Ingrid Agartz

• Blakstad, Eirik Gustav; Bakke, Laura Anne Wortinger; Jørgensen, Kjetil Nordbø; Nerland, Stener; Barth, Claudia & Andreou, Dimitrios [Show all 10 contributors for this article] (2026). Structural brain alterations of the subcortical limbic system in schizophrenia and bipolar disorders. Schizophrenia Research. ISSN 0920-9964. 296, p. 91–101. doi: 10.1016/j.schres.2026.07.007. Full text in Research Archive
• Vareilles, Héloïse de; Mitchell, Samantha C.; Garrison, Jane R.; Wu, Shun Chin Jim; Alvarez-Sanchez, Laura & Thomas, Reuben [Show all 14 contributors for this article] (2026). Evaluation of a New Paracingulate Sulcus Identification and Measurement Protocol. Human Brain Mapping. ISSN 1065-9471. 47(8). doi: 10.1002/hbm.70574. Full text in Research Archive
• Yang, Xi; Agartz, Ingrid; Andreassen, Ole; Bachman, Peter; Baeza, Inmaculada & Bartholomeusz, Cali [Show all 78 contributors for this article] (2026). Local chemoarchitecture explains widespread lower cortical thickness associated with clinical high risk for psychosis. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03586-4. Full text in Research Archive Show summary

  The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR Working Group’s large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest predictors of lower CT in CHR and psychosis transition (total dominance range: 62–69% and 58–87%, respectively), with contributions of monoamine systems being especially sensitive to medication exposure (8–23% change in dominance range). Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and opioid systems (total dominance range: 60–81%), with contributions of histamine being sensitive to medication exposure (9–19% change in dominance range). Combined, these results uniquely identify specific neurochemical systems – particularly monoaminergic, glutamatergic, and GABAergic pathways – as key molecular mechanisms associated with cortical thinning in people at high risk of developing psychosis.

• Warren, Aoife; Holleran, Laurena; Agartz, Ingrid; Andreassen, Ole; Banaj, Nerisa & Cannon, Dara M. [Show all 38 contributors for this article] (2026). An ENIGMA Consortium study of the relationship between white matter microstructure and positive and negative symptom severity in patients with schizophrenia. Schizophrenia. 12. doi: 10.1038/s41537-026-00728-z. Full text in Research Archive Show summary

  Symptom severity in schizophrenia has been repeatedly associated with thinner cortical gray matter. While global and regional white matter microstructure alterations in schizophrenia are well-documented, their association with clinical symptom severity remains unclear. As this is likely due to methodological heterogeneity across studies, we tested whether symptom severity in schizophrenia was associated with regional and global white matter alterations using standardized methods. We hypothesized that positive symptom severity would be associated with temporal white matter changes and that negative symptom severity would be associated with alterations in frontal white matter. Using a standardized fractional anisotropy (FA) analysis pipeline developed by the ENIGMA consortium, we conducted a meta-analysis of the association between white matter microstructure and symptom severity in n = 1025 (ages 16–68 years; 369 women/656 men) across 19 ENIGMA sites. Where significant heterogeneity was detected across sites, we examined whether variation in association strength between white matter microstructure and symptom severity was explained by duration of illness and/or current antipsychotic use. Positive symptom severity was significantly associated with white matter microstructure as measured using temporal lobe FA and global FA. Negative symptom severity showed no significant association with white matter microstructure as measured using frontal lobe FA or global FA. Significant heterogeneity across sites was observed for the negative symptom analysis, explained partly by duration of illness. Post-hoc exploratory analyses identified one site as disproportionately contributing to this heterogeneity, and when removed, negative symptom severity was significantly associated with both global and frontal FA. These findings support the view of schizophrenia as a disorder of brain connectivity, in a manner relevant to understanding variation in clinical symptom severity.

• Wallenwein, Lara A; Wortinger, Laura Anne; Barth, Claudia; Parekh, Pravesh; Jørgensen, Kjetil Nordbø & Palaniyappan, Lena [Show all 10 contributors for this article] (2026). Longitudinal Trajectories of Cortical Folding in Schizophrenia Spectrum Disorders: A 13-Year Follow-Up Study. Schizophrenia Bulletin. ISSN 0586-7614. 52(2). doi: 10.1093/schbul/sbaf245. Full text in Research Archive Show summary

  Background and Hypothesis Altered cortical folding is a well-established finding in schizophrenia spectrum disorders (SSD). Patients with SSD have been hypothesized to exhibit an accelerated decline in age-related cortical folding, quantified with the local gyrification index (LGI). Here, we assessed longitudinal and cross-sectional LGI differences in patients with chronic SSD relative to healthy controls across 13 years. Study Design The sample comprised patients with SSD (mean baseline age = 41.28 years) and healthy controls (mean baseline age = 41.56 years), with magnetic resonance imaging acquisitions at baseline (103 SSD patients and 99 controls) and follow-up after 5 (50 SSD patients and 57 controls) and 13 years (42 SSD patients and 60 controls). T1-weighted images were processed with the longitudinal pipeline in FreeSurfer. Spatiotemporal linear mixed-effects models were used to test for longitudinal and cross-sectional case-control differences in LGI, as well as the impact of symptom severity and antipsychotic medication dose among patients. Study Results Although cross-sectional LGI was lower in patients in extensive frontal, parietal, and occipital regions, we observed no significant differences in longitudinal trajectories between patients and controls after FDR correction. Medication dose was linked cross-sectionally to lower LGI of the anterior cingulate, orbitofrontal cortex, and postcentral gyrus. Conclusion In the longest longitudinal study on cortical folding in SSD patients to date, we found no evidence for accelerated progressive decline in cortical folding. Rather, chronic SSD appears to be characterized by a state of stable hypogyria relative to healthy controls, consistent with the interpretation of LGI as a marker of early gyrification disturbances in SSD.

• Slapø, Nora Berz; Jørgensen, Kjetil Nordbø; Nerland, Stener; Mørch-Johnsen, Lynn Egeland; Pettersen, Johanne Hagen & Roelfs, Daniel [Show all 23 contributors for this article] (2026). Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders. Schizophrenia. doi: 10.1038/s41537-025-00715-w. Full text in Research Archive Show summary

  Schizophrenia spectrum disorders (SCZspect) are associated with altered function in the auditory cortex (AC), indicated by lower N100 amplitude of the auditory evoked potential (AEP). Although the neural substrate behind lower N100 amplitude remains elusive, myelination in the AC may play a role. This study compared N100 amplitude and magnetic resonance imaging (MRI) T1 weighted and T2 weighted ratio (T1w/T2w-ratio), as a proxy of myelination, in the primary AC (AC1) and secondary AC (AC2) between SCZspect (n = 33, 48% women) and healthy controls (HC, n = 144, 49% women). We also examined the associations between N100 amplitude and T1w/T2w-ratios across groups. We finally explored N100 amplitude and T1w/T2w-ratios and the N100-T1w/T2w-ratio associations between male and female SCZspect and HC. N100 amplitude was significantly lower in male SCZspect compared to male HC (p = 0.01) and nominally lower in SCZspect compared to HC (p = 0.03). However, T1w/T2w-ratios in AC1/AC2 did not differ between groups, and no association was found between N100 amplitude and T1w/T2w-ratio in either group. These findings suggest that sex-specific effects should be considered in SCZspect neurophysiology research. Our results do not support the hypothesis of an association between lower N100 amplitude and lower T1w/T2w-ratio in the AC1/AC2 in SCZspect. More precise assessments of intracortical myelin are needed to understand the relationship between N100 amplitude and cortical myelination in the AC in SCZspect and in healthy controls.

• Nerland, Stener; Barth, Claudia; Jørgensen, Kjetil Nordbø; Bakke, Laura Anne Wortinger; Castro-Fornieles, Josefina & Díaz-Caneja, Covadonga M. [Show all 44 contributors for this article] (2026). Cerebral cortical alterations in adolescent early-onset psychosis: a surface-based morphometry mega-analysis. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03641-0. Full text in Research Archive Show summary

  Abstract Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d =-0.36/-0.31), surface area (left/right: d =-0.42/-0.41), cortical volume (left/right: d =-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d =-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r =-0.21; p FDR =0.014) and antidepressant users had smaller area ( d =-0.43; p FDR =0.034) and volume ( d =-0.50; p FDR =0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r =0.62) and bipolar disorders (BD; r =0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

• Colbert, Sarah M. C.; Monson, Eric T.; Andreassen, Ole; Ayinde, Olatunde O.; Barr, Peter B. & Bejan, Cosmin A. [Show all 314 contributors for this article] (2025). Defining suicidality phenotypes for genetic studies: perspectives of the Psychiatric Genomics Consortium Suicide Working Group. Molecular Psychiatry. ISSN 1359-4184. 30(12), p. 6144–6154. doi: 10.1038/s41380-025-03271-y. Full text in Research Archive Show summary

  Suicidality phenotypes, consisting of suicidal ideation (SI), suicide attempt (SA), and suicide death (SD), are all heritable but present unique challenges in genome-wide association studies (GWAS) due to their individual complexity, overlap with each other and with related self-harm phenotypes, and varying associations with psychiatric disorders. GWAS have uncovered several loci associated with suicidality phenotypes by meta-analyzing data from multiple cohorts. However, combining datasets from many research groups, where each group may use different study designs, phenotyping instruments, and definitions of suicidality phenotypes, presents challenges. Heterogeneity resulting from these differences can limit genetic discovery; harmonizing phenotype definitions to ensure consistency will greatly improve results. Here, we describe a standardized phenotyping protocol that draws on the expertise of a subgroup of clinicians, researchers, and experts from the Psychiatric Genomics Consortium Suicide Working Group to propose consensus definitions for SI, SA, and SD for genetic studies.

• Silva, Ana I.; Sønderby, Ida Elken; Kirov, George; Abdellaoui, Abdel; Agartz, Ingrid & Ames, David [Show all 106 contributors for this article] (2025). Penetrance of Neurodevelopmental Copy Number Variants Is Associated With Variations in Cortical Morphology. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 10(10), p. 1093–1106. doi: 10.1016/j.bpsc.2025.05.010. Full text in Research Archive Show summary

  Background: Copy number variants (CNVs) may increase the risk for neurodevelopmental conditions. The neurobiological mechanisms that link these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals who carry CNVs are associated with their degree of penetrance. Methods: We investigated whether increased CNV penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis)-CNV consortium. In the main analyses, we included 9268 individuals (aged 7–90 years, 54% female), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 noncarriers. CNV penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk of developing either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder, and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.

• Engchuan, Worrawat; Shanta, Omar; Kumar, Kuldeep; MacDonald, Jeffrey R.; Thiruvahindrapuram, Bhooma & Hamdan, Omar [Show all 250 contributors for this article] (2025). Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects. medRxiv. doi: 10.1101/2025.07.11.25331381. Full text in Research Archive Show summary

  Abstract Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.

• Wu, Shun-Chin Jim; Vareilles, Héloïse de; Mitchell, Samantha C; Al-Manea, Atheer; Garrison, Jane & Mamalakis, Michail [Show all 14 contributors for this article] (2025). Reassessing Asymmetry Reduction in Psychosis: Cingulate Folding and Gyrification Covariance in Patients with Auditory Hallucinations. Schizophrenia Bulletin. ISSN 0586-7614. doi: 10.1093/schbul/sbaf086. Full text in Research Archive Show summary

  Abstract Background and Hypothesis Prior research links a shorter paracingulate sulcus (PCS) to hallucinations in schizophrenia, but its symmetry hemispheric specificity and relevance to bipolar disorders remain unclear. We hypothesized that reduced PCS asymmetry and interhemispheric gyrification covariance in salience and auditory networks are associated with lifetime auditory hallucinations (AH) in psychotic spectrum disorders. Study Design We compared patients with and without AH, and healthy controls, focusing on PCS asymmetry in five ordinal classes, sulcal length and depth, and interhemispheric gyrification covariance. Study Results Among 351 patients with schizophrenia or bipolar spectrum disorders (SSD/BSD), 194 (55.3%) had AH, compared to 157 without and 278 healthy controls. We found no significant PCS class asymmetry between hemispheres (V = 6648.5, P = .097) and decreased leftward asymmetry in PCS length (F(2,621) = 3.19, P = .013) in patients with AH, compared with those without and healthy controls. Compared to patients without AH, those with AH showed increased gyrification covariance in the auditory network (F(2,625) = 42.5, P &lt; .001). In the salience network, patients with SSD and AH had increased covariance (F(2,625) = 299, P &lt; .001), while patients with BSD and AH displayed decreased covariance (F(2,625) = 102, P &lt; .001). Conclusions This study, featuring the largest cohort to date, links the AH trait to replicable reduced leftward PCS asymmetry and altered interhemispheric covariance in psychotic spectrum disorders, supporting theories of reduced asymmetry and altered brain network coordination as part of the mechanistic pathway to psychosis.

• Mamalakis, Michail; Vareilles, Héloïse de; Al-Manea, Atheer; Mitchell, Samantha C.; Agartz, Ingrid & Mørch-Johnsen, Lynn Egeland [Show all 11 contributors for this article] (2025). An explainable three dimensional framework to uncover learning patterns: A unified look in variable sulci recognition. Artificial Intelligence in Medicine. ISSN 0933-3657. 171. doi: 10.1016/j.artmed.2025.103286. Full text in Research Archive Show summary

  The significant features identified in a representative subset of the dataset during the learning process of an artificial intelligence model are referred to as a ‘global’ explanation. Three-dimensional (3D) global explanations are crucial in neuroimaging, where a complex representational space demands more than basic two-dimensional interpretations. However, current studies in the literature often lack the accuracy, comprehensibility, and 3D global explanations needed in neuroimaging and beyond. To address this gap, we developed an explainable artificial intelligence (XAI) 3D-Framework capable of providing accurate, low-complexity global explanations. We evaluated the framework using various 3D deep learning models trained on a well-annotated cohort of 596 structural MRIs. The binary classification task focused on detecting the presence or absence of the paracingulate sulcus (PCS), a highly variable brain structure associated with psychosis. Our framework integrates statistical features (Shape) and XAI methods (GradCam and SHAP) with dimensionality reduction, ensuring that explanations reflect both model learning and cohort-specific variability. By combining Shape, GradCam, and SHAP, our framework reduces inter-method variability, enhancing the faithfulness and reliability of global explanations. These robust explanations facilitated the identification of critical sub-regions, including the posterior temporal and internal parietal regions, as well as the cingulate region and thalamus, suggesting potential genetic or developmental influences. For the first time, this XAI 3D-Framework leverages global explanations to uncover the broader developmental context of specific cortical features. This approach advances the fields of deep learning and neuroscience by offering insights into normative brain development and atypical trajectories linked to mental illness, paving the way for more reliable and interpretable AI applications in neuroimaging.

