Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.

Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNß levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNß-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.

A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels.

AIM: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. METHOD: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. RESULTS: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. DISCUSSION: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.

Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior.

Major depressive disorder (MDD) is one of the most common and debilitating neuropsychiatric illnesses. Accumulating evidence suggests a potential role of the immune system in the pathophysiology of MDD. The complement system represents one of the major effector mechanisms of the innate immune system, and plays a critical role in inflammation. However, the role of complement components in MDD is not well understood. Here, we found significant increase in component 3 (C3) expression in the prefrontal cortex (PFC) of depressed suicide subjects. We tested the role of altered C3 expression in mouse model of depression and found that increased C3 expression in PFC as a result of chronic stress causes depressive-like behavior. Conversely, mice lacking C3 were resilient to stress-induced depressive-like behavior. Moreover, selective overexpression of C3 in PFC was sufficient to cause depressive-like behavior in mice. We found that C3a (activated product of C3) receptor, C3aR+ monocytes were infiltrated into PFC following chronic stress. However, C3aR knockout mice displayed significantly reduced monocyte recruitment into PFC and reduced levels of the proinflammatory cytokine IL-1ß in PFC after chronic stress. In addition, C3aR knockout mice did not exhibit chronic stress-induced behavior despair. Similarly, chronic stress-induced increases in C3aR+ monocytes and IL-1ß in PFC, and depressive-like behavior were attenuated by myeloid cell depletion. These postmortem and preclinical studies identify C3aR signaling as a key factor in MDD pathophysiology.

Transglutaminase 2 Induces Deficits in Social Behavior in Mice.

Impairments in social behavior are highly implicated in many neuropsychiatric disorders. Recent studies indicate a role for endoplasmic reticulum (ER) stress in altering social behavior, but the underlying mechanism is not known. In the present study, we examined the role of transglutaminase 2 (TG2), a calcium-dependent enzyme known to be induced following ER stress, in social behavior in mice. ER stress induced by tunicamycin administration increased TG2 protein levels in the mouse prefrontal cortex (PFC). PFC-specific inhibition of TG2 attenuated ER stress-induced deficits in social behavior. Conversely, overexpression of TG2 in the PFC resulted in social behavior impairments in mice. In addition, systemic administration of cysteamine, a TG2 inhibitor, attenuated social behavior deficits. Our preliminary findings using postmortem human brain samples found increases in TG2 mRNA and protein levels in the middle frontal gyrus of subjects with autism spectrum disorder. These findings in mice and human postmortem brain samples identify changes in TG2 activity in the possible dysregulation of social behavior.

The professional experiences of peer specialists in the Georgia Mental Health Consumer Network.

There has been an increase in the number of peer-led services within the mental health care system. There however remains little information about the experiences of peers serving in such helping roles. This study explored the professional experiences of peer specialists including the basic roles, benefits, and potential challenges of the peer specialist role. Peer specialists (N = 84) completed a battery of surveys and questionnaires. Qualitative analysis of participants' responses indicated that peer specialists face difficulties such as poor compensation, limited employment opportunities, work stress, emotional stress in helping others, and maintaining personal wellness. Quantitative analyses revealed that recovery attitudes may confer clinical and psychosocial benefits for peer specialists and employment may contribute to hope, empowerment, social engagement, and competence. Peer specialists would benefit from resources and supports aimed at their continued training and supervision. Fostering the vocational advancement of peer specialists could potentially enhance their experiential recovery and community functioning.

Performance on a contour integration task as a function of contour shape in schizophrenia and controls.

Contour Integration (CI) is the ability to integrate elemental features into objects and is a basic visual process essential for object perception and recognition, and for functioning in visual environments. It is now well documented that people with schizophrenia (SZ), in addition to having cognitive impairments, also have several visual perceptual deficits, including in CI. Here, we retrospectively characterize the performance of both SZ and neurotypical individuals (NT) on a series of contour shapes, made up of Gabor elements, that varied in terms of closure and curvature. Participants in both groups performed a CI training task that included 7 different families of shapes (Lines, Ellipse, Blobs, Squiggles, Spiral, Circle and Letters) for up to 40 sessions. Two parameters were manipulated in the training task: Orientation Jitter (OJ, i.e., orientation deviations of individual Gabor elements from ideal for each shape) and Inducer Number (IN, i.e., number of Gabor elements defining the shape). Results show that both OJ and IN thresholds significantly differed between the groups, with higher (OJ) and lower (IN) thresholds observed in the controls. Furthermore, we found significant effects as a function of the contour shapes, with differences between groups emerging with contours that were considered more complex, e.g., due to having a higher degree of curvature (Blobs, Spiral, Letters). These data can inform future work that aims to characterize visual integration impairments in schizophrenia.

