Torbjørn Elvsåshagen

• 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
• Mäki-Marttunen, Verónica; Sailer, Uta; Kopal, Jakub; Hagen, Espen; Shadrin, Alexey & Andreassen, Ole [Show all 8 contributors for this article] (2026). Large-Scale Neuroimaging and Genetic Analyses of the Human Thalamus in Loneliness. Biological Psychiatry: Global Open Science. 6(6), p. 100798–100798. doi: 10.1016/j.bpsgos.2026.100798. Full text in Research Archive
• Ng, Hui Xin; Abé, Christoph; Alda, Martin; Alonso-Lana, Silvia; Anmella, Gerard & Bauer, Jochen [Show all 97 contributors for this article] (2026). Brain aging in bipolar disorder using a neuroimaging and machine learning-derived metric: Findings from the ENIGMA BD Working Group. Journal of Affective Disorders. ISSN 0165-0327. 403. doi: 10.1016/j.jad.2026.121234. 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.

• McWilliams, Esther C.; Milanovic, Snezana M.; Elvsåshagen, Torbjørn; Lew, Robert; Hopkins, Seth C. & Andrews, Cynthia [Show all 11 contributors for this article] (2026). A brief visual evoked potential (VEP) modulation assessment of experience-dependent plasticity recorded via wireless dry-EEG headset in Phase 1 clinical units. Scientific Reports. 16. doi: 10.1038/s41598-025-29950-y. Full text in Research Archive Show summary

  Experience-dependent modulation of the visual evoked potential (VEP) can be used as a non-invasive human correlate of invasive measurements of long-term potentiation (LTP)-type neuroplasticity in animal research. However, conventional electroencephalogram (EEG) recording is high burden and time consuming, hindering adoption. Further, reliability of participant-level VEP modulation measures, even in highly controlled conditions, has been disappointing. To increase the practicality and utility of the assessment we trialled a short (11-min) paradigm with wireless dry-EEG headset and applied multiscale frequency-domain analyses to extract more precise measures of neuroplasticity. This approach was tested in healthy participants in laboratory (n = 17) and Phase 1 clinical studies (n = 33). Typical session duration was < 30 min. Test–retest reliability of VEP waveforms were compared to literature on full-length paradigms with wet-EEG hardware. Group-level time-domain event-related potential (ERP) analyses showed post-modulation P1 amplitude increase in both groups (Cohen’s d = 0.77, 0.78, respectively) and N1b amplitude decrease in clinical study group (Cohen’s d = − 0.52). Timeseries-based test–retest reliability of the VEP modulation effect was low but was substantially improved to moderate levels (some intraclass correlation ≥ 0.5) with a wavelet-based analysis. This suggests that VEP modulation assessments could be employed across multiple sites to objectively measure experience-dependent plasticity in real-world clinical trials of central nervous system therapies.

• Eissa, Ahmed; Fredrik Kismul, Jan; Pentz, Atle Bråthen; Elvsåshagen, Torbjørn; Metzner, Christoph & Akkouh, Ibrahim Ahmed [Show all 12 contributors for this article] (2026). Computational Modelling of Novelty Detection in the Mismatch Negativity Protocols and Its Impairments in Schizophrenia. European Journal of Neuroscience. ISSN 0953-816X. 63(6). doi: 10.1111/ejn.70453. Full text in Research Archive
• 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.

• Myren, Sverre; Jungilligens, Johannes; Diez, Ibai; Bøen, Erlend; Elvsåshagen, Torbjørn & Forstmann, Birte [Show all 8 contributors for this article] (2026). Ultra-high field brain MRI for functional neurological disorder: opportunities and challenges. NeuroImage: Clinical. 50. doi: 10.1016/j.nicl.2026.103972. Full text in Research Archive Show summary

  Functional neurological disorder (FND) is a common condition with debilitating neurological symptoms emerging from brain network alterations; yet, neuroimaging findings are often of unclear neurobiological significance. Contemporary mechanistic accounts indicate disturbances in hierarchical brain processing involving arousal, interoception, salience attribution, affective-motor integration, and self-agency. The findings of abnormal brain function with only partially consistent neuroimaging abnormalities imply that relevant pathology may occur below the resolution or contrast capabilities of conventional clinical MRI. Ultra-high field MRI (UHF, 7T and above) provides substantially improved spatial resolution, contrast sensitivity, and physiological specificity needed to interrogate microcircuit-, mesoscale-, and neurochemical-level mechanisms. We review how UHF-enhanced structural, diffusion, functional, and spectroscopic techniques can address long-standing mechanistic questions in FND. Selected targets that operate at different spatial scales are used to illustrate how UHF MRI can resolve features that are either inaccessible or not fully reliable at standard magnetic field strengths (1.5–3T). To synthesize these advances, we propose a biophysical multimodal MRI framework that integrates quantitative MRI, diffusion MRI, functional MRI, and MR spectroscopy to derive biologically interpretable markers spanning microstructure, white matter architecture, circuit dynamics, and neurometabolic domains. This approach aligns with contemporary computational and neurobiological models of FND and offers a scalable roadmap for future research. Together, UHF MRI and biophysically grounded multimodal imaging can enable a new generation of mechanistic studies in FND, with potential implications for diagnosis, subtype stratification, and biomarker development.

• 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.

• Smeland, Olav B.; Kutrolli, Gleda; Bahrami, Shahram; Fominykh, Vera; Parker, Nadine & Fuhrer, Julian [Show all 21 contributors for this article] (2025). A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders. Nature Neuroscience. ISSN 1097-6256. 28(12), p. 2439–2450. doi: 10.1038/s41593-025-02090-2. Full text in Research Archive Show summary

  Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

• Bøen, Erlend; Myren, Sverre; Wendel-Haga, Marte; Koht, Jeanette; Svalheim, Sigrid & Sveberg, Line [Show all 10 contributors for this article] (2025). Funksjonell nevrologisk lidelse. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145. doi: 10.4045/tidsskr.24.0574. Full text in Research Archive
• 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.

• 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.

• Bahrami, Shahram; Nordengen, Kaja; Rokicki, Jaroslav; Shadrin, Alexey; Rahman, Mohammad Zillur & Smeland, Olav Bjerkehagen [Show all 17 contributors for this article] (2024). The genetic landscape of basal ganglia and implications for common brain disorders. Nature Communications. 15(1). doi: 10.1038/s41467-024-52583-0. Full text in Research Archive Show summary

  The basal ganglia are subcortical brain structures involved in motor control, cognition, and emotion regulation. We conducted univariate and multivariate genome-wide association analyses (GWAS) to explore the genetic architecture of basal ganglia volumes using brain scans obtained from 34,794 Europeans with replication in 4,808 white and generalization in 5,220 non-white Europeans. Our multivariate GWAS identified 72 genetic loci associated with basal ganglia volumes with a replication rate of 55.6% at P < 0.05 and 87.5% showed the same direction, revealing a distributed genetic architecture across basal ganglia structures. Of these, 50 loci were novel, including exonic regions of APOE, NBR1 and HLAA. We examined the genetic overlap between basal ganglia volumes and several neurological and psychiatric disorders. The strongest genetic overlap was between basal ganglia and Parkinson’s disease, as supported by robust LD-score regression-based genetic correlations. Mendelian randomization indicated genetic liability to larger striatal volume as potentially causal for Parkinson’s disease, in addition to a suggestive causal effect of greater genetic liability to Alzheimer’s disease on smaller accumbens. Functional analyses implicated neurogenesis, neuron differentiation and development in basal ganglia volumes. These results enhance our understanding of the genetic architecture and molecular associations of basal ganglia structure and their role in brain disorders.

