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Intracranial volume (ICV) is frequently used in volumetric brain magnetic resonance imaging (MRI) studies, both as an adjustment factor for head size and as a variable of interest. Associations with age have been reported in both longitudinal and cross-sectional studies, but results have varied, potentially due to differences in ICV estimation methods. Here, we compared five commonly used ICV estimation methods and their cross-sectional and longitudinal associations with age. T1-weighted cross-sectional MRI data was included for 651 healthy individuals recruited through the NORMENT Centre (mean age = 46.1 years, range = 12.0-85.8 years) and 2,410 healthy individuals recruited through the UK Biobank study (UKB, mean age = 63.2 years, range = 47.0-80.3 years), where follow-up data was also available with a mean follow-up interval of 2.3 years. ICV was estimated with FreeSurfer (eTIV and sbTIV), SPM12, CAT12, and FSL. We assessed Pearson correlations, performed Bland-Altman analysis, and tested the explained variance of sex, height, body weight, and age on pairwise differences between ICV estimation methods. We fitted regression models to test linear and non-linear cross-sectional associations between age and ICV. For the UKB dataset, we further assessed longitudinal ICV change using linear mixed-effects (LME) models. We found overall high correlations across ICV estimation method, with the lowest correlations between FSL and eTIV (r=0.87) and between FSL and CAT12 (r=0.89). Widespread proportional bias was found in the Bland-Altman analyses, i.e., agreement between methods varying as a function of head size. Body weight, age, and sex explained the most variance in the differences between ICV estimation methods, indicating possible confounding by these variables for some estimation methods. In the NORMENT dataset, cross-sectional associations with age were found only for FSL and SPM12, indicating a positive association. For the UKB dataset, we observed negative cross-sectional associations with age for all ICV estimation methods. Longitudinal associations with age were found for all ICV estimation methods, with estimated annual percentage change ranging from −0.291 % to −0.416 % across the sampled age range. This convergence of longitudinal results across ICV estimation methods, in the largest dataset to date, offers strong evidence for age-related ICV reductions in mid- to late adulthood.HighlightsCorrelations between the five assessed estimation methods were very high (r>0.90) with the exception of FSL and eTIV (r=0.87), and FSL and CAT12 (r=0.89).Explained variance of estimated ICV differences by body weight, age, and sex indicate possible confounding for some ICV estimation methods.Positive cross-sectional associations with age, from adolescence to old age, were observed for the SPM12 and FSL estimation methods in one dataset.In the other dataset, negative cross-sectional associations with age, from mid- to late adulthood, were found for all estimation methods.Longitudinal ICV changes were observed for all estimation methods, indicating an annual percentage ICV reduction of −0.29 % to −0.42 % in mid- to late adulthood.

BackgroundStudies have linked auditory hallucinations (AH) in schizophrenia-spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the neuroanatomical distribution and specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI).MethodsWe included patients with SCZ with (AH+; n=59) and without (AH-; n=81) current AH, and 140 age-and-sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fibre tracts. We used principal component analysis (PCA) to identify general factors of variation across fibre tracts and DTI metrics. Regression models adjusted for sex, age, and age2were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics.ResultsWidespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in two fibre tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics.ConclusionsContrary to previous studies, DTI metrics differed mainly in patientswithoutcurrent AH compared to controls, indicating a widespread neuroanatomical distribution. Our results challenge the notion that altered DTI metrics in the LAPC is a specific feature underlying AH.

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset d = 0.37), posterior corona radiata (d = 0.32), and superior fronto‐occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Schizophrenia is thought to be a neurodevelopmental disorder with neuronal migration, differentiation and maturation disturbances. Tau is a microtubule-associated protein with a crucial role in these processes. Lower circulating tau levels have been reported in adults with schizophrenia, but this association has not been investigated in adolescent psychosis. We aimed to test the hypotheses that a) adolescents with early-onset psychosis (EOP; age of onset

ObjectiveThe hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD) and healthy controls.Methods1,521 participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; healthy controls, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models.ResultsSignificant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, HATA, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex healthy controls. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η2< 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD.ConclusionsUsing a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to healthy controls, due to higher volumetric deficits in males.