• Velzen, Laura S. van; Colic, Lejla; Ceja, Zuriel; Dauvermann, Maria R.; Villa, Luca M. & Savage, Hannah S. [Show all 129 contributors for this article] (2025). Transdiagnostic alterations in white matter microstructure associated with suicidal thoughts and behaviours in the ENIGMA Suicidal Thoughts and Behaviours consortium. Translational Psychiatry. 15, p. 1–11. doi: 10.1038/s41398-025-03602-1. Full text in Research Archive Show summary

  Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity and radial diffusivity) for 24 WM tracts and one global measure were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt ( n  = 652; mean age = 35.4 ± 14.7; female = 71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n  = 1871; mean age = 34 ± 14.8; female = 59.8%), and individuals with no psychiatric diagnosis and no STB (i.e., healthy controls; n  = 642; mean age = 29.6 ± 13.1; female = 62.9%). We also compared these measures among individuals with recent suicidal ideation ( n  = 714; mean age = 36.3 ± 15.3; female = 66.1%), clinical controls ( n  = 1184; mean age = 36.8 ± 15.6; female = 63.1%), and healthy controls ( n  = 1240; mean age = 31.6 ± 15.5; female = 61.0%). We found subtle but statistically significant effects, such as lower FA associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Recent suicidal ideation was associated with higher AD in the cingulum. Effect sizes were small (partial eta-squared < 0.015). This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt and recent suicidal ideation. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour or ideation.

• Liu, Siwei; Agartz, Ingrid; Allen, Paul; Amminger, G. Paul; Andreassen, Ole & Bachman, Peter [Show all 113 contributors for this article] (2025). Structural covariance network topology in individuals at clinical high risk for psychosis: the ENIGMA-CHR Study. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-025-03304-6. Full text in Research Archive Show summary

  Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen’s d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

• Calkova, Tereza; Vaskinn, Anja; Mørch-Johnsen, Lynn Egeland; Smelror, Runar; Jørgensen, Kjetil Nordbø & Wortinger, Laura Anne [Show all 18 contributors for this article] (2025). Early versus adult onset of schizophrenia: an examination of premorbid and current IQ. Schizophrenia Research: Cognition. 43, p. 100397–100397. doi: 10.1016/j.scog.2025.100397. Full text in Research Archive Show summary

  Background Cognitive deficits are core findings in schizophrenia, but whether the severity of impairments is related to the age of onset remains unclear. We hypothesized that early onset schizophrenia (EOS; onset before age 19) is associated with lower IQ compared to adult-onset schizophrenia (AOS; onset from age 19). Methods We included 99 adult patients with EOS (age of onset: 15.3 ± 2.8 years), 282 adult patients with AOS (age of onset: 26.5 ± 7.4 years), and 863 adult healthy controls (HC). We assessed current IQ with Wechsler Abbreviated Scale of Intelligence (WASI) and estimated premorbid IQ with National Adult Reading Test (NART). Results Both patient groups had lower current IQ than HC ( p < 0.001). Full-scale ( p = 0.004), performance ( p = 0.003) and verbal ( p = 0.011) current IQ were significantly lower in EOS than in AOS, with 5 IQ units difference for all three measures. EOS and AOS did not differ in premorbid IQ, but EOS showed a steeper IQ decline from premorbid levels than AOS (11.4 vs. 8 IQ units, respectively, p = 0.013). Conclusion EOS had lower current IQ than AOS, but did not differ in premorbid IQ, suggesting a larger decline from premorbid IQ levels. This could imply different neurodevelopmental processes underlying cognitive dysfunction related to age of onset in schizophrenia, underscoring the necessity for further inquiry into the mechanisms driving this decline and strategies for its prevention.

• Haukvik, Unn Kristin Hansen; Wolfers, Thomas; Tesli, Natalia; Bell, Christina; Hjell, Gabriela & Fischer-Vieler, Thomas [Show all 14 contributors for this article] (2025). Individual-level deviations from normative brain morphology in violence, psychosis, and psychopathy. Translational Psychiatry. 15(1), p. 1–8. doi: 10.1038/s41398-025-03343-1. Full text in Research Archive
• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Nerland, Stener; Ueland, Thor & Wortinger, Laura Anne [Show all 13 contributors for this article] (2025). Toxoplasma gondii associated with psychotic symptom load and cortisol in severe mental illness. Schizophrenia. 11(80). doi: 10.1038/s41537-025-00630-0. Full text in Research Archive Show summary

  Toxoplasma gondii (TG) is a prevalent parasite that establishes lifelong latency after primary infection. TG has been linked to severe mental illness (SMI), potentially through dopamine dysregulation in the brain. There is a bidirectional interaction between dopamine and the hypothalamic-pituitary-adrenal axis, where dopamine may influence cortisol regulation and cortisol may affect dopamine release. We hypothesised that TG would be associated with elevated circulatory cortisol levels, increased severity of psychotic symptoms, and structural brain aberrations in SMI. Our study included 765 patients with SMI (515 with schizophrenia spectrum disorders and 250 with bipolar disorders) and 541 healthy controls (HC). TG immunoglobulin G seropositivity and circulatory cortisol concentrations were measured with immunoassays, and T1-weighted MRI scans were processed using FreeSurfer. Psychotic symptom scores were evaluated using the Positive and Negative Syndrome Scale. In SMI, TG seropositivity was associated with higher cortisol levels (p = 0.002), but not in HC. Seropositive patients had lower total psychotic symptom scores (p = 0.006) than seronegative patients, driven by the schizophrenia subgroup (p = 0.002). This effect was observed for positive, negative, and general psychotic symptom scores, but only for patients with an illness duration of 10 years or more. In an exploratory analysis, TG seropositivity was nominally associated with smaller thalamus, nucleus accumbens, and middle temporal volumes in SMI, and with smaller fusiform, parahippocampal, and pars triangularis volumes in HC. In conclusion, TG exposure in SMI was linked to elevated cortisol levels and reduced psychotic symptom scores, suggesting that its impact on SMI may be more complex and context-dependent than previously assumed.

• Pentz, Atle Bråthen; Exposito, Veronica; Jole, Oda van; Nerland, Stener; Melle, Ingrid & Steen, Nils Eiel [Show all 13 contributors for this article] (2025). Auditory MMN is associated with the volume of thalamic higher order nuclei in individuals with psychotic disorders and healthy controls. Schizophrenia Research. ISSN 0920-9964. 276, p. 222–233. doi: 10.1016/j.schres.2025.01.031. Full text in Research Archive Show summary

  Objective Predictive coding is a theoretical framework that integrates models of brain dysconnectivity and psychopathology in psychosis. Thalamocortical dysconnectivity as well as reduced thalamic volumes have been reported in psychotic disorders. However, the role of the thalamus in predictive coding is not clear. We examined the relationship between magnetic resonance imaging (MRI)- based thalamic nuclei volumes and mismatch negativity (MMN), a purported index of prediction error signaling known to be impaired in psychosis. Methods We obtained MRI and MMN using a roving paradigm from individuals with SCZ spectrum disorder (SSD, n = 60) or bipolar disorder (BD, n = 69) and HC (n = 252). We segmented volumes of 25 thalamic nuclei bilaterally and tested their associations with MMN amplitude using linear models while covarying for age, sex, diagnosis, and intracranial volumes (ICV). Results We did not find group differences in thalamic volumes that could account for differences in MMN, neither did we find significant volume × diagnosis interactions on MMN for any of the 25 nuclei examined. Across the whole sample, significant positive associations were found between MMN amplitude and the volumes of several higher-order thalamic nuclei, including the mediodorsal medial and lateral nuclei, anterior and medial pulvinar, nucleus reuniens, as well as the lateral geniculate nucleus. Conclusion The results demonstrate a positive association between MMN amplitude and volumes of thalamic association nuclei in patients with psychotic disorders and HC. These findings may suggest a modulatory role of the thalamus in prediction error signaling.

• Tamnes, Christian Krog; Dahl, Andreas; Meer, Dennis van der; Agartz, Ingrid; Alnæs, Dag & Andreassen, Ole [Show all 13 contributors for this article] (2025). Relationships between wellbeing polygenic scores, brain structure, and psychopathology in children. Personality and Individual Differences. ISSN 0191-8869. 246. doi: 10.1016/j.paid.2025.113313. Full text in Research Archive Show summary

  Wellbeing is shaped by an interplay of genetic and environmental factors and is associated with both health and functioning. It remains unclear whether genetic influences on wellbeing are linked to brain structure and, in turn, early-life psychopathology. Here, we investigated associations between wellbeing polygenic scores (PGS), magnetic resonance imaging (MRI)-derived measures of brain structure, and parent-reported measures of child psychopathology in a large cross-sectional sample of children from the Adolescent Brain Cognitive Development (ABCD) Study (n = 8844; 8.9–11.0 years old). Preregistered analyses revealed no significant associations between wellbeing PGS and regional cortical thickness or subcortical volumes and only a small negative association with surface area of the parahippocampal cortex (β = −0.03, p = .002), while an exploratory analysis identified a small positive association with intracranial volume (ICV; β = 0.04, p < .001). Preregistered analyses showed small negative associations between wellbeing PGS and general psychopathology (β = −0.09, p < .001) and both internalizing (β = −0.09, p < .001) and externalizing problems (β = −0.07, p < .001). ICV partially mediated the relationships between wellbeing PGS and psychopathology, accounting for 1.3–3.3 % of these relationships. The findings suggest that while wellbeing PGS have limited associations with regional brain structure in children, they exhibit small protective effects against psychopathology.

• Mamalakis, Michail; Mamalakis, Antonios; Agartz, Ingrid; Mørch-Johnsen, Lynn Egeland; Murray, Graham K. & Suckling, John [Show all 7 contributors for this article] (2025). Solving the enigma: Enhancing faithfulness and comprehensibility in explanations of deep networks. AI Open. 6, p. 70–81. doi: 10.1016/j.aiopen.2025.02.001. Full text in Research Archive Show summary

  The accelerated progress of artificial intelligence (AI) has popularized deep learning models across various domains, yet their inherent opacity poses challenges, particularly in critical fields like healthcare, medicine, and the geosciences. Explainable AI (XAI) has emerged to shed light on these ’black box’ models, aiding in deciphering their decision-making processes. However, different XAI methods often produce significantly different explanations, leading to high inter-method variability that increases uncertainty and undermines trust in deep networks’ predictions. In this study, we address this challenge by introducing a novel framework designed to enhance the explainability of deep networks through a dual focus on maximizing both accuracy and comprehensibility in the explanations. Our framework integrates outputs from multiple established XAI methods and leverages a non-linear neural network model, termed the ‘Explanation optimizer,’ to construct a unified, optimal explanation. The optimizer uses two primary metrics — faithfulness and complexity — to evaluate the quality of the explanations. Faithfulness measures the accuracy with which the explanation reflects the network’s decision-making, while complexity assesses the comprehensibility of the explanation. By balancing these metrics, the optimizer provides explanations that are both accurate and accessible, addressing a central limitation in current XAI methods. Through experiments on multi-class and binary classification tasks in both 2D object and 3D neuroscience imaging, we validate the efficacy of our approach. Our explanation optimizer achieved superior faithfulness scores, averaging 155% and 63% higher than the best-performing individual XAI methods in the 3D and 2D applications, respectively, while also reducing complexity to enhance comprehensibility. These results demonstrate that optimal explanations based on specific quality criteria are achievable, offering a solution to the issue of inter-method variability in the current XAI literature and supporting more trustworthy deep network predictions.

• Nerland, Stener; Slapø, Nora Berz; Barth, Claudia; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø & Beck, Dani [Show all 13 contributors for this article] (2024). Current Auditory Hallucinations Are Not Associated With Specific White Matter Diffusion Alterations in Schizophrenia. Schizophrenia Bulletin Open. 5(1). doi: 10.1093/schizbullopen/sgae008. Full text in Research Archive Show summary

  Background and Hypothesis Studies have linked auditory hallucinations (AH) in schizophrenia spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI). Study Design We included patients with SCZ with (AH+; n = 59) and without (AH−; n = 81) current AH, and 140 age- and sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fiber tracts. We used principal component analysis (PCA) to identify general factors of variation across fiber tracts and DTI metrics. Regression models adjusted for sex, age, and age2 were used to compare tract-wise DTI metrics and PCA factors between AH+, AH−, and healthy controls and to assess associations with clinical characteristics. Study Results Widespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in 2 fiber tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH−, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics. Conclusions Contrary to previous studies, DTI metrics differed mainly in patients without current AH compared to controls, indicating a widespread neuroanatomical distribution. This challenges the notion that altered DTI metrics within the LAPC is a specific feature underlying AH.