• 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.

• Dietze, Lorielle M. F.; McWhinney, Sean R.; Favre, Pauline; Abé, Christoph; Alexander, Nina & Barkhau, Carlotta [Show all 81 contributors for this article] (2024). White matter microstructure in obesity and bipolar disorders: an ENIGMA bipolar disorder working group study in 2186 individuals. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-024-02784-2. Full text in Research Archive
• Gurholt, Tiril Pedersen; Elvsåshagen, Torbjørn; Bahrami, Shahram; Rahman, Mohammad Zillur; Shadrin, Alexey & Askeland-Gjerde, Daniel E. [Show all 13 contributors for this article] (2024). Large-scale brainstem neuroimaging and genetic analyses provide new insights into the neuronal mechanisms of hypertension. Human Genetics and Genomics Advances (HGG Advances). 6(1). doi: 10.1016/j.xhgg.2024.100392. Full text in Research Archive Show summary

  While brainstem regions are central regulators of blood pressure, the neuronal mechanisms underlying their role in hypertension remain poorly understood. Here, we investigated the structural and genetic relationships between global and regional brainstem volumes and blood pressure. We used magnetic resonance imaging data from n = 32,666 UK Biobank participants, and assessed the association of volumes of the whole brainstem and its main regions with blood pressure. We applied powerful statistical genetic tools, including bivariate causal mixture modeling (MiXeR) and conjunctional false discovery rate (conjFDR), to non-overlapping genome-wide association studies of brainstem volumes (n = 27,034) and blood pressure (n = 321,843) in the UK Biobank cohort. We observed negative associations between the whole brainstem and medulla oblongata volumes and systolic blood and pulse pressure, and positive relationships between midbrain and pons volumes and blood pressure traits when adjusting for the whole brainstem volume (all partial correlation coefficients ∣r∣ effects between 0.03 and 0.05, p ≤ 0.0042). We observed the largest genetic overlap for the whole brainstem, sharing 77% of its trait-influencing variants with blood pressure. We identified 65 shared loci between brainstem volumes and blood pressure traits and mapped these to 71 genes, implicating molecular pathways linked to sympathetic nervous system development, metal ion transport, and vascular homeostasis. The present findings support a link between brainstem structures and blood pressure and provide insights into their shared genetic underpinnings. The overlapping genetic architectures and mapped genes offer mechanistic information about the roles of brainstem regions in hypertension.

• Mäki-Marttunen, Tuomo; Blackwell, Kim T.; Akkouh, Ibrahim Ahmed; Shadrin, Alexey; Valstad, Mathias & Elvsåshagen, Torbjørn [Show all 10 contributors for this article] (2024). Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 121(34). doi: 10.1073/pnas.2312511121. Full text in Research Archive Show summary

  Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem, especially those in the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.

• McWhinney, Sean R.; Hlinka, Jaroslav; Bakstein, Eduard; Dietze, Lorielle M. F.; Corkum, Emily L. V. & Abé, Christoph [Show all 91 contributors for this article] (2024). Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders—ENIGMA study in people with bipolar disorders and obesity. Human Brain Mapping. ISSN 1065-9471. 45(8). doi: 10.1002/hbm.26682. Full text in Research Archive Show summary

  Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables.

• Zak, Nathalia; Moberget, Torgeir; Bøen, Erlend; Boye, Birgitte; Rygvold, Trine Waage & Malt, Ulrik Fredrik [Show all 10 contributors for this article] (2023). Baseline long-term potentiation-like cortical plasticity is associated with longitudinal cortical thinning in healthy adults and in adults with bipolar disorder type II. European Journal of Neuroscience. ISSN 0953-816X. 58(3), p. 2824–2837. doi: 10.1111/ejn.16038. Full text in Research Archive Show summary

  Abstract The precise neurobiological processes underlying cerebral cortical thinning in aging and psychiatric illnesses remain undetermined, yet aging‐ and synaptic dysfunction‐related loss of synapses are potentially important mechanisms. We used long‐term potentiation‐like plasticity of the visual evoked potential as an index of synaptic function in the cortex and hypothesized that plasticity at baseline would be negatively associated with future cortical thinning in healthy adults and in adults with bipolar disorder type II. Thirty‐two healthy adults and 15 adults with bipolar disorder type II underwent electroencephalography‐based measurement of visual evoked potential plasticity and 3T magnetic resonance imaging of the brain at baseline and a follow‐up brain scan on average 2.3 years later. The relationships between visual evoked potential plasticity at baseline and longitudinal cortical thickness changes were examined using Freesurfer and the Permutation Analysis of Linear Models tool. The analyses showed a negative association between the plasticity of the N1 visual evoked potential amplitude at baseline and thinning rate in the medial and lateral parietal and medial occipital cortices in healthy adults and in the right medial occipital cortex in the total sample of healthy adults and adults with bipolar disorder type II, indicating greater thinning over time in subjects with less N1 plasticity ( p FWER  &lt; .05). Although preliminary, the results indicate an association between visual evoked potential plasticity and the future rate of cortical thinning in healthy adults and in bipolar disorder type II, supporting the hypothesis that cortical thinning might be related to synaptic dysfunction.

• Mcwhinney, Sean R.; Abé, Christoph; Alda, Martin; Benedetti, Francesco; Bøen, Erlend & Bonnin, Caterina Del Mar [Show all 75 contributors for this article] (2023). Mega-analysis of association between obesity and cortical morphology in bipolar disorders: ENIGMA study in 2832 participants. Psychological Medicine. ISSN 0033-2917. 53(14), p. 6743–6753. doi: 10.1017/S0033291723000223. Full text in Research Archive Show summary

  Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact. Methods: We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 1231 BD and 1601 control individuals from 13 countries within the ENIGMA-BD Working Group. We jointly modeled the statistical effects of BD and BMI on brain structure using mixed effects and tested for interaction and mediation. We also investigated the impact of medications on the BMI-related associations. Results: BMI and BD additively impacted the structure of many of the same brain regions. Both BMI and BD were negatively associated with cortical thickness, but not surface area. In most regions the number of jointly used psychiatric medication classes remained associated with lower cortical thickness when controlling for BMI. In a single region, fusiform gyrus, about a third of the negative association between number of jointly used psychiatric medications and cortical thickness was mediated by association between the number of medications and higher BMI. Conclusions: We confirmed consistent associations between higher BMI and lower cortical thickness, but not surface area, across the cerebral mantle, in regions which were also associated with BD. Higher BMI in people with BD indicated more pronounced brain alterations. BMI is important for understanding the neuroanatomical changes in BD and the effects of psychiatric medications on the brain.

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

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

• 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.

• 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.

