Constraining spacetime torsion with LAGEOS

We compute the corrections to the orbital Lense-Thirring effect (or frame-dragging) in the presence of spacetime torsion. We derive the equations of motion of a test body in the gravitational field of a rotating axisymmetric massive body, using the parametrized framework of Mao, Tegmark, Guth and Cabi. We calculate the secular variations of the longitudes of the node and of the pericenter. We also show how the LAser GEOdynamics Satellites (LAGEOS) can be used to constrain torsion parameters. We report the experimental constraints obtained using both the nodes and perigee measurements of the orbital Lense-Thirring effect. This makes LAGEOS and Gravity Probe B (GPB) complementary frame-dragging and torsion experiments, since they constrain three different combinations of torsion parameters

Childhood trauma and adulthood inflammation:a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α

Childhood trauma confers higher risk of adulthood physical and mental illness; however, the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis to establish whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta-analysis, including 18 studies encompassing a sample of 16 870 individuals for C-reactive protein (CRP), 15 studies including 3751 individuals for interleukin-6 (IL-6) and 10 studies including 881 individuals for tumour necrosis factor-α (TNF-α). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher's z=0.10, 95% confidence interval (CI)=0.05-0.14), IL-6 (z=0.08, 95% CI=0.03-0.14) and TNF-α (z=0.23, 95% CI=0.14-0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta-regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-α. Age, body mass index (BMI) and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma.</p

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P &lt; 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

Cortisol awakening response is decreased in patients with first-episode psychosis and increased in healthy controls with a history of severe childhood abuse

Background: Childhood abuse is highly prevalent in psychosis patients, but whether/how it affects hypothalamic-pituitary-adrenal (HPA) axis at the onset of psychosis remains unclear. We aimed to investigate the effects of severity of childhood abuse on HPA axis activity, in first-episode psychosis (FEP) and healthy controls.Methods: We recruited 169 FEP patients and 133 controls with different degrees of childhood physical and sexual abuse (i.e. no abuse exposure, non-severe abuse exposure, and severe abuse exposure). Saliva samples were collected to measure cortisol awakening response with respect to ground (CARg), increase (CARi) and diurnal (CDD) cortisol levels. Two-way ANOVA analyses were conducted to test the relationships between severity of childhood abuse and psychosis on cortisol levels in individuals with psychosis and healthy controls with and without childhood abuse history. Results: A statistically significant interaction between childhood abuse and psychosis on CARg was found (F(2,262) = 4.60, p=0.011, ω2=0.42). Overall, controls showed a U-shaped relationship between abuse exposure and CARg, while patients showed an inverted U-shaped relationship. CARg values were markedly different between patients and controls with either no abuse history or exposure to severe childhood abuse. No significant differences were found when looking at CARi and CDD.Conclusions: Our results show a divergent effect of severe childhood abuse on HPA axis activity in patients with first-episode psychosis and in controls. In the presence of exposure to severe childhood abuse, a blunted CARg and a less reactive HPA axis may represent one of the biological mechanisms involved in the development of psychosis

Cortical thickness correlates of minor neurological signs in patients with first episode psychosis

Neurological soft signs (NSS) are subtle abnormalities of motor and sensory function that are present in the absence of localized brain pathological lesions. In psychoses they have been consistently associated with a distinct pattern of cortical and subcortical brain structural alterations at the level of the heteromodal cortex and basal ganglia. However, a more specific and accurate evaluation of the cytoarchitecture of the cortical mantle could further advance our understanding of the neurobiological substrate of psychosis. We investigated the relationship between brain structure and NSS in a sample of 66 patients at their first episode of psychosis. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and Freesurfer to explore cortical thickness and surface area. Higher rates of NSS were associated with a reduction of cortical thickness in the precentral and postcentral gyri, inferior-parietal, superior temporal, and fusiform gyri. Higher rates of NSS were also associated with smaller surface areas of superior temporal gyrus and frontal regions (including middle frontal, superior and orbito-frontal gyri). Finally, more sensory integration signs were also associated with larger surface area of the latero-occipital region. We conclude that the presence of NSS in psychosis is associated with distinct but widespread changes in cortical thickness and surface area, in areas crucial for sensory-motor integration and for the fluid execution of movement. Studying these morphological correlates with advanced neuroimaging techniques can continue to improve our knowledge on the neurobiological substrate of these important functional correlates of psychosis