• Jørgensen, Kjetil Nordbø; Nerland, Stener; Slapø, Nora Berz; Norbom, Linn Bonaventure; Mørch-Johnsen, Lynn Egeland & Wortinger, Laura Anne [Show all 13 contributors for this article] (2024). Assessing regional intracortical myelination in schizophrenia spectrum and bipolar disorders using the optimized T1w/T2w-ratio. Psychological Medicine. ISSN 0033-2917. 54(10), p. 2369–2379. doi: 10.1017/S0033291724000503. Full text in Research Archive Show summary

  Background Dysmyelination could be part of the pathophysiology of schizophrenia spectrum (SCZ) and bipolar disorders (BPD), yet few studies have examined myelination of the cerebral cortex. The ratio of T1- and T2-weighted magnetic resonance images (MRI) correlates with intracortical myelin. We investigated the T1w/T2w-ratio and its age trajectories in patients and healthy controls (CTR) and explored associations with antipsychotic medication use and psychotic symptoms. Methods Patients with SCZ (n = 64; mean age = 30.4 years, s.d. = 9.8), BPD (n = 91; mean age 31.0 years, s.d. = 10.2), and CTR (n = 155; mean age = 31.9 years, s.d. = 9.1) who participated in the TOP study (NORMENT, University of Oslo, Norway) were clinically assessed and scanned using a General Electric 3 T MRI system. T1w/T2w-ratio images were computed using an optimized pipeline with intensity normalization and field inhomogeneity correction. Vertex-wise regression models were used to compare groups and examine group × age interactions. In regions showing significant differences, we explored associations with antipsychotic medication use and psychotic symptoms. Results No main effect of diagnosis was found. However, age slopes of the T1w/T2w-ratio differed significantly between SCZ and CTR, predominantly in frontal and temporal lobe regions: Lower T1w/T2w-ratio values with higher age were found in CTR, but not in SCZ. Follow-up analyses revealed a more positive age slope in patients who were using antipsychotics and patients using higher chlorpromazine-equivalent doses. Conclusions While we found no evidence of reduced intracortical myelin in SCZ or BPD relative to CTR, different regional age trajectories in SCZ may suggest a promyelinating effect of antipsychotic medication.

• Crestol, Arielle; Lange, Ann-Marie Glasø de; Schindler, Louise S; Subramaniapillai, Sivaniya; Nerland, Stener & Oppenheimer, Hannah [Show all 11 contributors for this article] (2024). Linking menopause-related factors, history of depression, APOE ε4, and proxies of biological aging in the UK biobank cohort. Hormones and Behavior. ISSN 0018-506X. 164. doi: 10.1016/j.yhbeh.2024.105596. Full text in Research Archive Show summary

  In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors, mental disorders, and genetics may influence brain function and accelerate the rate of aging in the postmenopausal phase. Using multiple regressions corrected for age, in this preregistered study we investigated the associations between menopause-related factors (i.e., menopausal status, menopause type, age at menopause, and reproductive span) and proxies of cellular aging (leukocyte telomere length, LTL) and brain aging (white and gray matter brain age gap, BAG) in 13,780 females from the UK Biobank (age range 39–82). We then determined how these proxies of aging were associated with each other, and evaluated the effects of menopause-related factors, history of depression (= lifetime broad depression), and APOE ε4 genotype on BAG and LTL, examining both additive and interactive relationships. We found that postmenopausal status and older age at natural menopause were linked to longer LTL and lower BAG. Surgical menopause and longer natural reproductive span were also associated with longer LTL. BAG and LTL were not significantly associated with each other. The greatest variance in each proxy of biological aging was most consistently explained by models with the addition of both lifetime broad depression and APOE ε4 genotype. Overall, this study demonstrates a complex interplay between menopause-related factors, lifetime broad depression, APOE ε4 genotype, and proxies of biological aging. However, results are potentially influenced by a disproportionate number of healthier participants among postmenopausal females. Future longitudinal studies incorporating heterogeneous samples are an essential step towards advancing female health.

• Ruggeri, Aurora; Nerland, Stener; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Barth, Claudia & Bakke, Laura Anne Wortinger [Show all 9 contributors for this article] (2024). Hypothalamic Subunit Volumes in Schizophrenia and Bipolar Spectrum Disorders. Schizophrenia Bulletin. ISSN 0586-7614. 50(3), p. 533–544. doi: 10.1093/schbul/sbad176. Full text in Research Archive Show summary

  Background The hypothalamus is central to many hormonal and autonomous nervous system pathways. Emerging evidence indicates that these pathways may be disrupted in schizophrenia and bipolar disorder. Yet, few studies have examined the volumes of hypothalamic subunits in these patient groups. We compared hypothalamic subunit volumes in individuals with psychotic disorders to healthy controls. Study Design We included 344 patients with schizophrenia spectrum disorders (SCZ), 340 patients with bipolar disorders (BPD), and 684 age- and-sex-matched healthy controls (CTR). Total hypothalamus and five hypothalamic subunit volumes were extracted from T1-weighted magnetic resonance imaging (MRI) using an automated Bayesian segmentation method. Regression models, corrected for age, age2, sex, and segmentation-based intracranial volume (sbTIV), were used to examine diagnostic group differences, interactions with sex, and associations with clinical symptoms, antipsychotic medication, antidepressants and mood stabilizers. Study Results SCZ had larger volumes in the left inferior tubular subunit and smaller right anterior-inferior, right anterior-superior, and right posterior hypothalamic subunits compared to CTR. BPD did not differ significantly from CTR for any hypothalamic subunit volume, however, there was a significant sex-by-diagnosis interaction. Analyses stratified by sex showed smaller right hypothalamus and right posterior subunit volumes in male patients, but not female patients, relative to same-sex controls. There was a significant association between BPD currently taking antipsychotic medication and the left inferior tubular subunits volumes. Conclusions Our results show regional-specific alterations in hypothalamus subunit volumes in individuals with SCZ, with relevance to HPA-axis dysregulation, circadian rhythm disruption, and cognition impairment.

• Berthet, Pierre; Haatveit, Beathe; Kjelkenes, Rikka; Worker, Amanda; Kia, Seyed Mostafa & Wolfers, Thomas [Show all 21 contributors for this article] (2024). A 10-Year Longitudinal Study of Brain Cortical Thickness in People with First-Episode Psychosis Using Normative Models. Schizophrenia Bulletin. ISSN 0586-7614. 51(1), p. 95–107. doi: 10.1093/schbul/sbae107. Full text in Research Archive Show summary

  Background Clinical forecasting models have potential to optimize treatment and improve outcomes in psychosis, but predicting long-term outcomes is challenging and long-term follow-up data are scarce. In this 10-year longitudinal study, we aimed to characterize the temporal evolution of cortical correlates of psychosis and their associations with symptoms. Design Structural magnetic resonance imaging (MRI) from people with first-episode psychosis and controls (n = 79 and 218) were obtained at enrollment, after 12 months (n = 67 and 197), and 10 years (n = 23 and 77), within the Thematically Organized Psychosis (TOP) study. Normative models for cortical thickness estimated on public MRI datasets (n = 42 983) were applied to TOP data to obtain deviation scores for each region and timepoint. Positive and Negative Syndrome Scale (PANSS) scores were acquired at each timepoint along with registry data. Linear mixed effects models assessed effects of diagnosis, time, and their interactions on cortical deviations plus associations with symptoms. Results LMEs revealed conditional main effects of diagnosis and time × diagnosis interactions in a distributed cortical network, where negative deviations in patients attenuate over time. In patients, symptoms also attenuate over time. LMEs revealed effects of anterior cingulate on PANSS total, and insular and orbitofrontal regions on PANSS negative scores. Conclusions This long-term longitudinal study revealed a distributed pattern of cortical differences which attenuated over time together with a reduction in symptoms. These findings are not in line with a simple neurodegenerative account of schizophrenia, and deviations from normative models offer a promising avenue to develop biomarkers to track clinical trajectories over time.

• Si, Shuqing; Bi, Anbreen; Yu, Zhaoying; See, Cheryl; Kelly, Sinead & Ambrogi, Sonia [Show all 45 contributors for this article] (2024). Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-023-02343-1. Full text in Research Archive
• Norbom, Linn Bonaventure; Rokicki, Jaroslav; Eilertsen, Espen Moen; Wiker, Thea; Hanson, Jamie & Dahl, Andreas [Show all 13 contributors for this article] (2024). Parental education and income are linked to offspring cortical brain structure and psychopathology at 9–11 years. JCPP Advances. 4(1). doi: 10.1002/jcv2.12220. Full text in Research Archive Show summary

  Background A child's socioeconomic environment can shape central aspects of their life, including vulnerability to mental disorders. Negative environmental influences in youth may interfere with the extensive and dynamic brain development occurring at this time. Indeed, there are numerous yet diverging reports of associations between parental socioeconomic status (SES) and child cortical brain morphometry. Most of these studies have used single metric- or unimodal analyses of standard cortical morphometry that downplay the probable scenario where numerous biological pathways in sum account for SES-related cortical differences in youth. Methods To comprehensively capture such variability, using data from 9758 children aged 8.9–11.1 years from the ABCD Study®, we employed linked independent component analysis (LICA) and fused vertex-wise cortical thickness, surface area, curvature and grey-/white-matter contrast (GWC). LICA revealed 70 uni- and multimodal components. We then assessed the linear relationships between parental education, parental income and each of the cortical components, controlling for age, sex, genetic ancestry, and family relatedness. We also assessed whether cortical structure moderated the negative relationships between parental SES and child general psychopathology. Results Parental education and income were both associated with larger surface area and higher GWC globally, in addition to local increases in surface area and to a lesser extent bidirectional GWC and cortical thickness patterns. The negative relation between parental income and child psychopathology were attenuated in children with a multimodal pattern of larger frontal- and smaller occipital surface area, and lower medial occipital thickness and GWC. Conclusion Structural brain MRI is sensitive to SES diversity in childhood, with GWC emerging as a particularly relevant marker together with surface area. In low-income families, having a more developed cortex across MRI metrics, appears beneficial for mental health.

• Knol, Maria J.; Poot, Raymond A.; Evans, Tavia E.; Satizabal, Claudia L.; Mishra, Aniket & Sargurupremraj, Muralidharan [Show all 304 contributors for this article] (2024). Genetic variants for head size share genes and pathways with cancer. Cell Reports Medicine. 5(5). doi: 10.1016/j.xcrm.2024.101529. Full text in Research Archive
• Bell, Christina; Rokicki, Jaroslav; Tesli, Natalia; Gurholt, Tiril Pedersen; Hjell, Gabriela & Fischer-Vieler, Thomas [Show all 15 contributors for this article] (2024). Hypothalamic subunit volumes and relations to violence and psychopathy in male offenders with or without a psychotic disorder. European Archives of Psychiatry and Clinical Neuroscience. ISSN 0940-1334. doi: 10.1007/s00406-023-01725-4. Full text in Research Archive Show summary

  Abstract The hypothalamus is key to body homeostasis, including regulating cortisol, testosterone, vasopressin, and oxytocin hormones, modulating aggressive behavior. Animal studies have linked the morphology and function of the hypothalamus to aggression and afliation, with a subregional pattern refecting the functional division between the hypothalamic nuclei. We explored the relationship between hypothalamic subunit volumes in violent ofenders with (PSY-V) and without (NPV) a psychotic disorder, and the association with psychopathy traits. 3T MRI scans (n=628, all male 18–70 years) were obtained from PSY-V, n=38, NPV, n=20, non-violent psychosis patients (PSY-NV), n=134, and healthy controls (HC), n=436. The total hypothalamus volume and its eleven nuclei were delineated into fve subunits using Freesurfer v7.3. Psychopathy traits were assessed with Psychopathy Checklist-revised (PCL-R). ANCOVAs and linear regressions were used to analyze associations with subunit volumes. Both groups with a history of violence exhibited smaller anterior–superior subunit volumes than HC (NPV Cohen’s d=0.56, p=0.01 and PSY-V d=0.38, p=0.01). There were no signifcant diferences between HC and PSY-NV. PCL-R scores were positively associated with the inferior tubular subunit on a trend level (uncorrected p=0.045, Cohen’s d=0.04). We found distinct hypothalamic subunit volume reductions in persons with a history of violence independent of concomitant psychotic disorder but not in persons with psychosis alone. The results provide further information about the involvement of the hypothalamus in aggression, which ultimately may lead to the development of targeted treatment for the clinical and societal challenge of aggression and violent behavior.

• Andreou, Dimitrios; Steen, Nils Eiel; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne & Barth, Claudia [Show all 19 contributors for this article] (2024). Toxoplasma gondii infection associated with inflammasome activation and neuronal injury. Scientific Reports. 14(1). doi: 10.1038/s41598-024-55887-9. Full text in Research Archive Show summary

  Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

• Bakke, Laura Anne Wortinger; Stavrum, Anne-Kristin Støbakk; Shadrin, Alexey; Szabo, Attila; Rukke, Sondre Høeg & Nerland, Stener [Show all 17 contributors for this article] (2024). Divergent epigenetic responses to perinatal asphyxia in severe mental disorders. Translational Psychiatry. 14. doi: 10.1038/s41398-023-02709-7. Full text in Research Archive Show summary

  Epigenetic modifications influenced by environmental exposures are molecular sources of phenotypic heterogeneity found in schizophrenia and bipolar disorder and may contribute to shared etiopathogenetic mechanisms of these two disorders. Newborns who experienced perinatal asphyxia have suffered reduced oxygen delivery to the brain around the time of birth, which increases the risk of later psychiatric diagnosis. This study aimed to investigate DNA methylation in blood cells for associations with a history of perinatal asphyxia, a neurologically harmful condition occurring within the biological environment of birth. We utilized prospective data from the Medical Birth Registry of Norway to identify incidents of perinatal asphyxia in 643 individuals with schizophrenia or bipolar disorder and 676 healthy controls. We performed an epigenome wide association study to distinguish differentially methylated positions associated with perinatal asphyxia. We found an interaction between methylation and exposure to perinatal asphyxia on case–control status, wherein having a history of perinatal asphyxia was associated with an increase of methylation in healthy controls and a decrease of methylation in patients on 4 regions of DNA important for brain development and function. The differentially methylated regions were observed in genes involved in oligodendrocyte survival and axonal myelination and functional recovery (LINGO3); assembly, maturation and maintenance of the brain (BLCAP;NNAT and NANOS2) and axonal transport processes and neural plasticity (SLC2A14). These findings are consistent with the notion that an opposite epigenetic response to perinatal asphyxia, in patients compared with controls, may contribute to molecular mechanisms of risk for schizophrenia and bipolar disorder.

• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Show all 50 contributors for this article] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), p. 1310–1318. doi: 10.1038/s41588-024-01771-1. Full text in Research Archive
• García-Marín, Luis M.; Campos, Adrian I.; Diaz-Torres, Santiago; Rabinowitz, Jill A.; Ceja, Zuriel & Mitchell, Brittany L. [Show all 190 contributors for this article] (2024). Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries. Nature Genetics. ISSN 1061-4036. 56(11), p. 2333–2344. doi: 10.1038/s41588-024-01951-z. Full text in Research Archive
• Johansen, Ingrid Torp; Steen, Nils Eiel; Rødevand, Linn; Lunding, Synve Hoffart; Hjell, Gabriela & Ormerod, Monica Bettina E. Greenwood [Show all 11 contributors for this article] (2024). Sex differences in autonomic adverse effects related to antipsychotic treatment and associated hormone profiles. Schizophrenia. 10. doi: 10.1038/s41537-023-00430-4. Full text in Research Archive Show summary

  Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

• Zhu, Yinghan; Maikusa, Norihide; Radua, Joaquim; Sämann, Philipp G.; Fusar-Poli, Paolo & Agartz, Ingrid [Show all 82 contributors for this article] (2024). Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk. Molecular Psychiatry. ISSN 1359-4184. 29, p. 1465–1477. doi: 10.1038/s41380-024-02426-7. Full text in Research Archive Show summary

  Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

• Juvodden, Hilde Therese; Alnæs, Dag; Agartz, Ingrid; Andreassen, Ole A.; Server, Andrés & Thorsby, Per Medbøe [Show all 8 contributors for this article] (2024). Cortical thickness and sub-cortical volumes in post-H1N1 narcolepsy type 1: A brain-wide MRI case-control study. Sleep Medicine. ISSN 1389-9457. 116, p. 81–89. doi: 10.1016/j.sleep.2024.02.031. Full text in Research Archive Show summary

  There was more than a 10-fold increase in the incidence of narcolepsy type 1 (NT1) after the H1N1 mass vaccination in 2009/2010 in several countries. NT1 is associated with loss and increase of cell groups in the hypothalamus which may be associated with secondary affected sub-cortical and cortical gray matter. We performed a case-control comparison of MRI-based global and sub-cortical volume and cortical thickness in post-H1N1 NT1 patients compared with controls. Methods We included 54 post-H1N1 NT1 patients (51 with confirmed hypocretin-deficiency; 48 H1N1-vaccinated with Pandemrix®; 39 females, mean age 21.8 ± 11.0 years) and 114 healthy controls (77 females, mean age 23.2 ± 9.0 years). 3T MRI brain scans were obtained, and the T1-weighted MRI data were processed using FreeSurfer. Group differences among three global, 10 sub-cortical volume measures and 34 cortical thickness measures for bilateral brain regions were tested using general linear models with permutation testing. Results Patients had significantly thinner brain cortex bilaterally in the temporal poles (Cohen's d = 0.68, p = 0.00080), entorhinal cortex (d = 0.60, p = 0.0018) and superior temporal gyrus (d = 0.60, p = 0.0020) compared to healthy controls. The analysis revealed no significant group differences for sub-cortical volumes. Conclusions Post-H1N1(largely Pandemrix®-vaccinated) NT1 patients have significantly thinner cortex in temporal brain regions compared to controls. We speculate that this effect can be partly attributed to the hypothalamic neuronal change in NT1, including loss of function of the widely projecting hypocretin-producing neurons and secondary effects of the abnormal sleep-wake pattern in NT1 or could be specific for post-H1N1 (largely Pandemrix®-vaccinated) NT1 patients.

• Trastulla, Lucia; Dolgalev, Georgii; Moser, Sylvain; Jiménez-Barrón, Laura T.; Andlauer, Till F. M. & Scheidt, Moritz von [Show all 310 contributors for this article] (2024). Distinct genetic liability profiles define clinically relevant patient strata across common diseases. Nature Communications. 15(1). doi: 10.1038/s41467-024-49338-2. Full text in Research Archive Show summary

  Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.

• Ge, Ruiyang; Yu, Yuetong; Qi, Yi Xuan; Fan, Yu-nan; Chen, Shiyu & Gao, Chuntong [Show all 33 contributors for this article] (2024). Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation. The Lancet Digital Health. 6(3), p. e211–e221. doi: 10.1016/S2589-7500(23)00250-9. Full text in Research Archive Show summary

  The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3–90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain.

• Andreou, Dimitrios; Jørgensen, Kjetil Nordbø; Nerland, Stener; Calkova, Tereza; Mørch-Johnsen, Lynn Egeland & Smelror, Runar [Show all 13 contributors for this article] (2024). Caudate nucleus volume in medicated and unmedicated patients with early- and adult-onset schizophrenia. Scientific Reports. 14(1), p. 22755–22755. doi: 10.1038/s41598-024-73322-x. Full text in Research Archive Show summary

  The caudate nucleus is a part of the striatum, and striatal hyperdopaminergia is considered central to the pathophysiology of schizophrenia. How caudate volume is affected in schizophrenia and what role antipsychotics play remains unclear. In early-onset schizophrenia (EOS), where psychosis emerges during a neurodevelopmentally critical phase, the caudate may exhibit a heightened vulnerability to the effects of antipsychotic medications. We hypothesized effects of both antipsychotic medication use and age of onset on caudate in schizophrenia. We included adult patients with EOS (n = 83) and adult-onset schizophrenia (AOS) (n = 246), adult healthy controls (HC, n = 774), adolescent patients with non-affective psychosis (n = 56) and adolescent HC (n = 97). We obtained T1-weighted MRI scans using a 1.5T Siemens scanner and General Electric 3T scanners. In our main analysis, we tested for main and interaction effects of diagnosis and current antipsychotic medication use on caudate volume. Adult patients with EOS (p < 0.001) and AOS (p = 0.002) had both larger caudate than HC. Age of onset (EOS/AOS) interacted with antipsychotic use (p = 0.004) which was associated with larger caudate in EOS (p < 0.001) but not in AOS (p = 0.654). Conversely, among medicated patients only, EOS had larger caudate than AOS (p < 0.001). No other subcortical structures showed differences between medicated EOS and AOS. Medicated adolescent patients with non-affective psychosis and medicated adult patients with EOS showed similar caudate volumes. The results may indicate a schizophrenia-related and a medication-induced caudate increase, the latter restricted to patients with EOS and possibly occurring already in adolescence shortly after disease onset.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Ueland, Thor; Wortinger, Laura Anne & Mørch-Johnsen, Lynn Egeland [Show all 11 contributors for this article] (2024). Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness. Translational Psychiatry. 14(1). doi: 10.1038/s41398-024-03198-y. Full text in Research Archive Show summary

  Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.

• for, . ENIGMA Clinical High Risk; Haas, Shalaila S.; Ge, Ruiyang; Agartz, Ingrid; Amminger, G. Paul & Andreassen, Ole [Show all 51 contributors for this article] (2023). Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis. JAMA psychiatry. ISSN 2168-6238. 81(1), p. 77–88. doi: 10.1001/jamapsychiatry.2023.3850. Full text in Research Archive
• Wiker, Thea; Pedersen, Mads Lund; Ferschmann, Lia; Beck, Dani; Norbom, Linn Christin Bonaventure & Dahl, Andreas [Show all 13 contributors for this article] (2023). Assessing the Longitudinal Associations Between Decision-Making Processes and Attention Problems in Early Adolescence. Research on Child and Adolescent Psychopathology. ISSN 2730-7166. 52, p. 803–817. doi: 10.1007/s10802-023-01148-8. Full text in Research Archive Show summary

  Abstract Cognitive functions and psychopathology develop in parallel in childhood and adolescence, but the temporal dynamics of their associations are poorly understood. The present study sought to elucidate the intertwined development of decision-making processes and attention problems using longitudinal data from late childhood (9–10 years) to mid-adolescence (11–13 years) from the Adolescent Brain Cognitive Development (ABCD) Study (n = 8918). We utilised hierarchical drift-diffusion modelling of behavioural data from the stop-signal task, parent-reported attention problems from the Child Behavior Checklist (CBCL), and multigroup univariate and bivariate latent change score models. The results showed faster drift rate was associated with lower levels of inattention at baseline, as well as a greater reduction of inattention over time. Moreover, baseline drift rate negatively predicted change in attention problems in females, and baseline attention problems negatively predicted change in drift rate. Neither response caution (decision threshold) nor encoding- and responding processes (non-decision time) were significantly associated with attention problems. There were no significant sex differences in the associations between decision-making processes and attention problems. The study supports previous findings of reduced evidence accumulation in attention problems and additionally shows that development of this aspect of decision-making plays a role in developmental changes in attention problems in youth.

• Barth, Claudia; Tamnes, Christian Krog & Agartz, Ingrid (2023). Structural brain imaging in early-onset psychosis. In Agartz, Ingrid & Smelror, Runar (Ed.), Adolescent Psychosis: Clinical and Scientific Perspectives. Academic Press. ISSN 9780323898324. Full text in Research Archive
• Bøen, Rune; Kaufmann, Tobias Herbert; Meer, Dennis van der; Frei, Oleksandr; Agartz, Ingrid & Ames, David [Show all 53 contributors for this article] (2023). Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers. Biological Psychiatry. ISSN 0006-3223. 95(2), p. 147–160. doi: 10.1016/j.biopsych.2023.08.018. Full text in Research Archive Show summary

  Background Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

• Juvodden, Hilde Therese; Alnæs, Dag; Lund, Martina Jonette; Agartz, Ingrid; Andreassen, Ole & Server, Andrés [Show all 9 contributors for this article] (2023). Larger hypothalamic volume in narcolepsy type 1. Sleep. ISSN 0161-8105. 46(11). doi: 10.1093/sleep/zsad173. Full text in Research Archive Show summary

  Study Objectives: Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%–90% loss of the 50 000–70 000 hypocretin-producing neurons and 64%–94% increase in the 64 000–120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. Methods: We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. Results: The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen’s d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. Conclusions: In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.

• Wortinger, Laura Anne; Shadrin, Alexey; Szabo, Attila; Nerland, Stener; Smelror, Runar & Jørgensen, Kjetil Nordbø [Show all 13 contributors for this article] (2023). The impact of placental genomic risk for schizophrenia and birth asphyxia on brain development. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02639-4. Full text in Research Archive Show summary

  The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genomic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genomewide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t = 2.10, p = 0.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t = −2.43, p = 0.008), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t = −2.71, p = 0.005) and also found with their adult ICV (t = −1.97, p = 0.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

• Barth, Claudia; Nerland, Stener; Jørgensen, Kjetil Nordbø; Haatveit, Beathe; Bakke, Laura Anne Wortinger & Melle, Ingrid [Show all 10 contributors for this article] (2023). Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia. Schizophrenia Bulletin. ISSN 0586-7614. 50(1), p. 107–119. doi: 10.1093/schbul/sbad091. Full text in Research Archive Show summary

  Background and hypothesis: The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL). Study design: One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; CTL, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models. Study results: Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD. Conclusions: Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.

• Beck, Dani; Ferschmann, Lia; MacSweeney, Niamh; Norbom, Linn Christin Bonaventure; Wiker, Thea & Aksnes, Eira Ranheim [Show all 15 contributors for this article] (2023). Puberty differentially predicts brain maturation in male and female youth: A longitudinal ABCD Study. Developmental Cognitive Neuroscience. ISSN 1878-9293. 61. doi: 10.1016/j.dcn.2023.101261. Full text in Research Archive Show summary

  Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences. We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort. Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD). Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain.

• Slapø, Nora Berz; Nerland, Stener; Jørgensen, Kjetil Nordbø; Mørch-Johnsen, Lynn Egeland; Pettersen, Johanne Hagen & Roelfs, Daniel [Show all 22 contributors for this article] (2023). Auditory Cortex Thickness Is Associated With N100 Amplitude in Schizophrenia Spectrum Disorders. Schizophrenia Bulletin Open. 4(1). doi: 10.1093/schizbullopen/sgad015. Full text in Research Archive Show summary

  Background and Hypothesis: The auditory cortex (AC) may play a central role in the pathophysiology of schizophrenia and auditory hallucinations (AH). Previous schizophrenia studies report thinner AC and impaired AC function, as indicated by decreased N100 amplitude of the auditory evoked potential. However, whether these structural and functional alterations link to AH in schizophrenia remain poorly understood. Study Design: Patients with a schizophrenia spectrum disorder (SCZspect), including patients with a lifetime experience of AH (AH+), without (AH−), and healthy controls underwent magnetic resonance imaging (39 SCZ spect, 22 AH+, 17 AH−, and 146 HC) and electroencephalography (33 SCZ spect, 17 AH+, 16 AH−, and 144 HC). Cortical thickness of the primary (AC1, Heschl’s gyrus) and secondary (AC2, Heschl’s sulcus, and the planum temporale) AC was compared between SCZ spect and controls and between AH+, AH−, and controls. To examine if the association between AC thickness and N100 amplitude differed between groups, we used regression models with interaction terms. Study Results: N100 amplitude was nominally smaller in SCZ spect (P = .03, d = 0.42) and in AH− (P = .020, d = 0.61), while AC2 was nominally thinner in AH+ (P = .02, d = 0.53) compared with controls. AC1 thickness was positively associated with N100 amplitude in SCZspect (t = 2.56, P = .016) and AH− (t= 3.18, P = .008), while AC2 thickness was positively associated with N100 amplitude in SCZspect (t = 2.37, P = .024) and in AH+ (t = 2.68, P = .019). Conclusions: The novel indings of positive associations between AC thickness and N100 amplitude in SCZ spect, suggest that a common neural substrate may underlie AC thickness and N100 amplitude alterations.

