Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset.

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.

Cross-cohort replicable resting-state functional connectivity in predicting symptoms and cognition of schizophrenia.

Schizophrenia (SZ) is a debilitating mental illness characterized by adolescence or early adulthood onset of psychosis, positive and negative symptoms, as well as cognitive impairments. Despite a plethora of studies leveraging functional connectivity (FC) from functional magnetic resonance imaging (fMRI) to predict symptoms and cognitive impairments of SZ, the findings have exhibited great heterogeneity. We aimed to identify congruous and replicable connectivity patterns capable of predicting positive and negative symptoms as well as cognitive impairments in SZ. Predictable functional connections (FCs) were identified by employing an individualized prediction model, whose replicability was further evaluated across three independent cohorts (BSNIP, SZ = 174; COBRE, SZ = 100; FBIRN, SZ = 161). Across cohorts, we observed that altered FCs in frontal-temporal-cingulate-thalamic network were replicable in prediction of positive symptoms, while sensorimotor network was predictive of negative symptoms. Temporal-parahippocampal network was consistently identified to be associated with reduced cognitive function. These replicable 23 FCs effectively distinguished SZ from healthy controls (HC) across three cohorts (82.7%, 90.2%, and 86.1%). Furthermore, models built using these replicable FCs showed comparable accuracies to those built using the whole-brain features in predicting symptoms/cognition of SZ across the three cohorts (r = .17-.33, p < .05). Overall, our findings provide new insights into the neural underpinnings of SZ symptoms/cognition and offer potential targets for further research and possible clinical interventions.

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

A custom-built step exergame training programme to prevent falls in people with multiple sclerosis: A multicentre randomised controlled trial.

BACKGROUND: Cognitive-motor step training can improve stepping, balance and mobility in people with multiple sclerosis (MS), but effectiveness in preventing falls has not been demonstrated. OBJECTIVES: This multisite randomised controlled trial aimed to determine whether 6 months of home-based step exergame training could reduce falls and improve associated risk factors compared with usual care in people with MS. METHODS: In total, 461 people with MS aged 22-81 years were randomly allocated to usual care (control) or unsupervised home-based step exergame training (120 minutes/week) for 6 months. The primary outcome was rate of falls over 6 months from randomisation. Secondary outcomes included physical, cognitive and psychosocial function at 6 months and falls over 12 months. RESULTS: Mean (standard deviation (SD)) weekly training duration was 70 (51) minutes over 6 months. Fall rates did not differ between intervention and control groups (incidence rates (95% confidence interval (CI)): 2.13 (1.57-2.69) versus 2.24 (1.35-3.13), respectively, incidence rate ratio: 0.96 (95% CI: 0.69-1.34, p = 0.816)). Intervention participants performed faster in tests of choice-stepping reaction time at 6 months. No serious training-related adverse events were reported. CONCLUSION: The step exergame training programme did not reduce falls among people with MS. However, it significantly improved choice-stepping reaction time which is critical to ambulate safely in daily life environment.

The Benefits of Cochlear Implantation for Adults: A Systematic Umbrella Review.

OBJECTIVES: The uptake of cochlear implants among adults who could benefit (based on pure-tone audiometry) in developed countries is estimated to be less than 10%. Concerns about potential surgical complications, fear of losing residual hearing, and limited awareness about the benefits of this intervention contribute to the low adoption rate. To enhance quality of life and improve the uptake of cochlear implants, it is essential to have a clear understanding of their benefits. DESIGN: This umbrella review aims to summarize the major benefits of cochlear implant usage in adults, by synthesizing findings from published review articles. A comprehensive search of databases including MEDLINE, EMBASE, PsycINFO, and Google Scholar, was conducted. The search was limited to English-language review articles published between 1990 and 2022, focusing on cochlear implant outcomes in at least 5 adults (aged ≥18 years). Two independent reviewers screened titles, abstracts, and full-text articles, and conducted a quality assessment using the Joanna Briggs Checklist for Systematic Reviews and Research Syntheses. RESULTS: Forty-two articles were included in this review. There were 15 systematic reviews with meta-analysis, 25 systematic reviews without meta-analysis, and 2 systematic scoping reviews. All 42 articles underwent quality assessment using the Joanna Briggs Institute Checklist for Systematic Reviews and Research Syntheses, of which 40% (n = 17) satisfied 9 out of 11 quality criteria. This umbrella review shows that cochlear implants are associated with improvements in speech perception and recognition as well as improved quality of life and cognition. These benefits are observed in a significant proportion of adults undergoing the procedure, highlighting its effectiveness as a viable intervention for individuals with severe to profound hearing loss. CONCLUSIONS: The potential benefits of cochlear implantation appear to outweigh the risks and complications associated with the procedure. It is recommended that adults with severe to profound hearing loss in particular, engage in informed discussions with healthcare professionals to consider cochlear implantation as a viable treatment option.

