Bridge centrality network structure of negative symptoms in people with schizophrenia.

Negative symptoms are complex psychopathology. Although evidence generally supported the NIMH five consensus domains, research seldom examined measurement invariance of this model, and domain-specific correspondence across multiple scales. This study aimed to examine the interrelationship between negative symptom domains captured by different rating scales, and to examine the domain-specific correspondence across multiple scales. We administered the Brief Negative Symptom Scale (BNSS), the Self-evaluation of Negative Symptoms (SNS), and the Scale for Assessment of Negative Symptoms (SANS) to 204 individuals with schizophrenia. We used network analysis to examine the interrelationship between negative symptom domains. Besides regularized partial correlation network, we estimated bridge centrality indices to investigate domain-specific correspondence, while taking each scale as an independent community. The regularized partial correlation network showed that the SNS nodes clustered together, whereas the SANS and the BNSS nodes intermingled together. The SANS attention domain lied at the periphery of the network according to the Fruchterman-Reingold algorithm. The SANS anhedonia-asociality (strength = 1.48; EI = 1.48) and the SANS affective flattening (strength = 1.06; EI = 1.06) had the highest node strength and EI. Moreover, the five nodes of the BNSS bridged the nodes of the SANS and the SNS. BNSS blunted affect (strength = 0.76; EI = 0.76) and SANS anhedonia-asociality (strength = 0.76; EI = 0.74) showed the highest bridge strength and bridge EI. The BNSS captures negative symptoms and bridges the symptom domains measured by the SANS and the SNS. The three scales showed domain-specific correspondence.

The benefits of emotionally salient cues on event-based prospective memory in bipolar patients and schizophrenia patients.

Prospective memory (PM) refers to the ability to remember to carry out a delayed intention in the future. Evidence suggests that emotionally salient cues can enhance PM functions in healthy population, but whether the benefit exists in schizophrenia and bipolar patients remains unclear. This study aimed to examine and compare the potential enhancement effect of emotional PM cues in schizophrenia patients and bipolar patients. Twenty-eight clinically stable schizophrenia participants, 26 euthymic bipolar participants and 29 controls completed a computerized PM task involving PM cues with different types of valences (i.e., positive, neutral and negative). All the three groups showed better PM performance when negative PM cues were presented compared with positive and neutral PM cues. The sizes of the enhancement effects of negative PM cues were large (all Cohen's d ≥ 1.00) and comparable across three groups. Our findings suggested that patients with schizophrenia and bipolar disorders could benefit from negative PM cues to an extent similar to healthy individuals, thus extended the notion of psychosis continuum to the important area of emotion-cognition interaction.

Whole-exome sequencing in a Chinese sample provides preliminary evidence for the link between rare/low-frequency immune-related variants and early-onset schizophrenia.

Rare and low-frequency variants contribute to schizophrenia (SCZ), and may influence its age-at-onset (AAO). We examined the association of rare or low-frequency deleterious coding variants in Chinese patients with SCZ. We collected DNA samples in 197 patients with SCZ spectrum disorder and 82 healthy controls (HC), and performed exome sequencing. The AAO variable was ascertained in the majority of SCZ participants for identify the early-onset (EOS, AAO<=18) and adult-onset (AOS, AAO>18) subgroups. We examined the overall association of rare/low-frequency, damaging variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels using Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was conducted. Resampling was used to obtain empirical p-values and to control for family-wise error rate (FWER). In binary-trait association tests, we identified 5 potential candidate risk genes and 10 gene ontology biological processes (GOBP) terms, among which PADI2 reached FWER-adjusted significance. In quantitative rare-variant association tests, we found marginally significant correlations of AAO with alterations in 4 candidate risk genes, and 5 GOBP pathways. Together, the biological and functional profiles of these genes and gene sets supported the involvement of perturbations of neural systems in SCZ, and altered immune functions in EOS.

Pathway-Specific Polygenic Scores Improve Cross-Ancestry Prediction of Psychosis and Clinical Outcomes.