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

The placenta plays a role in fetal brain development, and pregnancy and birth complications can be signs of placental dysfunction. Birth asphyxia is associated with smaller head size and higher risk of developing schizophrenia (SZ), but whether birth asphyxia and placental genetic risk factors associated with SZ are related and how they might impact brain development is unclear. 433 adult patients with SZ and 870 healthy controls were clinically evaluated and underwent brain magnetic resonance imaging. Pregnancy and birth information were obtained from the Medical Birth Registry of Norway. Polygenic risk scores (PRS) from the latest genome-wide association study in SZ were differentiated into placental PRS (PlacPRS) and non-placental PRS. If the interaction between PRSs and birth asphyxia on case-control status was significant, neonatal head circumference (nHC) and adult intracranial volume (ICV) were further evaluated with these variables using multiple regression. PlacPRS in individuals with a history of birth asphyxia was associated with a higher likelihood of being a patient with SZ (t=2.10, p=.018). We found a significant interaction between PlacPRS and birth asphyxia on nHC in the whole sample (t=-2.14, p=.017), with higher placental PRS for SZ associated with lower nHC in those with birth asphyxia. This relationship was specific to males (t=-2.41, p=.010) and also found with their adult ICV (t=-1.97, p=.028). These findings suggest that placental pathophysiology and birth asphyxia may affect early and late trajectories of brain development, particularly in males with a higher vulnerability to SZ. This knowledge might lead to new strategies of treatment and prevention in SZ.

Cytomegalovirus (CMV) infection is usually inapparent in healthy adults but persists for life. Neural progenitor/stem cells are main CMV targets, and dentate gyrus (DG) a major neurogenic niche. Smaller DG volume has been repeatedly reported in severe mental illness (SMI). Considering the suggested immune system, blood–brain barrier and DG disturbances in SMI, we hypothesized that CMV exposure is associated with smaller DG volume in patients, but not healthy controls (HC). Due to the differential male and female immune response to CMV, we hypothesized sex-dependent associations. 381 adult patients with SMI (schizophrenia spectrum or bipolar spectrum disorders) and 396 HC were included. MRI scans were obtained with 1.5T Siemens MAGNETOM Sonata scanner or 3T General Electric Signa HDxt scanner, and processed with FreeSurfer v6.0. CMV immunoglobulin G antibody concentrations were measured by solid phase immunoassay. We investigated main and interaction effects of CMV status (antibody positivity/CMV + vs. negativity/CMV-) and sex on DG in patients and HC. Among patients, there was a significant CMV-by-sex interaction on DG (p = 0.009); CMV + male patients had significantly smaller DG volume than CMV- male patients (p = 0.001, 39 mm3 volume difference) whereas no CMV-DG association was found in female patients. Post-hoc analysis among male patients showed that the CMV-DG association was present in both hemispheres and in both patients with schizophrenia spectrum and bipolar spectrum disorders, and further, that higher CMV antibody titers were associated with smaller DG. No CMV-DG association was found in HC. The results indicate a DG vulnerability to CMV infection in men with SMI.

Corticostriatal projections form the input level of a circuitry that connects the cerebral cortex, basal ganglia, and thalamus. Three distinct, functional subcircuits exist according to the tripartite model: Sensorimotor cortices projecting mainly to the dorsolateral striatum; associative cortices projecting to the dorsomedial striatum and limbic cortices projecting to the ventral striatum. However, there is to date no atlas that allows researchers to label cortical projection areas belonging to each of these subcircuits separately.To address this research gap, the aim of this study was threefold: First, to systematically review anatomical tracing studies that focused on corticostriatal projections in non-human primates, and to classify their findings according to the tripartite model. Second, to develop an atlas of the human cerebral cortex based on this classification. Third, to test the hypothesis that labels in this atlas show structural connectivity with specific striatal subregions in humans using diffusion-based tractography in a sample of 24 healthy participants.In total, 98 studies met the inclusion criteria for our systematic review. Information about projections from the cortex to the striatum was systematically extracted by Brodmann area, and cortical areas were classified by their dominant efferent projections. Taking known homological and functional similarities and differences between non-human primate and human cortical regions into account, a new human corticostriatal projection (CSP) atlas was developed. Using human diffusion-based tractography analyses, we found that the limbic and sensorimotor atlas labels showed preferential structural connectivity with the ventral and dorsolateral striatum, respectively. However, the pattern of structural connectivity for the associative label showed the greatest degree of overlap with other labels.We provide this new atlas as a freely available tool for neuroimaging studies, where it allows for the first-time delineation of anatomically informed regions-of-interest to study functional subcircuits within the corticostriatal circuitry. This tool will enable specific investigations of subcircuits involved in the pathogenesis of neuropsychiatric illness such as schizophrenia and bipolar disorders.Highlights-Systematic review of anatomical projections from the cerebral cortex to the striatum in non-human primates.-Development of a novel cortical atlas for use in neuroimaging studies focusing on the corticostriatal brain circuitry.-Tractography in human diffusion-weighted imaging data to test if associative, limbic, and sensorimotor cortical atlas labels show preferential connectivity to regions within the striatum.