• Schijven, Dick; Postema, Merel C.; Fukunaga, Masaki; Matsumoto, Junya; Miura, Kenichiro & Zwarte, Sonja M.C. de [Show all 149 contributors for this article] (2023). Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(14). doi: 10.1073/pnas.2213880120. Full text in Research Archive Show summary

  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.

• Wiker, Thea; Norbom, Linn B.; Beck, Dani; Agartz, Ingrid; Andreassen, Ole A. & Alnæs, Dag [Show all 14 contributors for this article] (2023). Reaction Time Variability in Children Is Specifically Associated With Attention Problems and Regional White Matter Microstructure. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 8(8), p. 832–840. doi: 10.1016/j.bpsc.2023.03.010. Full text in Research Archive Show summary

  Background Increased intraindividual variability (IIV) in reaction times (RTs) has been suggested as a key cognitive and behavioral marker of attention problems, but findings for other dimensions of psychopathology are less consistent. Moreover, while studies have linked IIV to brain white matter microstructure, large studies testing the robustness of these associations are needed. Methods We used data from the Adolescent Brain Cognitive Development (ABCD) Study baseline assessment to test the associations between IIV and psychopathology (n = 8622, age = 8.9–11.1 years) and IIV and white matter microstructure (n = 7958, age = 8.9–11.1 years). IIV was investigated using an ex-Gaussian distribution analysis of RTs in correct response go trials in the stop signal task. Psychopathology was measured by the Child Behavior Checklist and a bifactor structural equation model was performed to extract a general p factor and specific factors reflecting internalizing, externalizing, and attention problems. To investigate white matter microstructure, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were examined in 23 atlas-based tracts. Results Increased IIV in both short and long RTs was positively associated with the specific attention problems factor (Cohen’s d = 0.13 and d = 0.15, respectively). Increased IIV in long RTs was also positively associated with radial diffusivity in the left and right corticospinal tract (both tracts, d = 0.12). Conclusions Using a large sample and a data-driven dimensional approach to psychopathology, the results provide novel evidence for a small but specific association between IIV and attention problems in children and support previous findings on the relevance of white matter microstructure for IIV.

• Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Barth, Claudia; Nerland, Stener; Bringslid, Ida Kippersund & Wortinger, Laura Anne [Show all 10 contributors for this article] (2023). Thalamic nuclei volumes in schizophrenia and bipolar spectrum disorders – Associations with diagnosis and clinical characteristics. Schizophrenia Research. ISSN 0920-9964. 256, p. 26–35. doi: 10.1016/j.schres.2023.04.008. Full text in Research Archive Show summary

  Background The thalamus is central to brain functions ranging from primary sensory processing to higher-order cognition. Structural deficits in thalamic association nuclei such as the pulvinar and mediodorsal nuclei have previously been reported in schizophrenia. However, the specificity with regards to clinical presentation, and whether or not bipolar disorder (BD) is associated with similar alterations is unclear. Methods We investigated thalamic nuclei volumes in 334 patients with schizophrenia spectrum disorders (SSD) (median age 29 years, 59 % male), 322 patients with BD (30 years, 40 % male), and 826 healthy controls (HC) (34 years, 54 % male). Volumes of 25 thalamic nuclei were extracted from T1-weighted magnetic resonance imaging using an automated Bayesian segmentation method and compared between groups. Furthermore, we explored associations with clinical characteristics across diagnostic groups, including psychotic and mood symptoms and medication use, as well as diagnostic subtype in BD. Results Significantly smaller volumes were found in the mediodorsal, pulvinar, and lateral and medial geniculate thalamic nuclei in SSD. Similarly, smaller volumes were found in BD in the same four regions, but mediodorsal nucleus volume alterations were limited to its lateral part and pulvinar alterations to its anterior region. Smaller volumes in BD compared to HC were seen only in BD type I, not BD type II. Across diagnoses, having more negative symptoms was associated with smaller pulvinar volumes. Conclusions Structural alterations were found in both SSD and BD, mainly in the thalamic association nuclei. Structural deficits in the pulvinar may be of relevance for negative symptoms.

• Slapø, Nora Berz; Jørgensen, Kjetil Nordbø; Elvsåshagen, Torbjørn; Nerland, Stener; Roelfs, Daniel & Valstad, Mathias [Show all 18 contributors for this article] (2023). Relationship between function and structure in the visual cortex in healthy individuals and in patients with severe mental disorders. Psychiatry Research : Neuroimaging. ISSN 0925-4927. 332. doi: 10.1016/j.pscychresns.2023.111633. Full text in Research Archive Show summary

  Patients with schizophrenia spectrum disorders (SCZspect) and bipolar disorders (BD) show impaired function in the primary visual cortex (V1), indicated by altered visual evoked potential (VEP). While the neural substrate for altered VEP in these patients remains elusive, altered V1 structure may play a role. One previous study found a positive relationship between the amplitude of the P100 component of the VEP and V1 surface area, but not V1 thickness, in a small sample of healthy individuals. Here, we aimed to replicate these findings in a larger healthy control (HC) sample (n = 307) and to examine the same relationship in patients with SCZspect (n = 30) or BD (n = 45). We also compared the mean P100 amplitude, V1 surface area and V1 thickness between controls and patients and found no significant group differences. In HC only, we found a significant positive P100-V1 surface area association, while there were no significant P100-V1 thickness relationships in HC, SCZspect or BD. Together, our results confirm previous findings of a positive P100-V1 surface area association in HC, whereas larger patient samples are needed to further clarify the function-structure relationship in V1 in SCZspect and BD.

• Almdahl, Ina Selseth; Martinussen, Liva Jenny; Ousdal, Olga Therese; Kraus, Miroslawa; Sowa, Piotr & Agartz, Ingrid [Show all 7 contributors for this article] (2023). Task-based functional connectivity reveals aberrance with the salience network during emotional interference in late-life depression. Aging & Mental Health. ISSN 1360-7863. 27(10), p. 2043–2051. doi: 10.1080/13607863.2023.2179972. Full text in Research Archive Show summary

  Objectives Late-life depression (LLD) is a common and debilitating disorder. Previously, resting-state studies have revealed abnormal functional connectivity (FC) of brain networks in LLD. Since LLD is associated with emotional-cognitive control deficits, the aim of this study was to compare FC of large-scale brain networks in older adults with and without a history of LLD during a cognitive control task with emotional stimuli. Methods Cross-sectional case-control study. Twenty participants diagnosed with LLD and 37 never-depressed adults 60–88 years of age underwent functional magnetic resonance imaging during an emotional Stroop task. Network-region-to-region FC was assessed with seed regions in the default mode, the frontoparietal, the dorsal attention, and the salience networks. Results FC between salience and sensorimotor network regions and between salience and dorsal attention network regions were reduced in LLD patients compared to controls during the processing of incongruent emotional stimuli. The normally positive FC between these networks were negative in LLD patients and inversely correlated with vascular risk and white matter hyperintensities. Conclusions Emotional-cognitive control in LLD is associated with aberrant functional coupling between salience and other networks. This expands on the network-based LLD model and proposes the salience network as a target for future interventions.

• Birkenæs, Viktoria; Bakken, Nora Refsum; Frei, Evgeniia; Jaholkowski, Piotr Pawel; Smeland, Olav Bjerkehagen & Woldeyohannes, Markos Tesfaye [Show all 15 contributors for this article] (2023). Psychometric Properties and Diagnostic Associations of the Short-Form Community Assessment of Psychic Experiences in a Population-Based Sample of 29 021 Adult Men. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), p. 1229–1238. doi: 10.1093/schbul/sbad074. Full text in Research Archive Show summary

  Abstract Background and Hypothesis Around 5%–7% of the adult population are estimated to have lifetime psychotic experiences (PEs), which are associated with psychosis risk. PEs assessed with Community Assessment of Psychic Experiences (CAPE) are associated with psychosis but also non-psychotic disorders, which could be partly explained by CAPE indirectly capturing emotional symptoms. We investigated the psychometric properties of a shorter version, CAPE-9, and whether CAPE-9 scores are associated with lifetime psychotic or non-psychotic mental disorders after controlling for current anxiety and depressive symptoms. Design CAPE-9 questionnaire data were obtained from 29 021 men (42.4 ± 5.6 yrs.) from the Norwegian Mother, Father, and Child Cohort Study. We investigated CAPE-9 reliability and factor structure. Logistic regression was used to test effects of current anxiety and depressive symptoms (SCL-12) on associations between CAPE-9 scores and psychiatric diagnoses. Results CAPE-9 fit a previously reported 3-factor structure and showed good reliability. Twenty-six percent reported at least one lifetime PE. CAPE-9 scores were significantly associated with most psychiatric disorders (schizophrenia, depression, bipolar disorder, substance abuse, anxiety, trauma-related disorders, and ADHD). After controlling for concurrent emotional symptoms, only associations with schizophrenia (OR = 1.29; 95% CI = 1.18–1.38) and trauma-related disorders (OR = 1.09; CI = 1.02–1.15) remained significant. Conclusions CAPE-9 showed good psychometric properties in this large population-based adult male sample, and PEs were more clearly associated with psychotic disorders after controlling for current emotional symptoms. These results support the use of the short CAPE-9 as a cost-effective tool for informing public health initiatives and advancing our understanding of the dimensionality of psychosis.

• Lindseth, Linn Renate Sjøveian; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Agartz, Ingrid; Westlye, Lars Tjelta & Tamnes, Christian Krog [Show all 7 contributors for this article] (2023). Associations between reproductive history, hormone use, APOE ε4 genotype and cognition in middle- to older-aged women from the UK Biobank. Frontiers in Aging Neuroscience. 14:1014605, p. 1–13. doi: 10.3389/fnagi.2022.1014605. Full text in Research Archive Show summary

  Introduction: Relative to men, women are at a higher risk of developing age-related neurocognitive disorders including Alzheimer’s disease. While women’s health has historically been understudied, emerging evidence suggests that reproductive life events such as pregnancy and hormone use may influence women’s cognition later in life. Methods: We investigated the associations between reproductive history, exogenous hormone use, apolipoprotein (APOE) ε4 genotype and cognition in 221,124 middle- to older-aged (mean age 56.2 ± 8.0 years) women from the UK Biobank. Performance on six cognitive tasks was assessed, covering four cognitive domains: episodic visual memory, numeric working memory, processing speed, and executive function. Results: A longer reproductive span, older age at menopause, older age at first and last birth, and use of hormonal contraceptives were positively associated with cognitive performance later in life. Number of live births, hysterectomy without oophorectomy and use of hormone therapy showed mixed findings, with task-specific positive and negative associations. Effect sizes were generally small (Cohen’s d < 0.1). While APOE ε4 genotype was associated with reduced processing speed and executive functioning, in a dose-dependent manner, it did not influence the observed associations between female-specific factors and cognition. Discussion: Our findings support previous evidence of associations between a broad range of female-specific factors and cognition. The positive association between a history of hormonal contraceptive use and cognition later in life showed the largest effect sizes (max. d = 0.1). More research targeting the long-term effects of female-specific factors on cognition and age-related neurocognitive disorders including Alzheimer’s disease is crucial for a better understanding of women’s brain health and to support women’s health care.

• Docherty, Anna R.; Mullins, Niamh; Ashley-Koch, Allison E.; Qin, Xuejun; Coleman, Jonathan R.I. & Shabalin, Andrey [Show all 51 contributors for this article] (2023). GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. American Journal of Psychiatry. ISSN 0002-953X. 180(10), p. 723–738. doi: 10.1176/appi.ajp.21121266. Full text in Research Archive Show summary

  Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10–8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10–80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

• Chen, Jiayu; Fu, Zening; Bustillo, Juan R.; Perrone-Bizzozero, Nora I.; Lin, Dongdong & Canive, Jose [Show all 25 contributors for this article] (2022). Genome-Transcriptome-Functional Connectivity-Cognition Link Differentiates Schizophrenia From Bipolar Disorder. Schizophrenia Bulletin. ISSN 0586-7614. 48(6), p. 1306–1317. doi: 10.1093/schbul/sbac088. Full text in Research Archive
• Tesli, Natalia; Bell, Christina; Hjell, Gabriela; Fischer-Vieler, Thomas; Maximov, Ivan & Richard, Geneviève [Show all 14 contributors for this article] (2022). The age of violence: Mapping brain age in psychosis and psychopathy. NeuroImage: Clinical. 36. doi: 10.1016/j.nicl.2022.103181. Full text in Research Archive Show summary

  Young chronological age is one of the strongest predictors for antisocial behaviour in the general population and for violent offending in individuals with psychotic disorders. An individual's age can be predicted with high accuracy using neuroimaging and machine-learning. The deviation between predicted and chronological age, i.e., brain age gap (BAG) has been suggested to reflect brain health, likely relating partly to neurodevelopmental and aging-related processes and specific disease mechanisms. Higher BAG has been demonstrated in patients with psychotic disorders. However, little is known about the brain-age in violent offenders with psychosis and the possible associations with psychopathy traits. We estimated brain-age in 782 male individuals using T1-weighted MRI scans. Three machine learning models (random forest, extreme gradient boosting with and without hyper parameter tuning) were first trained and tested on healthy controls (HC, n = 586). The obtained BAGs were compared between HC and age matched violent offenders with psychosis (PSY-V, n = 38), violent offenders without psychosis (NPV, n = 20) and non-violent psychosis patients (PSY-NV, n = 138). We ran additional comparisons between BAG of PSY-V and PSY-NV and associations with Positive and Negative Syndrome Scale (PANSS) total score as a measure of psychosis symptoms. Psychopathy traits in the violence groups were assessed with Psychopathy Checklist-revised (PCL-R) and investigated for associations with BAG. We found significantly higher BAG in PSY-V compared with HC (4.9 years, Cohen's d = 0.87) and in PSY-NV compared with HC (2.7 years, d = 0.41). Total PCL-R scores were negatively associated with BAG in the violence groups (d = 1.17, p < 0.05). Additionally, there was a positive association between psychosis symptoms and BAG in the psychosis groups (d = 1.12, p < 0.05). While the significant BAG differences related to psychosis and not violence suggest larger BAG for psychosis, the negative associations between BAG and psychopathy suggest a complex interplay with psychopathy traits. This proof-of-concept application of brain age prediction in severe mental disorders with a history of violence and psychopathy traits should be tested and replicated in larger samples.

