An evolutionary timeline of the oxytocin signaling pathway.

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are 'modern'. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, 'mya'), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are 'ancient', meaning their emergence dates back to cellular organisms and opisthokonta (3500-1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as 'medium-aged'. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

Parkinsonism, Psychomotor Slowing, Negative and Depressive Symptoms in Schizophrenia Spectrum and Mood Disorders: Exploring Their Intricate Nexus Using a Network Analytic Approach.

BACKGROUND AND HYPOTHESIS: Parkinsonism, psychomotor slowing, negative and depressive symptoms show evident phenomenological similarities across different mental disorders. However, the extent to which they interact with each other is currently unclear. Here, we hypothesized that parkinsonism is an independent motor abnormality showing limited associations with psychomotor slowing, negative and depressive symptoms in schizophrenia spectrum (SSD), and mood disorders (MOD). STUDY DESIGN: We applied network analysis and community detection methods to examine the interplay and centrality (expected influence [EI] and strength) between parkinsonism, psychomotor slowing, negative and depressive symptoms in 245 SSD and 99 MOD patients. Parkinsonism was assessed with the Simpson-Angus Scale (SAS). We used the Positive and Negative Syndrome Scale (PANSS) to examine psychomotor slowing (item #G7), negative symptoms (PANSS-N), and depressive symptoms (item #G6). STUDY RESULTS: In SSD and MOD, PANSS item #G7 and PANSS-N showed the largest EI and strength as measures of centrality. Parkinsonism had small or no influence on psychomotor slowing, negative and depressive symptoms in SSD and MOD. In SSD and MOD, exploratory graph analysis identified one community, but parkinsonism showed a small influence on its occurrence. Network Comparison Test yielded no significant differences between the SSD and MOD networks (global strength p value: .396 and omnibus tests p value: .574). CONCLUSIONS: The relationships between the individual domains followed a similar pattern in both SSD and MOD highlighting their transdiagnostic relevance. Despite evident phenomenological similarities, our results suggested that parkinsonism is more independent of negative and depressive symptoms than psychomotor slowing in both SSD and MOD.

Multimodal workflows optimally predict response to repetitive transcranial magnetic stimulation in patients with schizophrenia: a multisite machine learning analysis.

The response variability to repetitive transcranial magnetic stimulation (rTMS) challenges the effective use of this treatment option in patients with schizophrenia. This variability may be deciphered by leveraging predictive information in structural MRI, clinical, sociodemographic, and genetic data using artificial intelligence. We developed and cross-validated rTMS response prediction models in patients with schizophrenia drawn from the multisite RESIS trial. The models incorporated pre-treatment sMRI, clinical, sociodemographic, and polygenic risk score (PRS) data. Patients were randomly assigned to receive active (N = 45) or sham (N = 47) rTMS treatment. The prediction target was individual response, defined as ≥20% reduction in pre-treatment negative symptom sum scores of the Positive and Negative Syndrome Scale. Our multimodal sequential prediction workflow achieved a balanced accuracy (BAC) of 94% (non-responders: 92%, responders: 95%) in the active-treated group and 50% in the sham-treated group. The clinical, clinical + PRS, and sMRI-based classifiers yielded BACs of 65%, 76%, and 80%, respectively. Apparent sadness, inability to feel, educational attainment PRS, and unemployment were most predictive of non-response in the clinical + PRS model, while grey matter density reductions in the default mode, limbic networks, and the cerebellum were most predictive in the sMRI model. Our sequential modelling approach provided superior predictive performance while minimising the diagnostic burden in the clinical setting. Predictive patterns suggest that rTMS responders may have higher levels of brain grey matter in the default mode and salience networks which increases their likelihood of profiting from plasticity-inducing brain stimulation methods, such as rTMS. The future clinical implementation of our models requires findings to be replicated at the international scale using stratified clinical trial designs.

Deciphering the interplay between psychopathological symptoms, sensorimotor, cognitive and global functioning: a transdiagnostic network analysis.

