Signature of altered retinal microstructures and electrophysiology in schizophrenia spectrum disorders is associated with disease severity and polygenic risk.

BACKGROUND: Optical coherence tomography (OCT) and electroretinography (ERG) studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSD). However, it remains unclear which specific retinal layers are affected, how the retina, brain, and clinical symptomatology are connected, and how alterations of the visual system are related to genetic disease risk. METHODS: OCT, ERG, and brain magnetic resonance imaging (MRI) were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSD and 130 healthy control individuals. The sparse partial least squares (SPLS) algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with the individual polygenetic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual OCT and ERG parameter. RESULTS: The SPLS analysis yielded a phenotype-eye-brain signature of SSD in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSD had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. CONCLUSIONS: This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSD that are associated with disease severity and individual polygenetic burden.

Distinct multimodal biological and functional profiles of symptom-based subgroups in recent-onset psychosis.

Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.

Who is at risk for weight gain after weight-gain associated treatment with antipsychotics, antidepressants, and mood stabilizers: A machine learning approach.

BACKGROUND: Weight gain is a common side effect in psychopharmacology; however, targeted therapeutic interventions and prevention strategies are currently absent in day-to-day clinical practice. To promote the development of such strategies, the identification of factors indicative of patients at risk is essential. METHODS: In this study, we developed a transdiagnostic model using and comparing decision tree classifiers, logistic regression, XGboost, and a support vector machine to predict weight gain of ≥5% of body weight during the first 4 weeks of treatment with psychotropic drugs associated with weight gain in 103 psychiatric inpatients. We included established variables from the literature as well as an extended set with additional clinical variables and questionnaires. RESULTS: Baseline BMI, premorbid BMI, and age are known risk factors and were confirmed by our models. Additionally, waist circumference has emerged as a new and significant risk factor. Eating behavior next to blood glucose were found as additional potential predictor that may underlie therapeutic interventions and could be used for preventive strategies in a cohort at risk for psychotropics induced weight gain (PIWG). CONCLUSION: Our models validate existing findings and further uncover previously unknown modifiable factors, such as eating behavior and blood glucose, which can be used as targets for preventive strategies. These findings underscore the imperative for continued research in this domain to establish effective preventive measures for individuals undergoing psychotropic drug treatments.

Deconstructing depression by machine learning: the POKAL-PSY study.

Unipolar depression is a prevalent and disabling condition, often left untreated. In the outpatient setting, general practitioners fail to recognize depression in about 50% of cases mainly due to somatic comorbidities. Given the significant economic, social, and interpersonal impact of depression and its increasing prevalence, there is a need to improve its diagnosis and treatment in outpatient care. Various efforts have been made to isolate individual biological markers for depression to streamline diagnostic and therapeutic approaches. However, the intricate and dynamic interplay between neuroinflammation, metabolic abnormalities, and relevant neurobiological correlates of depression is not yet fully understood. To address this issue, we propose a naturalistic prospective study involving outpatients with unipolar depression, individuals without depression or comorbidities, and healthy controls. In addition to clinical assessments, cardiovascular parameters, metabolic factors, and inflammatory parameters are collected. For analysis we will use conventional statistics as well as machine learning algorithms. We aim to detect relevant participant subgroups by data-driven cluster algorithms and their impact on the subjects' long-term prognosis. The POKAL-PSY study is a subproject of the research network POKAL (Predictors and Clinical Outcomes in Depressive Disorders; GRK 2621).

Effects of Substance Use and Antisocial Personality on Neuroimaging-Based Machine Learning Prediction of Schizophrenia.

BACKGROUND AND HYPOTHESIS: Neuroimaging-based machine learning (ML) algorithms have the potential to aid the clinical diagnosis of schizophrenia. However, literature on the effect of prevalent comorbidities such as substance use disorder (SUD) and antisocial personality (ASPD) on these models' performance has remained unexplored. We investigated whether the presence of SUD or ASPD affects the performance of neuroimaging-based ML models trained to discern patients with schizophrenia (SCH) from controls. STUDY DESIGN: We trained an ML model on structural MRI data from public datasets to distinguish between SCH and controls (SCH = 347, controls = 341). We then investigated the model's performance in two independent samples of individuals undergoing forensic psychiatric examination: sample 1 was used for sensitivity analysis to discern ASPD (N = 52) from SCH (N = 66), and sample 2 was used for specificity analysis to discern ASPD (N = 26) from controls (N = 25). Both samples included individuals with SUD. STUDY RESULTS: In sample 1, 94.4% of SCH with comorbid ASPD and SUD were classified as SCH, followed by patients with SCH + SUD (78.8% classified as SCH) and patients with SCH (60.0% classified as SCH). The model failed to discern SCH without comorbidities from ASPD + SUD (AUC = 0.562, 95%CI = 0.400-0.723). In sample 2, the model's specificity to predict controls was 84.0%. In both samples, about half of the ASPD + SUD were misclassified as SCH. Data-driven functional characterization revealed associations between the classification as SCH and cognition-related brain regions. CONCLUSION: Altogether, ASPD and SUD appear to have effects on ML prediction performance, which potentially results from converging cognition-related brain abnormalities between SCH, ASPD, and SUD.

Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.

BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

Patterns of risk-Using machine learning and structural neuroimaging to identify pedophilic offenders.

Background: Child sexual abuse (CSA) has become a focal point for lawmakers, law enforcement, and mental health professionals. With high prevalence rates around the world and far-reaching, often chronic, individual, and societal implications, CSA and its leading risk factor, pedophilia, have been well investigated. This has led to a wide range of clinical tools and actuarial instruments for diagnosis and risk assessment regarding CSA. However, the neurobiological underpinnings of pedosexual behavior, specifically regarding hands-on pedophilic offenders (PO), remain elusive. Such biomarkers for PO individuals could potentially improve the early detection of high-risk PO individuals and enhance efforts to prevent future CSA. Aim: To use machine learning and MRI data to identify PO individuals. Methods: From a single-center male cohort of 14 PO individuals and 15 matched healthy control (HC) individuals, we acquired diffusion tensor imaging data (anisotropy, diffusivity, and fiber tracking) in literature-based regions of interest (prefrontal cortex, anterior cingulate cortex, amygdala, and corpus callosum). We trained a linear support vector machine to discriminate between PO and HC individuals using these WM microstructure data. Post hoc, we investigated the PO model decision scores with respect to sociodemographic (age, education, and IQ) and forensic characteristics (psychopathy, sexual deviance, and future risk of sexual violence) in the PO subpopulation. We assessed model specificity in an external cohort of 53 HC individuals. Results: The classifier discriminated PO from HC individuals with a balanced accuracy of 75.5% (sensitivity = 64.3%, specificity = 86.7%, P 5000 = 0.018) and an out-of-sample specificity to correctly identify HC individuals of 94.3%. The predictive brain pattern contained bilateral fractional anisotropy in the anterior cingulate cortex, diffusivity in the left amygdala, and structural prefrontal cortex-amygdala connectivity in both hemispheres. This brain pattern was associated with the number of previous child victims, the current stance on sexuality, and the professionally assessed risk of future sexual violent reoffending. Conclusion: Aberrant white matter microstructure in the prefronto-temporo-limbic circuit could be a potential neurobiological correlate for PO individuals at high-risk of reoffending with CSA. Although preliminary and exploratory at this point, our findings highlight the general potential of MRI-based biomarkers and particularly WM microstructure patterns for future CSA risk assessment and preventive efforts.

The non-specific nature of mental health and structural brain outcomes following childhood trauma.

BACKGROUND: Childhood trauma (CT) is associated with an increased risk of mental health disorders; however, it is unknown whether this represents a diagnosis-specific risk factor for specific psychopathology mediated by structural brain changes. Our aim was to explore whether (i) a predictive CT pattern for transdiagnostic psychopathology exists, and whether (ii) CT can differentiate between distinct diagnosis-dependent psychopathology. Furthermore, we aimed to identify the association between CT, psychopathology and brain structure. METHODS: We used multivariate pattern analysis in data from 643 participants of the Personalised Prognostic Tools for Early Psychosis Management study (PRONIA), including healthy controls (HC), recent onset psychosis (ROP), recent onset depression (ROD), and patients clinically at high-risk for psychosis (CHR). Participants completed structured interviews and self-report measures including the Childhood Trauma Questionnaire, SCID diagnostic interview, BDI-II, PANSS, Schizophrenia Proneness Instrument, Structured Interview for Prodromal Symptoms and structural MRI, analyzed by voxel-based morphometry. RESULTS: (i) Patients and HC could be distinguished by their CT pattern with a reasonable precision [balanced accuracy of 71.2% (sensitivity = 72.1%, specificity = 70.4%, p ≤ 0.001]. (ii) Subdomains 'emotional neglect' and 'emotional abuse' were most predictive for CHR and ROP, while in ROD 'physical abuse' and 'sexual abuse' were most important. The CT pattern was significantly associated with the severity of depressive symptoms in ROD, ROP, and CHR, as well as with the PANSS total and negative domain scores in the CHR patients. No associations between group-separating CT patterns and brain structure were found. CONCLUSIONS: These results indicate that CT poses a transdiagnostic risk factor for mental health disorders, possibly related to depressive symptoms. While differences in the quality of CT exposure exist, diagnostic differentiation was not possible suggesting a multi-factorial pathogenesis.