• Mlakar, Vid; Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Ormerod, Monica Bettina E. Greenwood; Quintana, Daniel & Ueland, Torill [Show all 13 contributors for this article] (2023). Telomere length and verbal learning in bipolar disorders. Journal of Affective Disorders. ISSN 0165-0327. 339, p. 555–560. doi: 10.1016/j.jad.2023.07.087. Full text in Research Archive Show summary

  Introduction: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning. Methods: The study consisted of 647 participants (bipolar disorder [n =246] and healthy controls [n =401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity. Results: Patients had shorter telomere lengths than healthy controls (Cohen’s d =0.11, p =0.01). Within patients’ , a positive association was observed for verbal learning and telomere length (β =0.14, p =0.025), along with a trend for verbal memory and telomere length (β =0.11, p =0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1). Conclusion: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.

• Granerud, Guro; Elvsåshagen, Torbjørn; Arntzen, Erik; Juhasz, Katalin; Emilsen, Nina Merete & Sønderby, Ida Elken [Show all 8 contributors for this article] (2022). A family study of symbolic learning and synaptic plasticity in autism spectrum disorder. Frontiers in Human Neuroscience. 16. doi: 10.3389/fnhum.2022.950922. Full text in Research Archive Show summary

  The current study presents a male with autism spectrum disorder (ASD) and a 3q29 deletion, and three healthy first-degree relatives. Our magnetic resonance imaging (MRI) dataset included a healthy control subset. We describe a comprehensive multimodal approach, including equivalence class formation, neurocognitive testing, MRI, and electroencephalography (EEG)-based cortical plasticity, which can provide new insights into sociocommunicative and learning impairments and neural underpinnings in ASD. On neurocognitive testing, the proband showed reduced processing speed, attending behavior, and executive function. He required more training trials in equivalence class training compared with family members and exhibited impaired priming of words compared with priming with images. The proband had smaller intracranial volume and surface area and a larger visual evoked potential (VEP) C1 amplitude than family members and intact long-term potentiation (LTP)-like visual cortex plasticity. Together, these results suggest that 3q29 deletion-related ASD is associated with impaired problem-solving strategies in complex socio-communicative and learning tasks, smaller intracranial and surface area, altered VEP amplitude, and normal LTP-like visual cortex plasticity. Further studies are needed to clarify whether this multimodal approach can be used to identify ASD subgroups with distinct neurobiological alterations and to uncover mechanisms underlying sociocommunicative and learning impairments. Lay Summary: We studied learning, brain activity, and brain structure in a person with autism and a genetic aberration, and his close relatives. Compared with relatives, the person with autism required more training for learning, and visual learning was better than verbal learning. This person had some changes in the activity of the visual cortex, and the size and the surface area of the brain were reduced. Knowledge about learning and brain mechanisms is valuable for the development of training programs for individuals with autism.

• Rygvold, Trine Waage; Hatlestad-Hall, Christoffer; Elvsåshagen, Torbjørn; Moberget, Torgeir & Andersson, Stein (2022). Long term potentiation-like neural plasticity and performance-based memory function. Neurobiology of Learning and Memory. ISSN 1074-7427. 196. doi: 10.1016/j.nlm.2022.107696. Full text in Research Archive
• Jensen, Søren Beck; Sheikh, Mashhood Ahmed; Akkouh, Ibrahim Ahmed; Szabo, Attila; O'Connell, Kevin Sean & Lekva, Tove [Show all 23 contributors for this article] (2022). Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness. Schizophrenia Bulletin. ISSN 0586-7614. 49(3), p. 635–645. doi: 10.1093/schbul/sbac191. Full text in Research Archive Show summary

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

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

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

• Voldsbekk, Irene; Bjørnerud, Atle; Groote, Inge Rasmus; Zak, Nathalia; Roelfs, Daniël & Maximov, Ivan [Show all 18 contributors for this article] (2022). Evidence for widespread alterations in cortical microstructure after 32 h of sleep deprivation. Translational Psychiatry. 12(161). doi: 10.1038/s41398-022-01909-x. Full text in Research Archive Show summary

  Cortical microstructure is influenced by circadian rhythm and sleep deprivation, yet the precise underpinnings of these effects remain unclear. The ratio between T1-weighted and T2-weighted magnetic resonance images (T1w/T2w ratio) has been linked to myelin levels and dendrite density and may offer novel insight into the intracortical microstructure of the sleep deprived brain. Here, we examined intracortical T1w/T2w ratio in 41 healthy young adults (26 women) before and after 32 h of either sleep deprivation (n = 18) or a normal sleep-wake cycle (n = 23). Linear models revealed significant group differences in T1w/T2w ratio change after 32 h in four clusters, including bilateral effects in the insular, cingulate, and superior temporal cortices, comprising regions involved in attentional, auditory and pain processing. Across clusters, the sleep deprived group showed an increased T1w/T2w ratio, while the normal sleep-wake group exhibited a reduced ratio. These changes were not explained by in-scanner head movement, and 95% of the effects across clusters remained significant after adjusting for cortical thickness and hydration. Compared with a normal sleep-wake cycle, 32 h of sleep deprivation yields intracortical T1w/T2w ratio increases. While the intracortical changes detected by this study could reflect alterations in myelin or dendritic density, or both, histological analyses are needed to clarify the precise underlying cortical processes.

• Rygvold, Trine Waage; Hatlestad-Hall, Christoffer; Elvsåshagen, Torbjørn; Moberget, Torgeir & Andersson, Stein (2022). Long-Term Potentiation-Like Visual Synaptic Plasticity Is Negatively Associated With Self-Reported Symptoms of Depression and Stress in Healthy Adults. Frontiers in Human Neuroscience. 16. doi: 10.3389/fnhum.2022.867675. Full text in Research Archive
• Brouwer, Rachel M.; Klein, Marieke; Grasby, Katrina L.; Schnack, Hugo G.; Jahanshad, Neda & Teeuw, Jalmar [Show all 200 contributors for this article] (2022). Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nature Neuroscience. ISSN 1097-6256. 25(4), p. 421–432. doi: 10.1038/s41593-022-01042-4. Full text in Research Archive
• McWhinney, Sean R.; Abé, Christoph; Alda, Martin; Benedetti, Francesco; Bøen, Erlend & Bonnin, Caterina del Mar [Show all 75 contributors for this article] (2021). Diagnosis of bipolar disorders and body mass index predict clustering based on similarities in cortical thickness—ENIGMA study in 2436 individuals. Bipolar Disorders. ISSN 1398-5647. p. 1–12. doi: 10.1111/bdi.13172. Full text in Research Archive
• Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Westlye, Lars Tjelta; Høegh, Margrethe Collier; Haram, Marit & Werner, Maren Caroline Frogner [Show all 14 contributors for this article] (2021). Telomeres are shorter and associated with number of suicide attempts in affective disorders. Journal of Affective Disorders. ISSN 0165-0327. 295, p. 1032–1039. doi: 10.1016/j.jad.2021.08.135. Full text in Research Archive
• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Chu, Yunhan; Shadrin, Alexey A. & O'Connell, Kevin Sean [Show all 14 contributors for this article] (2021). Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01527-z. Full text in Research Archive Show summary

  Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.

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

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

• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Lin, Aihua; Gani, Osman & Shadrin, Alexey A. [Show all 18 contributors for this article] (2021). Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms. Translational Psychiatry. 11(1). doi: 10.1038/s41398-020-01142-4. Full text in Research Archive Show summary

  Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

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

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

• 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.