BACKGROUND: Understanding the relationship between psychopathology and major domains of human neurobehavioral functioning may identify new transdiagnostic treatment targets. However, studies examining the interrelationship between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample are lacking. We hypothesized a close relationship between sensorimotor and cognitive functioning in a transdiagnostic patient sample. METHODS: We applied network analysis and community detection methods to examine the interplay and centrality [expected influence (EI) and strength] between psychopathological symptoms, sensorimotor, cognitive, and global functioning in a transdiagnostic sample consisting of 174 schizophrenia spectrum (SSD) and 38 mood disorder (MOD) patients. All patients (n = 212) were examined with the Positive and Negative Syndrome Scale (PANSS), the Heidelberg Neurological Soft Signs Scale (NSS), the Global Assessment of Functioning (GAF), and the Brief Cognitive Assessment Tool for Schizophrenia consisted of trail making test B (TMT-B), category fluency (CF) and digit symbol substitution test (DSST). RESULTS: NSS showed closer connections with TMT-B, CF, and DSST than with GAF and PANSS. DSST, PANSS general, and NSS motor coordination scores showed the highest EI. Sensory integration, DSST, and CF showed the highest strength. CONCLUSIONS: The close connection between sensorimotor and cognitive impairment as well as the high centrality of sensorimotor symptoms suggests that both domains share aspects of SSD and MOD pathophysiology. But, because the majority of the study population was diagnosed with SSD, the question as to whether sensorimotor symptoms are really a transdiagnostic therapeutic target needs to be examined in future studies including more balanced diagnostic groups.

Multimodal Associations of FKBP5 Methylation With Emotion-Regulatory Brain Circuits.

BACKGROUND: Understanding the biological processes that underlie individual differences in emotion regulation and stress responsivity is a key challenge for translational neuroscience. The gene FKBP5 is a core regulator in molecular stress signaling that is implicated in the development of psychiatric disorders. However, it remains unclear how FKBP5 DNA methylation in peripheral blood is related to individual differences in measures of neural structure and function and their relevance to daily-life stress responsivity. METHODS: Here, we characterized multimodal correlates of FKBP5 DNA methylation by combining epigenetic data with neuroimaging and ambulatory assessment in a sample of 395 healthy individuals. RESULTS: First, we showed that FKBP5 demethylation as a psychiatric risk factor was related to an anxiety-associated reduction of gray matter volume in the ventromedial prefrontal cortex, a brain area that is involved in emotion regulation and mental health risk and resilience. This effect of epigenetic upregulation of FKBP5 on neuronal structure is more pronounced where FKBP5 is epigenetically downregulated at baseline. Leveraging 208 functional magnetic resonance imaging scans during a well-established emotion-processing task, we found that FKBP5 DNA methylation in peripheral blood was associated with functional differences in prefrontal-limbic circuits that modulate affective responsivity to daily stressors, which we measured using ecological momentary assessment in daily life. CONCLUSIONS: Overall, we demonstrated how FKBP5 contributes to interindividual differences in neural and real-life affect regulation via structural and functional changes in prefrontal-limbic brain circuits.

A primer on the use of machine learning to distil knowledge from data in biological psychiatry.

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.

Psychomotor slowing in schizophrenia is associated with cortical thinning of primary motor cortex: A three cohort structural magnetic resonance imaging study.

Psychomotor slowing (PS) is characterized by slowed movements and lower activity levels. PS is frequently observed in schizophrenia (SZ) and distressing because it impairs performance of everyday tasks and social activities. Studying brain topography contributing to PS in SZ can help to understand the underlying neurobiological mechanisms as well as help to develop more effective treatments that specifically target affected brain areas. Here, we conducted structural magnetic resonance imaging (sMRI) of three independent cohorts of right-handed SZ patients (SZ#1: n = 72, SZ#2: n = 37, SZ#3: n = 25) and age, gender and education matched healthy controls (HC) (HC#1: n = 40, HC#2: n = 37, HC#3: n = 38). PS severity in the three SZ cohorts was determined using the Positive and Negative Syndrome Scale (PANSS) item #G7 (motor retardation) and Trail-Making-Test B (TMT-B). FreeSurfer v7.2 was used for automated parcellation and segmentation of cortical and subcortical regions. SZ#1 patients showed reduced cortical thickness in right precentral gyrus (M1; p = 0.04; Benjamini-Hochberg [BH] corr.). In SZ#1, cortical thinning in right M1 was associated with PANSS item #G7 (p = 0.04; BH corr.) and TMT-B performance (p = 0.002; BH corr.). In SZ#1, we found a significant correlation between PANSS item #G7 and TMT-B (p = 0.005, ρ=0.326). In conclusion, PANSS G#7 and TMT-B might have a surrogate value for predicting PS in SZ. Cortical thinning of M1 rather than alterations of subcortical structures may point towards cortical pathomechanism underlying PS in SZ.

