| 1. |
- Schijven, Dick, et al.
(författare)
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Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
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Tidskriftsartikel (refereegranskat)abstract
- Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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| 2. |
- Ge, R, et al.
(författare)
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Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization
- 2023
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Ingår i: bioRxiv : the preprint server for biology. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR<0.05 indicated that the MFPR-derived sex- and region-specific models with nonlinear polynomials for age and linear effects of global measures had superior predictive accuracy; the range of the MAE of the models of regional subcortical volumes was 70-520 mm3 and the corresponding ranges for regional cortical thickness and regional cortical surface area were 0.09-0.26 mm and 24-560 mm2, respectively. The MFPR-derived models were also computationally more efficient with a CPU time below one second compared to a range of 2 seconds to 60 minutes for the other algorithms. The performance of all sex- and region-specific MFPR models plateaued at sample sizes exceeding 3,000 and showed comparable MAEs across distinct 10-year age-bins covering the human lifespan. Interpretation: These results provide an empirically benchmarked framework for normative modeling of brain morphometry that is useful for interpreting prior literature and supporting future study designs. The model and tools described here are freely available through CentileBrain (https://centilebrain.org/), a user-friendly web platform.
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| 3. |
- Gracias, J., et al.
(författare)
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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia risk has been associated with the complement component 4 (C4) genes. Here the authors show that C4A is elevated in individuals with schizophrenia. Postsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
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| 4. |
- Sellgren, C. M., et al.
(författare)
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A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:10, s. 1342-1350
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Tidskriftsartikel (refereegranskat)abstract
- Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1 beta and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.
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| 5. |
- Cremaschi, Laura, et al.
(författare)
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Prevalences of autoimmune diseases in schizophrenia, bipolar I and II disorder, and controls
- 2017
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Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 258, s. 9-14
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies on the relationship between autoimmune diseases, schizophrenia, and bipolar disorder are mainly based on hospital discharge registers with insufficient coverage of outpatient data. Furthermore, data is scant on the prevalence of autoimmune diseases in bipolar subgroups. Here we estimate the self-reported prevalences of autoimmune diseases in schizophrenia, bipolar disorder type I and II, and controls. Lifetime prevalence of autoimmune diseases was assessed through a structured interview in a sample of 9076 patients (schizophrenia N = 5278, bipolar disorder type I N = 1952, type II N = 1846) and 6485 controls. Comparative analyses were performed using logistic regressions. The prevalence of diabetes type 1 did not differ between groups. Hyperthyroidism, hypothyroidism regardless of lithium effects, rheumatoid arthritis, and polymyalgia rheumatica were most common in bipolar disorder. Systemic lupus erythematosus was less common in bipolar disorder than in the other groups. The rate of autoimmune diseases did not differ significantly between bipolar subgroups. We conclude that prevalences of autoimmune diseases show clear differences between schizophrenia and bipolar disorder, but not between the bipolar subgroups. © 2017 Elsevier B.V.
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| 6. |
- Peeters, Els, et al.