• Engh, John; Ueland, Thor; Agartz, Ingrid; Andreou, Dimitrios; Aukrust, Pål & Boye, Birgitte [Show all 27 contributors for this article] (2021). Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study. Schizophrenia Bulletin. ISSN 0586-7614. 48(1), p. 37–46. doi: 10.1093/schbul/sbab106. Full text in Research Archive Show summary

  Background Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. Methods We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. Results Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen’s d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). Conclusions These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

• Tahmasian, Masoud; Aleman, André; Andreassen, Ole; Arab, Zahra; Baillet, Marion & Benedetti, Francesco [Show all 77 contributors for this article] (2021). ENIGMA-Sleep: Challenges, opportunities, and the road map. Journal of Sleep Research. ISSN 0962-1105. 30(6), p. 1–20. doi: 10.1111/jsr.13347. Full text in Research Archive Show summary

  Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

• McWhinney, Sean R.; Abé, Christoph; Alda, Martin; Benedetti, Francesco; Bøen, Erlend & Bonnin, Caterina del Mar [Show all 51 contributors for this article] (2021). Association between body mass index and subcortical brain volumes in bipolar disorders–ENIGMA study in 2735 individuals. Molecular Psychiatry. ISSN 1359-4184. 26(11), p. 6806–6819. doi: 10.1038/s41380-021-01098-x. Full text in Research Archive Show summary

  Abstract Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles  and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI ( Z  = 2.73, p  = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Smelror, Runar; Wedervang-Resell, Kirsten & Nerland, Stener [Show all 25 contributors for this article] (2021). Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness. Psychological Medicine. ISSN 0033-2917. p. 1–10. doi: 10.1017/S0033291721003056. Full text in Research Archive Show summary

  Background Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. Methods We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. Results We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. Conclusion We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.

• 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.

• Mullins, Niamh; Forstner, Andreas J.; O'Connell, Kevin Sean; Coombes, Brandon; Coleman, Jonathan R. I. & Qiao, Zhen [Show all 59 contributors for this article] (2021). Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genetics. ISSN 1061-4036. 53, p. 817–829. doi: 10.1038/s41588-021-00857-4. Full text in Research Archive
• Voldsbekk, Irene; Groote, Inge Rasmus; Zak, Nathalia; Roelfs, Daniël Thomas Heimen; Geier, Oliver & Due-Tønnessen, Paulina [Show all 14 contributors for this article] (2021). Sleep and sleep deprivation differentially alter white matter microstructure: A mixed model design utilising advanced diffusion modelling. NeuroImage. ISSN 1053-8119. 226. doi: 10.1016/j.neuroimage.2020.117540. Full text in Research Archive Show summary

  Sleep deprivation influences several critical functions, yet how it affects human brain white matter (WM) is not well understood. The aim of the present work was to investigate the effect of 32 hours of sleep deprivation on WM microstructure compared to changes observed in a normal sleep-wake cycle (SWC). To this end, we utilised diffusion weighted imaging (DWI) including the diffusion tensor model, diffusion kurtosis imaging and the spherical mean technique, a novel biophysical diffusion model. 46 healthy adults (23 sleep deprived vs 23 with normal SWC) underwent DWI across four time points (morning, evening, next day morning and next day afternoon, after a total of 32 hours). Linear mixed models revealed significant group × time interaction effects, indicating that sleep deprivation and normal SWC differentially affect WM microstructure. Voxel-wise comparisons showed that these effects spanned large, bilateral WM regions. These findings provide important insight into how sleep deprivation affects the human brain

• Kalman, Janos L.; Loohuis, Loes M. Olde; Vreeker, Annabel; McQuillin, Andrew; Stahl, Eli A. & Ruderfer, Douglas [Show all 50 contributors for this article] (2021). Characterisation of age and polarity at onset in bipolar disorder. British Journal of Psychiatry. ISSN 0007-1250. 219(6), p. 659–669. doi: 10.1192/bjp.2021.102. Full text in Research Archive Show summary

  Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

• Andlauer, Till F.M.; Guzman-Parra, José; Streit, Fabian; Strohmaier, Jana; González, Maria José & Flores, Susana Gil [Show all 50 contributors for this article] (2021). Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders. Molecular Psychiatry. ISSN 1359-4184. 26, p. 1286–1298. doi: 10.1038/s41380-019-0558-2. Full text in Research Archive Show summary

  Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

• Elvsåshagen, Torbjørn; Shadrin, Alexey; Frei, Oleksandr; Meer, Dennis van der; Bahrami, Shahram & Kumar, Vinod J. [Show all 10 contributors for this article] (2021). The genetic architecture of the human thalamus and its overlap with ten common brain disorders. Nature Communications. 12(1). doi: 10.1038/s41467-021-23175-z. Full text in Research Archive Show summary

  Abstract The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample ( n  = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P  = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.

• Han, Laura KM; Dinga, Richard; Hahn, Tim; Ching, Christopher R. K.; Eyler, Lisa T. & Aftanas, Lyubomir [Show all 50 contributors for this article] (2020). Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-020-0754-0. Full text in Research Archive Show summary

  Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18–75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI: 0.08–0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

• 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.

• Rygvold, Trine Waage; Hatlestad-Hall, Christoffer; Elvsåshagen, Torbjørn; Moberget, Torgeir & Andersson, Stein (2020). Do visual and auditory stimulus-specific response modulation reflect different mechanisms of neocortical plasticity? European Journal of Neuroscience. ISSN 0953-816X. p. 1–14. doi: 10.1111/ejn.14964. Full text in Research Archive Show summary

  Stimulus response modulation (SRM) of sensory evoked potentials represents a promising method as a non‐invasive index of long‐term potentiation (LTP)‐like synaptic plasticity in the human sensory cortices. As of today, however, no consensus exists regarding which experimental parameters elicit the most robust SRM response. The aim of the current study was twofold; firstly, we aimed to replicate former studies demonstrating visual SRM in healthy adults. Second, we integrated visual and auditory stimuli within the same SRM recording session to assay potential cross‐modal associations. Such an association between modalities would strengthen the assumption that the SRM effect reflects common mechanisms underlying synaptic plasticity rather than reflecting modality‐specific phenomena. A replication of previous findings showing robust potentiation of the visual evoked potential was evident, supporting the majority of previous work using similar paradigms, lending further support to the notion that high‐frequent visual stimulation is a viable probe into LTP‐like synaptic plasticity in the human visual cortex. The auditory evoked potentials (AEPs) did not, however, fully replicate previous work, though a significant increase of temporally later AEP components was found. In contrast to our hypothesis, there were no significant within‐subject cross‐modality correlations between the visual and auditory SRM. This lack of significant association might suggest that auditory and visual SRM depend on different mechanisms, and that further SRM studies on non‐invasive LTP‐like synaptic plasticity should focus on optimizing paradigms within the visual modality.