Early Social Adversity, Altered Brain Functional Connectivity, and Mental Health.

Early adverse environmental exposures during brain development are widespread risk factors for the onset of severe mental disorders and strong and consistent predictors of stress-related mental and physical illness and reduced life expectancy. Current evidence suggests that early negative experiences alter plasticity processes during developmentally sensitive time windows and affect the regular functional interaction of cortical and subcortical neural networks. This, in turn, may promote a maladapted development with negative consequences on the mental and physical health of exposed individuals. In this review, we discuss the role of functional magnetic resonance imaging-based functional connectivity phenotypes as potential biomarker candidates for the consequences of early environmental exposures-including but not limited to-childhood maltreatment. We take an expanded concept of developmentally relevant adverse experiences from infancy over childhood to adolescence as our starting point and focus our review of functional connectivity studies on a selected subset of functional magnetic resonance imaging-based phenotypes, including connectivity in the limbic and within the frontoparietal as well as default mode networks, for which we believe there is sufficient converging evidence for a more detailed discussion in a developmental context. Furthermore, we address specific methodological challenges and current knowledge gaps that complicate the interpretation of early stress effects on functional connectivity and deserve particular attention in future studies. Finally, we highlight the forthcoming prospects and challenges of this research area with regard to establishing functional connectivity measures as validated biomarkers for brain developmental processes and individual risk stratification and as target phenotypes for mechanism-based interventions.

Computational Modeling of the n-Back Task in the ABCD Study: Associations of Drift Diffusion Model Parameters to Polygenic Scores of Mental Disorders and Cardiometabolic Diseases.

BACKGROUND: Cognitive dysfunction is common in mental disorders and represents a potential risk factor in childhood. The nature and extent of associations between childhood cognitive function and polygenic risk for mental disorders is unclear. We applied computational modeling to gain insight into mechanistic processes underlying decision making and working memory in childhood and their associations with polygenic risk scores (PRSs) for mental disorders and comorbid cardiometabolic diseases. METHODS: We used the drift diffusion model to infer latent computational processes underlying decision making and working memory during the n-back task in 3707 children ages 9 to 10 years from the Adolescent Brain Cognitive Development (ABCD) Study. Single nucleotide polymorphism-based heritability was estimated for cognitive phenotypes, including computational parameters, aggregated n-back task performance, and neurocognitive assessments. PRSs were calculated for Alzheimer's disease, bipolar disorder, coronary artery disease (CAD), major depressive disorder, obsessive-compulsive disorder, schizophrenia, and type 2 diabetes. RESULTS: Heritability estimates of cognitive phenotypes ranged from 12% to 38%. Bayesian mixed models revealed that slower accumulation of evidence was associated with higher PRSs for CAD and schizophrenia. Longer nondecision time was associated with higher PRSs for Alzheimer's disease and lower PRSs for CAD. Narrower decision threshold was associated with higher PRSs for CAD. Load-dependent effects on nondecision time and decision threshold were associated with PRSs for Alzheimer's disease and CAD, respectively. Aggregated neurocognitive test scores were not associated with PRSs for any of the mental or cardiometabolic phenotypes. CONCLUSIONS: We identified distinct associations between computational cognitive processes and genetic risk for mental illness and cardiometabolic disease, which could represent childhood cognitive risk factors.

Advancing translational research in neuroscience through multi-task learning.