Abnormalities in amygdala volume are well-established in schizophrenia and commonly reported in bipolar disorders. However, the specificity of volumetric differences in individual amygdala nuclei is largely unknown. Patients with schizophrenia disorders (SCZ, N = 452, mean age 30.7 ± 9.2 [SD] years, females 44.4%), bipolar disorders (BP, N = 316, 33.7 ± 11.4, 58.5%), and healthy controls (N = 753, 34.1 ± 9.1, 40.9%) underwent T1-weighted magnetic resonance imaging. Total amygdala, nuclei, and intracranial volume (ICV) were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple linear regression models, adjusting for age, age2, ICV, and sex, were fitted to examine diagnostic group and subgroup differences in volume, respectively. Bilateral total amygdala and all nuclei volumes, except the medial and central nuclei, were significantly smaller in patients relative to controls. The largest effect sizes were found for the basal nucleus, accessory basal nucleus, and cortico-amygdaloid transition area (partial η2 > 0.02). The diagnostic subgroup analysis showed that reductions in amygdala nuclei volume were most widespread in schizophrenia, with the lateral, cortical, paralaminar, and central nuclei being solely reduced in this disorder. The right accessory basal nucleus was marginally smaller in SCZ relative to BP (t = 2.32, P = .05). Our study is the first to demonstrate distinct patterns of amygdala nuclei volume reductions in a well-powered sample of patients with schizophrenia and bipolar disorders. Volume differences in the basolateral complex (lateral, basal, and accessory basal nuclei), an integral part of the threat processing circuitry, were most prominent in schizophrenia.

BackgroundEmerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset MethodsOur sample included 321 adolescents with EOP (mean age: 16.3 ± 1.4 years, 46.4% females) and 265 adolescent CTR (mean age: 16.0 ± 1.7 years, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures.ResultsWe found widespread lower FA in EOP compared to CTR, with the largest effect sizes in the superior longitudinal fasciculus (Cohen’s d = 0.37), posterior corona radiata (d = 0.32), and superior fronto□occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status.ConclusionUsing the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male patients with early-onset schizophrenia and patients with a shorter duration of illness.

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., The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder.In the largest study of hippocampal subfields in bipolar disorder to date, from 23 sites worldwide, we report widespread reductions in nine of 12 subfields.The lack of differences between lithium users and healthy controls supports a possible protective role of lithium in bipolar disorder.

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

Background 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. Methods 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. Results 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. Conclusions 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.

Schizophrenia (SCZ) spectrum and bipolar disorder (BD) are severe mental disorders with unknown pathophysiology. Altered visual evoked potential (VEP), an electroencephalogram signal reflecting function in the primary visual cortex (V1), abnormal visual processing and visual hallucinations reported in these patients, all point towards V1 dysfunction. While the mechanisms contributing to V1 dysfunction remain unknown, structural alterations are possible candidates. Lack of insight into neural substrates of structure and functional in V1 has limited our ability to determine implications of altered V1 function. While combining VEP and magnetic resonance imaging has increased our understanding of the structure-function relationship in V1 in healthy individuals, no previous study has examined the same structure-function relationship in patients with SCZ spectrum and BD. Here, we aimed to confirm previous findings of a selective positive correlation between the amplitude of the P100 component of the VEP and V1 surface area (SA) in 307 healthy individuals and to examine whether this relationship was altered in patients with SCZ spectrum (n=30) and BD (n=45). The correlation between the P100 amplitude and the total, (r=0.16, p=0.006), right (r=0.14, p=0.013) and left V1 surface area (r=0.13, p=0.02) was significant in healthy individuals, but not in patients. The current results support previous findings of a selective relationship between P100 amplitude and V1 surface area in healthy individuals and suggests that other factors than V1 surface area or thickness explain V1 dysfunction reported in these patients.

Importance: Schizophrenia is a leading cause of disability worldwide, with an illness course that putatively deteriorates over time. Whether the notion of a progressive brain disease holds in its chronic stage is debated. Objective: To investigate brain volume change and the impact of iatrogenic factors in chronic schizophrenia patients (duration of illness at baseline 16.17 ± 8.14 years) and controls over 13 years. Design: Participants were recruited as part of the Human Brain Informatics study. Data acquisition took place between 1999 and 2018, including baseline, 5- and 13-years follow-up. Setting: Naturalistic longitudinal case-control study. Participants: The sample consisted of 143 participants, of whom 64 were patients with chronic schizophrenia (20% female, mean age at baseline 40.5 ± 7.7 years) and 79 healthy controls (37% female, mean age at baseline 42.8 ± 8.4 years). T1-weighted structural imaging and information about medication use were obtained at each time point. Exposure: Antipsychotic medication and other prescribed drugs. Main Outcome(s) and Measure(s): Individual total and tissue-specific brain volumes, as well as two-time point percentage brain and ventricle volume change. Results: Patients had lower total brain volume at baseline. Yet, trajectories in total brain volume and gray matter volume loss as well as ventricular enlargement did not differ relative to controls. White matter volume was similar between groups at baseline and 5-year but diverged between 5-year and 13-year follow-up, with accelerated loss in patients. While antipsychotic exposure did not show an association with brain volume loss over time, higher medication load was associated with lower brain volume across time points. Patients on second-generation antipsychotics alone showed lowest total brain volume, only after accounting for add-on drug use. Conclusion and Relevance: We found limited evidence for progressive brain volume loss in chronic schizophrenia, beyond normal aging. Stable differences in patient brain volumes relative to controls may primarily occur during the first years of illness. All prescribed drugs need to be considered when examining the impact of antipsychotic medication on brain structure.

