Erik Gunnar Jönsson

• Granerud, Guro; Arntzen, Erik; Nærland, Terje; Malt, Eva Albertsen; Hatlestad-Hall, Christoffer & Jönsson, Erik Gunnar [Show all 8 contributors for this article] (2026). Equivalence class formation, priming, and N400 in autism spectrum disorder. Learning and Motivation. ISSN 0023-9690. 95. doi: 10.1016/j.lmot.2026.102307. Full text in Research Archive
• Assis, Denis Reis de; Pentz, Atle Bråthen; Osete, Jordi Requena; Ievglevskyi, Oleksandr; Vandenberghe, Matthieu & Akkouh, Ibrahim Ahmed [Show all 12 contributors for this article] (2026). Investigating neural impairments in psychotic disorders using electroencephalography and cortical spheroids. Translational Psychiatry. 16(1). doi: 10.1038/s41398-026-03863-4. Full text in Research Archive Show summary

  Synaptic dysfunction is a candidate mechanism in psychotic disorders, yet the precise underlying substrates remain elusive. We investigated how combining in vivo electroencephalography (EEG) and in vitro human cortical spheroid (hCS)-based methods can further our understanding of psychosis pathophysiology during fetal stages of neurodevelopment. Ten individuals with schizophrenia (SZ) or bipolar disorder (BD; 5 males and 5 females) and five controls (CTRL; 3 males and 2 females) underwent EEG assessments, including long-term potentiation (LTP)-like cortical plasticity and mismatch negativity (MMN). hCS were generated from induced pluripotent stem cells of all participants, and immunohistochemistry, Seahorse bioenergetics and patch-clamp recordings were performed. EEG-based LTP-like plasticity was reduced in individuals with SZ and BD. Basal respiration was decreased in BD hCS and VGLUT1 levels were reduced in both SZ and BD hCS. There was a positive association between EEG-based LTP-like plasticity and hCS basal respiration which survived correction. Our data provide further support for roles of mitochondrial and glutamatergic impairments in the synaptic dysfunction of psychosis and demonstrate the potential of combining EEG- and hCS-based methods for early development mechanistic studies of brain disorders.

• Bang, Nina; Nesset, Merete Berg; Rasmussen, Kirsten; Dahl, Hilde; Bell, Christina & Fischer-Vieler, Thomas [Show all 12 contributors for this article] (2026). Glutamatergic neurotransmission in violence and psychosis: an LTP-like cortical plasticity study. Journal of Psychiatric Research. ISSN 0022-3956. doi: 10.1016/j.jpsychires.2026.04.017. Full text in Research Archive Show summary

  Among the various mechanisms implicated in abnormal aggression and violent behavior, impaired glutamatergic neurotransmission may represent one contributing factor. However, this hypothesis has been insufficiently explored in human studies.

• 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.

• 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.

• 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.

• Bang, Nina; Nesset, Merete Berg; Rasmussen, Kirsten; Dahl, Hilde; Bell, Christina & Fischer-Vieler, Thomas [Show all 13 contributors for this article] (2025). Long-range temporal correlations in violence and psychosis: An EEG-based study. Journal of Psychiatric Research. ISSN 0022-3956. 193, p. 188–197. doi: 10.1016/j.jpsychires.2025.11.013. Full text in Research Archive Show summary

  Background A subgroup of individuals with psychosis have increased violence risk. Long-range temporal correlations (LRTC) in electroencephalography (EEG) reflect neural dynamics, but their relevance to violence risk remains unclear. Methods Resting-state EEG was collected from four groups: healthy controls (HC, n = 134), individuals with psychosis and violence history (violent-PSY, n = 16), individuals with psychosis without such history (nonviolent-PSY, n = 38), and violent individuals without psychosis (violent non-PSY, n = 23). LRTC was quantified using detrended fluctuation analysis (DFA) of mean and peak amplitude dynamics in alpha and beta bands during eyes-closed (EC) and eyes-open (EO) conditions, yielding eight metrics: LRTC for mean and peak amplitudes of alphaEC, betaEC, alphaEO, and betaEO. Results No significant group differences in LRTC were observed in eyes-open conditions (all p > 0.05). In contrast, eyes-close conditions showed significantly reduced LRTC in the nonviolent-PSY group relative to controls for mean alphaEC, peak alphaEC, and mean betaEC (all p < 0.05; Cohen's d's = 0.49–0.59). No significant LRTC difference emerged between violent and nonviolent psychosis groups. Other group comparisons were non-significant. Lower alpha-band LRTC was associated with greater symptom severity, including higher total PANSS and depressive subscale scores (all p < 0.05; r's = −0.26 to −0.28). Conclusions LRTC was reduced in the nonviolent-PSY group compared to controls but not significantly altered in the violent-PSY group. Nor did it differentiate between psychosis with or without violence history. Although further studies are needed, these findings provide limited support for LRTC as a marker of violence propensity in psychosis.

• 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.

• 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.

• Pentz, Atle Bråthen; O'Connell, Kevin Sean; Jole, Oda van; Timpe, Clara Marie Fides; Slapø, Nora Berz & Melle, Ingrid [Show all 14 contributors for this article] (2024). Mismatch negativity and polygenic risk scores for schizophrenia and bipolar disorder. Schizophrenia Research. ISSN 0920-9964. 264, p. 314–326. doi: 10.1016/j.schres.2024.01.013. Full text in Research Archive Show summary

  Objective: Auditory mismatch negativity (MMN) impairment is a candidate endophenotype in psychotic disorders, yet the genetic underpinnings remain to be clarified. Here, we examined the relationships between auditory MMN and polygenic risk scores (PRS) for individuals with psychotic disorders, including schizophrenia spectrum disorders (SSD) and bipolar disorder (BD) and in healthy controls (HC). Methods: Genotyped and clinically well-characterized individuals with psychotic disorders (n = 102), including SSD (n = 43) and BD (n = 59), and HC (n = 397) underwent a roving MMN paradigm. In addition MMN, we measured the memory traces of the repetition positivity (RP) and the deviant negativity (DN), which is believed to reflect prediction encoding and prediction error signals, respectively. SCZ and BD PRS were computed using summary statistics from the latest genome-wide association studies. The relationships between the MMN, RP, and DN and the PRSs were assessed with linear regressions. Results: We found no significant association between the SCZ or BD PRS and grand average MMN in the psychotic disorders group or in the HCs group (all p > 0.05). SCZ PRS and BD PRS were negatively associated with RP in the psychotic disorders group (β = 0.46, t = 2.86, p = 0.005 and β = 0.29, t = 0.21, p = 0.034, respectively). No significant associations were found between DN and PRS. Conclusion: These findings suggest that genetic variants associated with SCZ and BD may be associated with MMN subcomponents linked to predictive coding among patients with psychotic disorders. Larger studies are needed to confirm these findings and further elucidate the genetic underpinnings of MMN impairment in psychotic disorders.

• 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.

• 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
• Bang, Nina; Pettersen, Johanne Hagen; Nesset, Merete Berg; Rasmussen, Kirsten; Dahl, Hilde & Tesli, Natalia [Show all 15 contributors for this article] (2024). The Startle Response and Prepulse Inhibition in Psychosis and Violence: A Combined Electromyography and Electroencephalography Study. Schizophrenia Bulletin Open. 6(1). doi: 10.1093/schizbullopen/sgae031. Full text in Research Archive Show summary

  There is a pressing need for biomarkers of violent behavior risk in psychosis. Previous research indicates that electrophysiological measures of automatic defensive reactions may have potential. The purpose of this study was to investigate associations between violent behavior in individuals with and without psychosis and electromyography (EMG) and electroencephalography (EEG) responses to startling auditory stimuli. Electromyography and EEG were recorded during an auditory startle paradigm from healthy controls (HC, n = 211), individuals with psychosis and a history of violent behavior (violent-PSY, n = 18), individuals with psychosis without a history of violence (nonviolent-PSY, n = 32), and individuals with a history of violence without psychosis (violent non-PSY, n = 22). We estimated the auditory startle response (ASR) and prepulse inhibition (PPI) using EMG (ie, EMGASR and EMGPPI) and the auditory-evoked potential (ie, AEPASR and AEPPPI) of the EEG. There were no significant effects of group on the EMGASR (P = .10) or the 30-, 60-, and 120-ms prepulse + pulse EMGPPI amplitudes (P = .11, P = .19, and P = .50, respectively). The N1 amplitude of the AEPASR was reduced in the violent-PSY group (P < .001) and the nonviolent-PSY group (P = .015) compared with HC. The P2 amplitude of the AEPASR was reduced in violent-PSY relative to nonviolent-PSY (P = .003), violent non-PSY (P = .016), and HC (P < .001). Together, these results show that EEG-based neural responses to startling auditory stimuli are promising biomarkers of violence risk in psychosis.