Psychotic disorders are debilitating conditions with disproportionately high public health burden. Genetic studies indicate high heritability, but current polygenic scores (PGS) account for only a fraction of variance in psychosis risk. PGS often show poor portability across ancestries, performing significantly worse in non-European populations. Pathway-specific PGS (pPGS), which restrict PGS to genomic locations within distinct biological units, could lead to increased mechanistic understanding of pathways that lead to risk and improve cross-ancestry prediction by reducing noise in genetic predictors. This study examined the predictive power of genome-wide PGS and nine pathway-specific pPGS in a unique Chinese-ancestry sample of deeply-phenotyped psychosis patients and non-psychiatric controls. We found strong evidence for the involvement of schizophrenia-associated risk variants within "nervous system development" (p=2.5e-4) and "regulation of neuron differentiation" pathways (p=3.0e-4) in predicting risk for psychosis. We also found the "ion channel complex" pPGS, with weights derived from GWAS of bipolar disorder, to be strongly associated with the number of inpatient psychiatry admissions a patient experiences (p=1.5e-3) and account for a majority of the signal in the overall bipolar PGS. Importantly, although the schizophrenia genome-wide PGS alone explained only 3.7% of the variance in liability to psychosis in this Chinese ancestry sample, the addition of the schizophrenia-weighted pPGS for "nervous system development" and "regulation of neuron differentiation" increased the variance explained to 6.9%, which is on-par with the predictive power of PGS in European ancestry samples. Thus, not only can pPGS provide greater insight into mechanisms underlying genetic risk for disease and clinical outcomes, but may also improve cross-ancestry risk prediction accuracy.

Early-onset schizophrenia is associated with immune-related rare variants in a Chinese sample.

Background: Rare variants are likely to contribute to schizophrenia (SCZ), given the large discrepancy between the heritability estimated from twin and GWAS studies. Furthermore, the nature of the rare-variant contribution to SCZ may vary with the "age-at-onset" (AAO), since early-onset has been suggested as being indicative of neurodevelopment deviance. Objective: To examine the association of rare deleterious coding variants in early- and adult-onset SCZ in a Chinese sample. Method: Exome sequencing was performed on DNA from 197 patients with SCZ spectrum disorder and 82 healthy controls (HC) of Chinese ancestry recruited in Hong Kong. We also gathered AAO information in the majority of SCZ samples. Patients were classified into early-onset (EOS, AAO<18) and adult-onset (AOS, AAO>18). We collapsed the rare variants to improve statistical power and examined the overall association of rare variants in SCZ versus HC, EOS versus HC, and AOS versus HC at the gene and gene-set levels by Sequence Kernel Association Test. The quantitative rare-variant association test of AAO was also conducted. We focused on variants which were predicted to have a medium or high impact on the protein-encoding process as defined by Ensembl. We applied a 100000-time permutation test to obtain empirical p-values, with significance threshold set at p < 1e -3 to control family-wise error rates. Moreover, we compared the burden of targeted rare variants in significant risk genes and gene sets in cases and controls. Results: Based on several binary-trait association tests (i.e., SCZ vs HC, EOS vs HC and AOS vs HC), we identified 7 candidate risk genes and 20 gene ontology biological processes (GOBP) terms, which exhibited higher burdens in SCZ than in controls. Based on quantitative rare-variant association tests, we found that alterations in 5 candidate risk genes and 7 GOBP pathways were significantly correlated with AAO. Based on biological and functional profiles of the candidate risk genes and gene sets, our findings suggested that, in addition to the involvement of perturbations in neural systems in SCZ in general, altered immune responses may be specifically implicated in EOS. Conclusion: Disrupted immune responses may exacerbate abnormal perturbations during neurodevelopment and trigger the early onset of SCZ. We provided evidence of rare variants increasing SCZ risk in the Chinese population.

Emotion-behaviour decoupling and experiential pleasure deficits predict negative symptoms and functional outcome in first-episode schizophrenia patients.