Antipsychotic treatment may affect brain morphology, and enlargement of the basal ganglia (BG) is a replicated finding. Here we investigated associations between antipsychotic treatment and BG volumes in patients with psychotic and bipolar disorders. We hypothesized that current treatment and, among those medicated, higher dosage, estimated D2R occupancy and being in remission would predict larger BG volumes. Structural covariance analysis was performed to examine if correlations between BG volumes and cortical thickness differed by treatment status. 224 patients treated with antipsychotics; 26 previously treated, 29 never treated and 301 healthy controls (HC) were included from the TOP study cohort (NORMENT, Norway). T1-weighted MR images were processed using FreeSurfer. D2R occupancy was estimated based on serum concentration measurements for patients receiving stable monotherapy. Statistical analyses were adjusted for age, gender and estimated intracranial volume (ICV). We found larger right (p 0.003) and left putamen (p 0.02) and right globus pallidus (GP) (p 0.03) in currently medicated patients compared to HC. Bilateral regional cortical thinning was also observed in currently and previously medicated patients compared to HC. In medicated patients, higher chlorpromazine equivalent dose (CPZ) was associated with larger left GP (p 0.04). There was no association with estimated D2R occupancy (n = 47) or remission status. Lower positive correlation between left putamen volume and cortical thickness of the left lateral occipital cortex was found in medicated patients compared to HC. We replicated the BG enlargement in medicated patients, but found no association with estimated D2R occupancy. Further studies are needed to clarify the underlying mechanisms.

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

BackgroundThe etiology of schizophrenia (SZ) is proposed to include an interplay between a genetic risk for disease development and the biological environment of pregnancy and birth, where early adversities may contribute to the poorer developmental outcome. We investigated whether a history of birth asphyxia (ASP) moderates the relationship between intracranial volume (ICV) and intelligence in SZ, bipolar disorder (BD) and healthy controls (HC).MethodsTwo hundred seventy-nine adult patients (18–42 years) on the SZ and BD spectrums and 216 HC were evaluated for ASP based on information from the Medical Birth Registry of Norway. Participants underwent structural magnetic resonance imaging (MRI) to estimate ICV and intelligence quotient (IQ) assessment using the Wechsler Abbreviated Scale of Intelligence (WASI). Multiple linear regressions were used for analyses.ResultsWe found a significant three-way interaction (ICV × ASP × diagnosis) on the outcome variable, IQ, indicating that the correlation between ICV and IQ was stronger in patients with SZ who experienced ASP compared to SZ patients without ASP. This moderation by ASP was not found in BD or HC groups. In patients with SZ, the interaction between ICV and a history of the ASP was specifically related to the verbal subcomponent of IQ as measured by WASI.ConclusionsThe significant positive association between ICV and IQ in patients with SZ who had experienced ASP might indicate abnormal neurodevelopment. Our findings give support for ICV together with verbal intellectual abilities as clinically relevant markers that can be added to prediction tools to enhance evaluations of SZ risk.

BackgroundBoth 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.

