Patients Union in the early 1970s. The analysis presented in the paper draws, to some extent, from conventional movement theory. In addition, however, it draws from the work of Pierre Bourdieu. This represents an innovation in movement analysis and the necessity of this innovation is argued for in an early section of the paper.

R. D. Laing and the British anti-psychiatry movement: a socio-historical analysis.

In this paper I present a socio historical analysis of the rise of the British anti-psychiatry movement. I have three aims. Firstly, to establish what anti-psychiatry was. Secondly, to investigate and explain its emergence. Thirdly, to consider its relationship to other "new social movements". This analysis is important because criticism and opposition, such as that of the anti-psychiatrists, has been an integral element of the psychiatric field since its earliest developments but has seldom been studied by social scientists, particularly in relation to the post-war period. Power and dominant discourses have been the key focus of analysis, to the detriment of a proper consideration of resistance and counter-discourses. This omission is problematic and should be corrected as social movements introduce plurality, dynamism and the potential for change into the psychiatric field, thus contributing quite centrally to its constitution. Anti-psychiatry is, of course, only one of many movements which require analysis in this connection but it was an important movement and we must begin somewhere. In addition, an analysis of anti-psychiatry serves as an important case study for the sociology of social movements, and particularly for the concern with "new social movements" (NSMs). An analysis of it necessarily makes a contribution to our understanding of NSMs.