• 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
• 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.

• Dur, Dur E Shahnaz; Jørgensen, Kjetil Nordbø; Bjella, Thomas; Nesvåg, Ragnar; Dieset, Ingrid & Melle, Ingrid [Show all 8 contributors for this article] (2024). Prescriptions of psychotropic and somatic medications among patients with severe mental disorders and healthy controls in a naturalistic study. Nordic Journal of Psychiatry. ISSN 0803-9488. 78(3), p. 212–219. doi: 10.1080/08039488.2024.2305806. Full text in Research Archive Show summary

  Purpose Psychotropic and somatic medications are both used in treating severe mental disorders (SMDs). Realistic estimates of the prevalence of use across medication categories are needed. We obtained this in a clinical cohort of patients with SMD and healthy controls (HCs). Materials and methods Prescriptions filled at Norwegian pharmacies the year before and after admittance to the Thematically Organized Psychosis (TOP) study were examined in 1406 patients with SMD (mean age 32.5 years, 48.2% women) and 920 HC (34.1 years, 46.2% women). Using data from the Norwegian Prescription Database (NorPD), the number of users in different anatomical therapeutic chemical (ATC) categories was compared using logistic regression. Population estimates were used as reference data. Results Use of antipsychotics (N05A), antiepileptics (N03A), antidepressants (N06A), anxiolytics (N05B), hypnotics and sedatives (N05C), anticholinergics (N04A), psychostimulants, attention deficit hyperactivity disorder and nootropic agents (N06B) and drugs for addiction disorders (N07B) was significantly more prevalent in patients with SMD than HC. Use of diabetes treatment (A10), antithrombotic drugs (B01), beta blockers (C07), lipid modifiers (C10), and thyroid and endocrine therapeutics (H03) was also more prevalent in patients with SMD, but with two exceptions somatic medication use was comparable to the general population. Among HC, there was low prevalence of use for most medication categories. Conclusion Patients were using psychiatric medications, but also several types of somatic medications, more often than HC. Still, somatic medication use was mostly not higher than in the general population. The results indicate that HC had low use of most medication types.

• 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.

• 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.

• Pentz, Atle Bråthen; Timpe, Clara Marie Fides; Normann, Elizabeth Marie; Slapø, Nora Berz; Melle, Ingrid & Lagerberg, Trine Vik [Show all 13 contributors for this article] (2023). Mismatch negativity in schizophrenia spectrum and bipolar disorders: Group and sex differences and associations with symptom severity. Schizophrenia Research. ISSN 0920-9964. 261, p. 80–93. doi: 10.1016/j.schres.2023.09.012. Full text in Research Archive Show summary

  Objective Research increasingly implicates glutamatergic dysfunction in the pathophysiologies of psychotic disorders. Auditory mismatch negativity (MMN) is an electroencephalography (EEG) waveform linked to glutamatergic neurotransmission and is consistently attenuated in schizophrenia (SCZ). MMN consists of two subcomponents, the repetition positivity (RP) and deviant negativity (DN) possibly reflecting different neural mechanisms. However, whether MMN reduction is present across different psychotic disorders, linked to distinct symptom clusters, or related to sex remain to be clarified. Methods Four hundred participants including healthy controls (HCs; n = 296) and individuals with SCZ (n = 39), bipolar disorder (BD) BD typeI (n = 35), or BD type II (n = 30) underwent a roving MMN paradigm and clinical evaluation. MMN, RP and DN as well their memory traces were recorded at the FCZ electrode. Analyses of variance and linear regression models were used both transdiagnostically and within clinical groups. Results MMN was reduced in SCZ compared to BD (p = 0.006, d = 0.55) and to HCs (p < 0.001, d = 0.63). There was a significant group × sex interaction (p < 0.003) and the MMN impairment was only detected in males with SCZ. MMN amplitude correlated positively with Positive and Negative Syndrome Scale total score and negatively with Global Assessment of Functioning Scale score. The deviant negativity was impaired in males with SCZ. No group differences in memory trace indices of the MMN, DN, or RP. Conclusion MMN was attenuated in SCZ and correlated with greater severity of psychotic symptoms and lower level of functioning. Our results may indicate sex-dependent differences of glutamatergic function in SCZ.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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
• 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.

• 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

• 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.

• Valstad, Mathias; Roelfs, Daniel; Slapø, Nora Berz; Timpe, Clara Marie Fides; Rai, Ahsan & Matziorinis, Anna Maria [Show all 24 contributors for this article] (2021). Evidence for Reduced Long-Term Potentiation-Like Visual Cortical Plasticity in Schizophrenia and Bipolar Disorder. Schizophrenia Bulletin. ISSN 0586-7614. 47(6), p. 1751–1760. doi: 10.1093/schbul/sbab049. Full text in Research Archive Show summary

  Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. We measured the VEP of patients with SZ spectrum disorders (n = 31), BDI (n = 34), BDII (n = 33), and other BD spectrum disorders (n = 2), and age-matched healthy control (HC) participants (n = 200) before and after prolonged visual stimulation. Compared to HCs, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ 2 = 35.1, P = 3.1 × 10−9) and BD spectrum (χ 2 = 7.0, P = 8.2 × 10−3), including BDI (χ 2 = 6.4, P = .012), but not BDII (χ 2 = 2.2, P = .14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ 2 = 14.2, P = 1.7 × 10−4). N1b modulation was not significantly associated with Positive and Negative Syndrome Scale (PANSS) negative or positive symptoms scores, number of psychotic episodes, Montgomery and Åsberg Depression Rating Scale (MADRS) scores, or Young Mania Rating Scale (YMRS) scores after multiple comparison correction, although a nominal association was observed between N1b modulation and PANSS negative symptoms scores among SZ spectrum patients. These results suggest that LTP-like plasticity is impaired in SZ and BD. Adding to previous genetic, pharmacological, and electrophysiological evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.

• Fagerberg, Tomas; Söderman, Erik; Gustavsson, J. Petter; Agartz, Ingrid & Jönsson, Erik Gunnar (2021). Swedish universities scales of personality: Relation to other personality instruments. Psychiatry Investigation. ISSN 1738-3684. 18(5), p. 373–384. doi: 10.30773/pi.2020.0052. Full text in Research Archive Show summary

  Objective To investigate associations between Swedish universities Scales of Personality (SSP) and scales of the following personality instruments: Structured Clinical Interview for DSM-III-R axis II screening questionnaire (SCID-II screen), revised NEO personality inventory (NEO-PI-R), revised Chapman scales (Chapman) and the psychotic traits questionnaire (STQ).Methods Healthy individuals (n=406) completed self-report personality questionnaires including SSP and at least one more personality inventory. Correlations were calculated between the 13 different SSP subscales as well as SSP’s three factors and factors and scales/subscales in SCID-II screen, NEO-PI-R, Chapman and STQ. The main factors of the various instruments were factor analysed. ICC were calculated.Results SSP Neuroticism factor correlated with SCID-II cluster C (r=0.71), NEO Neuroticism (r=0.80) and Chapman Social anhedonia (r=0.62). SSP Extraversion factor correlated with NEO Extraversion (r=0.63) and SSP Aggressiveness factor with NEO Agreeableness (r=-0.62). Strong correlations between SSP factors and scales and scales of the other instruments were sparse, although weaker correlations were common.Conclusion SSP is a useful investigation tool when measuring personality traits related to temperament-like features. SSP partly correlates well to especially three of the NEO-PI-R factors. The different personality inventories are not completely comparable to each other. Instead, they measure personality aspects in partly different ways.