• Bøen, Erlend; Hummelen, Benjamin; Boye, Birgitte; Elvsåshagen, Torbjørn & Malt, Ulrik Fredrik (2020). Borderline patients have difficulties describing feelings; bipolar II patients describe difficult feelings. An alexithymia study. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 142(3), p. 203–214. doi: 10.1111/acps.13204. Full text in Research Archive
• Drange, Ole Kristian; Sæther, Sverre Georg; Finseth, Per Ivar; Morken, Gunnar; Vaaler, Arne & Arntsen, Vibeke [Show all 11 contributors for this article] (2020). Differences in course of illness between patients with bipolar II disorder with and without epileptiform discharges or other sharp activity on electroencephalograms: a cross-sectional study. BMC Psychiatry. 20. doi: 10.1186/s12888-020-02968-4. Full text in Research Archive Show summary

  Background A diagnosis of bipolar II disorder requires that the symptoms cannot be better explained by a medical condition. Epilepsy is in some cases associated with an affective syndrome mimicking an unstable bipolar II disorder. Epileptiform discharges on electroencephalograms (EEGs) are typical, but not pathognomonic, for epilepsy. A previous study has found a high frequency of epileptiform discharges and other sharp activity among patients with bipolar disorder. The aim of the study was to identify if epileptic discharges or other sharp activity per se are associated with an altered course of illness among patients with bipolar II disorder. Methods Eighty six patients diagnosed with bipolar II disorder at two psychiatric departments were interviewed about prior course of illness and assessed with EEGs. The patients were split into two groups based on the presence (n = 12) or absence (n = 74) of epileptiform discharges or other sharp activity. Wilcoxon rank sum test, Fisher’s exact test, and Pearson’s chi squared test were used to assess differences between the groups on six variables of course of illness. Results Patients with epileptiform discharges or other sharp activity had a history of more hypomanic episodes per year (median (interquartile range (IQR)) 1.5 (3.2) vs. 0.61 (1.1), p = 0.0090) and a higher hypomania:depression ratio (median (IQR) 3.2 (16) vs. 1.0 (1.0), p = 0.00091) as compared to patients without. None of the patients with epileptiform discharges or other sharp activity had self-reported epileptic seizures in their history. Conclusions Epileptiform discharges or other sharp activity on EEGs are associated with more hypomanic episodes and an increased hypomania:depression ratio. Our results warrant replication in prospective studies, but suggest that EEG findings could be of prognostic importance for patients diagnosed with bipolar II disorder in psychiatric care.

• Voldsbekk, Irene; Maximov, Ivan; Zak, Nathalia; Roelfs, Daniël Thomas Heimen; Geier, Oliver & Due-Tønnessen, Paulina [Show all 10 contributors for this article] (2020). Evidence for wakefulness-related changes to extracellular space in human brain white matter from diffusion-weighted MRI. NeuroImage. ISSN 1053-8119. 212, p. 116682–116682. doi: 10.1016/j.neuroimage.2020.116682. Full text in Research Archive Show summary

  Recently, several magnetic resonance imaging (MRI) studies have reported time-of-day effects on brain structure and function. Due to the possibility that time-of-day effects reflect mechanisms of circadian regulation, the aim of this prospective study was to assess these effects while under strict experimental control of variables that might influence biological clocks, such as caffeine intake and exposure to blue-emitting light. In addition, the current study assessed whether time-of-day effects were driven by changes to extracellular space, by including estimations of non-Gaussian diffusion metrics obtained from diffusion kurtosis imaging, white matter tract integrity and the spherical mean technique, in addition to conventional diffusion tensor imaging -derived parameters. Participants were 47 healthy adults who underwent diffusion-weighted imaging in the morning and evening of the same day. Morning and evening scans were compared using voxel-wise tract based spatial statistics and permutation testing. A day of wakefulness was associated with widespread increases in fractional anisotropy, indices of kurtosis and indices of the axonal water fraction. In addition, wakefulness was associated with widespread decreases in radial diffusivity, both in the single compartment and in extra-axonal space. These results suggest that an increase in the intra-axonal space relative to the extra-axonal volume underlies time-of-day effects in human white matter, which is in line with activity-induced reductions to the extracellular volume. These findings provide important insight into possible mechanisms driving time-of-day effects in MRI.

• 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.

• Coleman, Jonathan R.I.; Gaspar, Helena A; Bryois, Julien; Byrne, Enda M; Forstner, Andreas J & Holmans, Peter A [Show all 51 contributors for this article] (2020). The Genetics of the Mood Disorder Spectrum: Genome-wide Association Analyses of More Than 185,000 Cases and 439,000 Controls. Biological Psychiatry. ISSN 0006-3223. doi: 10.1016/j.biopsych.2019.10.015. Full text in Research Archive Show summary

  Background: Mood disorders (including major depressive disorder and bipolar disorder) affect 10% to 20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of risk factors across mood disorders despite their diagnostic distinction. Methods: To clarify the shared molecular genetic basis of major depressive disorder and bipolar disorder and to highlight disorder-specific associations, we meta-analyzed data from the latest Psychiatric Genomics Consortium genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; nonoverlapping N = 609,424). Results: Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More loci from the Psychiatric Genomics Consortium analysis of major depression than from that for bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single-episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment-the relationship is positive in bipolar disorder but negative in major depressive disorder. Conclusions: The mood disorders share several genetic associations, and genetic studies of major depressive disorder and bipolar disorder can be combined effectively to enable the discovery of variants not identified by studying either disorder alone. However, we demonstrate several differences between these disorders. Analyzing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum.

• 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.

• Haukvik, Unn Kristin H.; Gurholt, Tiril Pedersen; Nerland, Stener; Elvsåshagen, Torbjørn; Akudjedu, Theophilus N. & Alda, Martin [Show all 97 contributors for this article] (2020). In vivo hippocampal subfield volumes in bipolar disorder—A mega‐analysis from The Enhancing Neuro Imaging Genetics through Meta‐Analysis Bipolar Disorder Working Group. Human Brain Mapping. ISSN 1065-9471. 43, p. 385–398. doi: 10.1002/hbm.25249. Full text in Research Archive Show summary

  The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

• Ching, Christopher R. K.; Hibar, Derrek P.; Gurholt, Tiril Pedersen; Nunes, Abraham; Thomopoulos, Sophia I. & Abé, Chritsoph [Show all 51 contributors for this article] (2020). What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group. Human Brain Mapping. ISSN 1065-9471. 43, p. 56–82. doi: 10.1002/hbm.25098. Full text in Research Archive Show summary

  MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness.

• 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.

• Mäki-Marttunen, Tuomo; Kaufmann, Tobias; Elvsåshagen, Torbjørn; Devor, Anna; Djurovic, Srdjan & Westlye, Lars Tjelta [Show all 23 contributors for this article] (2019). Biophysical Psychiatry—How Computational Neuroscience Can Help to Understand the Complex Mechanisms of Mental Disorders. Frontiers in Psychiatry. 10. doi: 10.3389/fpsyt.2019.00534. Full text in Research Archive Show summary

  The brain is the most complex of human organs, and the pathophysiology underlying abnormal brain function in psychiatric disorders is largely unknown. Despite the rapid development of diagnostic tools and treatments in most areas of medicine, our understanding of mental disorders and their treatment has made limited progress during the last decades. While recent advances in genetics and neuroscience have a large potential, the complexity and multidimensionality of the brain processes hinder the discovery of disease mechanisms that would link genetic findings to clinical symptoms and behavior. This applies also to schizophrenia, for which genome-wide association studies have identified a large number of genetic risk loci, spanning hundreds of genes with diverse functionalities. Importantly, the multitude of the associated variants and their prevalence in the healthy population limit the potential of a reductionist functional genetics approach as a stand-alone solution to discover the disease pathology. In this review, we outline the key concepts of a “biophysical psychiatry,” an approach that employs large-scale mechanistic, biophysics-founded computational modelling to increase transdisciplinary understanding of the pathophysiology and strive toward robust predictions. We discuss recent scientific advances that allow a synthesis of previously disparate fields of psychiatry, neurophysiology, functional genomics, and computational modelling to tackle open questions regarding the pathophysiology of heritable mental disorders. We argue that the complexity of the increasing amount of genetic data exceeds the capabilities of classical experimental assays and requires computational approaches. Biophysical psychiatry, based on modelling diseased brain networks using existing and future knowledge of basic genetic, biochemical, and functional properties on a single neuron to a microcircuit level, may allow a leap forward in deriving interpretable biomarkers and move the field toward novel treatment options.

