Childhood trauma, resilience, psychopathology and social functioning in schizophrenia: A network analysis.

The affective pathway to psychosis implicates affective symptoms and neuroticism as mediating steps between childhood trauma and symptoms of schizophrenia. Prior research seldom examined the interplay between childhood trauma, resilience, personality, social functioning and symptoms in schizophrenia patients. This study recruited 290 schizophrenia patients, and constructed a regularized partial correlation network of childhood trauma, resilience, big-five personality traits, symptoms and social functioning. We further applied flow diagram and shortest path analysis to clarify how different childhood trauma types would contribute to and reach different symptoms. In the network, emotional and physical abuse showed the highest expected influence, and resilience showed the highest strength. In flow diagrams, all nodes together contributed two-thirds of variance of social functioning (which had highest predictability). Among childhood trauma types, emotional abuse contributed most to positive symptoms; physical neglect contributed most to negative, depressive and disorganized symptoms. Childhood abuse reached positive symptoms via neuroticism and depressive symptoms, yet it reached negative symptoms via physical neglect and social functioning. Childhood neglect reached positive symptoms via resilience, conscientiousness, neuroticism and depressive symptoms, yet it reached negative symptoms via social functioning. Our findings support that different childhood trauma types contribute to different symptoms, and interacts with resilience, personality and social functioning.

Anhedonia Across and Beyond the Schizophrenia Spectrum.

Anhedonia refers to the diminished ability to experience pleasure, and is a core feature of schizophrenia (SCZ). The neurocognitive and neural correlates of anhedonia remain elusive. Based on several influential theoretical models for negative symptoms, this selective review proposed four important neurocognitive domains, which may unveil the neurobiological mechanisms of anhedonia. The authors critically reviewed the current evidence regarding value representation of reward, prospection, emotion-behavior decoupling, and belief updating in the Chinese setting, covering both behavioral and neuroimaging research. We observed a limited application of the transdiagnostic approach in previous studies on the four domains, and the lack of adequate measures to tap into the expressivity deficit in SCZ. Despite many behavioral paradigms for these four domains utilized both social and non-social stimuli, previous studies seldom focused on the social-versus-non-social differentiation. We further advocated several important directions for future research.

Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Differential manifestations of anhedonia in people with social anhedonia and subsyndromal depression.

Empirical findings suggested that anhedonia, a reduced capability to access pleasure and a core symptom in both schizophrenia and the major depressive disorder, can be present in people with high levels of social anhedonia and people with subsyndromal depression. Few studies have adopted a multidimensional framework to investigate anhedonia in these subclinical samples. We recruited 35 participants with high social anhedonia (SA), 53 participants with subsyndromal depression (SD), 20 participants with co-occurrence of both traits (CO), and 47 participants with low levels of both traits (CN) to complete a self-report questionnaire capturing the pleasure experience, and the Monetary Incentives Delay (MID) Task and the Social Incentives Delay (SID) Task capturing the motivation of reward. Results indicated that people with SA, SD and CO exhibited lower abstract anticipatory pleasure compared to CN. Moreover, people with SD and CO exhibited specific impairment in response to social incentives. Together, our findings characterized the multidimensional features of anhedonia performances of subclinical samples with SA, SD and CO, which may contribute to the formulation of early identification of at-risk groups.

A Transdiagnostic Network Analysis of Childhood Trauma and Psychopathology.

BACKGROUND AND HYPOTHESIS: Psychiatric comorbidities suggest that symptoms overlap across different diagnoses; the transdiagnostic network approach is valuable for studying psychopathology. Childhood trauma is a common transdiagnostic risk factor for psychiatric disorders, but the complex relationship between childhood trauma and psychopathology has seldom been investigated using a large cross-sectional transdiagnostic sample. STUDY DESIGN: This study recruited 869 patients with different diagnoses, including 418 schizophrenia, 215 bipolar disorder, and 236 major depressive disorder. Participants completed psychiatric interviews and self-report questionnaires. We constructed dimension- and item-level Least Absolute Shrinkage and Selection Operator-based (LASSO) networks to explore the relationship between childhood trauma, psychopathology, and duration of illness. Moreover, we constructed directed acyclic graphs (DAGs) to tentatively clarify the potential directions of associations among these variables. Network Comparison Tests (NCTs) were conducted for different diagnostic groups and gender-stratified groups. STUDY RESULTS: The transdiagnostic LASSO networks showed that different types of childhood trauma exerted distinct impacts on various psychopathological dimensions. Emotional abuse was linked to depressive symptoms, physical abuse to excited symptoms, sexual abuse to positive and disorganized symptoms, emotional neglect to depressive symptoms and motivation and pleasure (MAP) deficits factor of negative symptoms, and physical neglect to MAP factor. The DAG findings generally concurred with the LASSO network. The NCT showed comparable networks. CONCLUSIONS: Our findings suggest that childhood trauma is significantly associated with the development of psychopathology across different diagnostic groups. The affective pathway model suggests that early identification and tailored interventions would be needed for people with a history of childhood trauma.