• Jiang, Wenhao; Rootes-Murdy, Kelly; Chen, Jiayu; Bizzozero, Nora I.Perrone-; Calhoun, Vince D. & Erp, Theo G.M. van [Show all 16 contributors for this article] (2021). Multivariate alterations in insula - Medial prefrontal cortex linked to genetics in 12q24 in schizophrenia. Psychiatry Research. ISSN 0165-1781. 306. doi: 10.1016/j.psychres.2021.114237. Full text in Research Archive
• Sønderby, Ida Elken; Meer, Dennis van der; Moreau, Clara; Kaufmann, Tobias; Walters, G. Bragi & Ellegaard, Maria [Show all 76 contributors for this article] (2021). 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01213-0. Full text in Research Archive Show summary

  Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

• Blokland, Gabriella A. M.; Grove, Jakob; Chen, Chia-Yen; Cotsapas, Chris; Tobet, Stuart & Handa, Robert [Show all 50 contributors for this article] (2021). Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders. Biological Psychiatry. ISSN 0006-3223. 91, p. 102–117. doi: 10.1016/j.biopsych.2021.02.972. Full text in Research Archive Show summary

  Background Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• Smit, Dirk J. A.; Andreassen, Ole; Boomsma, Dorret I.; Burwell, Scott J.; Chorlian, David B. & Geus, Eco J C De [Show all 28 contributors for this article] (2021). Large-scale collaboration in ENIGMA-EEG: A perspective on the meta-analytic approach to link neurological and psychiatric liability genes to electrophysiological brain activity. Brain and Behavior. 11(8). doi: 10.1002/brb3.2188. Full text in Research Archive Show summary

  Background and purpose The ENIGMA-EEG working group was established to enable large-scale international collaborations among cohorts that investigate the genetics of brain function measured with electroencephalography (EEG). In this perspective, we will discuss why analyzing the genetics of functional brain activity may be crucial for understanding how neurological and psychiatric liability genes affect the brain. Methods We summarize how we have performed our currently largest genome-wide association study of oscillatory brain activity in EEG recordings by meta-analyzing the results across five participating cohorts, resulting in the first genome-wide significant hits for oscillatory brain function located in/near genes that were previously associated with psychiatric disorders. We describe how we have tackled methodological issues surrounding genetic meta-analysis of EEG features. We discuss the importance of harmonizing EEG signal processing, cleaning, and feature extraction. Finally, we explain our selection of EEG features currently being investigated, including the temporal dynamics of oscillations and the connectivity network based on synchronization of oscillations. Results We present data that show how to perform systematic quality control and evaluate how choices in reference electrode and montage affect individual differences in EEG parameters. Conclusion The long list of potential challenges to our large-scale meta-analytic approach requires extensive effort and organization between participating cohorts; however, our perspective shows that these challenges are surmountable. Our perspective argues that elucidating the genetic of EEG oscillatory activity is a worthwhile effort in order to elucidate the pathway from gene to disease liability.

• Grasby, Katrina L.; Jahanshad, Neda; Painter, Jodie N; Colodro-Conde, Lucía; Bralten, Janita & Hibar, DP [Show all 50 contributors for this article] (2020). The genetic architecture of the human cerebral cortex. Science. ISSN 0036-8075. 367(6484). doi: 10.1126/science.aay6690. Full text in Research Archive Show summary

  INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function.

• Barth, Claudia; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne; Nerland, Stener; Jönsson, Erik Gunnar & Agartz, Ingrid (2020). Trajectories of brain volume change over 13 years in chronic schizophrenia. Schizophrenia Research. ISSN 0920-9964. doi: 10.1016/j.schres.2020.05.014. Full text in Research Archive
• Valstad, Mathias; Moberget, Torgeir; Roelfs, Daniël Thomas Heimen; Slapø, Nora Berz; Timpe, Clara Marie Fides & Beck, Dani [Show all 18 contributors for this article] (2020). Experience-dependent modulation of the visual evoked potential: Testing effect sizes, retention over time, and associations with age in 415 healthy individuals. NeuroImage. ISSN 1053-8119. doi: 10.1016/j.neuroimage.2020.117302. Full text in Research Archive Show summary

  Experience-dependent modulation of the visual evoked potential (VEP) is a promising proxy measure of synaptic plasticity in the cerebral cortex. However, existing studies are limited by small to moderate sample sizes as well as by considerable variability in how VEP modulation is quantified. In the present study, we used a large sample (n = 415) of healthy volunteers to compare different quantifications of VEP modulation with regards to effect sizes and retention of the modulation effect over time. We observed significant modulation for VEP components C1 (Cohen's d = 0.53), P1 (d = 0.66), N1 (d=-0.27), N1b (d=-0.66), but not P2 (d = 0.08), and in three clusters of total power modulation, 2–4 min after 2 Hz prolonged visual stimulation. For components N1 (d=-0.21) and N1b (d=-0.38), as well for the total power clusters, this effect was retained after 54–56 min, by which time also the P2 component had gained modulation (d = 0.54). Moderate to high correlations (0.39≤ρ≤0.69) between modulation at different postintervention blocks revealed a relatively high temporal stability in the modulation effect for each VEP component. However, different VEP components also showed markedly different temporal retention patterns. Finally, participant age correlated negatively with C1 (χ2=30.4), and positively with P1 modulation (χ2=13.4), whereas P2 modulation was larger for female participants (χ2=15.4). There were no effects of either age or sex on N1 and N1b potentiation. These results provide strong support for VEP modulation, and especially N1b modulation, as a robust measure of synaptic plasticity, but underscore the need to differentiate between components, and to control for demographic confounders.

• Palomera, Aldo Còrdova; Meer, Dennis van der; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng & Alnæs, Dag [Show all 40 contributors for this article] (2020). Genetic control of variability in subcortical and intracranial volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–8. doi: 10.1038/s41380-020-0664-1. Full text in Research Archive Show summary

  Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in ten key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume, cortical surface area, and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n = 25,575 individuals; 8–89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in thalamus volume and cortical thickness. The variance-controlling loci involved genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

• Wierenga, Lara M.; Doucet, Gaëlle E.; Dima, Danai; Agartz, Ingrid; Aghajani, Moji & Akudjedu, Theophilus N. [Show all 50 contributors for this article] (2020). Greater male than female variability in regional brain structure across the lifespan. Human Brain Mapping. ISSN 1065-9471. 43, p. 470–499. doi: 10.1002/hbm.25204. Full text in Research Archive Show summary

  For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta‐Analysis) Consortium presents the largest‐ever mega‐analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1‐90 years old (47% females). We observed significant patterns of greater male than female between‐subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene‐environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex‐specific vulnerability to disorders.

• Sæther, Linn Sofie; Roelfs, Daniël Thomas Heimen; Moberget, Torgeir; Andreassen, Ole Andreas; Elvsåshagen, Torbjørn & Jönsson, Erik Gunnar [Show all 7 contributors for this article] (2020). Exploring neurophysiological markers of visual perspective taking: Methodological considerations. International Journal of Psychophysiology. ISSN 0167-8760. doi: 10.1016/j.ijpsycho.2020.12.006. Full text in Research Archive Show summary

  Rationale: For visual perspective taking (VPT) using the avatar task, examinations of neural processes using event related potentials (ERP) indicate a distinction between an early posterior perspective calculation process (P3) and a later frontal process (LFSW) managing perspective conflict. While it is unknown if these neural processes are affected in clinical populations, it is unclear if the avatar task can be applied to this group, due to the long duration and sensitivity to data loss. Thus, we performed a methodological study of the avatar task, testing the feasibility of a shortened experimental paradigm. Objective: To investigate whether previously reported behavioural and ERP effects in the avatar task can also be seen if analysing all trials (matching/non-matching) jointly, and whether they remain robust if only a subset of the data is analysed. Method: Healthy individuals (n = 20) completed the avatar task with ERP measurement. ERP components (P3, LFSW) and behavioural data were investigated by A) comparing use of only matching trials (n = 384) versus all trials (n = 768), and B) examining if reduced duration of assessment, by analysing only a subset of the data, impacts ERP findings. Results: We observed minimal differences when analysing data from only matching trial types compared to all trial types. Further, ERP amplitudes and latency findings were replicated when analysing only a subset of the data. Conclusions: The duration of the avatar task can be reduced to avoid long testing times, thus making it better suited for use in clinical populations.