• Stahl, Eli A.; Breen, Gerome; Forstner, Andreas J.; McQuillin, Andrew; Ripke, Stephan & Trubetskoy, Vassily [Show all 277 contributors for this article] (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics. ISSN 1061-4036. 51(5), p. 793–803. doi: 10.1038/s41588-019-0397-8. Full text in Research Archive Show summary

  Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

• Granerud-Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad, Christoffer & Malt, Eva Albertsen (2019). Equivalence Class Formation and the N400: Methodological Issues. The Psychological Record. ISSN 0033-2933. 69(2), p. 175–191. doi: 10.1007/s40732-019-00332-x. Full text in Research Archive
• Bøen, Erlend; Hjornevik, Trine; Hummelen, Benjamin; Elvsåshagen, Torbjørn; Moberget, Torgeir & Holtedahl, Jon Erik [Show all 10 contributors for this article] (2019). Patterns of altered regional brain glucose metabolism in borderline personality disorder and bipolar II disorder. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 139(3), p. 256–268. doi: 10.1111/acps.12997. Full text in Research Archive
• Aas, Monica; Elvsåshagen, Torbjørn; Westlye, Lars Tjelta; Kaufmann, Tobias; Athanasiu, Lavinia & Djurovic, Srdjan [Show all 12 contributors for this article] (2019). Telomere length is associated with childhood trauma in patients with severe mental disorders. Translational Psychiatry. 9. doi: 10.1038/s41398-019-0432-7. Full text in Research Archive Show summary

  Reduced telomere length (TL) and structural brain abnormalities have been reported in patients with schizophrenia (SZ) and bipolar disorder (BD). Childhood traumatic events are more frequent in SZ and BD than in healthy individuals (HC), and based on recent findings in healthy individuals could represent one important factor for TL and brain aberrations in patients. The study comprised 1024 individuals (SZ [n = 373]; BD [n = 249] and HC [n = 402]). TL was measured by quantitative polymerase chain reaction (qPCR), and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnosis was obtained by the Structured Clinical Interview (SCID) for the diagnostic and statistical manual of mental disorders-IV (DSM-IV). FreeSurfer was used to obtain regional and global brain volumes from T1-weighted magnetic resonance imaging (MRI) brain scans. All analyses were adjusted for current age and sex. Patients had on average shorter TL (F = 7.87, p = 0.005, Cohen’s d = 0.17) and reported more childhood trauma experiences than HC (χ2 = 148.9, p < 0.001). Patients with a history of childhood sexual, physical or emotional abuse had shorter TL relative to HC and to patients without a history of childhood abuse (F = 6.93, p = 0.006, Cohen’s d = 0.16). After adjusting for childhood abuse, no difference in TL was observed between patients and HC (p = 0.12). There was no statistically significant difference in reported childhood abuse exposure or TL between SZ and BD. Our analyses revealed no significant associations between TL and clinical characteristics or brain morphometry. We demonstrate shorter TL in SZ and BD compared with HC and showed that TL is sensitive to childhood trauma experiences. Further studies are needed to identify the biological mechanisms of this relationship.

• Drange, Ole Kristian; Smeland, Olav Bjerkehagen; Shadrin, Alexey A.; Finseth, Per Ivar; Witoelar, Aree & Frei, Oleksandr [Show all 52 contributors for this article] (2019). Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes. Frontiers in Neuroscience. ISSN 1662-4548. 13. doi: 10.3389/fnins.2019.00220. Full text in Research Archive Show summary

  Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits. Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework. Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect). Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

• Zak, Nathalia; Bøen, Erlend; Boye, Birgitte; Andreassen, Ole Andreas; Doan, Nhat Trung & Malt, Ulrik Fredrik [Show all 8 contributors for this article] (2019). Mood episodes are associated with increased cortical thinning: A longitudinal study of bipolar disorder type II. Bipolar Disorders. ISSN 1398-5647. 21, p. 525–538. doi: 10.1111/bdi.12771. Full text in Research Archive Show summary

  Objectives Previous studies found evidence for thinner frontotemporal cortices in bipolar disorder (BD), yet whether this represents a stable disease trait or an effect of mood episodes remains unknown. Here, we assessed the reproducibility of thinner frontotemporal cortices in BD type II, compared longitudinal changes in cortical thickness between individuals with BD type II and healthy controls (HCs), and examined the effect of mood episodes on cortical thickness change. Methods Thirty‐three HCs and 29 individuals with BD type II underwent 3T magnetic resonance imaging at baseline, as published previously, and 2.4 years later, at follow‐up. Cross‐sectional and longitudinal analyses of cortical thickness were performed using Freesurfer, and relationships with mood episodes from baseline to follow‐up were assessed. Results Individuals with BD type II had thinner left and right prefrontal and left temporal cortex clusters at follow‐up (all corrected P < 0.001), consistent with baseline results. Both groups showed widespread longitudinal cortical thinning, and patients had increased thinning in a left temporal cortex cluster compared to HCs (corrected P < 0.001). Patients with more (>2) depressive episodes between baseline and follow‐up had greater left temporal cortical thinning than patients with fewer depressive episodes (corrected P < 0.05). In addition, patients with more depressive episodes had greater thinning in bilateral ventromedial prefrontal clusters relative to HCs (uncorrected P < 0.05), yet these results did not survive correction for multiple comparisons. Conclusions Together, these findings support reduced frontotemporal cortical thickness in BD type II and provide the first preliminary evidence for an association between depressive episodes and increased cortical thinning.

• Rødevand, Linn; Steen, Nils Eiel; Elvsåshagen, Torbjørn; Quintana, Daniel; Reponen, Elina Johanna & Mørch, Ragni Helene [Show all 12 contributors for this article] (2019). Cardiovascular risk remains high in schizophrenia with modest improvements in bipolar disorder during past decade. Acta Psychiatrica Scandinavica. ISSN 0001-690X. 139(4), p. 348–360. doi: 10.1111/acps.13008. Full text in Research Archive Show summary

  Objective: While CVD risk has decreased in the general population during the last decade, the situation in patients with schizophrenia (SCZ) and bipolar disorder (BD) is unknown. Methods: We compared CVD risk factors in patients with SCZ and BD recruited from 2002‐2005 (2005 sample, N = 270) with patients recruited from 2006‐2017 (2017 sample, N = 1011) from the same catchment area in Norway. The 2017 sample was also compared with healthy controls (N = 922) and the general population (N range = 1285‐4587, Statistics Norway) from the same area and period. Results: Patients with SCZ and BD in the 2017 sample had significantly higher level of most CVD risk factors compared to healthy controls and the general population. There was no significant difference in the prevalence of CVD risk factors in SCZ between the 2005 and 2017 samples except a small increase in glucose in the 2017 sample. There were small‐to‐moderate reductions in hypertension, obesity, total cholesterol, low‐density lipoprotein, systolic and diastolic blood pressure in the BD 2017 sample compared to the 2005 sample. Conclusion: Despite major advances in health promotion during the past decade, there has been no reduction in the level of CVD risk factors in patients with SCZ and modest improvement in BD.