• Werner, Maren Caroline Frogner; Wirgenes, Katrine Verena; Shadrin, Alexey; Lunding, Synve Hoffart; Rødevand, Linn & Hjell, Gabriela [Show all 15 contributors for this article] (2022). Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis. Translational Psychiatry. 12(1). doi: 10.1038/s41398-022-01811-6. Full text in Research Archive Show summary

  Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

• Baldwin, Helen; Radua, Joaquim; Antoniades, Mathilde; Haas, Shalaila S.; Frangou, Sophia & Agartz, Ingrid [Show all 111 contributors for this article] (2022). Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis. Translational Psychiatry. 12(297). doi: 10.1038/s41398-022-02057-y. Full text in Research Archive Show summary

  Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

• Nerland, Stener; Stokkan, Therese; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne; Richard, Geneviève & Beck, Dani [Show all 11 contributors for this article] (2022). A comparison of intracranial volume estimation methods and their cross-sectional and longitudinal associations with age. Human Brain Mapping. ISSN 1065-9471. doi: 10.1002/hbm.25978. Full text in Research Archive Show summary

  Intracranial volume (ICV) is frequently used in volumetric magnetic resonance imaging (MRI) studies, both as a covariate and as a variable of interest. Findings of associations between ICV and age have varied, potentially due to differences in ICV estimation methods. Here, we compared five commonly used ICV estimation methods and their associations with age. T1-weighted cross-sectional MRI data was included for 651 healthy individuals recruited through the NORMENT Centre (mean age = 46.1 years, range = 12.0–85.8 years) and 2410 healthy individuals recruited through the UK Biobank study (UKB, mean age = 63.2 years, range = 47.0–80.3 years), where longitudinal data was also available. ICV was estimated with FreeSurfer (eTIV and sbTIV), SPM12, CAT12, and FSL. We found overall high correlations across ICV estimation method, with the lowest observed correlations between FSL and eTIV (r = .87) and between FSL and CAT12 (r = .89). Widespread proportional bias was found, indicating that the agreement between methods varied as a function of head size. Body weight, age, sex, and mean ICV across methods explained the most variance in the differences between ICV estimation methods, indicating possible confounding for some estimation methods. We found both positive and negative cross-sectional associations with age, depending on dataset and ICV estimation method. Longitudinal ICV reductions were found for all ICV estimation methods, with annual percentage change ranging from −0.293% to −0.416%. This convergence of longitudinal results across ICV estimation methods offers strong evidence for age-related ICV reductions in mid- to late adulthood.

• Patel, Yash; Shin, Jean; Abé, Christoph; Agartz, Ingrid; Alloza, Clara & Alnæs, Dag [Show all 51 contributors for this article] (2022). Virtual Ontogeny of Cortical Growth Preceding Mental Illness. Biological Psychiatry. ISSN 0006-3223. 92(4), p. 299–313. doi: 10.1016/j.biopsych.2022.02.959. Full text in Research Archive
• Jensen, Søren Beck; Sheikh, Mashhood Ahmed; Akkouh, Ibrahim Ahmed; Szabo, Attila; O'Connell, Kevin Sean & Lekva, Tove [Show all 23 contributors for this article] (2022). Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness. Schizophrenia Bulletin. ISSN 0586-7614. 49(3), p. 635–645. doi: 10.1093/schbul/sbac191. Full text in Research Archive Show summary

  Abstract Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

• Almdahl, Ina Selseth; Agartz, Ingrid; Hugdahl, Kenneth Jan; Korsnes, Maria Stylianou & Initiative, for the Alzheimer's Disease Neuroimaging (2022). Brain pathology and cognitive scores prior to onset of late‐life depression. International Journal of Geriatric Psychiatry. ISSN 0885-6230. 37(3), p. 1–15. doi: 10.1002/gps.5686. Full text in Research Archive
• Norbom, Linn Christin Bonaventure; Hanson, Jamie; Meer, Dennis van der; Ferschmann, Lia; Røysamb, Espen & Soest, Tilmann von [Show all 10 contributors for this article] (2022). Parental socioeconomic status is linked to cortical microstructure and language abilities in children and adolescents. Developmental Cognitive Neuroscience. ISSN 1878-9293. 56. doi: 10.1016/j.dcn.2022.101132. Full text in Research Archive Show summary

  Gradients in parental socioeconomic status (SES) are closely linked to important life outcomes in children and adolescents, such as cognitive abilities, school achievement, and mental health. Parental SES may also influence brain development, with several magnetic resonance imaging (MRI) studies reporting associations with youth brain morphometry. However, MRI signal intensity metrics have not been assessed, but could offer a microstructural correlate, thereby increasing our understanding of SES influences on neurobiology. We computed a parental SES score from family income, parental education and parental occupation, and assessed relations with cortical microstructure as measured by T1w/T2w ratio (n = 504, age = 3–21 years). We found negative age-stabile relations between parental SES and T1w/T2w ratio, indicating that youths from lower SES families have higher ratio in widespread frontal, temporal, medial parietal and occipital regions, possibly indicating a more developed cortex. Effect sizes were small, but larger than for conventional morphometric properties i.e. cortical surface area and thickness, which were not significantly associated with parental SES. Youths from lower SES families had poorer language related abilities, but microstructural differences did not mediate these relations. T1w/T2w ratio appears to be a sensitive imaging marker for further exploring the association between parental SES and child brain development.

• Andreou, Dimitrios; Jørgensen, Kjetil Nordbø; Nerland, Stener; Ueland, Torill; Vaskinn, Anja & Haukvik, Unn Kristin Hansen [Show all 9 contributors for this article] (2022). Herpes simplex virus 1 infection on grey matter and general intelligence in severe mental illness. Translational Psychiatry. 12(1). doi: 10.1038/s41398-022-02044-3. Full text in Research Archive Show summary

  Abstract Schizophrenia and bipolar disorder are severe mental illnesses (SMI) linked to both genetic and environmental factors. Herpes simplex virus 1 (HSV1) is a common neurotropic pathogen which after the primary infection establishes latency with periodic reactivations. We hypothesized that the latent HSV1 infection is associated with brain structural abnormalities and cognitive impairment, especially in SMI. We included 420 adult patients with SMI (schizophrenia or bipolar spectrum) and 481 healthy controls. Circulating HSV1 immunoglobulin G concentrations were measured with immunoassays. We measured the total grey matter volume (TGMV), cortical, subcortical, cerebellar and regional cortical volumes based on T1-weighted MRI scans processed in FreeSurfer v6.0.0. Intelligence quotient (IQ) was assessed with the Wechsler Abbreviated Scale of Intelligence. Seropositive patients had significantly smaller TGMV than seronegative patients (642 cm 3 and 654 cm 3 , respectively; p  = 0.019) and lower IQ (104 and 107, respectively; p  = 0.018). No TGMV or IQ differences were found between seropositive and seronegative healthy controls. Post-hoc analysis showed that (a) in both schizophrenia and bipolar spectrum, seropositive patients had similarly smaller TGMV than seronegative patients, whereas the HSV1-IQ association was driven by the schizophrenia spectrum group, and (b) among all patients, seropositivity was associated with smaller total cortical ( p  = 0.016), but not subcortical or cerebellar grey matter volumes, and with smaller left caudal middle frontal, precentral, lingual, middle temporal and banks of superior temporal sulcus regional cortical grey matter volumes. The results of this cross-sectional study indicate that HSV1 may be an environmental factor associated with brain structural abnormalities and cognitive impairment in SMI.

• Sheikh, Mashhood Ahmed; O'Connell, Kevin Sean; Lekva, Tove; Szabo, Attila; Akkouh, Ibrahim Ahmed & Osete, Jordi Requena [Show all 31 contributors for this article] (2022). Systemic cell adhesion molecules in severe mental illness: Potential role of intercellular CAM-1 in linking peripheral and neuroinflammation. Biological Psychiatry. ISSN 0006-3223. 93, p. 187–196. doi: 10.1016/j.biopsych.2022.06.029. Full text in Research Archive Show summary

  Background Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. Methods We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). Results Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ. Conclusions Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

• Mullins, Niamh; Kang, JooEun; Campos, Adrian I.; Coleman, Jonathan R.I.; Edwards, Alexis C. & Galfalvy, Hanga [Show all 52 contributors for this article] (2022). Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors. Biological Psychiatry. ISSN 0006-3223. 91(3), p. 313–327. doi: 10.1016/j.biopsych.2021.05.029. Full text in Research Archive Show summary

  Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

• Rootes-Murdy, Kelly; Edmond, Jesse T.; Jiang, Wenhao; Rahaman, Md A.; Chen, Jiayu & Perrone-Bizzozero, Nora I. [Show all 24 contributors for this article] (2022). Clinical and cortical similarities identified between bipolar disorder I and schizophrenia: A multivariate approach. Frontiers in Human Neuroscience. 16. doi: 10.3389/fnhum.2022.1001692. Full text in Research Archive Show summary

  Background Structural neuroimaging studies have identified similarities in the brains of individuals diagnosed with schizophrenia (SZ) and bipolar I disorder (BP), with overlap in regions of gray matter (GM) deficits between the two disorders. Recent studies have also shown that the symptom phenotypes associated with SZ and BP may allow for a more precise categorization than the current diagnostic criteria. In this study, we sought to identify GM alterations that were unique to each disorder and whether those alterations were also related to unique symptom profiles. Materials and methods We analyzed the GM patterns and clinical symptom presentations using independent component analysis (ICA), hierarchical clustering, and n-way biclustering in a large ( N ∼ 3,000), merged dataset of neuroimaging data from healthy volunteers (HV), and individuals with either SZ or BP. Results Component A showed a SZ and BP &amp;lt; HV GM pattern in the bilateral insula and cingulate gyrus. Component B showed a SZ and BP &amp;lt; HV GM pattern in the cerebellum and vermis. There were no significant differences between diagnostic groups in these components. Component C showed a SZ &amp;lt; HV and BP GM pattern bilaterally in the temporal poles. Hierarchical clustering of the PANSS scores and the ICA components did not yield new subgroups. N-way biclustering identified three unique subgroups of individuals within the sample that mapped onto different combinations of ICA components and symptom profiles categorized by the PANSS but no distinct diagnostic group differences. Conclusion These multivariate results show that diagnostic boundaries are not clearly related to structural differences or distinct symptom profiles. Our findings add support that (1) BP tend to have less severe symptom profiles when compared to SZ on the PANSS without a clear distinction, and (2) all the gray matter alterations follow the pattern of SZ &amp;lt; BP &amp;lt; HV without a clear distinction between SZ and BP.

• Barth, Claudia; Kelly, Sinead; Nerland, Stener; Jahanshad, Neda; Alloza, Clara & Ambrogi, Sonia [Show all 44 contributors for this article] (2022). In vivo white matter microstructure in adolescents with early-onset psychosis: a multi-site mega-analysis. Molecular Psychiatry. ISSN 1359-4184. p. 1–11. doi: 10.1038/s41380-022-01901-3. Full text in Research Archive Show summary

  Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s d = 0.37), posterior corona radiata (d = 0.32), and superior fronto‐occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

• Johansen, Ingrid Torp; Steen, Nils Eiel; Rødevand, Linn; Werner, Maren Caroline Frogner; Lunding, Synve Hoffart & Hjell, Gabriela [Show all 12 contributors for this article] (2022). Sex-specific associations between metabolic hormones, severe mental disorders and antipsychotic treatment. Psychoneuroendocrinology. ISSN 0306-4530. 146. doi: 10.1016/j.psyneuen.2022.105927. Full text in Research Archive
• Trubetskoy, Vassily; Pardiñas, Antonio F.; Qi, Ting; Panagiotaropoulou, Georgia; Awasthi, Swapnil & Bigdeli, Tim B. [Show all 434 contributors for this article] (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. ISSN 0028-0836. 604(7906), p. 502–508. doi: 10.1038/s41586-022-04434-5. Full text in Research Archive Show summary

  Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

• Bell, Christina; Tesli, Natalia; Gurholt, Tiril Pedersen; Rokicki, Jaroslav; Hjell, Gabriela & Fischer-Vieler, Thomas [Show all 14 contributors for this article] (2022). Psychopathy subdomains in violent offenders with and without a psychotic disorder. Nordic Journal of Psychiatry. ISSN 0803-9488. doi: 10.1080/08039488.2022.2128869. Full text in Research Archive Show summary

  Background Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. Methods 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. Results Total PCL-R scores did not differ between the groups (p = 0.61, Cohen’s d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen’s d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. Conclusion Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

• Mørch-Johnsen, Lynn Egeland; Smelror, Runar; Andreou, Dimitrios; Barth, Claudia; Johannessen, Cecilie Haggag & Wedervang-Resell, Kirsten [Show all 15 contributors for this article] (2022). Negative Symptom Domains Are Associated With Verbal Learning in Adolescents With Early Onset Psychosis. Frontiers in Psychiatry. 12. doi: 10.3389/fpsyt.2021.825681. Full text in Research Archive Show summary

  Background: Early-onset psychosis (EOP) is among the leading causes of disease burden in adolescents. Negative symptoms and cognitive deficits predicts poorer functional outcome. A better understanding of the association between negative symptoms and cognitive impairment may inform theories on underlying mechanisms and elucidate targets for development of new treatments. Two domains of negative symptoms have been described in adult patients with schizophrenia: apathy and diminished expression , however, the factorial structure of negative symptoms has not been investigated in EOP. We aimed to explore the factorial structure of negative symptoms and investigate associations between cognitive performance and negative symptom domains in adolescents with EOP. We hypothesized that (1) two negative symptom factors would be identifiable, and that (2) diminished expression would be more strongly associated with cognitive performance, similar to adult psychosis patients. Methods: Adolescent patients with non-affective EOP ( n = 169) were included from three cohorts: Youth-TOP, Norway ( n = 45), Early-Onset Study, Norway ( n = 27) and Adolescent Schizophrenia Study, Mexico ( n = 97). An exploratory factor analysis was performed to investigate the underlying structure of negative symptoms (measured with the Positive and Negative Syndrome Scale (PANSS)). Factor-models were further assessed using confirmatory factor analyses. Associations between negative symptom domains and six cognitive domains were assessed using multiple linear regression models controlling for age, sex and cohort. The neurocognitive domains from the MATRICS Consensus Cognitive Battery included: speed of processing, attention, working memory, verbal learning, visual learning, and reasoning and problem solving. Results: The exploratory factor analysis of PANSS negative symptoms suggested retaining only a single factor, but a forced two factor solution corroborated previously described factors of apathy and diminished expression in adult-onset schizophrenia. Results from confirmatory factor analysis indicated a better fit for the two-factor model than for the one-factor model. For both negative symptom domains, negative symptom scores were inversely associated with verbal learning scores. Conclusion: The results support the presence of two domains of negative symptoms in EOP; apathy and diminished expression. Future studies on negative symptoms in EOP should examine putative differential effects of these symptom domains. For both domains, negative symptom scores were significantly inversely associated with verbal learning.