Exploring current smartphone-based cognitive assessments in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder are associated with cognitive deficits that contribute significantly to disability. However, traditional in-lab cognitive assessments are time-consuming and not optimized for remote administration. Recent advancements in smartphone technology enable momentary cognitive assessments in a real-world context. This brief report reviews recent research in momentary cognitive assessments in individuals with schizophrenia and bipolar disorder through reviewing mobile platforms and cognitive assessments studied. A total of 14 experimental articles were reviewed, focusing on cognitive domains including visual working memory, processing speed, executive function, verbal fluency, verbal memory, social cognition, and typing patterns. The review highlights the feasibility of remote cognitive assessment with smartphones, and provides a layout of domains studied in this context, but illustrates a low volume of current research, the need for additional studies, and the potential for innovations like digital phenotyping.

Neuroimaging schizophrenia: a picture is worth a thousand words, but is it saying anything important?

Schizophrenia is characterized by neurostructural and neurofunctional aberrations that have now been demonstrated through neuroimaging research. The article reviews recent studies that have attempted to use neuroimaging to understand the relation between neurological abnormalities and aspects of the phenomenology of schizophrenia. Neuroimaging studies show that neurostructural and neurofunctional abnormalities are present in people with schizophrenia and their close relatives and may represent putative endophenotypes. Neuroimaging phenotypes predict the emergence of psychosis in individuals classified as high-risk. Neuroimaging studies have linked structural and functional abnormalities to symptoms; and progressive structural changes to clinical course and functional outcome. Neuroimaging has successfully indexed the neurotoxic and neuroprotective effects of schizophrenia treatments. Pictures can inform about aspects of the phenomenology of schizophrenia including etiology, onset, symptoms, clinical course, and treatment effects but this assertion is tempered by the scientific and practical limitations of neuroimaging.

Computerized cognitive and social cognition training in schizophrenia for impulsive aggression.

BACKGROUND: Schizophrenia is associated with an elevated risk for impulsive aggression for which there are few psychosocial treatment options. Neurocognitive and social cognitive deficits have been associated with aggression with social cognitive deficits seemingly a more proximal contributor. The current study examined the effects of combining cognitive and social cognition treatment on impulsive aggression among inpatients with chronic schizophrenia and schizoaffective disorder and a history of aggression compared to cognitive remediation treatment alone. METHODS: The two-center study randomized 130 participants to receive 36 sessions of either a combination of cognitive remediation and social cognition treatment or cognitive remediation plus a computer-based control. Participants had at least one aggressive incident within the past year or a Life History of Aggression (LHA) score of 5 or more. Participants completed measures of neurocognition, social cognition, symptom severity, and aggression at baseline and endpoint. RESULTS: Study participants were mostly male (84.5 %), had a mean age 34.9 years, and 11.5 years of education. Both Cognitive Remediation Training (CRT) plus Social Cognition Training (SCT) and CRT plus control groups were associated with significant reductions in aggression measures with no group differences except on a block of the Taylor Aggression Paradigm (TAP), a behavioral task of aggression which favored the CRT plus SCT group. Both groups showed significant improvements in neurocognition and social cognition measures with CRT plus SCT being associated with greater improvements. CONCLUSION: CRT proved to be an effective non-pharmacological treatment in reducing impulsive aggression in schizophrenia inpatient participants with a history of aggressive episodes. The addition of social cognitive training did not enhance this anti-aggression treatment effect but did augment the CRT effect on cognitive functions, on emotion recognition and on mentalizing capacity of our participants.

Association between adverse childhood experiences and suicidal behavior in schizophrenia spectrum disorders: A systematic review and meta-analysis.

Assessing and managing suicide behaviors is highly relevant to individuals with schizophrenia spectrum disorders. Our study aims to assess the association between adverse childhood experiences and suicidal behaviors in individuals with schizophrenia spectrum disorders. We included observational studies comparing the probability of suicide behaviors in adults with schizophrenia spectrum disorders exposed and unexposed to adverse childhood experiences. Odds ratio estimates were obtained by pooling data using a random-effects pairwise meta-analysis. Standardized criteria were used to assess the strength of the association of the pooled estimate. We found 21 eligible studies reporting outcomes for 6257 individuals from 11 countries. The primary outcome revealed an association between any suicidal behavior and adverse childhood experiences, which resulted "highly suggestive" according to validated Umbrella Criteria. Similarly, a positive association was confirmed for suicidal ideation and suicide attempt and for any subtype of adverse childhood experience. This meta-analysis showed that exposure to adverse childhood experiences strongly increases the probability of suicide behaviors in people with schizophrenia spectrum disorders.

Five negative symptom domains are differentially associated with resting state amplitude of low frequency fluctuations in Schizophrenia.