• 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.

• Mäki-Marttunen, Tuomo; Krull, Florian; Bettella, Francesco; Hagen, Espen; Næss, Solveig & Ness, Torbjørn V [Show all 16 contributors for this article] (2019). Alterations in schizophrenia-associated genes can lead to increased power in delta oscillations. Cerebral Cortex. ISSN 1047-3211. 29(2), p. 875–891. doi: 10.1093/cercor/bhy291. Full text in Research Archive Show summary

  Genome-wide association studies have implicated many ion channels in schizophrenia pathophysiology. Although the functions of these channels are relatively well characterized by single-cell studies, the contributions of common variation in these channels to neurophysiological biomarkers and symptoms of schizophrenia remain elusive. Here, using computational modeling, we show that a common biomarker of schizophrenia, namely, an increase in delta-oscillation power, may be a direct consequence of altered expression or kinetics of voltage-gated ion channels or calcium transporters. Our model of a circuit of layer V pyramidal cells highlights multiple types of schizophrenia-related variants that contribute to altered dynamics in the delta-frequency band. Moreover, our model predicts that the same membrane mechanisms that increase the layer V pyramidal cell network gain and response to delta-frequency oscillations may also cause a deficit in a single-cell correlate of the prepulse inhibition, which is a behavioral biomarker highly associated with schizophrenia.

• 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.

• Hibar, Derrek; Westlye, Lars Tjelta; Doan, Nhat Trung; Jahanshad, Neda; Cheung, J. W. & Ching, Christopher R K [Show all 123 contributors for this article] (2018). Cortical abnormalities in bipolar disorder: An MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group. Molecular Psychiatry. ISSN 1359-4184. 23, p. 932–942. doi: 10.1038/mp.2017.73. Full text in Research Archive Show summary

  Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen’s d=−0.293; P=1.71 × 10−21), left fusiform gyrus (d=−0.288; P=8.25 × 10−21) and left rostral middle frontal cortex (d=−0.276; P=2.99 × 10−19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

• Consorti, Bipolar Sczhizophrenia Psychiatric Genomics; Ruderfer, Douglas M.; Ripke, Stephan; McQuillin, Andrew; Boocock, James & Stahl, Eli A. [Show all 52 contributors for this article] (2018). Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell. ISSN 0092-8674. 173(7), p. 1705–1715. doi: 10.1016/j.cell.2018.05.046. Full text in Research Archive
• 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
• Nunes, Abraham; Schnack, Hugo G.; Ching, Christopher R.K.; Agartz, Ingrid; Akudjedu, Theophilus N. & Alda, Martin [Show all 74 contributors for this article] (2018). Using structural MRI to identify bipolar disorders ? 13 site machine learning study in 3020 individuals from the ENIGMA Bipolar Disorders Working Group. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-018-0228-9. Full text in Research Archive Show summary

  Bipolar disorders (BDs) are among the leading causes of morbidity and disability. Objective biological markers, such as those based on brain imaging, could aid in clinical management of BD. Machine learning (ML) brings neuroimaging analyses to individual subject level and may potentially allow for their diagnostic use. However, fair and optimal application of ML requires large, multi-site datasets. We applied ML (support vector machines) to MRI data (regional cortical thickness, surface area, subcortical volumes) from 853 BD and 2167 control participants from 13 cohorts in the ENIGMA consortium. We attempted to differentiate BD from control participants, investigated different data handling strategies and studied the neuroimaging/clinical features most important for classification. Individual site accuracies ranged from 45.23% to 81.07%. Aggregate subject-level analyses yielded the highest accuracy (65.23%, 95% CI = 63.47–67.00, ROC-AUC = 71.49%, 95% CI = 69.39–73.59), followed by leave-one-site-out cross-validation (accuracy = 58.67%, 95% CI = 56.70–60.63). Meta-analysis of individual site accuracies did not provide above chance results. There was substantial agreement between the regions that contributed to identification of BD participants in the best performing site and in the aggregate dataset (Cohen’s Kappa = 0.83, 95% CI = 0.829–0.831). Treatment with anticonvulsants and age were associated with greater odds of correct classification. Although short of the 80% clinically relevant accuracy threshold, the results are promising and provide a fair and realistic estimate of classification performance, which can be achieved in a large, ecologically valid, multi-site sample of BD participants based on regional neurostructural measures. Furthermore, the significant classification in different samples was based on plausible and similar neuroanatomical features. Future multi-site studies should move towards sharing of raw/voxelwise neuroimaging data.

• Elvsåshagen, Torbjørn; Mutsaerts, Henri J.M.M; Zak, Nathalia; Norbom, Linn Christin Bonaventure; Quiraishi, Sophia & Pedersen, Per Øystein Heiberg [Show all 11 contributors for this article] (2018). Cerebral blood flow changes after a day of wake, sleep, and sleep deprivation. NeuroImage. ISSN 1053-8119. 186, p. 497–509. doi: 10.1016/j.neuroimage.2018.11.032. Full text in Research Archive Show summary

  Elucidating the neurobiological effects of sleep and wake is an important goal of the neurosciences. Whether and how human cerebral blood flow (CBF) changes during the sleep-wake cycle remain to be clarified. Based on the synaptic homeostasis hypothesis of sleep and wake, we hypothesized that a day of wake and a night of sleep deprivation would be associated with gray matter resting CBF (rCBF) increases and that sleep would be associated with rCBF decreases. Thirty-eight healthy adult males (age 22.1 ± 2.5 years) underwent arterial spin labeling perfusion magnetic resonance imaging at three time points: in the morning after a regular night's sleep, the evening of the same day, and the next morning, either after total sleep deprivation (n = 19) or a night of sleep (n = 19). All analyses were adjusted for hematocrit and head motion. rCBF increased from morning to evening and decreased after a night of sleep. These effects were most prominent in bilateral hippocampus, amygdala, thalamus, and in the occipital and sensorimotor cortices. Group × time interaction analyses for evening versus next morning revealed significant interaction in bilateral lateral and medial occipital cortices and in bilateral insula, driven by rCBF increases in the sleep deprived individuals and decreases in the sleepers, respectively. Furthermore, group × time interaction analyses for first morning versus next morning showed significant effects in medial and lateral occipital cortices, in anterior cingulate gyrus, and in the insula, in both hemispheres. These effects were mainly driven by CBF increases from TP1 to TP3 in the sleep deprived individuals. There were no associations between the rCBF changes and sleep characteristics, vigilant attention, or subjective sleepiness that remained significant after adjustments for multiple analyses. Altogether, these results encourage future studies to clarify mechanisms underlying sleep-related rCBF changes.