• Tønnesen, Siren; Kaufmann, Tobias; Lange, Ann-Marie Glasø de; Richard, Geneviève; Doan, Nhat Trung & Alnæs, Dag [Show all 33 contributors for this article] (2020). Brain age prediction reveals aberrant brain white matter in schizophrenia and bipolar disorder: A multisample diffusion tensor imaging study. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. ISSN 2451-9022. 5(12), p. 1095–1103. doi: 10.1016/j.bpsc.2020.06.014. Full text in Research Archive Show summary

  Background Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts. Methods We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18–94 years of age) and applied the models to the test sets including 648 patients with SZ (18–66 years of age), 185 patients with BD (18–64 years of age), and 990 HC subjects (17–68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results. Results Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen’s d = −0.29) and patients with BD (Cohen’s d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy–based models showed larger group differences than the models based on other DTI-derived metrics. Conclusions Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

• Zwarte, Sonja M. C. de; Brouwer, Rachel M; Agartz, Ingrid; Alda, Martin; Alonso-Lana, Silvia & Bearden, Carrie E [Show all 50 contributors for this article] (2020). Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder. Human Brain Mapping. ISSN 1065-9471. doi: 10.1002/hbm.25206. Full text in Research Archive Show summary

  First‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

• Elvsåshagen, Torbjørn; Bahrami, Shahram; Meer, Dennis van der; Agartz, Ingrid; Alnæs, Dag & Barch, Deanna M. [Show all 76 contributors for this article] (2020). The genetic architecture of human brainstem structures and their involvement in common brain disorders. Nature Communications. 11. doi: 10.1038/s41467-020-17376-1. Full text in Research Archive Show summary

  Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

• Gurholt, Tiril Pedersen; Haukvik, Unn Kristin H.; Lonning, Vera; Jönsson, Erik Gunnar; Pasternak, Ofer & Agartz, Ingrid (2020). Microstructural white matter and links with subcortical structures in chronic schizophrenia: A free-water imaging approach. Frontiers in Psychiatry. 11. doi: 10.3389/fpsyt.2020.00056. Full text in Research Archive Show summary

  Schizophrenia is a severe mental disorder with often a chronic course. Neuroimaging studies report brain abnormalities in both white and gray matter structures. However, the relationship between microstructural white matter differences and volumetric subcortical structures is not known. We investigated 30 long-term treated patients with schizophrenia and schizoaffective disorder (mean age 51.1 ± 7.9 years, mean illness duration 27.6 ± 8.0 years) and 42 healthy controls (mean age 54.1 ± 9.1 years) using 3 T diffusion and structural magnetic resonance imaging. The free-water imaging method was used to model the diffusion signal, and subcortical volumes were obtained from FreeSurfer. We applied multiple linear regression to investigate associations between (i) patient status and regional white matter microstructure, (ii) medication dose or clinical symptoms on white matter microstructure in patients, and (iii) for interactions between subcortical volumes and diagnosis on microstructural white matter regions showing significant patient-control differences. The patients had significantly decreased free-water corrected fractional anisotropy (FAt), explained by decreased axial diffusivity and increased radial diffusivity (RDt) bilaterally in the anterior corona radiata (ACR) and the left anterior limb of the internal capsule (ALIC) compared to controls. In the fornix, the patients had significantly increased RDt. In patients, positive symptoms were associated with localized increased free-water and negative symptoms with localized decreased FAt and increased RDt. There were significant interactions between patient status and several subcortical structures on white matter microstructure and the free-water compartment for left ACR and fornix, and limited to the free-water compartment for right ACR and left ALIC. The Cohen's d effect sizes were medium to large (0.61 to 1.20, absolute values). The results suggest a specific pattern of frontal white matter axonal degeneration and demyelination and fornix demyelination that is attenuated in the presence of larger structures of the limbic system in patients with chronic schizophrenia and schizoaffective disorder. Findings warrant replication in larger samples.

• Andreou, Dimitrios; Saetre, Peter; Fors, Björn Milesson; Nilsson, Björn Mikael; Kullberg, Joel & Jönsson, Erik Gunnar [Show all 8 contributors for this article] (2020). Cardiac left ventricular ejection fraction in men and women with schizophrenia on long-term antipsychotic treatment. Schizophrenia Research. ISSN 0920-9964. p. 226–232. doi: 10.1016/j.schres.2019.12.042. Full text in Research Archive Show summary

  Patients with schizophrenia exhibit a higher cardiovascular mortality compared to the general population which has been attributed to life-style factors, genetic susceptibility and antipsychotic medication. Recent echocardiographic studies have pointed to an association between clozapine treatment and reduced left ventricular ejection fraction (LVEF), a measure that has been inversely associated with adverse outcomes including all-cause mortality. Cardiovascular magnetic resonance (CMR) is considered the reference method for LVEF measurement. The aim of the present study was to investigate the LVEF in patients with schizophrenia on long-term treatment with antipsychotics and healthy controls. Twenty-nine adult patients with schizophrenia on long-term medication with antipsychotics and 27 age-, sex- and body mass index-matched healthy controls (mean ages 44 and 45 years, respectively) were recruited from outpatient psychiatric clinics in Uppsala, Sweden. The participants were interviewed and underwent physical examination, biochemical analyses, electrocardiogram and CMR. Men with schizophrenia on long-term antipsychotic treatment showed significantly lower LVEF than controls (p = 0.0076), whereas no such difference was evident among women (p = 0.44). Specifically, clozapine-treated male patients had 10.6% lower LVEF than male controls (p = 0.0064), whereas the LVEF was 5.5% below that of controls among male patients treated with non-clozapine antipsychotics (p = 0.047). Among medicated men with schizophrenia, we found significantly lower LVEF compared to healthy individuals, suggesting the need of routine cardiac monitoring in this patient group. This is the first study showing a significant negative association between treatment with non-clozapine antipsychotics and LVEF.

• Benjamin, Silje Beatrice Rognås; Valstad, Mathias; Elvsåshagen, Torbjørn; Jönsson, Erik Gunnar; Moberget, Torgeir & Winterton, Adriano [Show all 14 contributors for this article] (2020). Heart rate variability is associated with disease severity in psychosis spectrum disorders. Progress in Neuro-psychopharmacology and Biological Psychiatry. ISSN 0278-5846. 00:110108, p. 1–8. doi: 10.1016/j.pnpbp.2020.110108. Full text in Research Archive Show summary

  While a growing literature links cardiac autonomic dysregulation to a variety of psychiatric disorders, the relationship between cardiac autonomic functioning and specific symptoms in schizophrenia (SZ) and bipolar disorder (BD) remains elusive. Thus, we investigated heart rate variability (HRV), a proxy for vagal activity, as a biological marker for symptom severity in patients with SZ and BD. HRV was calculated in 35 patients with SZ and 52 patients with BD, as well as in 149 healthy controls. In the patient groups, symptom severity and function were measured by the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale. Results showed that HRV was significantly lower in both clinical groups compared to the healthy controls, with no significant HRV differences between patient groups. PANSS general psychopathology scores, GAF symptom scores, and GAF function scores showed statistically significant associations with HRV across groups. These results suggest that disease severity is associated with autonomic dysfunction and that HRV may provide a potential biomarker of disease severity in SZ and BD.