BackgroundAbnormalities in amygdala volume are well-established in schizophrenia and commonly reported in bipolar disorders. However, the specificity of volumetric differences in individual amygdala nuclei is largely unknown.MethodsPatients with schizophrenia disorders (SCZ, n=452, including schizophrenia, schizoaffective and other psychotic disorders, mean age 30.7±9.2 (SD), females 44.4%), bipolar disorders (BP, n=316, including bipolar I and II, 33.7±11.4, 58.5%) and healthy controls (n=753, 34.1±9.1, 40.9%) underwent T1-weighted magnetic resonance imaging. Total amygdala and nuclei volumes as well as intracranial volume (ICV) were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple linear regression models, adjusting for age, age2, ICV and sex, were fitted to examine diagnostic group and subgroup differences in volume, respectively.ResultsBilateral total amygdala and all nuclei volumes, except the medial and central nuclei, were significantly smaller in patients relative to controls. The largest effect sizes were found for the basal nucleus, accessory basal nucleus and cortico-amygdaloid transition area (partial η2 > 0.02). The diagnostic subgroup analysis showed that reductions in amygdala nuclei volume were most widespread in schizophrenia, with the lateral, cortical, paralaminar and central nuclei being solely reduced in this disorder. The right accessory basal nucleus was marginally smaller in SCZ relative to BP (t = 2.32, p = 0.05).ConclusionsOur study is the first to demonstrate distinct patterns of amygdala nuclei volume reductions in a well-powered sample of patients with schizophrenia and bipolar disorders. Volume differences in the basolateral complex (lateral, basal, accessory basal nuclei) may be putative neuroimaging markers for differentiating schizophrenia and bipolar disorders.

Key Points Question Are signs of insufficient brain oxygenation before, during, and immediately after birth, known as birth asphyxia, associated with white matter abnormalities in adult patients with schizophrenia and bipolar disorder compared with healthy control participants? Findings In this case-control study of 850 adult patients and healthy individuals with birth registry and diffusion-weighted imaging data, measures of birth asphyxia were significantly associated with lower fractional anisotropy and higher radial diffusivity in the posterior limb of the internal capsule in the patients with bipolar disorder and schizophrenia but not in the control group. Meaning White matter abnormalities in the posterior limb of the internal capsule could suggest early changes or impeded brain development because of an increased susceptibility to birth asphyxia in patients, which is not present in healthy adults., This case-control study examines the association between birth asphyxia and white matter abnormalities in adult patients with schizophrenia and bipolar disorders., Importance White matter (WM) abnormalities are commonly reported in psychiatric disorders. Whether peripartum insufficiencies in brain oxygenation, known as birth asphyxia, are associated with WM of patients with severe mental disorders is unclear. Objective To examine the association between birth asphyxia and WM in adult patients with schizophrenia and bipolar disorders (BDs) compared with healthy adults. Design, Setting, and Participants In this case-control study, all individuals participating in the ongoing Thematically Organized Psychosis project were linked to the Medical Birth Registry of Norway (MBRN), where a subset of 271 patients (case group) and 529 healthy individuals (control group) had undergone diffusion-weighted imaging (DWI). Statistical analyses were performed from June 16, 2020, to March 9, 2021. Exposures Birth asphyxia was defined based on measures from standardized reporting at birth in the MBRN. Main Outcomes and Measures Associations between birth asphyxia and WM regions of interest diffusion metrics, ie, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), were compared between groups using analysis of covariance, adjusted for age, age squared, and sex. Results Of the 850 adults included in the study, 271 were in the case group (140 [52%] female individuals; mean [SD] age, 28.64 [7.43] years) and 579 were in the control group (245 [42%] female individuals; mean [SD] age, 33.54 [8.31] years). Birth asphyxia measures were identified in 15% to 16% of participants, independent of group. The posterior limb of the internal capsule (PLIC) showed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 11.46; P = .001), reflecting a stronger association between birth asphyxia and FA in the case group than the control group. RD, but not AD, also displayed a significant diagnostic group × birth asphyxia interaction (F(1, 843) = 9.28; P = .002) in the PLIC, with higher values in patients with birth asphyxia and similar effect sizes as observed for FA. Conclusions and Relevance In this case-control study, abnormalities in the PLIC of adult patients with birth asphyxia may suggest a greater susceptibility to hypoxia in patients with severe mental illness, which could lead to myelin damage or impeded brain development. Echoing recent early-stage schizophrenia studies, abnormalities of the PLIC are relevant to psychiatric disorders, as the PLIC contains important WM brain pathways associated with language, cognitive function, and sensory function, which are impaired in schizophrenia and BDs.

Objectives We aimed to investigate morphometric correlates of auditory hallucinations in bipolar disorder (BD) by comparing cortical thickness and cortical surface area in bipolar disorder patients with (BD+) and without (BD−) a lifetime history of auditory hallucinations. Based on previous findings in schizophrenia patients, we hypothesized that the cortex would be thinner in the auditory cortex in BD+ compared to BD−. Methods Bipolar disorder spectrum (n = 157) patients and healthy controls (n = 279) underwent 1.5T magnetic resonance imaging (MRI) scanning. Hypothesis-driven analyses of cortical thickness and surface area in regions of the auditory cortex (Heschl's gyrus [HG], planum temporale and superior temporal gyrus) were conducted comparing BD+ (n = 49) and BD− (n = 108) using linear regression models, covaried for age and sex. Furthermore, we explored vertex-wise group differences in thickness and surface area across the whole cerebral cortex. Results Hypothesis-driven analyses:BD+ had significantly thicker cortex in the left HG compared to BD− (B = 0.128, P = .0046). The finding was not explained by duration of illness, global functioning, bipolar subtype, IQ or use of antipsychotic, antidepressant or antiepileptic medication, or by lithium. Exploratory analyses: A small region of thicker cortex in BD+ compared to BD− was seen in the left superior parietal lobule (false discovery rate