Translational research in neuroscience is increasingly focusing on the analysis of multi-modal data, in order to account for the biological complexity of suspected disease mechanisms. Recent advances in machine learning have the potential to substantially advance such translational research through the simultaneous analysis of different data modalities. This review focuses on one of such approaches, the so-called "multi-task learning" (MTL), and describes its potential utility for multi-modal data analyses in neuroscience. We summarize the methodological development of MTL starting from conventional machine learning, and present several scenarios that appear particularly suitable for its application. For these scenarios, we highlight different types of MTL algorithms, discuss emerging technological adaptations, and provide a step-by-step guide for readers to apply the MTL approach in their own studies. With its ability to simultaneously analyze multiple data modalities, MTL may become an important element of the analytics repertoire used in future neuroscience research and beyond.

dsMTL: a computational framework for privacy-preserving, distributed multi-task machine learning.

MOTIVATION: In multi-cohort machine learning studies, it is critical to differentiate between effects that are reproducible across cohorts and those that are cohort-specific. Multi-task learning (MTL) is a machine learning approach that facilitates this differentiation through the simultaneous learning of prediction tasks across cohorts. Since multi-cohort data can often not be combined into a single storage solution, there would be the substantial utility of an MTL application for geographically distributed data sources. RESULTS: Here, we describe the development of 'dsMTL', a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. First, we derive the theoretical properties of these methods and the relevant machine learning workflows to ensure the validity of the software implementation. Second, we implement dsMTL as a library for the R programming language, building on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. Third, we demonstrate the applicability of dsMTL for comorbidity modeling in distributed data. We show that comorbidity modeling using dsMTL outperformed conventional, federated machine learning, as well as the aggregation of multiple models built on the distributed datasets individually. The application of dsMTL was computationally efficient and highly scalable when applied to moderate-size (n < 500), real expression data given the actual network latency. AVAILABILITY AND IMPLEMENTATION: dsMTL is freely available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

Association of polygenic risk for schizophrenia with fast sleep spindle density depends on pro-cognitive variants.

Cognitive impairment is a common feature in schizophrenia and the strongest prognostic factor for long-term outcome. Identifying a trait associated with the genetic background for cognitive outcome in schizophrenia may aid in a deeper understanding of clinical disease subtypes. Fast sleep spindles may represent such a biomarker as they are strongly genetically determined, associated with cognitive functioning and impaired in schizophrenia and unaffected relatives. We measured fast sleep spindle density in 150 healthy adults and investigated its association with a genome-wide polygenic score for schizophrenia (SCZ-PGS). The association between SCZ-PGS and fast spindle density was further characterized by stratifying it to the genetic background of intelligence. SCZ-PGS was positively associated with fast spindle density. This association mainly depended on pro-cognitive genetic variants. Our results strengthen the evidence for a genetic background of spindle abnormalities in schizophrenia. Spindle density might represent an easily accessible marker for a favourable cognitive outcome which should be further investigated in clinical samples.

Oxytocin receptor expression patterns in the human brain across development.

Oxytocin plays a vital role in social behavior and homeostatic processes, with animal models indicating that oxytocin receptor (OXTR) expression patterns in the brain influence behavior and physiology. However, the developmental trajectory of OXTR gene expression is unclear. By analyzing gene expression data in human post-mortem brain samples, from the prenatal period to late adulthood, we demonstrate distinct patterns of OXTR gene expression in the developing brain, with increasing OXTR expression along the course of the prenatal period culminating in a peak during early childhood. This early life OXTR expression peak pattern appears slightly earlier in a comparative macaque sample, which is consistent with the relative immaturity of the human brain during early life compared to macaques. We also show that a network of genes with strong spatiotemporal couplings with OXTR is enriched in several psychiatric illness and body composition phenotypes. Taken together, these results demonstrate that oxytocin signaling plays an important role in a diverse set of psychological and somatic processes across the lifespan.

A Developmental Perspective on Facets of Impulsivity and Brain Activity Correlates From Adolescence to Adulthood.