Negative symptoms in treatment-resistant schizophrenia and its relationship with functioning.

BACKGROUND: Recent operational criteria for treatment-resistant schizophrenia (TRS) recognized positive and negative symptoms. TRS patients may have heterogeneity in negative symptoms, but empirical data were lacking. We aimed to characterize TRS patients based on negative symptoms using cluster analysis, and to examine between-cluster differences in social functioning. METHODS: We administered the Clinical Assessment Interview of Negative symptoms (CAINS), Brief Negative Symptom Scale (BNSS), the Positive and Negative Syndrome Scale (PANSS) and the Social and Occupational Functional Assessment (SOFAS to 126 TRS outpatients. All patients also completed the Temporal Experience of Pleasure Scale (TEPS), the Emotion Expressivity Scale (EES), and the Social Functional Scale (SFS). A two-stage hierarchical cluster analysis was performed with the CAINS, TEPS and EES as clustering variables. We validated the clusters using ANOVAs to compare group differences in the BNSS, PANSS, SOFAS and SFS. RESULTS: Clustering indices supported a 3-cluster solution. Clusters 1 (n = 46) and 3 (n = 16) exhibited higher CAINS scores than Cluster 2 (n = 64), and were negative-symptom TRS subtypes. Cluster 1 reported lower TEPS than Cluster 3; but Cluster 3 reported lower EES than Cluster 1. Upon validation, Clusters 1 and 3 exhibited higher BNSS scores than Cluster 2, but only Cluster 1 exhibited lower SOFAS and higher PANSS general symptoms than Cluster 2. Both Clusters 1 and 3 had higher self-report functioning than Cluster 2. CONCLUSION: We provided evidence for heterogeneity of negative symptoms in TRS. Negative symptoms can characterize TRS patients and predict functional outcome.

Neuropsychology and Neurobiology of Negative Schizotypy: A Selective Review.

Schizotypy refers to a latent personality organization that reflects liability to schizophrenia. Because schizotypy is a multidimensional construct, people with schizotypy vary in behavioral and neurobiological features. In this article, we selectively review the neuropsychological and neurobiological profiles of people with schizotypy, with a focus on negative schizotypy. Empirical evidence is presented for alterations of neuropsychological performance in negative schizotypy. We also cover the Research Domain Criteria domains of positive valence, social process, and sensorimotor systems. Moreover, we systematically summarize the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. The convergence and inconsistency of the evidence are critically reviewed. Regarding theoretical and clinical implications, we argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

This perspective paper provides empirical evidence to show that schizotypy, and especially negative schizotypy, are associated with alterations of positive valence, social process, and sensorimotor systems domains within the Research Domain Criteria (RDoC). This perspective paper also systematically summarizes the neurobiological correlates of negative schizotypy at the structural, resting-state, and task-based neural levels, as well as the neurochemical level. We argue that negative schizotypy represents a useful organizational framework for studying neuropsychology and neurobiology across different psychiatric disorders.

The Future-oriented Repetitive Thought (FoRT) scale: Validation in Chinese samples and application in the schizophrenia spectrum.