Civilian moral injury: associations with trauma type and high-frequency heart rate variability in two trauma-exposed community-based samples.

BACKGROUND: Moral injury exposure (MIE) and distress (MID) may indirectly affect the relationship between trauma exposure and alterations in autonomic regulation [assessed via high-frequency heart rate variability (hfHRV)] in civilians, but this has not been tested in prior research. We conducted two exploratory studies to examine trauma types' associations with MIE and MID among civilian medical patients (Study 1) and explore how these facets may indirectly affect the relationship between trauma type and hfHRV among civilians seeking mental health services (Study 2). METHODS: Participants recruited from a public hospital and/or community advertisements (Study 1, n = 72, 87.5% Black, 83.3% women; Study 2, n = 46, 71.7% Black, 97.8% women) completed measures assessing trauma type, MIE, and MID. In Study 1, trauma types that emerged as significant correlates of MIE and MID were entered into separate linear regression analyses. Trauma types identified were included as predictors in indirect effects models with MIE or MID as the mediator and resting hfHRV (assayed via electrocardiography) as the outcome. RESULTS: Childhood sexual abuse emerged as the only significant predictor of MIE, b = 0.38, p < 0.001; childhood sexual abuse, b = 0.26, p < 0.05, and adulthood sexual assault, b = 0.23, p < 0.05 were significant predictors of MID. Participants with greater MIE and MID demonstrated lower hfHRV. Adulthood sexual assault showed an indirect effect on hfHRV through MID, B = -0.10, s.e. = 0.06, 95%CI (-0.232 to -0.005). CONCLUSIONS: Moral injury was uniquely associated with sexual violence and lower hfHRV in civilians. Data highlight moral injury as a pathway through which autonomic dysregulation may emerge and its salience for trauma treatment selection.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

Revisiting Functional Dysconnectivity: a Review of Three Model Frameworks in Schizophrenia.

PURPOSE OF REVIEW: Over the last decade, evidence suggests that a combination of behavioral and neuroimaging findings can help illuminate changes in functional dysconnectivity in schizophrenia. We review the recent connectivity literature considering several vital models, considering connectivity findings, and relationships with clinical symptoms. We reviewed resting state fMRI studies from 2017 to 2023. We summarized the role of two sets of brain networks (cerebello-thalamo-cortical (CTCC) and the triple network set) across three hypothesized models of schizophrenia etiology (neurodevelopmental, vulnerability-stress, and neurotransmitter hypotheses). RECENT FINDINGS: The neurotransmitter and neurodevelopmental models best explained CTCC-subcortical dysfunction, which was consistently connected to symptom severity and motor symptoms. Triple network dysconnectivity was linked to deficits in executive functioning, and the salience network (SN)-default mode network dysconnectivity was tied to disordered thought and attentional deficits. This paper links behavioral symptoms of schizophrenia (symptom severity, motor, executive functioning, and attentional deficits) to various hypothesized mechanisms.

Tilapia lake virus (TiLV) causes severe anaemia and systemic disease in tilapia.