• Maier, Robert M.; Zhu, Zhihong; Lee, Sang Hong; Trzaskowski, Maciej; Ruderfer, Douglas M. & Stahl, Eli A. [Show all 17 contributors for this article] (2018). Improving genetic prediction by leveraging genetic correlations among human diseases and traits. Nature Communications. 9:989, p. 1–17. doi: 10.1038/s41467-017-02769-6. Full text in Research Archive
• Zak, Nathalia; Moberget, Torgeir; Bøen, Erlend; Boye, Birgitte; Waage, Trine Rygvold & Dietrichs, Espen [Show all 12 contributors for this article] (2018). Longitudinal and cross-sectional investigations of long-term potentiation-like cortical plasticity in bipolar disorder type II and healthy individuals. Translational Psychiatry. 8(103). doi: 10.1038/s41398-018-0151-5. Full text in Research Archive Show summary

  Visual evoked potential (VEP) plasticity is a promising assay for noninvasive examination of long-term potentiation (LTP)-like synaptic processes in the cerebral cortex. We conducted longitudinal and cross-sectional investigations of VEP plasticity in controls and individuals with bipolar disorder (BD) type II. VEP plasticity was assessed at baseline, as described previously (Elvsåshagen et al. Biol Psychiatry 2012), and 2.2 years later, at follow-up. The longitudinal sample with VEP data from both time points comprised 29 controls and 16 patients. VEP data were available from 13 additional patients at follow-up (total n = 58). VEPs were evoked by checkerboard reversals in two premodulation blocks before and six blocks after a plasticity-inducing block of prolonged (10 min) visual stimulation. VEP plasticity was computed by subtracting premodulation VEP amplitudes from postmodulation amplitudes. Saliva samples for cortisol analysis were collected immediately after awakening in the morning, 30 min later, and at 12:30 PM, at follow-up. We found reduced VEP plasticity in BD type II, that impaired plasticity was present in the euthymic phases of the illness, and that VEP plasticity correlated negatively with depression severity. There was a positive association between VEP plasticity and saliva cortisol in controls, possibly reflecting an inverted U-shaped relationship between cortisol and synaptic plasticity. VEP plasticity exhibited moderate temporal stability over a period of 2.2 years. The present study provides additional evidence for impaired LTP-like cortical plasticity in BD type II. VEP plasticity is an accessible method, which may help elucidate the pathophysiological and clinical significance of synaptic dysfunction in psychiatric disorders.

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• Voldsbekk, Irene; Groote, Inge Rasmus; Zak, Nathalia; Roelfs, Daniël; Geier, Oliver & Due-Tønnessen, Paulina [Show all 14 contributors for this article] (2023). Corrigendum to “Sleep and sleep deprivation differentially alter white matter microstructure: A mixed model design utilising advanced diffusion modelling”. NeuroImage. ISSN 1053-8119. 270. doi: 10.1016/j.neuroimage.2023.119939. Full text in Research Archive
• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2023). Equivalence Class Formation and Priming in Participants with High Functioning Autism. Full text in Research Archive
• Melteig, Elina & Elvsåshagen, Torbjørn (2022). Hjernens elektriske signaler kan gi bedre svar om alzheimer og schizofreni. [Journal]. Titan.uio.no. Full text in Research Archive
• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2022). Høytfungerende autisme, stimulusekvivalens og priming med bilder og ord. Full text in Research Archive
• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2022). High functioning autism, equivalence class formation and priming with meaningful stimuli and words. Full text in Research Archive
• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2021). Updated Results on the Project “N400 in Participants with High Function Autism. Full text in Research Archive Show summary

  The event-related-potential observed 400 ms after presentation of unrelated stimulus pair compared with related is called N400. When comparing N400 in participants with autism, some experiments have demonstrated the N400, and some have not. In the current experiment, one group of adults without ASD and one group of adults with high function autism were trained on six conditional discriminations with C-stimuli as meaningful stimuli. They all conducted a priming procedure with unrelated stimuli pairs and stimulus pair related through symmetry and transitivity/equivalence

• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2021). Equivalence Class Formation, N400 and Autism Spectrum. Full text in Research Archive Show summary

  Equivalence class formation is reflected in the electrophysiological (EEG) component N400, research has demonstrated. Stimuli pair related through symmetry and transitivity/equivalence do not produce a N400 ms after stimuli presentation while unrelated do. In the current experiment, 24 adults with high function autism and 28 normally developed adults participated. 6 conditional discriminations with C-stimuli as meaningful where trained before a priming test, conducted with EEG-measures. Related and unrelated stimuli pairs were presented and the participant was instructed to response to the pairs, related or unrelated. The results show that the unrelated pairs produced N400 and related pair did not. This was the matter in both groups, but the N400 peak was slightly smaller in the group with Autism spectrum disorder. The conclusion is that unrelated stimuli pair produced a change in the N400 component compared with stimuli pair related through symmetry and transitivity/equivalence in both groups

• Granerud, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2020). N400 Compared Between Adults With and Without High Functioning Autism. Full text in Research Archive Show summary

  The N400 is an event-related brain potential sensitive to the semantic relations in naturally occurring language. To illustrate, when words are semantically related (e.g., butter-bread) the N400 will be more negative than N400 evoked by unrelated words (e.g., grease-bread). The the peak amplitudes can be used to differentiate the types of experimentally-defined stimulus relations established by Matching-to-Sample (MTS) procedures. That is, the N400 will be more negative for the “non-equivalent” than to the “equivalent” stimulus-stimulus relations. Research reported here concerns the impact of MTS training parameters, specifically, the explicit training of name-object relations, in the N400 waveforms.In this regard, a between groups design was used, in which both groups were exposed to the same experimental procedures, except for the stimuli used, so that Group 1 used only abstract figures, and Group 2 used both pseudowords and abstract figures, during MTS training. Waverforms obtained from participants shows a clear N400 effect for Group 2, but not for Group 1. These results are discussed considering the possibility that this effect reflects a difference between groups in the degree of relatedness between stimuli in equivalence classes.

• 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
• Granerud-Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2019). Equivalence Class Formation, N400 and Autism Spectrum; the Role of Meaningful Stimuli in Unrelated Stimulus Pair. Full text in Research Archive
• Granerud-Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2019). N400 in Participants with High Function Autism and Controls. Full text in Research Archive
• Granerud-Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn & Malt, Eva Albertsen (2019). Equivalence Class Formation and Priming with Words and Pictures. Full text in Research Archive
• Granerud-Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad-Hall, Christoffer & Malt, Eva Albertsen (2019). Individual Differences in N400 After Equivalence Class Formation. 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
• Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad, Christoffer & Malt, Eva Albertsen (2018). Stimulusekvivalens og N400. Full text in Research Archive
• Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn & Malt, Eva Albertsen (2018). N400; an EEG Measure of Relational Strength? Full text in Research Archive
• Andreassen, Ole Andreas; Malt, Eva Albertsen; Elvsåshagen, Torbjørn; Steen, Vidar Martin & Aarsland, Dag (2018). Molekylærgenetikk og nevrologi. In Malt, Ulrik Fredrik; Andreassen, Ole Andreas; Malt, Eva Albertsen; Melle, Ingrid & Aarsland, Dag (Ed.), Lærebok i psykiatri. Gyldendal Akademisk. ISSN 9788205494633. p. 85–118. Full text in Research Archive
• Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad, Christoffer & Malt, Eva Albertsen (2018). Equivalence Class Formation and the EEG-Based N400 Component. Full text in Research Archive
• Dunvoll, Guro; Arntzen, Erik; Elvsåshagen, Torbjørn; Hatlestad, Christoffer & Malt, Eva Albertsen (2018). Equivalence Class Formation and N400 in Participants with High Functioning Autism Spectrum Disorder. 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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