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There is a lack of knowledge regarding the relationship between proneness to dimensional psychopathological syndromes and the underlying pathogenesis across major psychiatric disorders, i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizoaffective Disorder (SZA), and Schizophrenia (SZ). Lifetime psychopathology was assessed using the OPerational CRITeria (OPCRIT) system in 1,038 patients meeting DSM-IV-TR criteria for MDD, BD, SZ, or SZA. The cohort was split into two samples for exploratory and confirmatory factor analyses. All patients were scanned with 3-T MRI, and data was analyzed with the CAT-12 toolbox in SPM12. Psychopathological factor scores were correlated with gray matter volume (GMV) and cortical thickness (CT). Finally, factor scores were used for exploratory genetic analyses including genome-wide association studies (GWAS) and polygenic risk score (PRS) association analyses. Three factors (paranoid-hallucinatory syndrome, PHS; mania, MA; depression, DEP) were identified and cross-validated. PHS was negatively correlated with four GMV clusters comprising parts of the hippocampus, amygdala, angular, middle occipital, and middle frontal gyri. PHS was also negatively associated with the bilateral superior temporal, left parietal operculum, and right angular gyrus CT. No significant brain correlates were observed for the two other psychopathological factors. We identified genome-wide significant associations for MA and DEP. PRS for MDD and SZ showed a positive effect on PHS, while PRS for BD showed a positive effect on all three factors. This study investigated the relationship of lifetime psychopathological factors and brain morphometric and genetic markers. Results highlight the need for dimensional approaches, overcoming the limitations of the current psychiatric nosology., (© 2024. The Author(s).)

Background: The psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders., Methods: Using FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n= 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural connectome measures, we employed linear regression models. We used network-based statistic to identify subnetworks of white matter fiber tracts associated with FTD symptomatology., Results: Three psychopathological FTD dimensions were delineated, i.e., disorganization, emptiness, and incoherence. Disorganization and incoherence were associated with global dysconnectivity. Network-based statistics identified subnetworks associated with the FTD dimensions disorganization and emptiness but not with the FTD dimension incoherence. Post hoc analyses on subnetworks did not reveal diagnosis × FTD dimension interaction effects. Results remained stable after correcting for medication and disease severity. Confirmatory analyses showed a substantial overlap of nodes from both subnetworks with cortical brain regions previously associated with FTD in SZ., Conclusions: We demonstrated white matter subnetwork dysconnectivity in major depressive disorder, bipolar disorder, and SZ associated with FTD dimensions that predominantly comprise brain regions implicated in speech. Results open an avenue for transdiagnostic, psychopathology-informed, dimensional studies in pathogenetic research., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Multivariate data-driven statistical approaches offer the opportunity to study multi-dimensional interdependences between a large set of biological parameters, such as high-dimensional brain imaging data. For gyrification, a putative marker of early neurodevelopment, direct comparisons of patterns among multiple psychiatric disorders and investigations of potential heterogeneity of gyrification within one disorder and a transdiagnostic characterization of neuroanatomical features are lacking., Methods: In this study we used a data-driven, multivariate statistical approach to analyze cortical gyrification in a large cohort of N = 1028 patients with major psychiatric disorders (Major depressive disorder: n = 783, bipolar disorder: n = 129, schizoaffective disorder: n = 44, schizophrenia: n = 72) to identify cluster patterns of gyrification beyond diagnostic categories., Results: Cluster analysis applied on gyrification data of 68 brain regions (DK-40 atlas) identified three clusters showing difference in overall (global) gyrification and minor regional variation (regions). Newly, data-driven subgroups are further discriminative in cognition and transdiagnostic disease risk factors., Conclusions: Results indicate that gyrification is associated with transdiagnostic risk factors rather than diagnostic categories and further imply a more global role of gyrification related to mental health than a disorder specific one. Our findings support previous studies highlighting the importance of association cortices involved in psychopathology. Explorative, data-driven approaches like ours can help to elucidate if the brain imaging data on hand and its a priori applied grouping actually has the potential to find meaningful effects or if previous hypotheses about the phenotype as well as its grouping have to be revisited., Competing Interests: Declaration of Competing Interest Biomedical financial interests or potential conflicts of interest: Tilo Kircher received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. All other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Schizotypy has become an increasingly important construct for elaborating psychotic disorders that vary along the schizophrenic spectrum. However, different schizotypy inventories vary in conceptual approach and measurement. In addition, commonly used schizotypy scales have been seen as qualitatively different from screening instruments for prodromal schizophrenia like the Prodromal Questionnaire-16 (PQ-16). Our study investigated the psychometric properties of three schizotypy questionnaires (the Schizotypal Personality Questionnaire-Brief, Oxford-Liverpool Inventory of Feelings and Experiences, and the Multidimensional Schizotypy Scale) as well as the PQ-16 in a cohort of 383 non-clinical subjects. We initially evaluated their factor structure using Principal Component Analysis (PCA) and used Confirmatory Factor Analysis (CFA) to test a newly proposed composition of factors. PCA results support