Tilapia lake virus disease (TiLVD) is an emerging disease in tilapia that is associated with mass mortality affecting global tilapia aquaculture. In this study, red hybrid tilapias (Oreochromis spp.) were experimentally infected by intracoelomic injection with Tilapia lake virus (TiLV) to gain a better understanding of the clinicopathological changes during infection. Pale bodies and gill were observed in infected fish after 7 days of post-challenge (dpc) associated with severe anaemia. Further haematological analysis in TiLV-infected fish revealed decreased levels of haemoglobin and haematocrit at 3 dpc. Common pathological findings included pale and friable liver, pale intestine with catarrhal content, and dark and shrunken spleen in TiLV-infected fish at 7 dpc and 14 dpc. Histologically, reduced numbers of red blood cells and accumulation of melano-macrophage centre in the spleen were found in infected fish at 3 dpc, and severe lesions were more commonly observed at 7 and 14 dpc. Lymphocyte infiltration, syncytial cell formation and multifocal necrotic hepatitis were the prominent pathological findings in the liver of infected fish. The severity of pathological changes was associated with TiLV-infection with higher viral loads and with the expression pattern of pro-inflammatory cytokines and antiviral genes, including interferon regulatory factor 1 (irf1), interleukin (il-8), radical s-adenosyl methionine domain containing 2 (rsad2) and mx. Our study provides a comprehensive analysis of the haematological profile and pathological changes in tilapia during TiLV infection. Overall, lesions present in various organs, together with alteration of host immune response in TiLV-infected fish, indicate the systemic infection of this virus. The knowledge gained from this study improves our understanding of how TiLV causes pathological and haematological changes in tilapia.

Maternity care provision for women living with female genital mutilation/cutting: A qualitative study from a high asylum-seeking dispersal context in the UK.

OBJECTIVE: To explore the perspectives of midwives and obstetrician/gynaecologists providing maternity care to women living with female genital mutilation/cutting (FGM/C) in a high asylum-seeker dispersal area in the North West of England. METHODS: We carried out a qualitative study in four hospitals providing maternal health services within the North West of England, with the highest population of asylum-seeking individuals (many from high-prevalence FGM/C countries) in the UK. Participants included 13 practicing midwives and an obstetrician/gynaecologist. In-depth interviews were conducted with study participants. Data collection and analysis were carried out concurrently until theoretical saturation was reached. Data were analysed thematically to generate three key overarching themes. RESULTS: There is a disconnect between Home Office dispersal policy and healthcare policy. Participants indicated that there was inconsistent identification or disclosure of FGM/C, constraining appropriate follow-up and care prior to labour and childbirth. All participants noted existing safeguarding policies and protocols, which were seen by most as being important to protect female dependants, but potentially detrimental to the patient-provider relationship and to the woman's care. Unique challenges around accessing and maintaining continuity of care for asylum-seeking women due to dispersal schemes were indicated. All participants highlighted a lack of specialised training for FGM/C to support provision of clinically appropriate and culturally sensitive care. CONCLUSIONS: There is a clear need for harmony between health and social policy as well as specialised training that centres holistic wellbeing for the woman living with FGM/C, particularly where there are increased numbers of asylum-seeking women from high-prevalence FGM/C countries.

Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity.

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10-3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10-6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10-6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10-27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

The Enhancing NeuroImaging Genetics through Meta-Analysis Consortium: 10 Years of Global Collaborations in Human Brain Mapping.

This Special Issue of Human Brain Mapping is dedicated to a 10-year anniversary of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium. It reports updates from a broad range of international neuroimaging projects that pool data from around the world to answer fundamental questions in neuroscience. Since ENIGMA was formed in December 2009, the initiative grew into a worldwide effort with over 2,000 participating scientists from 45 countries, and over 50 working groups leading large-scale studies of human brain disorders. Over the last decade, many lessons were learned on how best to pool brain data from diverse sources. Working groups were created to develop methods to analyze worldwide data from anatomical and diffusion magnetic resonance imaging (MRI), resting state and task-based functional MRI, electroencephalography (EEG), magnetoencephalography (MEG), and magnetic resonance spectroscopy (MRS). The quest to understand genetic effects on human brain development and disease also led to analyses of brain scans on an unprecedented scale. Genetic roadmaps of the human cortex were created by researchers worldwide who collaborated to perform statistically well-powered analyses of common and rare genetic variants on brain measures and rates of brain development and aging. Here, we summarize the 31 papers in this Special Issue, covering: (a) technical approaches to harmonize analysis of different types of brain imaging data, (b) reviews of the last decade of work by several of ENIGMA's clinical and technical working groups, and (c) new empirical papers reporting large-scale international brain mapping analyses in patients with substance use disorders, schizophrenia, bipolar disorders, major depression, posttraumatic stress disorder, obsessive compulsive disorder, epilepsy, and stroke.