ImportanceSchizophrenia is a leading cause of disability worldwide, with an illness course that putatively deteriorates over time. Whether the notion of a progressive brain disease holds in its chronic stage is debated.ObjectiveTo investigate brain volume change and the impact of iatrogenic factors in chronic schizophrenia patients (duration of illness at baseline 16.17 ± 8.14 years) and controls over 13 years.DesignParticipants were recruited as part of the Human Brain Informatics study. Data acquisition took place between 1999 and 2018, including baseline, 5- and 13-years follow-up.SettingNaturalistic longitudinal case-control study.ParticipantsThe sample consisted of 143 participants, of whom 64 were patients with chronic schizophrenia (20% female, mean age at baseline 40.5 ± 7.7 years) and 79 healthy controls (37% female, mean age at baseline 42.8 ± 8.4 years). T1-weighted structural imaging and information about medication use were obtained at each time point.ExposureAntipsychotic medication and other prescribed drugs.Main Outcome(s) and Measure(s)Individual total and tissue-specific brain volumes, as well as two-time point percentage brain and ventricle volume change.ResultsPatients had lower total brain volume at baseline. Yet, trajectories in total brain volume and gray matter volume loss as well as ventricular enlargement did not differ relative to controls. White matter volume was similar between groups at baseline and 5-year but diverged between 5-year and 13-year follow-up, with accelerated loss in patients. While antipsychotic exposure did not show an association with brain volume loss over time, higher medication load was associated with lower brain volume across time points. Patients on second-generation antipsychotics alone showed lowest total brain volume, only after accounting for add-on drug use.Conclusion and RelevanceWe found limited evidence for progressive brain volume loss in chronic schizophrenia, beyond normal aging. Stable differences in patient brain volumes relative to controls may primarily occur during the first years of illness. All prescribed drugs need to be considered when examining the impact of antipsychotic medication on brain structure.Key PointsQuestionIs chronic schizophrenia associated with progressive brain volume loss beyond normal aging?FindingsWhile brain volume was lower at baseline, patient trajectories of brain volume change over a 13-year follow-up period differed little from healthy individuals. Small effects indicated greater white matter volume loss in patients during the late phase of follow-up. Stable differences in patient brain volumes seem explicable by antipsychotic medication class and respective add-on drugs.MeaningWe found limited evidence of progressive brain volume loss, beyond normal aging, in chronic schizophrenia over 13 years.

Objective The effect of antipsychotic medication on brain structure remains unclear. Given the prevalence of weight gain as a side-effect, body mass index (BMI) change could be a confounder. Method Patients with first-episode psychosis (n = 78) and healthy controls (n = 119) underwent two 1.5T MRI scans with a 1-year follow-up interval. siena (fsl 5.0) was used to measure whole-brain volume change. Weight and height were measured at both time points. Antipsychotic medication use at baseline and follow-up was converted into chlorpromazine equivalent dose and averaged. Results Patients did not show significantly larger brain volume loss compared with healthy controls. In the whole sample (n = 197), BMI change was negatively associated with brain volume change (β = −0.19, P = 0.008); there was no interaction effect of group. Among patients, higher antipsychotic medication dosage was associated with greater brain volume loss (β = −0.45, P < 0.001). This association was not affected by adjusting for BMI change. Conclusion Weight gain was related to brain volume reductions to a similar degree among patients and controls. Antipsychotic dosage-related reductions of brain volume were not confounded by BMI change. Generalizability to contexts involving severe weight gain needs to be established. Furthermore, disentangling effects of medication from illness severity remains a challenge.