Exploring Links Between Psychosis and Frontotemporal Dementia Using Multimodal Machine Learning: Dementia Praecox Revisited.

Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2 = 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2 = 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

Challenges of Multiplex Assays for COVID-19 Research: A Machine Learning Perspective.

Multiplex assays that provide simultaneous measurement of multiple analytes in biological samples have now developed into widely used technologies in the study of diseases, drug discovery, and other medical areas. These approaches span multiple assay systems and can provide readouts of specific assay components with similar accuracy as the respective single assay measurements. Multiplexing allows the consumption of lower sample volumes, lower costs, and higher throughput compared with carrying out single assays. A number of recent studies have demonstrated the impact of multiplex assays in the study of the SARS-CoV-2 virus, the infectious agent responsible for the current COVID-19 pandemic. In this respect, machine learning techniques have proven to be highly valuable in capturing complex disease phenotypes and converting these insights into models which can be applied in real-world settings. This chapter gives an overview of opportunities and challenges of multiplexed biomarker analysis, with a focus on the use of machine learning aimed at identification of biological signatures for increasing our understanding of COVID-19 disease, and for improved diagnostics and prediction of disease outcomes.

Clinical, Brain, and Multilevel Clustering in Early Psychosis and Affective Stages.

Importance: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. Objective: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. Design, Setting, and Participants: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. Main Outcomes and Measures: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. Results: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. Conclusions and Relevance: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.

The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study.

BACKGROUND: Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. METHODS: 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (pfdr < 0.001) and role (pfdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (pfdr < 0.001) and phonological verbal fluency (pfdr < 0.001), short-term verbal memory (pfdr = 0.002) and abstract thinking (pfdr = 0.010), in comparison to FTD-Low group. CONCLUSIONS: Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.

Classical blood biomarkers identify patients with higher risk for relapse 6 months after alcohol withdrawal treatment.

This naturalistic study among patients with alcohol dependence examined whether routine blood biomarkers could help to identify patients with high risk for relapse after withdrawal treatment. In a longitudinal study with 6-month follow-up among 133 patients with alcohol dependence who received inpatient alcohol withdrawal treatment, we investigated the usefulness of routine blood biomarkers and clinical and sociodemographic factors for potential outcome prediction and risk stratification. Baseline routine blood biomarkers (gamma-glutamyl transferase [GGT], alanine aminotransferase [ALT/GPT], aspartate aminotransferase [AST/GOT], mean cell volume of erythrocytes [MCV]), and clinical and sociodemographic characteristics were recorded at admission. Standardized 6 months' follow-up assessed outcome variables continuous abstinence, days of continuous abstinence, daily alcohol consumption and current abstinence. The combined threshold criterion of an AST:ALT ratio > 1.00 and MCV > 90.0 fl helped to identify high-risk patients. They had lower abstinence rates (P = 0.001), higher rates of daily alcohol consumption (P < 0.001) and shorter periods of continuous abstinence (P = 0.027) compared with low-risk patients who did not meet the threshold criterion. Regression analysis confirmed our hypothesis that the combination criterion is an individual baseline variable that significantly predicted parts of the respective outcome variances. Routinely assessed indirect alcohol biomarkers help to identify patients with high risk for relapse after alcohol withdrawal treatment. Clinical decision algorithms to identify patients with high risk for relapse after alcohol withdrawal treatment could include classical blood biomarkers in addition to clinical and sociodemographic items.

Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression.

Importance: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. Objectives: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. Design, Setting, and Participants: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. Main Outcomes and Measures: Accuracy and generalizability of prognostic systems. Results: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. Conclusions and Relevance: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.

Präzisionspsychiatrie und der Beitrag von Brain Imaging und anderen Biomarkern.