• Hess, JL; Tylee, JS; Mattheisen, M; Agartz, Ingrid; Andreassen, Ole Andreas & Djurovic, Srdjan [Show all 11 contributors for this article] (2019). A polygenic resilience score moderates the genetic risk for schizophrenia. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-019-0463-8. Full text in Research Archive
• Vedal, Trude Seselie Jahr; Steen, Nils Eiel; Birkeland, Kåre I.; Dieset, Ingrid; Reponen, Elina Johanna & Anderssen, Jannicke Fjæra [Show all 11 contributors for this article] (2019). Adipokine levels are associated with insulin resistance in antipsychotics users independently of BMI. Psychoneuroendocrinology. ISSN 0306-4530. 103, p. 87–95. doi: 10.1016/j.psyneuen.2019.01.001. Full text in Research Archive Show summary

  Background The prevalence of obesity, metabolic syndrome and type 2 diabetes mellitus is increased among patients with severe mental disorders, and particularly use of second generation antipsychotic drugs is associated with metabolic side effects. Antipsychotics have been found to alter levels of adipokines which regulate insulin sensitivity, but their role in antipsychotic-associated insulin resistance is not established, and it is unclear whether adipokines affect insulin resistance independently of body mass index (BMI). Methods We included 1050 patients with severe mental disorders and 112 healthy controls aged 18–65 years from the Oslo area, Norway. Clinical variables, BMI and use of medication were assessed, fasting blood samples were obtained for calculation of the leptin/adiponectin ratio (L/A ratio) and estimate of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Case-control analyses were followed by mediation analyses to evaluate the possible direct effect of antipsychotics on HOMA-IR and indirect effect mediated via the L/A ratio. This was performed both with and without adjustment for BMI, in the total sample and in an antipsychotic monotherapy subsample (N = 387). Results BMI, L/A ratio and HOMA-IR were significantly higher in patients than controls (p < 0.001-p = 0.01). There was a significant direct effect from use of antipsychotics in general on HOMA-IR both without (b = 0.03, p = 0.007) and with adjustment for BMI (b = 0.03, p = 0.013), as well as a significant mediating effect via L/A ratio both without (b = 0.03, p < 0.001) and with adjustment for BMI (b = 0.01, p = 0.041). Use of olanzapine (b = 0.03, p < 0.001) or aripiprazole (b = 0.04, p < 0.001) in monotherapy showed significant effects on HOMA-IR mediated via L/A ratio. Conclusions The study suggests that use of antipsychotics may alter adipokine levels, and that increased L/A ratio may play a role in the development of insulin resistance associated with use of antipsychotics also independently of BMI.

• Richards, Alexander L.; Pardiñas, Antonio F.; Frizzati, Aura; Tansey, Katherine E.; Lynham, Amy J. & Holmans, Peter [Show all 48 contributors for this article] (2019). The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia. Schizophrenia Bulletin. ISSN 0586-7614. doi: 10.1093/schbul/sbz061. Full text in Research Archive Show summary

  BACKGROUND: Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. METHODS: We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. RESULTS: PRS for both population IQ (P = 4.39 x 10-28) and EA (P = 1.27 x 10-26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. CONCLUSIONS: Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

• Steen, Nils Eiel; Dieset, Ingrid; Hope, Sigrun; Vedal, Trude Seselie Jahr; Smeland, Olav Bjerkehagen & Matson, Wayne [Show all 13 contributors for this article] (2019). Metabolic dysfunctions in the kynurenine pathway, noradrenergic and purine metabolism in schizophrenia and bipolar disorders. Psychological Medicine. ISSN 0033-2917. 17(2). doi: 10.1017/S0033291719000400. Full text in Research Archive Show summary

  Background: We aimed at exploring potential pathophysiological processes across psychotic disorders, applying metabolomics in a large and well-characterized sample of patients and healthy controls. Methods: Patients with schizophrenia and bipolar disorders (N = 212) and healthy controls (N = 68) had blood sampling with subsequent metabolomics analyses using electrochemical coulometric array detection. Concentrations of 52 metabolites including tyrosine, tryptophan and purine pathways were compared between patients and controls while controlling for demographic and clinical characteristics. Significant findings were further tested in medication-free subsamples. Results: Significantly decreased plasma concentrations in patients compared to healthy controls were found for 3-hydroxykynurenine (3OHKY, p = 0.0008), xanthurenic acid (XANU, p = 1.5×10−5), vanillylmandelic acid (VMA, p = 4.5×10−5) and metanephrine (MN, p = 0.0001). Plasma concentration of xanthine (XAN) was increased in the patient group (p = 3.5×10−5). Differences of 3OHKY, XANU, VMA and XAN were replicated across schizophrenia spectrum disorders and bipolar disorders subsamples of medication-free individuals. Conclusions: Although prone to residual confounding, the present results suggest the kynurenine pathway of tryptophan metabolism, noradrenergic and purinergic system dysfunction as trait factors in schizophrenia spectrum and bipolar disorders. Of special interest is XANU, a metabolite previously not found to be associated with bipolar disorders.

• Zwarte, Sonja M.C. de; Brouwer, Rachel M.; Agartz, Ingrid; Alda, Martin; Aleman, André & Alpert, Kathryn I. [Show all 91 contributors for this article] (2019). The association between familial risk and brain abnormalities is disease specific: An ENIGMA-relatives study of schizophrenia and bipolar disorder. Biological Psychiatry. ISSN 0006-3223. 86(7), p. 545–556. doi: 10.1016/j.biopsych.2019.03.985. Full text in Research Archive Show summary

  Background Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. Methods We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. Results FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = −0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < −0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. Conclusions Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

• Alnæs, Dag; Kaufmann, Tobias; Meer, Dennis van der; Palomera, Aldo Còrdova; Rokicki, Jaroslav & Moberget, Torgeir [Show all 30 contributors for this article] (2019). Brain heterogeneity in schizophrenia and its association with polygenic risk. JAMA psychiatry. ISSN 2168-6238. 76(7), p. 739–748. doi: 10.1001/jamapsychiatry.2019.0257. Full text in Research Archive
• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 84 contributors for this article] (2019). Common brain disorders are associated with heritable patterns of apparent aging of the brain. Nature Neuroscience. ISSN 1097-6256. 22(10), p. 1617–1623. doi: 10.1038/s41593-019-0471-7. Full text in Research Archive Show summary

  Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

• Meer, Dennis van der; Sønderby, Ida Elken; Kaufmann, Tobias; Walters, G. Bragi; Abdellaoui, Abdel & Ames, David [Show all 132 contributors for this article] (2019). Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition. JAMA psychiatry. ISSN 2168-6238. doi: 10.1001/jamapsychiatry.2019.3779. Full text in Research Archive Show summary

  IMPORTANCE: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. OBJECTIVE: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. DESIGN, SETTING, AND PARTICIPANTS: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. MAIN OUTCOMES AND MEASURES: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2 , sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. RESULTS: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = −0.41; SE, 0.08; P = 4.9 × 10−8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10−7), and a smaller nucleus accumbens (Cohen d = −0.27; SE, 0.07; P = 7.3 × 10−5). There was also a significant negative dose response on cortical thickness (β = −0.24; SE, 0.05; P = 6.8 × 10−7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. CONCLUSIONS AND RELEVANCE: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders

• Satizabal, Claudia L.; Adams, Hieab H.H.; Hibar, Derrek; White, Charles C.; Knol, Maria J. & Stein, Jason L. [Show all 289 contributors for this article] (2019). Genetic architecture of subcortical brain structures in 38,851 individuals. Nature Genetics. ISSN 1061-4036. 51, p. 1624–1636. doi: 10.1038/s41588-019-0511-y. Full text in Research Archive Show summary

  Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

• Lee, Phil H.; Antilla, Verneri; Won, Hyejung; Feng, Yen-Chen A.; Rosenthal, Jacob & Zhu, Zhaozhong [Show all 66 contributors for this article] (2019). Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders. Cell. ISSN 0092-8674. 179(7), p. 1469–1482. doi: 10.1016/j.cell.2019.11.020. Full text in Research Archive Show summary

  Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.