BACKGROUND: Repetitive thoughts are usually associated with psychopathology. The Future-oriented Repetitive Thought (FoRT) Scale is a measure designed to capture frequency of repetitive thought about positive and negative future events. However, the validity of the scale in Chinese population and its application in the schizophrenia spectrum have not been examined. METHODS: The current study aimed to examine the psychometric properties of the Chinese version of the FoRT scale and to apply it to the schizophrenia spectrum. In Study 1, three samples (total N = 1875) of university students were recruited for exploratory factor analysis, confirmatory factor analysis, and validity test, respectively. In Study 2, we identified subsamples with high schizotypal traits (N = 89) and low schizotypal traits (N = 89), and recruited 36 inpatients with schizophrenia and 41 matched healthy controls. RESULTS: The three-factor (pessimistic repetitive future thinking, repetitive thinking about future goals, and positive indulging about the future) structure of the FoRT scale with one item deleted, fitted the Chinese samples. And the scale could distinguish patients with schizophrenia and individuals with high schizotypal traits from controls. CONCLUSION: These findings support that the Chinese version of the FoRT scale is a valid tool and provide evidence for the potential applications in the schizophrenia spectrum.

Neural substrates of the interaction between effort-expenditure reward decision-making and outcome anticipation.

OBJECTIVE: Reward anticipation is important for future decision-making, possibly due to re-evaluation of prior decisions. However, the exact relationship between reward anticipation and prior effort-expenditure decision-making, and its neural substrates are unknown. METHOD: Thirty-three healthy participants underwent fMRI scanning while performing the Effort-based Pleasure Experience Task (E-pet). Participants were required to make effort-expenditure decisions and anticipate the reward. RESULTS: We found that stronger anticipatory activation at the posterior cingulate cortex was correlated with slower reaction time while making decisions with a high-probability of reward. Moreover, the substantia nigra was significantly activated in the prior decision-making phase, and involved in reward-anticipation in view of its strengthened functional connectivity with the mammillary body and the putamen in trial conditions with a high probability of reward. CONCLUSIONS: These findings support the role of reward anticipation in re-evaluating decisions based on the brain-behaviour correlation. Moreover, the study revealed the neural interaction between reward anticipation and decision-making.

Exploring phenotypic overlap across schizotypy and autism spectrum conditions in American and Chinese young adults.

Competing theories have been proposed to explain the considerable overlap in social-cognitive features and risk factors across schizotypy and autism spectrum conditions (ASCs). Six previous factor analyses have been reported in the literature, yet all have major limitations; evidence for the clear superiority of any of the competing theories is insufficient and warrants further investigation. The primary aim of the present research was to identify dimensions that cut across schizotypy and ASCs while addressing limitations of past research. Data were collected from three independent samples (n = 1006, 544, and 2469) in the U.S. and China using the Autism-Spectrum Quotient, the Schizotypal Personality Questionnaire, and the Wisconsin Schizotypy Scales. Exploratory factor analyses in Sample 1 identified an interpretable three-factor structure, which was replicated in Samples 2 and 3 using confirmatory factor analyses. We found consistent evidence for three dimensions (Aberrant Salience, Asociality, and Concrete Thinking) underlying schizotypy and ASCs. This three-dimension model is consistent with a common vulnerability model of schizotypy and ASCs. Implications of these findings for the schizotypy and ASCs literature are discussed.

Empathic accuracy in individuals with schizotypal personality traits.

Empirical research using the Empathic Accuracy Task (EAT) has suggested that schizophrenia patients and people with schizotypal personality disorder exhibit lower empathic accuracy than healthy people. However, empathic accuracy in a subclinical sample with high levels of schizotypy has seldom been studied. Our study aimed to investigate empathy in a subclinical sample using the Chinese version of the EAT and a self-report empathy measure. Forty participants with high levels of schizotypy (HS participants) and 40 with low levels of schizotypy (LS participants), as measured by the Schizotypal Personality Questionnaire (SPQ), were recruited. All participants completed the Chinese version of the EAT and the self-report Questionnaire of Cognitive and Affective Empathy. Empathic accuracy (EA) scores and the intra-individual variability of EA scores were calculated. Independent samples t tests and Pearson correlation analyses were performed to examine group differences in empathy and the relationship between empathy and schizotypy respectively. HS participants exhibited reduced EA for both positive and negative videos, and larger intra-individual variability of EA for negative videos than LS participants. However, HS and LS participants did not differ in self-report cognitive empathy. Moreover, the interpersonal dimension of the SPQ was negatively correlated with EAT performance and self-report cognitive empathy in LS participants. Individuals with HS show poorer performance-based EA but relatively intact self-report cognitive empathy. This study provides empirical evidence for the ontogeny of empathy deficits in subclinical populations at risk of developing schizophrenia, supporting early interventions for social cognitive deficits.