'Precision Psychiatry' as the psychiatric variant of 'Precision Medicine' aims to provide high-level diagnosis and treatment based on robust biomarkers and tailored to the individual clinical, neurobiological, and genetic constitution of the patient. The specific peculiarity of psychiatry, in which disease entities are normatively defined based on clinical experience and are also significantly influenced by contemporary history, society and philosophy, has so far made the search for valid and reliable psychobiological connections difficult. Nevertheless, considerable progress has now been made in all areas of psychiatric research, made possible above all by the critical review and renewal of previous concepts of disease and psychopathology, the increased orientation towards neurobiology and genetics, and in particular the use of machine learning methods. Notably, modern machine learning methods make it possible to integrate high-dimensional and multimodal data sets and generate models which provide new psychobiological insights and offer the possibility of individualized, biomarker-driven single-subject prediction of diagnosis, therapy response and prognosis. The aim of the present review is therefore to introduce the concept of 'Precision Psychiatry' to the interested reader, to concisely present modern, machine learning methods required for this, and to clearly present the current state and future of biomarker-based 'precision psychiatry'.

Traces of Trauma: A Multivariate Pattern Analysis of Childhood Trauma, Brain Structure, and Clinical Phenotypes.

BACKGROUND: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. METHODS: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. RESULTS: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. CONCLUSIONS: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

Childhood Trauma in Schizophrenia: Current Findings and Research Perspectives.

Schizophrenia is a severe neuropsychiatric disorder with persistence of symptoms throughout adult life in most of the affected patients. This unfavorable course is associated with multiple episodes and residual symptoms, mainly negative symptoms and cognitive deficits. The neural diathesis-stress model proposes that psychosocial stress acts on a pre-existing vulnerability and thus triggers the symptoms of schizophrenia. Childhood trauma is a severe form of stress that renders individuals more vulnerable to developing schizophrenia; neurobiological effects of such trauma on the endocrine system and epigenetic mechanisms are discussed. Childhood trauma is associated with impaired working memory, executive function, verbal learning, and attention in schizophrenia patients, including those at ultra-high risk to develop psychosis. In these patients, higher levels of childhood trauma were correlated with higher levels of attenuated positive symptoms, general symptoms, and depressive symptoms; lower levels of global functioning; and poorer cognitive performance in visual episodic memory end executive functions. In this review, we discuss effects of specific gene variants that interact with childhood trauma in patients with schizophrenia and describe new findings on the brain structural and functional level. Additive effects between childhood trauma and brain-derived neurotrophic factor methionine carriers on volume loss of the hippocampal subregions cornu ammonis (CA)4/dentate gyrus and CA2/3 have been reported in schizophrenia patients. A functional magnetic resonance imaging study showed that childhood trauma exposure resulted in aberrant function of parietal areas involved in working memory and of visual cortical areas involved in attention. In a theory of mind task reflecting social cognition, childhood trauma was associated with activation of the posterior cingulate gyrus, precuneus, and dorsomedial prefrontal cortex in patients with schizophrenia. In addition, decreased connectivity was shown between the posterior cingulate/precuneus region and the amygdala in patients with high levels of physical neglect and sexual abuse during childhood, suggesting that disturbances in specific brain networks underlie cognitive abilities. Finally, we discuss some of the questionnaires that are commonly used to assess childhood trauma and outline possibilities to use recent biostatistical methods, such as machine learning, to analyze the resulting datasets.

Short and long-lasting behavioral consequences of agonistic encounters between male Drosophila melanogaster.

In many animal species, learning and memory have been found to play important roles in regulating intra- and interspecific behavioral interactions in varying environments. In such contexts, aggression is commonly used to obtain desired resources. Previous defeats or victories during aggressive interactions have been shown to influence the outcome of later contests, revealing loser and winner effects. In this study, we asked whether short- and/or long-term behavioral consequences accompany victories and defeats in dyadic pairings between male Drosophila melanogaster and how long those effects remain. The results demonstrated that single fights induced important behavioral changes in both combatants and resulted in the formation of short-term loser and winner effects. These decayed over several hours, with the duration depending on the level of familiarity of the opponents. Repeated defeats induced a long-lasting loser effect that was dependent on de novo protein synthesis, whereas repeated victories had no long-term behavioral consequences. This suggests that separate mechanisms govern the formation of loser and winner effects. These studies aim to lay a foundation for future investigations exploring the molecular mechanisms and circuitry underlying the nervous system changes induced by winning and losing bouts during agonistic encounters.