BackgroundExcessive alcohol use is associated with brain damage but less is known about brain effects from moderate alcohol use. Previous findings indicate that patients with severe mental illness, particularly schizophrenia, are vulnerable to alcohol-related brain damage. We investigated the association between levels of alcohol consumption and cortical and subcortical brain structures in schizophrenia and bipolar disorder patients and healthy controls, and investigated for group differences for this association.Method1.5 T structural magnetic resonance images were acquired of 609 alcohol-using participants (165 schizophrenia patients, 172 bipolar disorder patients, 272 healthy controls), mean (s.d.) age 34.2 (9.9) years, 52% men. Past year alcohol use was assessed with the Alcohol Use Disorder Identification Test – Consumption part (AUDIT-C). General linear models were used to investigate associations between AUDIT-C score and cortical thickness, surface area, and total brain and subcortical volumes.ResultsIncreasing AUDIT-C score was linearly associated with thinner cortex in medial and dorsolateral frontal and parieto-occipital regions, and with larger left lateral ventricle volume. There was no significant interaction between AUDIT-C score and diagnostic group. The findings remained significant after controlling for substance use disorders, antipsychotic medication and illness severity.ConclusionThe results show a dose-dependent relationship between alcohol use and thinner cortex and ventricular expansion. The findings are present also at lower levels of alcohol consumption and do not differ between schizophrenia or bipolar disorder patients compared to healthy controls. Our results do not support previous findings of increased vulnerability for alcohol-related brain damage in severe mental illness.

Clinical studies of patients with schizophrenia and a history of violence are challenging both from an ethical and practical perspective, and the neurobiological underpinnings remain largely unknown. We here present a comprehensive account of the brain cortical characteristics associated with violence in schizophrenia. We obtained 3T MRI scans and thorough clinical characterization of schizophrenia patients with a history of violence (murder, attempted murder, criminal assault, SCZ-V, n = 11), schizophrenia patients with no history of violence (SCZ-NV, n = 17), and healthy controls (HC, n = 19). Cortical thickness, area, and folding were analyzed vertex-wise across the cortical mantle (FreeSurfer). SCZ-V had significantly increased cortical folding in the visual and orbitofrontal cortex, and reduced cortical thickness within the precentral-, parietal-, temporal-, and fusiform cortex compared to SCZ-NV, as well as widespread regional thinning and increased folding compared to HC. There were no group differences in cortical area. A major limitation is the small subject sample. If replicated, the results from this pilot study suggest cortical abnormalities in areas involved in sensory processing, emotion recognition, and reward to be of importance to the neurobiology of violence in schizophrenia.

BackgroundFirst-episode psychosis (FEP) patients show structural brain abnormalities. Whether the changes are progressive or not remain under debate, and the results from longitudinal magnetic resonance imaging (MRI) studies are mixed. We investigated if FEP patients showed a different pattern of regional brain structural change over a 1-year period compared with healthy controls, and if putative changes correlated with clinical characteristics and outcome.MethodMRIs of 79 FEP patients [SCID-I-verified diagnoses: schizophrenia, psychotic bipolar disorder, or other psychoses, mean age 27.6 (s.d. = 7.7) years, 66% male] and 82 healthy controls [age 29.3 (s.d. = 7.2) years, 66% male] were acquired from the same 1.5 T scanner at baseline and 1-year follow-up as part of the Thematically Organized Psychosis (TOP) study, Oslo, Norway. Scans were automatically processed with the longitudinal stream in FreeSurfer that creates an unbiased within-subject template image. General linear models were used to analyse longitudinal change in a wide range of subcortical volumes and detailed thickness and surface area estimates across the entire cortex, and associations with clinical characteristics.ResultsFEP patients and controls did not differ significantly in annual percentage change in cortical thickness or area in any cortical region, or in any of the subcortical structures after adjustment for multiple comparisons. Within the FEP group, duration of untreated psychosis, age at illness onset, antipsychotic medication use and remission at follow-up were not related to longitudinal brain change.ConclusionsWe found no significant longitudinal brain changes over a 1-year period in FEP patients. Our results do not support early progressive brain changes in psychotic disorders.