• Werner, Maren Caroline Frogner; Wirgenes, Katrine Verena; Shadrin, Alexey; Lunding, Synve Hoffart; Rødevand, Linn & Hjell, Gabriela [Show all 15 contributors for this article] (2022). Limited association between infections, autoimmune disease and genetic risk and immune activation in severe mental disorders. Progress in Neuro-psychopharmacology and Biological Psychiatry. ISSN 0278-5846. 116. doi: 10.1016/j.pnpbp.2022.110511. Full text in Research Archive Show summary

  Background Low-grade inflammation may be part of the underlying mechanism of schizophrenia and bipolar disorder. We investigated if genetic susceptibility, infections or autoimmunity could explain the immune activation. Methods Seven immune markers were selected based on indicated associations to severe mental disorders (IL-1Ra, sIL-2R, IL-18, sgp130, sTNFR-1, APRIL, ICAM-1) and measured in plasma of patients with schizophrenia (SCZ, N = 732) and bipolar spectrum disorders (BD, N = 460) and healthy controls (HC, N = 938). Information on rate of infections and autoimmune diseases were obtained from Norwegian national health registries for a twelve-year period. Polygenic risk scores (PRS) of SCZ and BD were calculated from genome-wide association studies. Analysis of covariance were used to test effects of infection rate, autoimmune disease and PRS on differences in immune markers between patients and HC. Results Infection rate differed between all groups (BD > HC > SCZ, all p < 0.001) whereas autoimmune disease was more frequent in BD compared to SCZ (p = 0.004) and HC (p = 0.003). sIL-2R was positively associated with autoimmune disease (p = 0.001) and negatively associated with PRS of SCZ (p = 0.006) across SCZ and HC; however, associations represented only small changes in the difference of sIL-2R levels between SCZ and HC. Conclusion There were few significant associations between rate of infections, autoimmune disease or PRS and altered immune markers in SCZ and BD, and the detected associations represented only small changes in the immune aberrations. The findings suggest that most of the low-grade inflammation in SCZ and BD is explained by other factors than the underlying PRS, autoimmunity and infection rates.

• Frangou, Sophia; Modabbernia, Amirhossein; Williams, Steven C. R.; Papachristou, Efstathios; Doucet, Gaëlle E. & Agartz, Ingrid [Show all 63 contributors for this article] (2022). Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 431–451. doi: 10.1002/hbm.25364. Full text in Research Archive Show summary

  Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

• Dima, Danai; Modabbernia, Amirhossein; Papachristou, Efstathios; Doucet, Gaëlle E.; Agartz, Ingrid & Aghajani, Moji [Show all 52 contributors for this article] (2022). Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years. Human Brain Mapping. ISSN 1065-9471. 43(1), p. 452–469. doi: 10.1002/hbm.25320. Full text in Research Archive Show summary

  Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns.

• Meer, Dennis van der; Shadrin, Alexey; O'Connell, Kevin Sean; Bettella, Francesco; Djurovic, Srdjan & Wolfers, Thomas [Show all 17 contributors for this article] (2022). Boosting Schizophrenia Genetics by Utilizing Genetic Overlap With Brain Morphology. Biological Psychiatry. ISSN 0006-3223. 92(4), p. 291–298. doi: 10.1016/j.biopsych.2021.12.007. Full text in Research Archive Show summary

  Background Schizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome. Methods We ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls. Results We found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios. Conclusions Our results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue–specific genetic variants and its use in polygenic risk frameworks.

• Lundberg, Mathias; Bohman, Hannes; Curbo, Sophie; Mansouri, Shiva; Agartz, Ingrid & Areström, Irene [Show all 7 contributors for this article] (2022). Development of an ELISA displaying similar reactivity with reduced and oxidized human Thioredoxin-1 (Trx1): The plasma level of Trx1 in early onset psychosis disorders. Journal of Immunological Methods (JIM). ISSN 0022-1759. 510. doi: 10.1016/j.jim.2022.113347. Full text in Research Archive
• Brouwer, Rachel M.; Klein, Marieke; Grasby, Katrina L.; Schnack, Hugo G.; Jahanshad, Neda & Teeuw, Jalmar [Show all 200 contributors for this article] (2022). Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nature Neuroscience. ISSN 1097-6256. 25(4), p. 421–432. doi: 10.1038/s41593-022-01042-4. Full text in Research Archive
• Andreou, Dimitrios; Jørgensen, Kjetil Nordbø; Nerland, Stener; Yolken, Robert H.; Haukvik, Unn Kristin Hansen & Andreassen, Ole [Show all 7 contributors for this article] (2022). Cytomegalovirus Infection Associated with Smaller Total Cortical Surface Area in Schizophrenia Spectrum Disorders. Schizophrenia Bulletin. ISSN 0586-7614. 48(5), p. 1164–1173. doi: 10.1093/schbul/sbac036. Full text in Research Archive Show summary

  Abstract Objectives Cytomegalovirus (CMV) congenital infection and in immunodeficiency can have deleterious effects on human cortex. In immunocompetent adults, the putative association between CMV infection and cortical measures has not been explored. We hypothesized that CMV exposure is associated with smaller cortical surface area or cortical thinning mainly in patients with schizophrenia spectrum disorders. Study Design We included 67 adult patients with schizophrenia spectrum disorders and 262 adult healthy controls. We measured circulating CMV IgG antibody concentrations with solid-phase immunoassay techniques. We measured the total cortical surface area, regional cortical surface areas and the overall mean cortical thickness based on T1-weighted MRI scans processed in FreeSurfer v6.0. Study Results In the whole sample analysis, we found a significant diagnostic group-by-CMV status interaction on the total surface area (P = .020). Among patients, CMV antibody positivity was significantly associated with smaller total surface area (P = .002, partial eta2 = 0.138) whereas no such association was found in healthy controls (P = .059). Post hoc analysis among patients showed that higher CMV antibody concentrations were also significantly associated with smaller total surface area (P = .038), and that CMV antibody positivity was significantly inversely associated with 14 left and 16 right regional surface areas mainly in the frontal and temporal lobes. CMV infection was not associated with the overall mean cortical thickness. Conclusions The results are indicative of a cortical surface area vulnerability to CMV infection in patients with schizophrenia spectrum disorders but not in healthy controls. CMV infection may contribute to the established cortical surface area aberrations in schizophrenia.

• Johansen, Ingrid Torp; Steen, Nils Eiel; Haram, Marit; Rødevand, Linn; Werner, Maren Caroline Frogner & Lunding, Synve Hoffart [Show all 13 contributors for this article] (2022). Sex differences in antipsychotic-related triglyceride levels are associated with metabolic hormone differences in patients with severe mental disorders. Schizophrenia Research. ISSN 0920-9964. 243, p. 55–63. doi: 10.1016/j.schres.2022.02.015. Full text in Research Archive Show summary

  Background Adverse effects of antipsychotics (AP) contribute to cardiovascular disease (CVD) risk in patients with severe mental disorders (SMD). We investigated sex differences in AP-related CVD risk factors and the role of metabolic hormones. Methods Patients with SMD (N = 1791) receiving AP with different CVD risk were recruited and grouped into olanzapine and/or clozapine (N = 532), other APs (N = 744) or no use of APs (N = 515). Associations between CVD risk factor (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), body mass index (BMI), glucose, blood pressure), sex and AP groups were tested in multiple linear regression with interactions, controlling for diagnostic group, lifestyle factors, polypharmacy, age and ethnicity. Next, we tested associations between sex differences in AP-related CVD risk factors and metabolic regulatory hormones. Results AP groups and male sex were significantly associated with higher levels of LDL-C, TG and BMI, and lower levels of HDL-C. Significant interaction between AP groups and sex were found for TG (p = 0.017), with larger increase in males. Serum adiponectin, insulin, cortisol, leptin, testosterone, free thyroxine and thyroid-stimulating hormone (TSH) were associated with TG levels (all p ≤ 0.001), and a significant interaction with sex for insulin (p = 0.005), cortisol (p = 0.016), leptin (p < 0.001) and TSH (p = 0.001). Conclusions We found more severe AP-related CVD risk factors in male patients with SMD. The male-dependent increase in TG levels was associated with leptin, insulin, cortisol and TSH levels. Clinicians treating patients with SMD should be aware of increased vulnerability for AP-related lipid abnormalities in males.

• Leonardsen, Esten Høyland; Peng, Han; Kaufmann, Tobias; Agartz, Ingrid; Andreassen, Ole & Celius, Elisabeth Gulowsen [Show all 19 contributors for this article] (2022). Deep neural networks learn general and clinically relevant representations of the ageing brain. NeuroImage. ISSN 1053-8119. 256. doi: 10.1016/j.neuroimage.2022.119210. Full text in Research Archive Show summary

  The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

• Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Westlye, Lars Tjelta; Høegh, Margrethe Collier; Haram, Marit & Werner, Maren Caroline Frogner [Show all 14 contributors for this article] (2021). Telomeres are shorter and associated with number of suicide attempts in affective disorders. Journal of Affective Disorders. ISSN 0165-0327. 295, p. 1032–1039. doi: 10.1016/j.jad.2021.08.135. Full text in Research Archive
• Andreou, Dimitrios; Jørgensen, Kjetil Nordbø; Nerland, Stener; Smelror, Runar; Wedervang-Resell, Kirsten & Johannessen, Cecilie Haggag [Show all 11 contributors for this article] (2021). Lower plasma total tau in adolescent psychosis: Involvement of the orbitofrontal cortex. Journal of Psychiatric Research. ISSN 0022-3956. 144, p. 255–261. doi: 10.1016/j.jpsychires.2021.10.031. Full text in Research Archive Show summary

  Schizophrenia is thought to be a neurodevelopmental disorder with neuronal migration, differentiation and maturation disturbances. Tau is a microtubule-associated protein with a crucial role in these processes. Lower circulating tau levels have been reported in adults with schizophrenia, but this association has not been investigated in adolescent psychosis. We aimed to test the hypotheses that a) adolescents with early-onset psychosis (EOP; age of onset <18 years) display lower plasma tau concentrations compared to healthy controls, and b) among patients with psychosis, tau levels are linked to structural brain measures associated with the microtubule-associated tau (MAPT) gene and psychosis. We included 37 adolescent patients with EOP (mean age 16.4 years) and 59 adolescent healthy controls (mean age 16.2 years). We investigated putative patient-control differences in plasma total tau concentrations measured by a Single molecule array (Simoa) immunoassay. We explored the correlations between tau and selected structural brain measures based on T1-weighted MRI scans processed in FreeSurfer v6.0. We found significantly lower plasma tau concentrations in patients compared to healthy controls (p = 0.017, partial eta-squared = 0.061). Tau was not associated with antipsychotic use or the antipsychotic dosage. Among patients but not healthy controls, tau levels were positively correlated with the cortical orbitofrontal surface area (p = 0.013, R-squared = 0.24). The results are suggestive of a tau-related neurodevelopmental disturbance in adolescent psychosis.

• Fagerberg, Tomas; Söderman, Erik; Gustavsson, Petter; Agartz, Ingrid; Jönsson, Erik G. & Jönsson, Erik Gunnar (2021). Thirteen-year follow-up of long-term treated psychotic disorder: personality aspects. Nordic Journal of Psychiatry. ISSN 0803-9488. p. 1–9. doi: 10.1080/08039488.2021.1981436. Full text in Research Archive Show summary

  Objective Personality is an aspect that can affect the symptoms and social function in individuals with psychotic disorders. Several studies have investigated personality in schizophrenia and other long-term psychotic disorders. No study has examined the stability of personality traits exceeding five years in patients with schizophrenia and related disorders. The aim of this study was to investigate the stability of personality traits over a 13-year period among patients with schizophrenia and related disorders and healthy individuals and to evaluate case-control differences. Methods At three occasions during a 13-year period patients with schizophrenia and related disorders (n = 28) and healthy individuals (n = 57) completed Swedish universities Scales of Personality (SSP). Mean-level change and case-control differences were investigated for all the individuals using within- and between-subject analyses, respectively. Analyses were performed on three occasions for all 13 subscales and the three overall factors of SSP. Also, correlations, means, and SDs were calculated. Results Tests of within-subject correlations showed differences in two subscales: Lack of Assertiveness, which were influenced by age, and Physical Trait Aggression, where patients’ ratings were stable, whereas controls rated themselves less aggressive at a higher age. Between-subjects correlations showed differences regarding diagnosis, time, age, gender, or age × gender in nine of the 13 subscales as well as in factor Neuroticism. Conclusion Long-term follow-up showed generally high stability of personality traits measured with SSP. Between-subject analyses over the 13 years showed that patients differed compared to controls for the SSP factor Neuroticism as well as the subscale Detachment, which is in accordance with previous studies within this population.