a three-factor structure of schizotypy that accounts for 71 % of the total variance, but also shows cross-loadings of some schizotypy subscales. CFA of the newly composed schizotypy factors (together with an added neuroticism factor) shows good fit. Analyses including the PQ-16 indicate considerable overlap with measures of trait schizotypy, suggesting that the PQ-16 might not be quantitatively or qualitatively different from schizotypy measurements. Taken together, results indicate that there is good support for a three-factor structure of schizotypy but also that different schizotypy measurements grasp facets of schizotypy differently. This points towards the need for an integrative approach for assessing the construct of schizotypy., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: There is a lack of knowledge regarding the relationship between dimensional psychopathological syndromes and neurocognitive functions, particularly across the major psychiatric disorders (i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), and Schizophrenia (SZ))., Method: SANS, SAPS, HAMA, HAM-D, and YMRS were assessed in 1064 patients meeting DSM-IV-TR criteria for MDD, BD, SZ or schizoaffective disorder (SZA). In addition, a comprehensive neuropsychological test battery was administered. Psychopathological syndromes derived from factor analysis and present state of illness were used to explore psychopathology-cognition relationships. Correlational analyses were corrected for age, sex, verbal IQ, years of education, and DSM-IV-TR diagnosis. Age of onset and total duration of hospitalizations as proxies for illness severity were tested as moderators on the cognition - psychopathology relationship., Results: The negative syndrome, positive formal thought disorder as well as the paranoid-hallucinatory syndrome exhibited associations with neuro-cognition in an illness state-dependent manner, while the psychopathological factors depression and increased appetite only showed weak associations. Illness severity showed moderating effects on the neurocognitive-psychopathology relationship only for the negative syndrome and positive formal thought disorder., Limitations: No healthy control subjects were entered into the analyses because of lack of variance in psychopathological symptoms, which prevents from drawing conclusions regarding the relative level of potential cognitive impairments., Conclusions: This study suggests the relationship of neuro-cognition and psychopathology to be highly state of illness-dependent across affective and psychotic disorders. Results hint at the moderating effects of illness severity on psychopathological factors that might be more treatment resistant., Competing Interests: Conflict of interest Tilo Kircher received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. All other authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Factorial dimensions and neurobiological underpinnings of formal thought disorders (FTD) have been extensively investigated in schizophrenia spectrum disorders (SSD). However, FTD are also highly prevalent in other disorders. Still, there is a lack of knowledge about transdiagnostic, structural brain correlates of FTD. In N = 1071 patients suffering from DSM-IV major depressive disorder, bipolar disorder, or SSD, we calculated a psychopathological factor model of FTD based on the SAPS and SANS scales. We tested the association of FTD dimensions with 3 T MRI measured gray matter volume (GMV) and white matter fractional anisotropy (FA) using regression and interaction models in SPM12. We performed post hoc confirmatory analyses in diagnostically equally distributed, age- and sex-matched sub-samples to test whether results were driven by diagnostic categories. Cross-validation (explorative and confirmatory) factor analyses revealed three psychopathological FTD factors: disorganization, emptiness, and incoherence. Disorganization was negatively correlated with a GMV cluster comprising parts of the middle occipital and angular gyri and positively with FA in the right posterior cingulum bundle and inferior longitudinal fascicle. Emptiness was negatively associated with left hippocampus and thalamus GMV. Incoherence was negatively associated with FA in bilateral anterior thalamic radiation, and positively with the hippocampal part of the right cingulum bundle. None of the gray or white matter associations interacted with diagnosis. Our results provide a refined mapping of cross-disorder FTD phenotype dimensions. For the first time, we demonstrated that their neuroanatomical signatures are associated with language-related gray and white matter structures independent of diagnosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: More than a century of research on the neurobiological underpinnings of major psychiatric disorders (major depressive disorder [MDD], bipolar disorder [BD], schizophrenia [SZ], and schizoaffective disorder [SZA]) has been unable to identify diagnostic markers. An alternative approach is to study dimensional psychopathological syndromes that cut across categorical diagnoses. The aim of the current study was to identify gray matter volume (GMV) correlates of transdiagnostic symptom dimensions., Methods: We tested the association of 5 psychopathological factors with GMV using multiple regression models in a sample of N = 1069 patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for MDD (n = 818), BD (n = 132), and SZ/SZA (n = 119). T1-weighted brain images were acquired with 3-Tesla magnetic resonance imaging and preprocessed with CAT12. Interactions analyses (diagnosis × psychopathological factor) were performed to test whether local GMV associations were driven by DSM-IV diagnosis. We further tested syndrome specific regions of interest (ROIs)., Results: Whole brain analysis showed a significant negative association of the positive formal thought disorder factor with GMV in the right middle frontal gyrus, the paranoid-hallucinatory syndrome in the right fusiform, and the left middle frontal gyri. ROI analyses further showed additional negative associations, including the negative syndrome with bilateral frontal opercula, positive formal thought disorder with the left amygdala-hippocampus complex, and the paranoid-hallucinatory syndrome with the left angular gyrus. None of the