Translating ENIGMA schizophrenia findings using the regional vulnerability index: Association with cognition, symptoms, and disease trajectory.

Patients with schizophrenia have patterns of brain deficits including reduced cortical thickness, subcortical gray matter volumes, and cerebral white matter integrity. We proposed the regional vulnerability index (RVI) to translate the results of Enhancing Neuro Imaging Genetics Meta-Analysis studies to the individual level. We calculated RVIs for cortical, subcortical, and white matter measurements and a multimodality RVI. We evaluated RVI as a measure sensitive to schizophrenia-specific neuroanatomical deficits and symptoms and studied the timeline of deficit formations in: early (≤5 years since diagnosis, N = 45, age = 28.8 ± 8.5); intermediate (6-20 years, N = 30, age 43.3 ± 8.6); and chronic (21+ years, N = 44, age = 52.5 ± 5.2) patients and healthy controls (N = 76, age = 38.6 ± 12.4). All RVIs were significantly elevated in patients compared to controls, with the multimodal RVI showing the largest effect size, followed by cortical, white matter and subcortical RVIs (d = 1.57, 1.23, 1.09, and 0.61, all p < 10-6 ). Multimodal RVI was significantly correlated with multiple cognitive variables including measures of visual learning, working memory and the total score of the MATRICS consensus cognitive battery, and with negative symptoms. The multimodality and white matter RVIs were significantly elevated in the intermediate and chronic versus early diagnosis group, consistent with ongoing progression. Cortical RVI was stable in the three disease-duration groups, suggesting neurodevelopmental origins of cortical deficits. In summary, neuroanatomical deficits in schizophrenia affect the entire brain; the heterochronicity of their appearance indicates both the neurodevelopmental and progressive nature of this illness. These deficit patterns may be useful for early diagnosis and as quantitative targets for more effective treatment strategies aiming to alter these neuroanatomical deficit patterns.

Mapping brain asymmetry in health and disease through the ENIGMA consortium.

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research.

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.

Phosphodiesterase-5 inhibitors in pregnancy: Systematic review and meta-analysis of maternal and perinatal safety and clinical outcomes.

BACKGROUND: The efficacy and safety profile of phosphodiesterase-5 inhibitors (PDE-5i) in pregnancy are unclear from the few relatively small diverse studies that have used them. OBJECTIVE: To assess the safety profile and clinical outcomes of PDE-5i use in pregnancy. SEARCH STRATEGY: We searched Embase, PubMed, CENTRAL, Prospero and Google Scholar to identify randomised controlled trials (RCTs) reporting the use of any PDE-5i in pregnancy up to September 2021. SELECTION CRITERIA: RCTs reporting obstetric or perinatal outcomes or maternal adverse outcomes in women taking PDE5i in pregnancy. DATA COLLECTION AND ANALYSIS: Risk ratios (RR), 95% confidence intervals (95% CI) and 95% prediction intervals were calculated and pooled for analysis. RESULTS: We identified 1324 citations, of which 10 studies including 1090 participants met the inclusion criteria. Only tadalafil and sildenafil were reported as used in pregnancy. Two studies using tadalafil and eight sildenafil. Nine of ten studies were assessed at having of low risk of bias. PDE-5i use was associated with an increased risk of headaches (RR 1.41, 95% CI 0.97-2.05), flushing (RR 2.59, 95% CI 0.69-9.90) and nasal bleeding (RR 10.53, 95% CI 1.36-81.3); an increase in vaginal birth when used for non-fetal growth restriction (FGR) indications (RR 1.24, 95% CI 1.00-1.55) and a reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38-0.88). There was no evidence of any increase in risk of perinatal death (RR 0.89, 95% CI 0.56-1.43). However, use for the treatment of FGR increased the risk of persistent pulmonary hypertension of the newborn (PPHN) (RR 2.52, 95% CI 1.00-6.32). CONCLUSIONS: This meta-analysis suggests PDE-5i use in pregnancy is associated with mild maternal side effects and lower risk of operative birth for intrapartum fetal distress. Prolonged use for the treatment of FGR may increase the risk of PPHN. TWEETABLE ABSTRACT: PDE-5i use in pregnancy is associated with mild maternal side effects, lower operative birth for intrapartum fetal distress and a possible increase in persistent pulmonary hypertension of the newborn when used for the treatment of fetal growth restriction.