BACKGROUND: Emotion-behaviour decoupling refers to the failure to translate emotion into motivated behaviour, and is a putative marker for schizophrenia. The heterogeneity of experiential pleasure and emotion expressivity deficits has been reported in schizophrenia patients. These three constructs are believed to contribute to negative symptoms, but very few studies have examined their predictive ability for clinical and functional outcome of schizophrenia. This study aimed to clarify whether these three constructs influence clinical and functional outcome of schizophrenia. METHOD: At baseline, 127 first-episode schizophrenia patients completed a behavioural paradigm for emotion-behaviour decoupling, and self-report scales for experiential pleasure and emotion expressivity deficits. Cluster-analysis was applied to characterize schizophrenia subgroups based on these three constructs. At end-point (mean follow-up = 5.37 years, SD = 1.03 years), 85 schizophrenia patients were reassessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and a clinician-rated social functioning scale. RESULTS: Cluster 1 (n = 74) did not show emotion-behaviour decoupling, and had intact experiential pleasure and emotion expressivity. Cluster 2 (n = 29) showed emotion-behaviour decoupling and experiential pleasure deficits. Cluster 3 (n = 24) showed emotion expressivity deficits. At endpoint, the three clusters differed significantly in CAINS MAP factor (p = 0.016) and social functioning (p = 0.019), but not CAINS EXP factor. Specifically, Cluster 2 (n = 18) showed more severe negative symptoms of CAINS MAP factor (p = 0.046) and poorer social functioning (p = 0.022) than Cluster 1 (n = 49). Cluster 3 (n = 18) did not differ from Cluster 1 and Cluster 2 in negative symptoms and social functioning. DISCUSSION: Emotion-behaviour decoupling and experiential pleasure deficits predicted clinical and functional outcome of schizophrenia.

Different trajectories of neurological soft signs progression between treatment-responsive and treatment-resistant schizophrenia patients.

Schizophrenia patients exhibit subtle and non-localizing neurological abnormalities, known as neurological soft signs (NSS). Life-span evidence suggests that NSS vary along the course of schizophrenia. An association between NSS and treatment response has been proposed, suggesting that NSS reflect the underlying neuropathology development in schizophrenia. However, few studies have investigated the relationship between NSS and treatment resistance in first-episode schizophrenia patients. We conducted a longitudinal study on 52 first-episode schizophrenia patients, who were assessed at baseline, the sixth month, and the fifth year using the abridged version of the Cambridge Neurological Inventory. The trajectories of NSS between 29 treatment-responsive patients (with full symptomatic remission) and 23 treatment-resistant patients (who received clozapine) were compared using mixed model ANOVA. We also controlled for the effect of age and estimated IQ, using a mixed ANCOVA model. Although the two schizophrenia groups had comparable NSS at the baseline, their trajectories of NSS differed significantly. Compared with their treatment-responsive counterparts, treatment-resistant schizophrenia patients had worsening of NSS over time. Our findings support the potential utility of NSS in identifying treatment resistance in first-episode schizophrenia. Progressive worsening of NSS in treatment-resistant schizophrenia patients may reflect the development of underlying neuropathology. Further studies using large samples of treatment-resistant schizophrenia patients are needed.

Theory of mind performances in first-episode schizophrenia patients: An 18-month follow-up study.

This study examined the change of Theory of Mind (ToM) performances in patients with first-episode schizophrenia over an 18-month period since illness onset. A computerised behavioural task was utilised to assess the affective and cognitive facets of visual-based ToM. Patients' ToM performances were standardised using the norms of gender-stratified, age- and IQ-matched controls. The results showed that schizophrenia patients exhibited poorer second-order affective and cognitive ToM at baseline, but their ToM ability improved after 18 months of follow-up. Our findings do not support a longitudinal dissociation of affective from cognitive ToM in schizophrenia.

Clustering of Schizotypal Features in Unaffected First-Degree Relatives of Schizophrenia Patients.

