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

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

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d = −0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.

Schizophrenia (SCZ) is associated with an increased risk of violence compared to the general population. Previous studies have indicated smaller hippocampal and amygdala volumes in violent than non-violent psychotic patients. However, little is known about volumetric differences at the subdivision level of these structures. In the present study, hippocampal subfields and amygdala nuclei volumes were estimated with FreeSurfer from 3 T MRI of SCZ patients with (SCZ-V, n = 24) and without (SCZ-NV, n = 51) a history of severe violence and 90 healthy controls (HC). Volumetric differences between groups were explored with a general linear model covarying for confounders, in addition to follow-up analyses in patient groups controlling for clinical characteristics such as antipsychotic medication, duration of illness and illicit substance use. SCZ-V had smaller total hippocampal volume and smaller CA1, HATA, fimbria, and molecular layer of DG volumes compared to HC. Total amygdala volume together with basal nucleus, accessory basal nucleus, CTA, and paralaminar nucleus volumes were smaller in SCZ-V compared to HC. In SCZ-NV, compared to HC, the observed smaller volumes were limited to basal and paralaminar nucleus. There were no significant differences in hippocampal subfield and amygdala nuclei volumes between SCZ-V and SCZ-NV. Follow-up analyses showed that the results in patient groups were not affected by clinical characteristics. The results suggest that smaller hippocampal subfield and amygdala nuclei volumes may be relevant to violence risk in SCZ. However, the neurobiological signature of violence in SCZ should be further investigated in larger cohorts.

•Reproducibility of regional T1w/T2w-ratio distributions was overall good, with the exception of one dataset.•Bias correction improved reproducibility of regional distributions in this dataset, while partial volume and outlier corrections had limited effects.•Test-retest reliability of the T1w/T2w-ratio was poor both regionally and across the cortex.•Intensity normalisation with Whitestripe and Z-Score improved test-retest reliability. The ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) images is often used as a proxy measure of cortical myelin. However, the T1w/T2w-ratio is based on signal intensities that are inherently non-quantitative and known to be affected by extrinsic factors. To account for this a variety of processing methods have been proposed, but a systematic evaluation of their efficacy is lacking. Given the dependence of the T1w/T2w-ratio on scanner hardware and T1w and T2w protocols, it is important to ensure that processing pipelines perform well also across different sites. We assessed a variety of processing methods for computing cortical T1w/T2w-ratio maps, including correction methods for nonlinear field inhomogeneities, local outliers, and partial volume effects as well as intensity normalisation. These were implemented in 33 processing pipelines which were applied to four test-retest datasets, with a total of 170 pairs of T1w and T2w images acquired on four different MRI scanners. We assessed processing pipelines across datasets in terms of their reproducibility of expected regional distributions of cortical myelin, lateral intensity biases, and test-retest reliability regionally and across the cortex. Regional distributions were compared both qualitatively with histology and quantitatively with two reference datasets, YA-BC and YA-B1+, from the Human Connectome Project. Reproducibility of raw T1w/T2w-ratio distributions was overall high with the exception of one dataset. For this dataset, Spearman rank correlations increased from 0.27 to 0.70 after N3 bias correction relative to the YA-BC reference and from -0.04 to 0.66 after N4ITK bias correction relative to the YA-B1+ reference. Partial volume and outlier corrections had only marginal effects on the reproducibility of T1w/T2w-ratio maps and test-retest reliability. Before intensity normalisation, we found large coefficients of variation (CVs) and low intraclass correlation coefficients (ICCs), with total whole-cortex CV of 10.13% and whole-cortex ICC of 0.58 for the raw T1w/T2w-ratio. Intensity normalisation with WhiteStripe, RAVEL, and Z-Score improved total whole-cortex CVs to 5.91%, 5.68%, and 5.19% respectively, whereas Z-Score and Least Squares improved whole-cortex ICCs to 0.96 and 0.97 respectively. In the presence of large intensity nonuniformities, bias field correction is necessary to achieve acceptable correspondence with known distributions of cortical myelin, but it can be detrimental in datasets with less intensity inhomogeneity. Intensity normalisation can improve test-retest reliability and inter-subject comparability. However, both bias field correction and intensity normalisation methods vary greatly in their efficacy and may affect the interpretation of results. The choice of T1w/T2w-ratio processing method must therefore be informed by both scanner and acquisition protocol as well as the given study objective. Our results highlight limitations of the T1w/T2w-ratio, but also suggest concrete ways to enhance its usefulness in future studies.