• Szabo, Attila; O'Connell, Kevin Sean; Ueland, Thor; Sheikh, Mashhood Ahmed; Agartz, Ingrid & Andreou, Dimitrios [Show all 31 contributors for this article] (2021). Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation. Brain, Behavior, and Immunity. ISSN 0889-1591. 99, p. 299–306. doi: 10.1016/j.bbi.2021.10.017. Full text in Research Archive Show summary

  Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

• Tesli, Natalia; Rokicki, Jaroslav; Maximov, Ivan; Bell, Christina; Hjell, Gabriela & Gurholt, Tiril Pedersen [Show all 17 contributors for this article] (2021). White Matter Matters: Unraveling Violence in Psychosis and Psychopathy. Schizophrenia Bulletin Open. 2(1). doi: 10.1093/schizbullopen/sgab026. Full text in Research Archive Show summary

  Individuals with psychotic disorders have an increased risk of committing acts of violence. Neurobiological support for the extent to which violence in psychosis is driven by psychotic symptoms and/or antisocial traits could have clinical and legal implications. Neuroimaging studies have reported white matter (WM) abnormalities in individuals with psychosis and in those with antisocial traits. However, it is unknown whether WM abnormalities in psychosis patients with a history of violence (violent-PSY) resemble those found in nonviolent psychosis patients (nonviolent PSY), violent nonpsychotic individuals (violent non-PSY), or both. Diffusion tensor imaging scans from 301 males including violent-PSY (n = 28), violent non-PSY (n = 20), nonviolent PSY (n = 58), and healthy controls (HC, n = 195) were analyzed with tract-based spatial statistics. Fractional anisotropy (FA), mean, axial and radial (RD) diffusivity were compared between groups. Psychopathic traits in the violent groups were measured with Psychopathy Checklist-revisited (PCL-R). Violent-PSY had globally lower FA and higher RD, compared with nonviolent PSY. Both psychosis groups and violent non-PSY group had widespread disruptions in WM compared with HC. There were no significant WM differences between violent-PSY and violent non-PSY. PCL-R scores did not differ between the violence groups and were associated with higher RD in corpus callosum. Here we demonstrate a widespread pattern of reduced WM integrity in violent-PSY compared with nonviolent PSY. The lack of significant WM and PCL-R differences between the violence groups, together with the positive association between PCL-R and WM deficits in violent-PSY and violent non-PSY may indicate shared neurobiological underpinnings of trait violence.

• Hilland, Eva; Johannessen, Cecilie Haggag; Jonassen, Rune; Alnæs, Dag; Jørgensen, Kjetil Nordbø & Barth, Claudia [Show all 17 contributors for this article] (2021). Aberrant default mode connectivity in adolescents with early-onset psychosis: A resting state fMRI study. NeuroImage: Clinical. 33. doi: 10.1016/j.nicl.2021.102881. Full text in Research Archive Show summary

  Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics. A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant’s DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength. The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication. In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP

• Abé, Christoph; Ching, Christopher R.K.; Liberg, Benny; Lebedev, Alexander V.; Agartz, Ingrid & Akudjedu, Theophilus N. [Show all 72 contributors for this article] (2021). Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group. Biological Psychiatry. ISSN 0006-3223. p. 1–11. doi: 10.1016/j.biopsych.2021.09.008. Full text in Research Archive Show summary

  Background Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

• Wolfers, Thomas; Rokicki, Jaroslav; Alnæs, Dag; Berthet, Pierre; Agartz, Ingrid & Kia, Seyed Mostafa [Show all 14 contributors for this article] (2021). Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder. Human Brain Mapping. ISSN 1065-9471. 42(8), p. 2546–2555. doi: 10.1002/hbm.25386. Full text in Research Archive Show summary

  Identifying brain processes involved in the risk and development of mental disorders is a major aim. We recently reported substantial interindividual heterogeneity in brain structural aberrations among patients with schizophrenia and bipolar disorder. Estimating the normative range of voxel-based morphometry (VBM) data among healthy individuals using a Gaussian process regression (GPR) enables us to map individual deviations from the healthy range in unseen datasets. Here, we aim to replicate our previous results in two independent samples of patients with schizophrenia (n1 = 94; n2 = 105), bipolar disorder (n1 = 116; n2 = 61), and healthy individuals (n1 = 400; n2 = 312). In line with previous findings with exception of the cerebellum our results revealed robust group level differences between patients and healthy individuals, yet only a small proportion of patients with schizophrenia or bipolar disorder exhibited extreme negative deviations from normality in the same brain regions. These direct replications support that group level-differences in brain structure disguise considerable individual differences in brain aberrations, with important implications for the interpretation and generalization of group-level brain imaging findings to the individual with a mental disorder.

• Aas, Monica; Ueland, Torill; Mørch, Ragni Helene; Laskemoen, Jannicke Fjæra; Lunding, Synve Hoffart & Reponen, Elina Johanna [Show all 11 contributors for this article] (2021). Physical activity and childhood trauma experiences in patients with schizophrenia or bipolar disorders. World Journal of Biological Psychiatry. ISSN 1562-2975. 22(8), p. 637–645. doi: 10.1080/15622975.2021.1907707. Full text in Research Archive Show summary

  Background Physical activity promotes resilience and reduces stress. Here we aimed to clarify the impact of physical activity and childhood trauma experiences on current mood and cognitive function in patients with schizophrenia (SZ) or bipolar disorders (BD). Methods Three-hundred-and-six patients with DSM-IV schizophrenia (SZ) or bipolar disorder (BD) were included in the study. Diagnoses were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Physical activity was measured as hours spent on any regular physical activity per week. All patients underwent a neuropsychological test battery. History of Childhood trauma was assessed using the Childhood Trauma Questionnaire and mood symptoms were assessed with the Inventory of Depressive Symptoms. Results Patients with childhood trauma who were physically inactive (˂90 min per week) had the most severe clinical profile, characterised by the highest depressive symptoms (p ˂ 0.001) and lowest performance on working memory tasks (p ˂ 0.001). Among patients with childhood trauma, those who were physically active (≥90 min per week) had better working memory performance than physically inactive patients (p = 0.02). Discussion A history of childhood trauma was associated with poorer working memory and more depressive symptoms only in patients who were physically inactive, suggesting a possible protective factor of physical activity in severe mental disorder.

• Chen, Jiayu; Li, Xiang; Calhoun, Vince D.; Turner, Jessica A.; Erp, Theo G.M. van & Wang, Lei [Show all 16 contributors for this article] (2021). Sparse deep neural networks on imaging genetics for schizophrenia case–control classification. Human Brain Mapping. ISSN 1065-9471. 42(8), p. 2556–2568. doi: 10.1002/hbm.25387. Full text in Research Archive Show summary

  Deep learning methods hold strong promise for identifying biomarkers for clinical application. However, current approaches for psychiatric classification or prediction do not allow direct interpretation of original features. In the present study, we introduce a sparse deep neural network (DNN) approach to identify sparse and interpretable features for schizophrenia (SZ) case–control classification. An L0-norm regularization is implemented on the input layer of the network for sparse feature selection, which can later be interpreted based on importance weights. We applied the proposed approach on a large multi-study cohort with gray matter volume (GMV) and single nucleotide polymorphism (SNP) data for SZ classification. A total of 634 individuals served as training samples, and the classification model was evaluated for generalizability on three independent datasets of different scanning protocols (N = 394, 255, and 160, respectively). We examined the classification power of pure GMV features, as well as combined GMV and SNP features. Empirical experiments demonstrated that sparse DNN slightly outperformed independent component analysis + support vector machine (ICA + SVM) framework, and more effectively fused GMV and SNP features for SZ discrimination, with an average error rate of 28.98% on external data. The importance weights suggested that the DNN model prioritized to select frontal and superior temporal gyrus for SZ classification with high sparsity, with parietal regions further included with lower sparsity, echoing previous literature. The results validate the application of the proposed approach to SZ classification, and promise extended utility on other data modalities and traits which ultimately may result in clinically useful tools.

• Andreou, Dimitrios; Jørgensen, Kjetil Nordbø; Bakke, Laura A Wortinger; Engen, Kristine; Vaskinn, Anja & Ueland, Torill [Show all 9 contributors for this article] (2021). Cytomegalovirus infection and IQ in patients with severe mental illness and healthy individuals. Psychiatry Research. ISSN 0165-1781. doi: 10.1016/j.psychres.2021.113929. Full text in Research Archive Show summary

  Cytomegalovirus (CMV) infection in immunocompetent adults is usually asymptomatic, but results in lifelong latency. Infection occurring congenitally or in immunodeficiency can lead to cognitive impairment. We aimed to investigate the associations between CMV exposure and intelligence quotient (IQ) in patients with schizophrenia spectrum disorders (SZS), bipolar spectrum disorders (BDS) and healthy controls (HC). CMV immunoglobulin G antibody concentrations were measured by immunoassay and expressed as dichotomous measures (seropositive/CMV+ vs. seronegative/CMV-). Based on a significant CMV-by-diagnosis-by-sex interaction on IQ, we investigated main and interaction effects of CMV and sex on IQ in each diagnostic category. Significant CMV-by-sex interactions were found in patient groups. In SZS, CMV+ female patients (n = 50) had significantly lower IQ than CMV- female patients (n = 33), whereas CMV+ (n = 48) and CMV- (n = 45) male patients did not differ in IQ. In BDS, CMV+ (n = 49) and CMV- (n = 37) female patients did not differ in IQ, whereas CMV+ male patients (n = 33) had significantly higher IQ than CMV- male patients (n = 32). Among HC, CMV+ (n = 138) and CMV- (n = 118) male participants as well as CMV+ (n = 125) and CMV- (n = 93) female participants did not differ in IQ. Our findings suggest that CMV exposure may affect IQ in patients with severe mental illness but not HC.

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• Agartz, Ingrid & Smelror, Runar (2023). Adolescent Psychosis: Clinical and Scientific Perspectives. Academic Press. ISBN 9780323898324. 350 p. Full text in Research Archive

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• Torp, Nor Christian; Rognli, Erling; Nerland, Stener; Smelror, Runar Elle; Ivarsson, Tord & Agartz, Ingrid (2025). Early-Onset Schizophrenia and Obsessive Compulsive Disorder: Different brain signatures are noted, though overlapping features exist. Full text in Research Archive Show summary

  Aims: EOS and OCD are severe disorders with impairment, severe anxiety and limited insight. While EOS shows gross misinterpretations of both external and internal information leading to disorganized behaviour and withdrawal, OCD shows over-estimations of risks (intrusive and persistent) rendering organized repetitive goal-directed behaviours and avoidance. We hypothesize that brain structure differs between EOS, OCD and healthy controls. Methods: Adolescent patients with EOS (n=23) or OCD (n=19) and healthy controls (n=100), ages 12-18 years, both genders, were diagnosed with semi-structured interviews. T1-weighted MRI images were processed with FreeSurfer (v7) and Sequence Adaptive Multimodal SEGmentation (SAMSEG). Cortical thickness and area were estimated for cerebral cortex lobes and volumes were computed for eight subcortical structures. We fitted separate Bayesian hierarchical log-linear regression models to measurements of cortical thickness and area, and subcortical volumes. Models were specified with random effects for anatomical area and subject, with the random effects for subjects predicted by intracranial volume. We fitted slopes for OCD and EOS for each anatomical structure, adjusted for age and gender. Weakly informative hierarchical priors were used. Graphical posterior predictive checks indicated good model fit. Results and Conclusions: We observed notable differences between EOS and OCD, as well as in comparison to controls. We also identified some shared characteristics in both cortical measures and subcortical volumes. These findings support the perspective that EOS and OCD are developmental disorders with overlapping yet distinct patterns of brain volume changes, characterized by volume reductions in both conditions and enlargements specific to EOS respectively OCD.

• Funderud, Cecilie Klem; Fjeldstad, Anette; Agartz, Ingrid; Steen, Nils Eiel; Andreassen, Ole & Aas, Monica [Show all 7 contributors for this article] (2024). The Role of IL-18 and Childhood Trauma in Early-Onset Psychosis. Full text in Research Archive
• Norbom, Linn Christin Bonaventure; Hanson, Jamie; Meer, Dennis van der; Ferschmann, Lia; Røysamb, Espen & Soest, Tilmann von [Show all 10 contributors for this article] (2023). Erratum to “Parental socioeconomic status is linked to cortical microstructure and language abilities in children and adolescents” [Dev. Cogn. Neurosci. 56C (2022) 101132] (Developmental Cognitive Neuroscience (2022) 56, (S1878929322000755), (10.1016/j.dcn.2022.101132)). Developmental Cognitive Neuroscience. ISSN 1878-9293. 61. doi: 10.1016/j.dcn.2023.101225. Full text in Research Archive
• Beck, Dani; Ferschmann, Lia; MacSweeney, Niamh; Fridman, Linn Bonaventure; Wiker, Thea & Aksnes, Eira Ranheim [Show all 15 contributors for this article] (2023). Puberty differentially predicts brain maturation in males and females: A longitudinal ABCD Study. Full text in Research Archive

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