Meehl conceptualized schizotypy as the phenotypic manifestations of a neural integrative defect resulting from a schizophrenia diathesis. The majority of schizotypy studies recruited subjects from the general population and revealed a multidimensional construct. This 2-phase investigation first examined the clustering of schizotypy in 194 unaffected relatives of schizophrenia patients using the Chapman Psychosis Proneness scales and then directly compared the cognitive profiles of negative schizotypal individuals and positive schizotypal individuals with schizophrenia patients and controls. In the first phase, cluster analysis categorized 194 unaffected relatives of schizophrenia patients into positive schizotypy (n = 33), negative schizotypy (n = 66), mixed schizotypy (n = 27), and low schizotypy (n = 64). Positive schizotypal participants showed more self-report pleasure experiences than negative schizotypal participants, replicating earlier cluster analytic findings. In the second phase, 27 negative schizotypal individuals, 18 positive schizotypal individuals, 19 schizophrenia patients, and 29 controls were recruited. Although the groups were matched in terms of age, gender, and IQ, they differed significantly in cognitive profiles. While schizophrenia patients exhibited the broadest cognitive impairments, negative schizotypal participants exhibited visual memory, working memory, and verbal fluency impairments, and positive schizotypal participants exhibited logical memory, visual memory, working memory, and theory-of-mind impairments. Among people with familial risk of schizophrenia, individuals exhibiting positive rather than negative schizotypal features resembled schizophrenia patients in cognitive profiles. Using the psychometric-familial method to identify schizotypy, our findings support the heterogeneity of schizotypy as well as the potential utility of the positive schizotypy dimension in genetically high-risk individuals to predict the risk of developing schizophrenia.

Cross Cultural Validation and Extension of the Clinical Assessment Interview for Negative Symptoms (CAINS) in the Chinese Context: Evidence from a Spectrum Perspective.

The Clinical Assessment Interview for Negative Symptoms (CAINS) was designed in accordance with the recent theory and research in social affective neuroscience and to address the psychometric and conceptual limitations of other instruments assessing negative symptoms. The present study aimed to provide a large-scale validation of the CAINS in China and examine its applicability and validity evidence across the schizophrenia spectrum. Using confirmatory factor analysis, our results replicated the original findings in the US development samples that the CAINS possesses a stable 2-factor structure, namely "motivation/pleasure" and "expression". We also found significant correlations between the CAINS and other negative symptom measures. The CAINS demonstrated good discriminant validity in differentiating negative symptoms in people with schizophrenia, nonpsychotic first-degree relatives and people with social anhedonia. People with schizophrenia exhibited significantly higher CAINS subscale scores than first-degree relatives and healthy controls. In addition, first-degree relatives had higher "motivation/pleasure" scores than healthy controls. The "motivation/pleasure" subscale scores of individuals with social anhedonia were also significantly higher than healthy controls.

Theory of mind impairments in patients with first-episode schizophrenia and their unaffected siblings.

BACKGROUND: Theory of mind (ToM) impairment has been consistently demonstrated in patients with schizophrenia, but whether ToM impairments exist in unaffected siblings of patients with schizophrenia remains unclear. Few studies have examined the affective and cognitive components of ToM in schizophrenia. This study aimed to examine whether ToM impairments exist in patients with first-episode schizophrenia and their unaffected siblings, and whether there is any dissociation between the affective and cognitive components of ToM. METHOD: We adopted a family-based case-control design. Participants were 41 patients with first-episode schizophrenia, 43 unaffected siblings, and 42 healthy controls. The Yoni Task which measures the participants' ability to understand first- and second-order affective versus cognitive ToM and the Faux Pas Task which taps into integration of the affective and cognitive components of ToM were administered. Multivariate and univariate ANCOVAs were used to examine the group differences in ToM, while controlling for other neurocognitive functions. RESULTS: Compared with controls, patients with schizophrenia and their unaffected siblings performed poorer on the Faux Pas Task (p<0.001), with siblings having intermediate performance between patients and controls. Patients with schizophrenia performed worse than controls on second-order affective condition of the Yoni Task (p=0.004), but their unaffected siblings did not (p=0.063). We did not find any significant Group-by-Condition interaction in the Yoni Task (p=0.358). CONCLUSION: Patients with first-episode schizophrenia and their unaffected siblings exhibit ToM impairments, but no dissociation between affective and cognitive component of ToM was found. Our findings support the notion that ToM deficit may be a trait marker of schizophrenia.