Interoception, somatic symptoms, and somatization tendency in Chinese individuals with subsyndromal depression: A follow-up study.

Interoception refers to the sensation and perception of internal bodily sensations, and may be related to depressive symptoms. Schemata concerning the body vary across different cultures and may influence interoception and symptom presentations of depression. This study explored the relationship between interoception, depressive symptoms, and schema of somatic focus in Chinese people with subsyndromal depression. Thirty-nine individuals with subsyndromal depression (SD) and 40 healthy controls (HCs) were assessed at baseline and after 3 months. Participants completed the self-report questionnaires for assessing interoceptive sensibility, somatic and psychological symptoms of depression, and somatization tendency. They also completed the heartbeat perception behavioral task for estimating interoceptive accuracy. The results showed that both the SD and the HC groups showed similar interoceptive accuracy, although the SD group showed heightened interoceptive sensibility. The discrepancy between interoceptive sensibility and interoceptive accuracy is termed the interoceptive trait prediction error (ITPE). The ITPE was positive in SD participants but was negative in HCs. In the entire sample, interoceptive sensibility and the ITPE were correlated with somatic symptoms rather than with psychological symptoms of depression. Interoceptive sensibility partially mediated the relationship between somatization tendency and somatic symptoms, after controlling for psychological symptoms of depression. These results remained stable after 3 months. The shortcomings of the present study were a lack of clinical interview to ascertain diagnosis and a short follow-up duration. In conclusion, our study suggests that altered interoception occurs in subsyndromal depression. Interoception is related to somatic symptoms of depression. The schema of body was related to depressive symptoms, partially through interoception, in Chinese people with subsyndromal depression.

Individuals with high levels of autistic traits exhibit impaired cognitive but not affective theory of mind and empathy.

Theory of mind (ToM) and empathy are considered key components of social cognition that are often impaired in individuals with autism spectrum disorders (ASD). However, it remains unclear whether individuals with high levels of autistic traits exhibit similar impairments in these two functions. This study examined the affective and cognitive domains of ToM and empathy in individuals with high levels of autistic traits. We recruited 84 participants with high levels and 78 participants with low levels of autistic traits to complete a set of self-reported checklists and performance-based tasks capturing affective and cognitive components of ToM and empathy. The results showed that participants with high levels of autistic traits exhibited significant impairments in cognitive but not in affective ToM and empathy compared with their counterparts with low levels of autistic traits. We also found that empathy impairments in people with high levels of autistic traits were confounded by alexithymia and depressive traits.

Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.

The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study.

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.

Social and non-social reward processing in subclinical depression.

This study applied two incentive delay tasks involving social and non-social incentive types to 76 pairs of participants with high and low depressive symptoms. The results suggest that higher levels of depressive symptoms are correlated with abnormalities in social and non-social reward processing even in the healthy populations.

Unveiling the potential of machine learning in schizophrenia diagnosis: A meta-analytic study of task-based neuroimaging data.

The emergence of machine learning (ML) techniques has opened up new avenues for identifying biomarkers associated with schizophrenia (SCZ) using task-related fMRI (t-fMRI) designs. To evaluate the effectiveness of this approach, we conducted a comprehensive meta-analysis of 31 t-fMRI studies using a bivariate model. Our findings revealed a high overall sensitivity of 0.83 and specificity of 0.82 for t-fMRI studies. Notably, neuropsychological domains modulated the classification performance, with selective attention demonstrating a significantly higher specificity than working memory (ß = 0.98, z = 2.11, P = 0.04). Studies involving older, chronic patients with SCZ reported higher sensitivity (P <0.015) and specificity (P <0.001) than those involving younger, first-episode patients or high-risk individuals for psychosis. Additionally, we found that the severity of negative symptoms was positively associated with the specificity of the classification model (ß = 7.19, z = 2.20, P = 0.03). Taken together, these results support the potential of using task-based fMRI data in combination with machine learning techniques to identify biomarkers related to symptom outcomes in SCZ, providing a promising avenue for improving diagnostic accuracy and treatment efficacy. Future attempts to deploy ML classification should consider the factors of algorithm choice, data quality and quantity, as well as issues related to generalization.