Using Normalisation Process Theory (NPT) to develop an intervention to improve referral and uptake rates for self-management education for patients with type 2 diabetes in UK primary care.

BACKGROUND: Referral and uptake rates of structured self-management education (SSME) for Type 2 diabetes (T2DM) in the UK are variable and relatively low. Research has documented contributing factors at patient, practitioner and organisational levels. We report a project to develop an intervention to improve referral to and uptake of SSME, involving an integrative synthesis of existing datasets and stakeholder consultation and using Normalisation Process Theory (NPT) as a flexible framework to inform the development process. METHODS: A three-phase mixed-methods development process involved: (1) synthesis of existing evidence; (2) stakeholder consultation; and (3) intervention design. The first phase included a secondary analysis of data from existing studies of T2DM SSME programmes and a systematic review of the literature on application of NPT in primary care. Influences on referral and uptake of diabetes SSME were identified, along with insights into implementation processes, using NPT constructs to inform analysis. This gave rise to desirable attributes for an intervention to improve uptake of SSME. The second phase involved engaging with stakeholders to prioritise and then rank these attributes, and develop a list of associated resources needed for delivery. The third phase addressed intervention design. It involved translating the ranked attributes into essential components of a complex intervention, and then further refinement of components and associated resources. RESULTS: In phase 1, synthesised analysis of 64 transcripts and 23 articles generated a longlist of 46 attributes of an embedded SSME, mapped into four overarching domains: valued, integrated, permeable and effectively delivered. Stakeholder engagement in phase 2 progressed this to a priority ranked list of 11. In phase 3, four essential components attending to the prioritised attributes and forming the basis of the intervention were identified: 1) a clear marketing strategy for SSME; 2) a user friendly and effective referral pathway; 3) new/amended professional roles; and 4) a toolkit of resources. CONCLUSIONS: NPT provides a flexible framework for synthesising evidence for the purpose of developing a complex intervention designed to increase and reduce variation in uptake to SSME programmes in primary care settings.

Cross disorder comparisons of brain structure in schizophrenia, bipolar disorder, major depressive disorder, and 22q11.2 deletion syndrome: A review of ENIGMA findings.

This review compares the main brain abnormalities in schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and 22q11.2 Deletion Syndrome (22q11DS) determined by ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium investigations. We obtained ranked effect sizes for subcortical volumes, regional cortical thickness, cortical surface area, and diffusion tensor imaging abnormalities, comparing each of these disorders relative to healthy controls. In addition, the studies report on significant associations between brain imaging metrics and disorder-related factors such as symptom severity and treatments. Visual comparison of effect size profiles shows that effect sizes are generally in the same direction and scale in severity with the disorders (in the order SZ > BD > MDD). The effect sizes for 22q11DS, a rare genetic syndrome that increases the risk for psychiatric disorders, appear to be much larger than for either of the complex psychiatric disorders. This is consistent with the idea of generally larger effects on the brain of rare compared to common genetic variants. Cortical thickness and surface area effect sizes for 22q11DS with psychosis compared to 22q11DS without psychosis are more similar to those of SZ and BD than those of MDD; a pattern not observed for subcortical brain structures and fractional anisotropy effect sizes. The observed similarities in effect size profiles for cortical measures across the psychiatric disorders mimic those observed for shared genetic variance between these disorders reported based on family and genetic studies and are consistent with shared genetic risk for SZ and BD and structural brain phenotypes.