GMV associations interacted with DSM-IV diagnosis., Conclusions: We found associations between psychopathological syndromes and regional GMV independent of diagnosis. Our findings open a new avenue for neurobiological research across disorders, using syndrome-based approaches rather than categorical diagnoses., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Schizotypy and psychotic-like experiences (PLE) form part of the wider psychosis continuum and may have brain structural correlates in nonclinical cohorts. This study aimed to compare the effects of differential schizotypy dimensions, PLE, and their interaction on hippocampal subfields and amygdala volumes in the absence of clinical psychopathology. In a cohort of 367 psychiatrically healthy individuals, we assessed schizotypal traits using the Oxford-Liverpool Inventory of Life Experiences (O-LIFE) and PLE using the short form of the Prodromal Questionnaire (PQ-16). Based on high-resolution structural MRI scans, we used automated segmentation to estimate volumes of limbic structures. Sex and total intracranial volume (Step 1), PLE and schizotypy dimensions (Step 2), and their interaction terms (Step 3) were entered as regressors for bilateral amygdala and hippocampal subfield volumes in hierarchical multiple linear regression models. Positive schizotypy, but not PLE, was negatively associated with left amygdala and subiculum volumes. O-LIFE Impulsive Nonconformity, as well as the two-way interaction between positive schizotypy and PLE, were associated with larger left subiculum volumes. None of the estimators for right hemispheric hippocampal subfield volumes survived correction for multiple comparisons. Our findings support differential associations of hippocampus subfield volumes with trait dimensions rather than PLE, and support overlap and interactions between psychometric positive schizotypy and PLE. In a healthy cohort without current psychosis risk syndromes, the positive association between PLE and hippocampal subfield volume occurred at a high expression of positive schizotypy. Further studies combining stable, transient, and genetic parameters are required., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

In the general population, psychosis risk phenotypes occur independently of attenuated prodromal syndromes. Neurobiological correlates of vulnerability could help to understand their meaningfulness. Interactions between the occurrence of psychotic-like experiences (PLE) and other psychological factors e.g., distress related to PLE, may distinguish psychosis-prone individuals from those without risk of future psychotic disorder. We aimed to investigate whether (a) correlates of total PLE and distress, and (b) symptom dimension-specific moderation effects exist at the brain structural level in non-help-seeking adults reporting PLE below and above the screening criterion for clinical high-risk (CHR). We obtained T1-weighted whole-brain MRI scans from 104 healthy adults from the community without psychosis CHR states for voxel-based morphometry (VBM). Brain structural associations with PLE and PLE distress were analysed with multiple linear regression models. Moderation of PLE by distress severity of two types of positive symptoms from the Prodromal Questionnaire (PQ-16) screening inventory was explored in regions-of-interest after VBM. Total PQ-16 score was positively associated with grey matter volume (GMV) in prefrontal regions, occipital fusiform and lingual gyri (p < 0.05, FDR peak-level corrected). Overall distress severity and GMV were not associated. Examination of distress severity on the positive symptom dimensions as moderators showed reduced strength of the association between PLE and rSFG volume with increased distress severity for perceptual PLE. In this study, brain structural variation was related to PLE level, but not distress severity, suggesting specificity. In healthy individuals, positive relationships between PLE and prefrontal volumes may indicate protective features, which supports the insufficiency of PLE for the prediction of CHR. Additional indicators of vulnerability, such as distress associated with perceptual PLE, change the positive brain structure relationship. Brain structural findings may strengthen clinical objectives through disentanglement of innocuous and risk-related PLE., (© 2021. The Author(s).)

Numerous studies have implicated involvement of the hippocampus in the etiology and expression of schizophrenia-spectrum psychopathology, and reduced hippocampal volume is one of the most robust brain abnormalities reported in schizophrenia. Recent studies indicate that early stages of schizophrenia are specifically characterized by reductions in anterior hippocampal volume; however, studies have not examined hippocampal volume reductions in subclinical schizotypy. The present study was the first to examine the associations of positive, negative, and disorganized schizotypy dimensions with hippocampal subfield volumes in a large sample (n = 195) of nonclinically ascertained young adults, phenotyped using the Multidimensional Schizotypy Scale (MSS). Hippocampal subfields were analyzed from high-resolution 3 Tesla structural magnetic resonance imaging scans testing anatomical models, including anterior vs posterior regions and the cornu ammonis (CA), dentate gyrus (DG), and subiculum subfields separately for the left and right hemispheres. We demonstrate differential spatial effects across anterior vs posterior hippocampus segments across different dimensions of the schizotypy risk phenotype. The interaction of negative and disorganized schizotypy robustly predicted left hemisphere volumetric reductions for the anterior and total hippocampus, and anterior CA and DG, and the largest reductions were seen in participants high in negative and disorganized schizotypy. These findings extend previous early psychosis studies and together with behavioral studies of hippocampal-related memory impairments provide the basis for a dimensional neurobiological hippocampal model of schizophrenia risk. Subtle hippocampal subfield volume reductions may be prevalent prior to the onset of detectable prodromal clinical symptoms of psychosis and play a role in the etiology and development of such conditions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)