• Jokinen, Jussi; Königsson, Johan; Moberg, Tomas; Jönsson, Erik Gunnar; Tiihonen, Jari & Nordström, Peter [Show all 8 contributors for this article] (2018). Platelet monoamine oxidase activity and interpersonal violence in male suicide attempters. Psychiatry Research. ISSN 0165-1781. 260, p. 173|–176. doi: 10.1016/j.psychres.2017.11.057. Full text in Research Archive Show summary

  Low platelet monoamine oxidase B (MAO-B) activity, proxy of low central serotonergic functions, has been shown to correlate with criminal behavior in adolescents that come from an unfavorable psychosocial environment but not in adolescents from good conditions, indicating a link between environment, MAO-B activity and aggressive behavior. The purpose of this study was to examine the association between MAO-B activity and lifetime interpersonal violence in suicide attempters. The study included a total of 28 suicide attempters (18 men and 10 women). Assessments of childhood exposure to and expressed interpersonal violence during childhood and as an adult were carried out with the Karolinska Interpersonal Violence Scale (KIVS). Platelet MAO-B activity was measured with 2-phenylethylamine (b-PEA) as substrate. Broken down by gender, the correlations between platelet MAO-B activity and both exposure scores to interpersonal violence as a child and expressed lifetime interpersonal violence were significant in male suicide attempters (r = -0.61, p = 0.035; r = -0.84, p = 0.0005), but not in women. Our finding of significant associations between interpersonal violence and low MAO-B activity need to be replicated in other cohorts of suicide attempters.

• Erp, Theo G.M. Van; Walton, Esther; Hibar, Derrek; Schmaal, Lianne; Jiang, Wenhao & Glahn, David C. [Show all 151 contributors for this article] (2018). Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) Consortium. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2018.04.023. Full text in Research Archive Show summary

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

• Kong, Xiang-Zhen; Mathias, Samuel R.; Guadalupe, Tulio; Agartz, Ingrid; Andreassen, Ole Andreas & Bøen, Erlend [Show all 33 contributors for this article] (2018). Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 115(22), p. E5154–E5163. doi: 10.1073/pnas.1718418115. Full text in Research Archive
• Clapham, Eric; Boden, Robert; Brandt, Lena; Jönsson, Erik Gunnar; Bahmanyar, Shahram & Ekbom, Anders [Show all 8 contributors for this article] (2018). Suicide Ideation and Behavior as Risk Factors for Subsequent Suicide in Schizophrenia: A Nested Case?Control Study. Suicide and Life-Threatening Behaviour. ISSN 0363-0234. doi: 10.1111/sltb.12499. Full text in Research Archive
• Ni, Guiyan; Gratten, Jacob; Wray, Naomi R.; Lee, Sang Hong; Agartz, Ingrid & Djurovic, Srdjan [Show all 11 contributors for this article] (2018). Age at first birth in women is genetically associated with increased risk of schizophrenia. Scientific Reports. 8. doi: 10.1038/s41598-018-28160-z. Full text in Research Archive Show summary

  Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is −0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.

• Vedal, Trude Seselie Jahr; Steen, Nils Eiel; Birkeland, Kåre I.; Dieset, Ingrid; Reponen, Elina Johanna & Anderssen, Jannicke Fjæra [Show all 11 contributors for this article] (2018). Free thyroxine and thyroid-stimulating hormone in severe mental disorders: A naturalistic study with focus on antipsychotic medication. Journal of Psychiatric Research. ISSN 0022-3956. 106, p. 74–81. doi: 10.1016/j.jpsychires.2018.09.014. Full text in Research Archive
• Kelly, S; Jahanshad, Neda; Zalesky, A; P, Kochunov; Agartz, Ingrid & Alloza, C [Show all 158 contributors for this article] (2018). Widespread white matter microstructural differences in schizophrenia across 4322 individuals: Results from the ENIGMA Schizophrenia DTI Working Group. Molecular Psychiatry. ISSN 1359-4184. 23, p. 1261–1269. doi: 10.1038/mp.2017.170. Full text in Research Archive Show summary

  The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

• Walton, E; Hibar, Derrek; Erp, Theo G M Van; Potkin, Steven G; Roiz-Santiañez, Roberto & Crespo-Facorro, B [Show all 58 contributors for this article] (2018). Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium. Psychological Medicine. ISSN 0033-2917. 48(1), p. 82–94. doi: 10.1017/S0033291717001283. Full text in Research Archive Show summary

  Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Previous research has shown that impairments in executive functioning, which have been associated with prefrontal brain areas (particularly in the medial orbitofrontal cortex (MOFC)), give rise to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. This study included 1 985 individuals with schizophrenia from seventeen research groups around the world contributing to the ENIGMA Schizophrenia Working Group. MOFC thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis was conducted over effect sizes from a model predicting mean left or right MOFC thickness by negative symptom score (harmonized SANS or PANSS scores). Secondary models were run to investigate the effects of antipsychotic medication, duration of illness, overall illness severity, and handedness. Meta-analytical results showed that left MOFC thickness was significantly associated with negative symptom severity (βstd=−0.075; p=0.019) after accounting for age, gender and site. This effect remained significant (p=0.036) in a model including overall illness severity. Covarying for duration of illness, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia. This article has been accepted and published by Cambridge University Press © 2018

• Iversen, Trude Seselie Jahr; Steen, Nils Eiel; Dieset, Ingrid; Hope, Sigrun; Mørch, Ragni Helene & Gardsjord, Erlend Strand [Show all 11 contributors for this article] (2018). Side effect burden of antipsychotic drugs in real life - Impact of gender and polypharmacy. Progress in Neuro-psychopharmacology and Biological Psychiatry. ISSN 0278-5846. 82, p. 263–271. doi: 10.1016/j.pnpbp.2017.11.004. Full text in Research Archive
• Meer, Dennis van der; Rokicki, Jaroslav; Kaufmann, Tobias; Palomera, Aldo Còrdova; Moberget, Torgeir & Alnæs, Dag [Show all 54 contributors for this article] (2018). Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes. Molecular Psychiatry. ISSN 1359-4184. p. 1–13. doi: 10.1038/s41380-018-0262-7. Full text in Research Archive Show summary

  The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

• Hjärpe, Josefin; Söderman, Erik; Andreou, Dimitrios; Sedvall, Göran C.; Agartz, Ingrid & Jönsson, Erik Gunnar (2018). No major influence of regular tobacco smoking on cerebrospinal fluid monoamine metabolite concentrations in patients with psychotic disorder and healthy individuals. Psychiatry Research. ISSN 0165-1781. 263, p. 30–34. doi: 10.1016/j.psychres.2018.02.036. Full text in Research Archive
• Zuber, Verena; Jönsson, Erik Gunnar; Frei, Oleksandr; Witoelar, Aree; Thompson, Wesley Kurt & Schork, Andrew J. [Show all 18 contributors for this article] (2018). Identification of shared genetic variants between schizophrenia and lung cancer. Scientific Reports. 674(8), p. 1–8. doi: 10.1038/s41598-017-16481-4. Full text in Research Archive Show summary

  Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.

• Fagerberg, Tomas; Söderman, Erik; Gustavsson, J. Petter; Agartz, Ingrid & Jönsson, Erik Gunnar (2018). Stability of personality traits over a five-year period in Swedish patients with schizophrenia spectrum disorder and non-psychotic individuals: a study using the Swedish universities Scales of Personality. BMC Psychiatry. 18(54). doi: 10.1186/s12888-018-1617-y. Full text in Research Archive Show summary

  Background Personality is considered as an important aspect in persons with psychotic disorders. Several studies have investigated personality in schizophrenia. However, no study has investigated stability of personality traits exceeding three years in patients with schizophrenia. This study aims to investigate the stability of personality traits over a five-year period among patients with schizophrenia and non-psychotic individuals and to evaluate case-control differences. Methods Patients with psychotic disorders (n = 36) and non-psychotic individuals (n = 76) completed Swedish universities Scales of Personality (SSP) at two occasions five years apart. SSP scores were analysed for effect of time and case-control differences by multiple analysis of covariance (MANCOVA) and within-subjects correlation. Results MANCOVA within-subjects analysis did not show any effect of time. Thus, SSP mean scale scores did not significantly vary during the five-year interval. Within subject correlations (Spearman) ranged 0.30–0.68 and 0.54–0.75 for the different SSP scales in patients and controls, respectively. Patients scored higher than controls in SSP scales Somatic Trait Anxiety, Psychic Trait Anxiety, Stress Susceptibility, Lack of Assertiveness, Detachment, Embitterment, and Mistrust. Conclusion The stability of the SSP personality trait was reasonably high among patients with psychotic disorder, although lower than among non-psychotic individuals, which is in accordance with previous research.