This study examined associations between resting-state amplitude of low frequency fluctuations (ALFF) and negative symptoms represented by total scores, second-order dimension (motivation and pleasure, expressivity), and first-order domain (anhedonia, avolition, asociality, alogia, blunted affect) factor scores in schizophrenia (n = 57). Total negative symptom scores showed positive associations with ALFF in temporal and frontal brain regions. Negative symptom domain scores showed predominantly stronger associations with regional ALFF compared to total scores, suggesting domain scores may better map to neural signatures than total scores. Improving our understanding of the neuropathology underlying negative symptoms may aid in addressing this unmet therapeutic need in schizophrenia.

What Do These Findings Tell Us? Comment on Tinella et al. Cognitive Efficiency and Fitness-to-Drive along the Lifespan: The Mediation Effect of Visuospatial Transformations. Brain Sci. 2021, 11, 1028.

Tinella et al.'s recent article [...].

Latent structure of cognitive tests is invariant in men and women with schizophrenia.

Studies comparing the cognitive functioning of men and women with schizophrenia have produced conflicting results which could arise from sex-based differences in the latent structure of cognitive abilities. The current study used multigroup confirmatory factor analysis to examine invariance in latent structure of cognitive abilities to between men and women with schizophrenia. Confirmatory factor analysis of an initial neurocognitive assessment (men n = 612, women n = 201) and cross-validation using second assessment (men n = 549, women n = 198) demonstrated that a bifactor seven-factor model fit the data best for both men and women. Invariance analyses further indicated this model was invariant across men and women at both assessments. Group comparisons indicated women had significantly higher scores for Semantic Memory, Verbal Memory, and General Cognitive factors, whereas men exhibited better performance on the Vigilance factor. Results indicate that cognition in SZ is characterized by both a general cognitive factor and specific domains for both men and women. Invariance analysis provides evidence that cognitive differences between men and women do not result from sex-based differences in the latent structure of cognitive abilities. Current results also indicate small but statistically significant neurocognitive differences between men and women with schizophrenia.

Two Factors, Five Factors, or Both? External Validation Studies of Negative Symptom Dimensions in Schizophrenia.

OBJECTIVES: Negative symptom studies frequently use single composite scores as indicators of symptom severity and as primary endpoints in clinical trials. Factor analytic and external validation studies do not support this practice but rather suggest a multidimensional construct. The current study used structural equation modeling (SEM) to compare competing dimensional models of negative symptoms to determine the number of latent dimensions that best capture variance in biological, psychological, and clinical variables known to have associations with negative symptoms. METHODS: Three independent studies (total n = 632) compared unidimensional, two-factor, five-factor, and hierarchical conceptualizations of negative symptoms in relation to cognition, psychopathology, and community functioning (Study 1); trait emotional experience and defeatist performance beliefs (Study 2); and glutamate and gamma-aminobutyric acid levels in the anterior cingulate cortex quantified using proton magnetic resonance spectroscopy (Study 3). RESULTS: SEM favored the five-factor and hierarchical models over the unidimensional and two-factor models regardless of the negative symptom measure or external validator. The five dimensions-anhedonia, asociality, avolition, blunted affect, and alogia-proved vital either as stand-alone domains or as first-order domains influenced by second-order dimensions-motivation and pleasure and emotional expression. The two broader dimensions sometimes masked important associations unique to the five narrower domains. Avolition, anhedonia, and blunted affect showed the most domain-specific associations with external variables across study samples. CONCLUSIONS: Five domains and a hierarchical model reflect the optimal conceptualization of negative symptoms in relation to external variables. Clinical trials should consider using the two dimensions as primary endpoints and the five domains as secondary endpoints.

ENIGMA + COINSTAC: Improving Findability, Accessibility, Interoperability, and Re-usability.

The FAIR principles, as applied to clinical and neuroimaging data, reflect the goal of making research products Findable, Accessible, Interoperable, and Reusable. The use of the Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymized Computation (COINSTAC) platform in the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium combines the technological approach of decentralized analyses with the sociological approach of sharing data. In addition, ENIGMA + COINSTAC provides a platform to facilitate the use of machine-actionable data objects. We first present how ENIGMA and COINSTAC support the FAIR principles, and then showcase their integration with a decentralized meta-analysis of sex differences in negative symptom severity in schizophrenia, and finally present ongoing activities and plans to advance FAIR principles in ENIGMA + COINSTAC. ENIGMA and COINSTAC currently represent efforts toward improved Access, Interoperability, and Reusability. We highlight additional improvements needed in these areas, as well as future connections to other resources for expanded Findability.

Latent structure of unipolar and bipolar mood symptoms.