White matter abnormalities are well-established in adult patients with psychosis. Less is known about abnormalities in the rarely occurring adolescent early onset psychosis (EOP). In particular, whether antipsychotic medication might impact white matter microstructure is not known. Using 3T diffusion weighted imaging, we investigated differences in white matter microstructure and the impact of antipsychotic medication status in medicated (n = 11) and unmedicated (n = 11) EOP patients relative to healthy controls (n = 33), aged between 12-18 years. Using Tract-based Spatial Statistics, we calculate case-control differences in scalar diffusion measures, i.e. fractional anisotropy (FA), axial diffusion (AD) and radial diffusion (RD), and investigated their association with antipsychotic medication in patients. We found significantly lower FA in the left genu of the corpus callosum, the left anterior corona radiata (ACR) and the right superior longitudinal fasciculus in EOP patients relative to healthy controls. AD values were also lower in the left ACR, largely overlapping with the FA findings. Mean FA in the left ACR was significantly associated with antipsychotic medication status (Cohen's d = 1.37, 95% CI [0.01, 2.68], p = 0.008), showing higher FA values in medicated compared to unmedicated EOP patients. The present study is the first to link antipsychotic medication status to altered regional FA in the left ACR, a region hypothesized to contribute to the etiology of psychosis. Replications are warranted to draw firm conclusions about putatively enhancing effects of antipsychotic medication on white matter microstructure in adolescent-onset psychosis.

Schizophrenia (SCZ) is associated with increased risk of violence compared to the general population. Neuroimaging research suggests SCZ to be a disorder of disrupted connectivity, with diffusion tensor imaging (DTI) indicating white matter (WM) abnormalities. It has been hypothesized that SCZ patients with a history of violence (SCZ-V) have brain abnormalities distinguishing them from SCZ patients with no history of violence (SCZ-NV). Yet, a thorough investigation of the neurobiological underpinnings of state and trait measures of violence and aggression in SCZ derived from DTI indices is lacking. Using tract-based spatial statistics, we compared DTI-derived microstructural indices: fractional anisotropy (FA), mean, axial (AD) and radial diffusivity across the brain; (1) between SCZ-V (history of murder, attempted murder, or severe assault towards other people, n = 24), SCZ-NV (n = 52) and healthy controls (HC, n = 94), and (2) associations with current aggression scores among both SCZ groups. Then, hypothesis-driven region of interest analyses of the uncinate fasciculus and clinical characteristics including medication use were performed. SCZ-V and SCZ-NV showed decreased FA and AD in widespread regions compared to HC. There were no significant differences on any DTI-based measures between SCZ-V and SCZ-NV, and no significant associations between state or trait measures of aggression and any of the DTI metrics in the ROI analyses. The DTI-derived WM differences between SCZ and HC are in line with previous findings, but the results do not support the hypothesis of specific brain WM microstructural correlates of violence or aggression in SCZ.

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.

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

Ketamine administration is a well-established approach to mimic experimentally some aspects of schizophrenia. Adult neurogenesis dysregulation is associated with psychiatric disorders, including schizophrenia. The potential role of neurogenesis in the ketamine-induced phenotype is largely unknown. Recent results from human genetic studies have shown the pituitary adenylate cyclase-activating polypeptide (PACAP) gene is a risk factor for schizophrenia. Its potential role on the regulation of neurogenesis in experimental model of schizophrenia remains to be investigated. We aimed to determine whether ketamine affects the viability of adult neural stem cells (NSC). We also investigated whether the detrimental effect mediated by ketamine could be counteracted by PACAP. NSCs were isolated from the subventricular zone of the mouse and exposed to ketamine with/without PACAP. After 24 hours, cell viability, potential involvement of apoptosis, endoplasmic reticulum (ER) stress, mTOR and AMPA pathway activation were assessed by quantitative RT-PCR and Western blot analysis. We show that ketamine impairs NSC viability in correlation with increased apoptosis, ER stress and mTOR activation. The results also suggest that the effect of ketamine occurs via AMPA receptor activation. Finally, we show that PACAP counteracted the decreased NSC viability induced by ketamine via the specific activation of the PAC-1 receptor subtype. Our study shows that the NSC viability may be negatively affected by ketamine with putative importance for the development of a schizophrenia phenotype in the ketamine induced animal model of schizophrenia. The neuroprotective effect via PAC-1 activation suggests a potentially novel pharmacological target for the treatment of schizophrenia, via neurogenesis normalization.