• Hibar, Derrek; Adams, Hieab H.H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L. & Hofer, Edith [Show all 332 contributors for this article] (2017). Novel genetic loci associated with hippocampal volume. Nature Communications. 8:13624, p. 1–12. doi: 10.1038/ncomms13624. Full text in Research Archive Show summary

  The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer’s disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

• Smeland, Olav Bjerkehagen; Frei, Oleksandr; Kauppi, Karolina; Hill, W. David; Li, Wen & Wang, Yunpeng [Show all 22 contributors for this article] (2017). Identification of genetic loci jointly influencing schizophrenia risk and the cognitive traits of verbal-numerical reasoning, reaction time, and general cognitive function. JAMA psychiatry. ISSN 2168-6238. 74(10), p. 1065–1075. doi: 10.1001/jamapsychiatry.2017.1986. Full text in Research Archive Show summary

  Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10−7), general cognitive function (z score, –4.43; P = 9.42 × 10−6), and verbal-numerical reasoning (z score, –5.43; P = 5.64 × 10−8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain. Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

• Nesvåg, Ragnar; Jönsson, Erik Gunnar; Bakken, Inger Johanne; Knudsen, Gun Peggy; Bjella, Thomas & Reichborn-Kjennerud, Ted [Show all 8 contributors for this article] (2017). The quality of severe mental disorder diagnoses in a national health registry as compared to research diagnoses based on structured interview. BMC Psychiatry. 17(1). doi: 10.1186/s12888-017-1256-8. Full text in Research Archive Show summary

  Background Utilization of diagnostic information from national patient registries rests on the quality of the registered diagnoses. We aimed to investigate the agreement and consistency of diagnoses of psychotic and bipolar disorders in the Norwegian Patient Registry (NPR) compared to structured interview-based diagnoses given as part of a clinical research project. Methods Diagnostic data from NPR were obtained for the period 01.01.2008–31.12.2013 for all patients who had been included in the Thematically Organized Psychosis (TOP) study between 18.10.2002 and 01.09.2014 with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of schizophrenia (n = 537), delusional disorder (n = 48), schizoaffective disorder (n = 118) or bipolar disorder (n = 408). Diagnostic agreement between the primary DSM-IV diagnosis in TOP and the International Classification of Diseases, 10th revision (ICD-10) diagnoses in NPR was evaluated using Cohen’s unweighted nominal kappa (κ). Diagnostic consistency was calculated as the proportion of all registered severe mental disorder diagnoses in NPR that were equivalent to the primary diagnosis given in the TOP study. Results The proportion of patients registered with the equivalent ICD-10 diagnosis as the primary DSM-IV diagnosis given in TOP was 84.2% for the schizophrenia group, 68.8% for the delusional disorder group, 76.3% for the schizoaffective disorder group, and 78.4% for the bipolar disorder group. Diagnostic agreement was good for schizophrenia (κ = 0.74) and bipolar disorder (κ = 0.72), fair for schizoaffective disorder (κ = 0.63), and poor for delusional disorder (κ = 0.39). Among patients with DSM-IV schizophrenia, 4.7% were diagnosed with ICD-10 bipolar disorder, and among patients with DSM-IV bipolar disorder, 2.5% were diagnosed with ICD-10 schizophrenia. Diagnostic consistency was 84.9% for schizophrenia, 59.1% for delusional disorder, 65.9% for schizoaffective disorder, and 91.0% for bipolar disorder. Conclusions When compared to research-based diagnoses, clinical diagnoses of schizophrenia and bipolar disorder in the NPR are accurate and consistent, with minimal diagnostic overlap between the two disorders.

• Walton, Esther Fintan; Hibar, Derrek; Erp, Theo G.M. Van; Potkin, Steven G.; Roiz-Santiáñez, Roberto & Crespo-Facorro, Benedicto [Show all 59 contributors for this article] (2017). Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 135(5), p. 439–447. doi: 10.1111/acps.12718. Full text in Research Archive
• Marshall, Christian R.; Howrigan, Daniel P.; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wu, Wenting & Greer, Douglas S. [Show all 263 contributors for this article] (2017). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics. ISSN 1061-4036. 49, p. 27–35. doi: 10.1038/ng.3725. Full text in Research Archive
• Comasco, Erika; Vumma, Ravi; Toffoletto, Simone; Johansson, Jessica; Flyckt, Lena & Lewander, Tommy [Show all 14 contributors for this article] (2017). Genetic and functional study of L -Type amino acid transporter 1 in schizophrenia. Neuropsychobiology. ISSN 0302-282X. 74(2), p. 96–103. doi: 10.1159/000455234. Full text in Research Archive
• Moberget, Torgeir; Doan, Nhat Trung; Alnæs, Dag; Kaufmann, Tobias; Palomera, Aldo Còrdova & Lagerberg, Trine Vik [Show all 22 contributors for this article] (2017). Cerebellar volume and cerebellocerebral structural covariance in schizophrenia: a multisite mega-analysis of 983 patients and 1349 healthy controls. Molecular Psychiatry. ISSN 1359-4184. 23(6), p. 1512–1520. doi: 10.1038/mp.2017.106. Full text in Research Archive
• Guadalupe, Tulio; Mathias, Samuel R.; VanErp, Theo G.M.; Whelan, Christopher D.; Zwiers, Marcel P. & Abe, Yoshinari [Show all 161 contributors for this article] (2016). Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging and Behavior. ISSN 1931-7557. Published ahead of print, p. 1–18. doi: 10.1007/s11682-016-9629-z. Full text in Research Archive
• Adams, Hieab H.H.; Hibar, Derrek; Chouraki, Vincent; Stein, Jason L.; Nyquist, Paul A. & Renteriá, Miguel E. [Show all 342 contributors for this article] (2016). Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nature Neuroscience. ISSN 1097-6256. 19(12), p. 1569–1582. doi: 10.1038/nn.4398. Full text in Research Archive
• Fagerberg, Tomas; Söderman, Erik; Gustavsson, Petter; Agartz, Ingrid & Jönsson, Erik Gunnar (2016). Personality traits in established schizophrenia: aspects of usability and differences between patients and controls using the Swedish universities Scales of Personality. Nordic Journal of Psychiatry. ISSN 0803-9488. 70(6), p. 462–469. doi: 10.3109/08039488.2016.1159331. Full text in Research Archive
• Skåtun, Kristina Cecilie; Kaufmann, Tobias; Doan, Nhat Trung; Alnæs, Dag; Palomera, Aldo Còrdova & Jönsson, Erik Gunnar [Show all 12 contributors for this article] (2016). Consistent functional connectivity alterations in schizophrenia spectrum disorder: a multisite study. Schizophrenia Bulletin. ISSN 0586-7614. 43(4), p. 914–924. doi: 10.1093/schbul/sbw145. Full text in Research Archive
• Reutfors, Johan; Clapham, Eric; Bahmanyar, Shahram; Brandt, Lena; Jönsson, Erik Gunnar & Ekbom, Anders [Show all 8 contributors for this article] (2016). Suicide risk and antipsychotic side effects in schizophrenia: nested case–control study. Human Psychopharmacology: Clinical and Experimental. ISSN 0885-6222. p. 341–345. doi: 10.1002/hup.2536. Full text in Research Archive
• Borg, Jacqueline; Cervenka, Simon; Kuja-Halkola, Ralf; Matheson, Granville; Jönsson, Erik Gunnar & Lichtenstein, Paul [Show all 12 contributors for this article] (2016). Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain. Molecular Psychiatry. ISSN 1359-4184. 21(8), p. 1077–1084. doi: 10.1038/mp.2015.147. Full text in Research Archive
• Ladenberger, Anna; Demetriades, Alecos; Reimann, Clemens; Birke, Manfred; Sadeghi, Martiya & Uhlbäck, Jo [Show all 84 contributors for this article] (2015). GEMAS: Indium in agricultural and grazing land soil of Europe - Its source and geochemical distribution patterns. Journal of Geochemical Exploration. ISSN 0375-6742. 154, p. 61–80. doi: 10.1016/j.gexplo.2014.11.020. Full text in Research Archive
• Fazio, Patrik; Svenningsson, Per; Forsberg, Anton; Jönsson, Erik Gunnar; Amini, Nahid & Nakao, Ryuji [Show all 10 contributors for this article] (2015). Quantitative analysis of &amp;lt;sup&amp;gt;18&amp;lt;/sup&amp;gt;F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4'-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson disease. Journal of Nuclear Medicine. ISSN 0161-5505. 56(5), p. 714–720. doi: 10.2967/jnumed.114.152421. Full text in Research Archive
• Erp, Theo GM van; Hibar, Derrek; Rasmussen, JM; Glahn, David C; Pearlson, Godfrey D & Andreassen, Ole Andreas [Show all 58 contributors for this article] (2015). Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Molecular Psychiatry. ISSN 1359-4184. 21(4), p. 547–553. doi: 10.1038/mp.2015.63. Full text in Research Archive Show summary