OBJECTIVES: The taxonic versus dimensional status of mood symptoms has been the subject of debate among mental health professionals. Conventional diagnostic models suggest that mood disorders are categorical; however, the inability of categorical models to adequately account for subthreshold unipolar and bipolar presentations and the heterotypic continuity of symptoms in unipolar and bipolar cases has resulted in growing support for dimensional views. The current study sought to evaluate the relative viabilities of categorical and dimensional models of mood symptoms within a taxometric framework. METHODS: We examined the latent structure of mood symptoms in an epidemiological sample drawn from the Collaborative Psychiatric Epidemiological Surveys. Using three taxometric procedures (MAMBAC, MAXEIG, and L-Mode), we analyzed indicators of mania and depression created from the mood symptoms section of the survey. RESULTS: The taxometric analyses supported a taxonic rather than dimensional structure for mania and depression. Membership in the mania and depressive taxa was associated with meeting criteria for DSM-IV lifetime manic episode and major depressive disorder, respectively. We identified a subset of 700 individuals falling into both taxa; membership in this subset was associated with lifetime bipolar disorder status. Group membership predicted designated external variables including help-seeking, family history, and duration of impairment. Within taxon and/or complement groups, severity scores still appeared to predict external variables. CONCLUSION: Our findings suggest that although taxonic, mood disorders possess meaningful dimensional variation.

The Quest for Psychiatric Advancement through Theory, beyond Serendipity.

Over the past century, advancements in psychiatric treatments have freed countless individuals from the burden of life-long, incapacitating mental illness. These treatments have largely been discovered by chance. Theory has driven advancement in the natural sciences and other branches of medicine, but psychiatry remains a field in its "infancy". The targets for healing in psychiatry lie within the realm of the mind's subjective experience and thought, which we cannot yet describe in terms of their biological underpinnings in the brain. Our technology is sufficiently advanced to study brain neurons and their interactions on an electrophysiological and molecular level, but we cannot say how these form a single feeling or thought. While psychiatry waits for its "Copernican Revolution", we continue the work in developing theories and associated experiments based on our existing diagnostic systems, for example, the Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD), or the more newly introduced Research Domain Criteria (RDoC) framework. Understanding the subjective reality of the mind in biological terms would doubtless lead to huge advances in psychiatry, as well as to ethical dilemmas, from which we are spared for the time being.

Validation of the traditional script Chinese version of the brief negative symptom scale.

Negative symptoms are a core feature of schizophrenia and account for much of the long-term morbidity and poor functional outcome of people with schizophrenia. The Brief Negative Symptom Scale (BNSS) was developed to address the main limitations of the existing scales for the assessment of negative symptoms. The BNSS has been translated into Italian, Spanish, German, Turkish and simplified Chinese versions with excellent psychometric properties. In this study, a Chinese (traditional script) version of the Brief Negative Symptom Scale (C-BNSS) was developed and validated to facilitate future research on the Chinese population in Hong Kong. Psychometric properties were examined in 149 individuals with schizophrenia. The C-BNSS showed excellent internal consistency (α = 0.96), high inter-rater reliability (intra-class correlation = 0.98), and high test-retest reliability (Spearman's r = 0.96). Convergent validity was supported by high correlations between C-BNSS total score and subscales with the Scale for Assessment of Negative Symptoms (SANS), Negative Symptom subscale of the Positive and Negative Syndrome Scale (PANSS), and Global Assessment of Functioning (GAF) score. Discriminant validity was supported by low correlations between the C-BNSS total score and the PANSS positive subscale, Calgary Depression Scale, and Simpson-Angus Scale for extrapyramidal symptoms. The C-BNSS showed a five- factor structure on Confirmatory Factor Analysis (CFA), confirming findings of previous studies. Findings indicate that the C-BNSS demonstrates excellent psychometric properties, which are comparable to the original English version. It is a promising instrument for use in clinical trials as well as in clinical practice.

Bifactor model of cognition in schizophrenia: Evidence for general and specific abilities.

BACKGROUND: Despite extensive study of cognition in schizophrenia, it remains unclear as to whether cognitive deficits and their latent structure are best characterized as reflecting a generalized deficit, specific deficits, or some combination of general and specific constructs. METHOD: To clarify latent structure of cognitive abilities, confirmatory factor analysis was used to examine the latent structure of cognitive data collected for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) for Schizophrenia study. Baseline assessment data (n = 813) were randomly divided into calibration (n = 413) and cross-validation samples (n = 400). To examine whether generalized or specific deficit models provided better explanation of the data, we estimated first-order, hierarchical, and bifactor models. RESULTS: A bifactor model with seven specific factors and one general factor provided the best fit to the data for both the calibration and cross-validation samples. CONCLUSIONS: These findings lend support for a replicable bifactor model of cognition in schizophrenia, characterized by both a general cognitive factor and specific domains. This suggests that cognitive deficits in schizophrenia might be best understood by separate general and specific contributions.