IntroductionSmaller auditory cortex volume in schizophrenia patients with auditory hallucinations (AH) may be a result of reduced cortical surface area and/or cortical thickness. A neuro–imaging study from our group demonstrated that adult schizophrenia spectrum patients with AH had significantly thinner cortex in the left side Heschl's gyrus (HG), compared to patients without AH, and healthy controls (HC).ObjectivesThis study aims to investigate if adolescents with early-onset psychosis (EOP) and AH demonstrate thinner cortices in HG, as found in Mørch-Johnsen et al. in 2016, compared to EOP patients without AH, and HC.MethodsEOP patients (schizophrenia spectrum, psychotic disorder not otherwise specified) (n = 29) underwent MRI. Mean volume, cortical thickness and surface area in auditory cortex regions (HG, superior temporal gyrus [STG]) were compared between patients with AH (n = 20) and without AH (n = 9), measured with item P3 from the Positive And Negative Syndrome Scale (PANSS), and 48 HC.ResultsPreliminary results show no significant differences between patients with and without AH and HC in mean volume, cortical thickness, or surface area in HG or STG. There were no significant side differences across hemispheres for these structures.ConclusionsAH in EOP were not related to smaller volume, thinner cortex or reduced surface area in auditory cortex regions. To overcome the limitation of having a relatively small sample size, the sample will be expanded with other EOP cohorts. Investigations into HG structure variation in relation to AH in EOP will also be conducted.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionCortical brain abnormalities are frequently observed in adults with psychotic disorders, but few studies have investigated adolescents with early-onset psychosis (EOP). A previous magnetic resonance imaging (MRI) study from the NORMENT group in Norway, found widespread cortical thinning and smaller subcortical volumes in adult patients with psychotic disorders, particularly schizophrenia, compared to healthy controls.MethodsParticipants from the ongoing NORMENT adolescent EOP-study, 30 patients (age: 13.3–18.3 years, mean age: 16.5, 66% female) and 45 healthy adolescents (age: 13.6–18.8 years, mean age: 16.2, 58% female), underwent 3 T MRI on the same scanner. Surface-based morphometric analyses were performed using FreeSurfer version 5.3.0. Group differences in vertex-wise cortical volume, thickness and surface area were investigated by fitting general linear models at each vertex on the surface. Age, sex and group were entered as covariates, and a non-parametric cluster-wise correction method for multiple comparisons was applied and cluster-forming and cluster-wise threshold set at 0.05.ResultsPreliminary results show thinner cortex in the left medial frontal lobe and smaller surface area in the left temporoparietal junction in EOP patients compared to healthy controls after correction for multiple comparisons.ConclusionSurface-based analysis is sensitive to alterations in cortical morphology in an adolescent EOP sample. The regions exhibiting reduced cortical thickness and area in EOP overlap with findings in an adult psychosis sample. Large-scale studies are warranted to better identify the pattern of abnormalities and clarify effects of age, diagnosis and medication.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background First-episode psychosis (FEP) patients show structural brain abnormalities. Whether the changes are progressive or not remain under debate, and the results from longitudinal magnetic resonance imaging (MRI) studies are mixed. We investigated if FEP patients showed a different pattern of regional brain structural change over a one-year period compared to healthy controls, and if putative changes correlated with clinical characteristics and outcome. Methods MRIs of 79 FEP (SCID-I verified diagnoses: schizophrenia, psychotic bipolar disorder, or other psychoses, mean age 27.6 (SD 7.7), 66% male) and 82 healthy controls (age 29.3 (SD 7.2) 66% male) were acquired from the same 1.5T scanner at baseline and one-year follow up as part of the TOP study, Oslo, Norway. Scans were automatically processed with the longitudinal stream in FreeSurfer. General linear models were used to analyze longitudinal change in a wide range of subcortical volumes and detailed thickness and surface area estimates across the entire cortex, and associations to clinical characteristics. Results FEP and controls did not differ significantly in annual percentage change in cortical thickness or area in any cortical region, or in any of the subcortical structures after adjustment for multiple comparisons. Within the FEP group, duration of untreated psychosis, age at illness onset, antipsychotic medication use, and remission at follow-up were not related to longitudinal brain change. Conclusion We found no longitudinal brain changes over a one-year period in FEP compared to controls. Our results do not support early progressive brain changes in psychotic disorders.

BackgroundSchizophrenia and bipolar disorder share genetic risk factors and one possible illness mechanism is abnormal myelination. T1-weighted magnetic resonance imaging (MRI) tissue intensities are sensitive to myelin content. Therefore, the contrast between grey- and white-matter intensities may reflect myelination along the cortical surface.MethodMRI images were obtained from patients with schizophrenia (n = 214), bipolar disorder (n = 185), and healthy controls (n = 278) and processed in FreeSurfer. The grey/white-matter contrast was computed at each vertex as the difference between average grey-matter intensity (sampled 0–60% into the cortical ribbon) and average white-matter intensity (sampled 0–1.5 mm into subcortical white matter), normalized by their average. Group differences were tested using linear models covarying for age and sex.ResultsPatients with schizophrenia had increased contrast compared to controls bilaterally in the post- and precentral gyri, the transverse temporal gyri and posterior insulae, and in parieto-occipital regions. In bipolar disorder, increased contrast was primarily localized in the left precentral gyrus. There were no significant differences between schizophrenia and bipolar disorder. Findings of increased contrast remained after adjusting for cortical area, thickness, and gyrification. We found no association with antipsychotic medication dose.ConclusionsIncreased contrast was found in highly myelinated low-level sensory and motor regions in schizophrenia, and to a lesser extent in bipolar disorder. We propose that these findings indicate reduced intracortical myelin. In accordance with the corollary discharge hypothesis, this could cause disinhibition of sensory input, resulting in distorted perceptual processing leading to the characteristic positive symptoms of schizophrenia.