  The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d = − 0.46), amygdala (d = − 0.31), thalamus (d = − 0.31), accumbens (d = − 0.25) and intracranial volumes (d = − 0.12), as well as larger pallidum (d = 0.21) and lateral ventricle volumes (d = 0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

• Andreou, Dimitrios; Söderman, Erik; Axelsson, Tomas; Sedvall, Göran C.; Terenius, Lars & Agartz, Ingrid [Show all 7 contributors for this article] (2015). Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis. Psychiatry Research. ISSN 0165-1781. 229(1-2), p. 497–504. doi: 10.1016/j.psychres.2015.06.023. Full text in Research Archive
• Hibar, Derrek; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivieres, Sylvane & Jahanshad, Neda [Show all 287 contributors for this article] (2015). Common genetic variants influence human subcortical brain structures. Nature. ISSN 0028-0836. 520(7546), p. 224–229. doi: 10.1038/nature14101. Full text in Research Archive
• Jørgensen, Kjetil Nordbø; Nesvåg, Ragnar; Gunleiksrud, Sindre; Raballo, Andrea; Jönsson, Erik Gunnar & Agartz, Ingrid (2015). First- and second-generation antipsychotic drug treatment and subcortical brain morphology in schizophrenia. European Archives of Psychiatry and Clinical Neuroscience. ISSN 0940-1334. doi: 10.1007/s00406-015-0650-9. Full text in Research Archive
• Moberg, Tomas; Stenbacka, Marlene; Tengström, Anders; Jönsson, Erik Gunnar; Nordström, Peter & Jokinen, Jussi (2015). Psychiatric and neurological disorders in late adolescence and risk of convictions for violent crime in men. BMC Psychiatry. 15:299, p. 1–9. doi: 10.1186/s12888-015-0683-7. Full text in Research Archive

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• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Show all 97 contributors for this article] (2020). Publisher Correction: Common brain disorders are associated with heritable patterns of apparent aging of the brain (Nature Neuroscience, (2019), 22, 10, (1617-1623), 10.1038/s41593-019-0471-7). Nature Neuroscience. ISSN 1097-6256. 23(2), p. 295–295. doi: 10.1038/s41593-019-0553-6. Full text in Research Archive
• Fagerberg, Tomas; Söderman, Erik; Gustavsson, J. Petter; Agartz, Ingrid & Jönsson, Erik Gunnar (2019). Correction to: Stability of personality traits over a five-year period in Swedish patients with schizophrenia spectrum disorder and nonpsychotic individuals: A study using the Swedish universities scales of personality. BMC Psychiatry. 19(109). doi: 10.1186/s12888-019-2086-7. Full text in Research Archive
• Santillo, Alexander F; Lundgren, Sofia; Xu, C; Orhan, Funda; Fatouros-Bergman, Helena & Blennow, Kaj [Show all 12 contributors for this article] (2019). Neurogranin as a potential synaptic marker in the cerebrospinal fluid of patients with a first episode psychosis. Schizophrenia Research. ISSN 0920-9964. 208, p. 490–492. doi: 10.1016/j.schres.2019.01.010. Full text in Research Archive
• Jørgensen, Kjetil Nordbø; Nerland, Stener; Moberget, Torgeir; Elvsåshagen, Torbjørn; Jönsson, Erik Gunnar & Andreassen, Ole Andreas [Show all 7 contributors for this article] (2019). Optimizing the T1/T2 ratio for analysis within and between subjects. Full text in Research Archive
• Vedal, Trude Seselie Jahr; Steen, Nils Eiel; Birkeland, Kåre I.; Dieset, Ingrid; Reponen, Elina Johanna & Laskemoen, Jannicke F. [Show all 11 contributors for this article] (2018). Response: Are thyroid abnormalities only related to antipsychotic treatment in patients with severe mental disorders? Journal of Psychiatric Research. ISSN 0022-3956. doi: 10.1016/j.jpsychires.2018.11.012. Full text in Research Archive
• Slapø, Nora Berz; Jørgensen, Kjetil Nordbø; Jönsson, Erik Gunnar; Moberget, Torgeir & Elvsåshagen, Torbjørn (2026). Relationship Between Function and Structure in the Visual and Auditory Cortices in Psychotic Disorders. Universitetet i Oslo. ISSN 9788234807848. Full text in Research Archive Show summary

  Psychotic disorders are severe conditions that often involve changes in perception, such as visual and auditory hallucinations. Previous research has suggested that the brain regions responsible for processing visual and auditory information may function differently in these disorders. However, it is unclear why these functional changes occur. The main aim of this thesis was to investigate how brain function and brain structure are related in the visual and the auditory cortices, both in healthy individuals and in people with psychotic disorders. Brain function was measured using electroencephalography (EEG), specifically event related potentials (ERPs), which capture the brain’s electrical responses to external sensory stimuli. Brain structure was assessed using magnetic resonance imaging (MRI) to provide information about cortical surface area, thickness, and myelination. In this thesis, I focused specifically on examining both the function and the structural characteristics of the visual and auditory cortices, in order to better understand how alterations in these regions may be linked to psychotic disorders. The study included healthy control participants as well as individuals diagnosed with schizophrenia spectrum disorders or bipolar disorder. In healthy individuals, the results showed a positive relationship between the strength (amplitude) of the P100 component of the visual evoked potential (VEP) - an EEG measure reflecting function in the visual cortex - and the surface area of the visual cortex. In other words, a larger visual cortical surface area was associated with a stronger neural response to visual stimuli. Among individuals with schizophrenia spectrum disorders, a lower amplitude of the N100 component of the auditory evoked potential (AEP) - an EEG measure reflecting activity in the auditory cortex - was associated with a thinner auditory cortex. This association was particularly evident in individuals who had experienced auditory hallucinations. These findings suggest that structural and functional changes in the auditory cortex may be linked and could reflect a shared neural mechanism related to auditory hallucinations. The results also indicated that biological sex may play a role in how psychotic disorders affect brain function. Males with schizophrenia spectrum disorders showed lower N100 amplitudes compared to healthy males, whereas no comparable differences were observed among women. This highlights the importance of considering biological sex in neurobiological research and may help why illness trajectory and treatment response often differ between men and women. Measures of myelin in the auditory cortex did not explain the observed correlations between reduced auditory function (lower N100 amplitude) and thinner auditory cortex in individuals with schizophrenia spectrum disorders. The findings show a clear link between brain structure and function in the visual cortex of healthy individuals and in the auditory cortex of individuals with schizophrenia spectrum disorders. They highlight the importance of studying basic sensory processes to better understand psychotic symptoms, as early sensory alterations may form part of the neurobiological basis of these disorders. The results also emphasize the need to consider biological sex in future research. Greater insight into these mechanisms may ultimately contribute to improved diagnostics and more targeted, effective treatments for psychotic disorders.

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