BACKGROUND: On a theoretical level, impulsivity represents a multidimensional construct associated with acting without foresight, inefficient inhibitory response control, and alterations in reward processing. On an empirical level, relationships and changes in associations between different measures of impulsivity from adolescence into young adulthood and their relation to neural activity during inhibitory control and reward anticipation have not been fully understood. METHODS: We used data from IMAGEN, a longitudinal multicenter, population-based cohort study in which 2034 healthy adolescents were investigated at age 14, and 1383 were reassessed as young adults at age 19. We measured the construct of trait impulsivity using self-report questionnaires and neurocognitive indices of decisional impulsivity. With functional magnetic resonance imaging, we assessed brain activity during inhibition error processing using the stop signal task and during reward anticipation in the monetary incentive delay task. Correlations were analyzed, and mixed-effect models were fitted to explore developmental and predictive effects. RESULTS: All self-report and neurocognitive measures of impulsivity proved to be correlated during adolescence and young adulthood. Further, pre-supplementary motor area and inferior frontal gyrus activity during inhibition error processing was associated with trait impulsivity in adolescence, whereas in young adulthood, a trend-level association with reward anticipation activity in the ventral striatum was found. For adult delay discounting, a trend-level predictive effect of adolescent neural activity during inhibition error processing emerged. CONCLUSIONS: Our findings help to inform theories of impulsivity about the development of its multidimensional nature and associated brain activity patterns and highlight the need for taking functional brain development into account when evaluating neuromarker candidates.

Ventral Striatal-Hippocampus Coupling During Reward Processing as a Stratification Biomarker for Psychotic Disorders.

BACKGROUND: Altered ventral striatal (vST) activation to reward expectancy is a well-established intermediate phenotype for psychiatric disorders, specifically schizophrenia (SZ). Preclinical research suggests that striatal alterations are related to a reduced inhibition by the hippocampal formation, but its role in human transdiagnostic reward-network dysfunctions is not well understood. METHODS: We performed functional magnetic resonance imaging during reward processing in 728 individuals including healthy control subjects (n = 396), patients (SZ: n = 46; bipolar disorder: n = 45; major depressive disorder: n = 60), and unaffected first-degree relatives (SZ: n = 46; bipolar disorder: n = 50; major depressive disorder: n = 85). We assessed disorder-specific differences in functional vST-hippocampus coupling and transdiagnostic associations with dimensional measures of positive, negative, and cognitive symptoms. We also probed the genetic underpinning using polygenic risk scores for SZ in a subset of healthy participants (n = 295). RESULTS: Functional vST-hippocampus coupling was 1) reduced in patients with SZ and bipolar disorder (pFWE < .05, small-volume corrected [SVC]); 2) associated transdiagnostically to dimensional measures of positive (pFWE = .01, SVC) and cognitive (pFWE = .02, SVC), but not negative, (pFWE > .05, SVC) symptoms; and 3) reduced in first-degree relatives of patients with SZ (pFWE = .017, SVC) and linked to the genetic risk for SZ in healthy participants (p = .035). CONCLUSIONS: We provide evidence that reduced vST-hippocampus coupling during reward processing is an endophenotype for SZ linked to positive and cognitive symptoms, supporting current preclinical models of the emergence of psychosis. Moreover, our data indicate that vST-hippocampus coupling is familial and linked to polygenic scores for SZ, supporting the use of this measure as an intermediate phenotype for psychotic disorders.

Brain structural correlates of upward social mobility in ethnic minority individuals.

PURPOSE: Perigenual anterior cingulate cortex (pACC) is a neural convergence site for social stress-related risk factors for mental health, including ethnic minority status. Current social status, a strong predictor of mental and somatic health, has been related to gray matter volume in this region, but the effects of social mobility over the lifespan are unknown and may differ in minorities. Recent studies suggest a diminished health return of upward social mobility for ethnic minority individuals, potentially due to sustained stress-associated experiences and subsequent activation of the neural stress response system. METHODS: To address this issue, we studied an ethnic minority sample with strong upward social mobility. In a cross-sectional design, we examined 64 young adult native German and 76 ethnic minority individuals with comparable sociodemographic attributes using whole-brain structural magnetic resonance imaging. RESULTS: Results showed a significant group-dependent interaction between perceived upward social mobility and pACC gray matter volume, with a significant negative association in the ethnic minority individuals. Post-hoc analysis showed a significant mediation of the relationship between perceived upward social mobility and pACC volume by perceived chronic stress, a variable that was significantly correlated with perceived discrimination in our ethnic minority group. CONCLUSION: Our findings extend prior work by pointing to a biological signature of the "allostatic costs" of socioeconomic attainment in socially disadvantaged upwardly mobile individuals in a key neural node implicated in the regulation of stress and negative affect.