Validation of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS): a preliminary report.

The present study aimed to examine the psychometric properties of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS). We recruited 68 patients with schizophrenia from the Chinese setting. The findings showed a generally consistent two-factor structure with the original version, namely "expression" and "motivation-pleasure." There is a minor cultural variation in perceiving these items in the Chinese culture. However, the present study demonstrated that the Chinese version of the CAINS appears to be a valid and reliable clinical tool for the assessment of negative symptoms in the Chinese setting.

Course of neurological soft signs in first-episode schizophrenia: Relationship with negative symptoms and cognitive performances.

This prospective study examined the course of neurological soft signs (NSS) in patients with first-episode schizophrenia and its relationship with negative symptoms and cognitive functions. One hundred and forty-five patients with first-episode schizophrenia were recruited, 29 were classified as having prominent negative symptoms. NSS and neuropsychological measures were administered to all patients and 62 healthy controls at baseline. Patients were then followed-up prospectively at six-month intervals for up to a year. Patients with prominent negative symptoms exhibited significantly more motor coordination signs and total NSS than patients without prominent negative symptoms. Patients with prominent negative symptoms performed worse than patients without negative symptoms in working memory functions but not other fronto-parietal or fronto-temporal functions. Linear growth model for binary data showed that the prominent negative symptoms were stable over time. Despite general improvement in NSS and neuropsychological functions, the prominent negative symptoms group still exhibited poorer motor coordination and higher levels of NSS, as well as poorer working memory than patients without prominent negative symptoms. Two distinct subtypes of first-episode patients could be distinguished by NSS and prominent negative symptoms.

Re-visiting the nature and relationships between neurological signs and neurocognitive functions in first-episode schizophrenia: An invariance model across time.

The present study examined different types of neurological signs in patients with first-episode schizophrenia and their relationships with neurocognitive functions. Both cross-sectional and longitudinal designs were adopted with the use of the abridged Cambridge Neurological Inventory which comprises items capturing motor coordination, sensory integration and disinhibition. A total of 157 patients with first-episode schizophrenia were assessed at baseline and 101 of them were re-assessed at six-month interval. A structural equation model (SEM) with invariance model across time was used for data analysis. The model fitted well with the data at baseline assessment, X^2(21) = 21.78, p = 0.413, NFI = 0.95, NNFI = 1.00, CFI = 1.00, IFI = 1.00, RMSEA = 0.015. Subsequent SEM analysis with invariance model at six-month interval also demonstrated the same stable pattern across time and showed strong measurement invariance and structure invariance across time. Our findings suggest that neurological signs capture more or less the same construct captured by conventional neurocognitive tests in patients with schizophrenia. The measurement and structure of these relationships appear to be stable over time.

Validation of the Chinese strengths and weaknesses of ADHD-symptoms and normal-behaviors questionnaire in Hong Kong.

OBJECTIVE: Unlike rating scales that focus on the severity of ADHD symptoms, the Strengths and Weaknesses of ADHD-symptoms and normal-behaviors (SWAN) rating scale is phrased in neutral or positive terms for carers to compare the index child's behaviors with that of their peers. This study explores its psychometric properties when applied to Chinese children in Hong Kong. METHOD: Ratings from the Chinese SWAN scale collected from parents and teachers of a community sample of 3,722 6- to 12-year-old students recruited by stratified random sampling were compared with 247 clinic children with a diagnosis of ADHD. Reliability, validity, factor structure, and cutoff scores were calculated. RESULTS: Favorable psychometrics and a two-factor structure identical to the original were reproduced. Cutoff scores were supported by satisfactory sensitivities and specificities. CONCLUSION: The SWAN scale is a reliable and valid instrument for the assessment of ADHD symptoms in Chinese children in Hong Kong.