(författare)
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PDRs4All: III. JWST's NIR spectroscopic view of the Orion Bar
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 685
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Tidskriftsartikel (refereegranskat)abstract
- Context. JWST has taken the sharpest and most sensitive infrared (IR) spectral imaging observations ever of the Orion Bar photodis-sociation region (PDR), which is part of the nearest massive star-forming region the Orion Nebula, and often considered to be the 'prototypical'strongly illuminated PDR. Aims. We investigate the impact of radiative feedback from massive stars on their natal cloud and focus on the transition from the H II region to the atomic PDR -crossing the ionisation front (IF) -, and the subsequent transition to the molecular PDR -crossing the dissociation front (DF). Given the prevalence of PDRs in the interstellar medium and their dominant contribution to IR radiation, understanding the response of the PDR gas to far-ultraviolet (FUV) photons and the associated physical and chemical processes is fundamental to our understanding of star and planet formation and for the interpretation of any unresolved PDR as seen by JWST. Methods. We used high-resolution near-IR integral field spectroscopic data from NIRSpec on JWST to observe the Orion Bar PDR as part of the PDRs4All JWST Early Release Science programme. We constructed a 3″ × 25″ spatio-spectral mosaic covering 0.97-5.27 μm at a spectral resolution R of ~2700 and an angular resolution of 0.075″-0.173″. To study the properties of key regions captured in this mosaic, we extracted five template spectra in apertures centred on the three H2 dissociation fronts, the atomic PDR, and the H II region. This wealth of detailed spatial-spectral information was analysed in terms of variations in the physical conditions-incident UV field, density, and temperature -of the PDR gas. Results. The NIRSpec data reveal a forest of lines including, but not limited to, He I, H I, and C I recombination lines; ionic lines (e.g. Fe III and Fe II); O I and N I fluorescence lines; aromatic infrared bands (AIBs, including aromatic CH, aliphatic CH, and their CD counterparts); pure rotational and ro-vibrational lines from H2; and ro-vibrational lines from HD, CO, and CH+, with most of them having been detected for the first time towards a PDR. Their spatial distribution resolves the H and He ionisation structure in the Huygens region, gives insight into the geometry of the Bar, and confirms the large-scale stratification of PDRs. In addition, we observed numerous smaller-scale structures whose typical size decreases with distance from θ1 Ori C and IR lines from C I, if solely arising from radiative recombination and cascade, reveal very high gas temperatures (a few 1000 K) consistent with the hot irradiated surface of small-scale dense clumps inside the PDR. The morphology of the Bar, in particular that of the H2 lines, reveals multiple prominent filaments that exhibit different characteristics. This leaves the impression of a 'terraced'transition from the predominantly atomic surface region to the CO-rich molecular zone deeper in. We attribute the different characteristics of the H2 filaments to their varying depth into the PDR and, in some cases, not reaching the C+/C/CO transition. These observations thus reveal what local conditions are required to drive the physical and chemical processes needed to explain the different characteristics of the DFs and the photochemical evolution of the AIB carriers. Conclusions. This study showcases the discovery space created by JWST to further our understanding of the impact radiation from young stars has on their natal molecular cloud and proto-planetary disk, which touches on star and planet formation as well as galaxy evolution.
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| 7. |
- Abe, C., et al.
(författare)
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Genetic risk for bipolar disorder and schizophrenia predicts structure and function of the ventromedial prefrontal cortex
- 2021
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Ingår i: Journal of Psychiatry & Neuroscience. - : CMA Joule Inc.. - 1180-4882 .- 1488-2434. ; 46:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Bipolar disorder is highly heritable and polygenic. The polygenic risk for bipolar disorder overlaps with that of schizophrenia, and polygenic scores are normally distributed in the population. Bipolar disorder has been associated with structural brain abnormalities, but it is unknown how these are linked to genetic risk factors for psychotic disorders. Methods: We tested whether polygenic risk scores for bipolar disorder and schizophrenia predict structural brain alterations in 98 patients with bipolar disorder and 81 healthy controls. We derived brain cortical thickness, surface area and volume from structural MRI scans. In post-hoc analyses, we correlated polygenic risk with functional hub strength, derived from resting-state functional MRI and brain connectomics. Results: Higher polygenic risk scores for both bipolar disorder and schizophrenia were associated with a thinner ventromedial prefrontal cortex (vmPFC). We found these associations in the combined group, and separately in patients and drug-naive controls. Polygenic risk for bipolar disorder was correlated with the functional hub strength of the vmPFC within the default mode network. Limitations: Polygenic risk is a cumulative measure of genomic burden. Detailed genetic mechanisms underlying brain alterations and their cognitive consequences still need to be determined. Conclusion: Our multimodal neuroimaging study linked genomic burden and brain endophenotype by demonstrating an association between polygenic risk scores for bipolar disorder and schizophrenia and the structure and function of the vmPFC. Our findings suggest that genetic factors might confer risk for psychotic disorders by influencing the integrity of the vmPFC, a brain region involved in self-referential processes and emotional regulation. Our study may also provide an imaging-genetics vulnerability marker that can be used to help identify individuals at risk for developing bipolar disorder.
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| 8. |
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| 9. |
- Berne, Olivier, et al.
(författare)
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PDRs4All : A JWST Early Release Science Program on Radiative Feedback from Massive Stars
- 2022
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Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 134:1035
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Tidskriftsartikel (refereegranskat)abstract
- Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter- and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.
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| 10. |
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