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Salivary cortisol measures across the clinical stages of psychosis: An individual participant data (IPD) meta-analysis

Background: Studies of salivary cortisol levels in psychosis have yielded inconsistent findings, which may be attributable to heterogeneity in cortisol measurement, illness stage, and approaches to dealing with sampling factors and potential confounders. To address these issues, we performed an individual participant data (IPD) meta-analysis comparing individuals at different stages of psychosis to controls using five different salivary cortisol measures and explored potential effect modifiers. Methods: Salivary cortisol data from five London-based cohorts were used to derive the cortisol awakening response, total daytime cortisol output, basal cortisol, and diurnal slope measures (wake-to-evening and peak-to-evening). Linear regression models were first performed to obtain standardised beta coefficients (β), representing the difference in each cortisol metric between each clinical stage group (cases) and healthy individuals (controls) after accounting for relevant sampling factors; we then used random-effects meta-analyses and meta-regression models to investigate the effect of psychosis stage and sample characteristics on effect sizes. Results: Data were available for 352 individuals distributed across psychosis clinical stages (1a – distress disorder: N = 35; 1b – clinical high-risk for psychosis: N = 90; 2a – first-episode psychosis: N = 197; 2b – single episode remitted: N = 5; 3 – relapsing/remitting illness: N = 18; 4 – severe and persistent illness: N = 7) and 292 controls. A significant overall main effect of clinical stage on peak-to-evening diurnal slope was observed (χ 2=12.83, p = 0.025), with both the clinical high-risk (β=0.21, 95 % CI: 0.06, 0.36) and first-episode psychosis (β=0.20, 95 % CI: 0.10, 0.31) groups characterised by flatter slopes than controls. The clinical stage groups and controls did not differ on any other cortisol measure. Several sample characteristics were significantly associated with diurnal slope effect sizes, but after accounting for clinical stage, only the association between mean age in cases and wake-to-evening diurnal slope retained significance. Conclusion: Clinical high-risk and first-episode psychosis participants differed from healthy controls in the peak-to-evening diurnal cortisol slope. This measure has not been examined in these populations before, and its potential predictive and prognostic utility for psychotic disorders merits further investigation.</p

Effect of vitamin D supplementation on outcomes in people with early psychosis

Importance People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes. Objective To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP. Design, Setting, and Participants This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019. Interventions Monthly augmentation with 120 000 IU of cholecalciferol or placebo. Main Outcomes and Measures The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline. Results A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, −1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, −0.98; 95% CI, −2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, −0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, −1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, −0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, −2.09; 95% CI, −4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, −1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, −4.60 to 4.94); Global Assessment of Function disability score (mean difference, −0.01; 95% CI, −5.25 to 5.23), or Calgary Depression Scale score (mean difference, −0.39; 95% CI, −2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations. Conclusions and Relevance In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies. Trial Registration isrctn.org Identifier: ISRCTN1242484

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis

Background Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Methods Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. Results FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease-gyrus rectus-was negatively correlated with the severity of positive and negative symptoms. Conclusions This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.This study was supported by the European Commission (PSYSCAN – Translating neuroimaging findings from research into clinical practice) (P.M., grant number 603196); International Cooperation and Exchange of the National Natural Science Foundation of China (Q.G. and A.M., grant numbers 81220108013, 8122010801, 81621003, 81761128023 and 81227002); Wellcome Trusts Innovator Award (A.M., grant number 208519/ Z/17/Z) Italian Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (C.R, grant number art.1, commi 314-337 legge 232/2016) and the Foundation for Science and Technology (FCT) (S.V., grant number SFRH/BD/ 103907/2014)