Increased Parenchymal Macrophages are associated with decreased Tyrosine Hydroxylase mRNA levels in the Substantia Nigra of people with Schizophrenia and Bipolar Disorder.

Increased activation of inflammatory macrophages and altered expression of dopamine markers are found in the midbrains of people with schizophrenia (SZ). The relationship of midbrain macrophages to dopamine neurons has not been explored, nor is it known if changes in midbrain macrophages are also present in bipolar disorder (BD) or major depressive disorder (MDD). Herein, we determined whether there were differences in CD163+ cell density in the Substantia Nigra (SN), and cerebral peduncles (CP) of SZ, BD, and MDD compared to controls (CTRL). We also analyzed whether CD163 protein and dopamine-synthesizing enzyme tyrosine hydroxylase (TH) mRNA levels differed among diagnostic groups and if they correlated with the density of macrophages. Overall, perivascular CD163+ cell density was higher in the gray matter (SN) than in the white matter (CP). Compared to CTRL, we found increased density of parenchymal CD163+ cells in the SN of the three psychiatric groups and increased CD163 protein levels in SZ. CD163 protein was positively correlated with density of perivascular CD163+ cells. TH mRNA was reduced in SZ and BD and negatively correlated with parenchymal CD163+ cell density. We provide the first quantitative and molecular evidence of an increase in the density of parenchymal macrophages in the midbrain of major mental illnesses and show that the presence of these macrophages may negatively impact dopaminergic neurons.

Mental Health Nurses' Perception of Overnight Observations on Mental Health Inpatient Units: A Qualitative Study.

Overnight observations of mental health inpatients have been criticised for interrupting inpatients' sleep and potentially undermining recovery. No studies have examined the perceptions of mental health nurses who complete overnight observations, limiting key information necessary to guide improvements. This study aims to understand mental health nurses' perceptions on overnight observations and views on practice re-evaluations, as well as assess whether nurses' perceptions align with inpatients as reported in previous research. To fulfil the aims ten mental health nurses working on mental health inpatient units engaged in semi-structured interviews which were analysed using Content Analysis. Nine themes were identified and grouped into three categories: (1) staff and inpatient experiences, (2) impacts on treatment, recovery, and risk management, and (3) opinions on change. Majority of participants were critical of overnight observations, describing their negative impacts on inpatients' sleep and wellbeing. This aligns with previously reported inpatient views. There is scope for reassessment on how overnight observations are conducted to promote inpatients' sleep, recovery, and safety.

Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes.

Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12-14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology.

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation.

A subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation (n = 13) and high inflammation (n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway 'Hepatic Fibrosis/Hepatic Stellate-Cell Activation'. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix's regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche.

Single-Nucleus RNA-Seq Characterizes the Cell Types Along the Neuronal Lineage in the Adult Human Subependymal Zone and Reveals Reduced Oligodendrocyte Progenitor Abundance with Age.

The subependymal zone (SEZ), also known as the subventricular zone (SVZ), constitutes a neurogenic niche that persists during postnatal life. In humans, the neurogenic potential of the SEZ declines after the first year of life. However, studies discovering markers of stem and progenitor cells highlight the neurogenic capacity of progenitors in the adult human SEZ, with increased neurogenic activity occurring under pathological conditions. In the present study, the complete cellular niche of the adult human SEZ was characterized by single-nucleus RNA sequencing, and compared between four youth (age 16-22) and four middle-aged adults (age 44-53). We identified 11 cellular clusters including clusters expressing marker genes for neural stem cells (NSCs), neuroblasts, immature neurons, and oligodendrocyte progenitor cells. The relative abundance of NSC and neuroblast clusters did not differ between the two age groups, indicating that the pool of SEZ NSCs does not decline in this age range. The relative abundance of oligodendrocyte progenitors and microglia decreased in middle-age, indicating that the cellular composition of human SEZ is remodeled between youth and adulthood. The expression of genes related to nervous system development was higher across different cell types, including NSCs, in youth as compared with middle-age. These transcriptional changes suggest ongoing central nervous system plasticity in the SEZ in youth, which declined in middle-age.

Psychological interventions for pre-event and post-event rumination in social anxiety: A systematic review and meta-analysis.

Pre-event and post-event rumination have been consistently identified by cognitive models as important maintaining factors in Social Anxiety Disorder (SAD). This systematic review and meta-analysis aimed to investigate the effectiveness of psychological treatment in reducing pre-event and post-event rumination in adults with social anxiety. A comprehensive literature search identified 26 eligible studies, with 1524 total participants. Psychological treatments demonstrated large significant within-group effect sizes (from pre- to post-treatment) in reducing pre-event rumination (g = 0.86) and post-event rumination (g = 0.83). Subgroups analysed showed CBT to have large significant effect sizes in reducing pre-event rumination (g = 0.97) and post-event rumination (g = 0.85). Interventions that specifically addressed rumination were found to be significantly more effective in reducing pre-event rumination than those that did not (p = .006). Both individual and group treatment formats were equally effective in reducing pre-event rumination and post-event rumination. Meta-regressions revealed that pre-event rumination treatment effects were significantly larger in individuals with higher baseline social anxiety, meanwhile post-event rumination treatment effects were larger for those with higher baseline depression. Overall findings show that pre-event and post-event rumination are effectively reduced through psychological treatment, and clinical implications for the enhancement of evidence-based treatment protocols are discussed.

Psychometric properties of self-report measures of eating disorder cognitions: a systematic review.

BACKGROUND: Although eating disorder (ED) models display some differences in theory and treatment approach, cognitive-behavioural, schema-focused, and disorder-specific models all highlight the fundamental nature of cognitions as key factors in ED development and maintenance processes. As such, it is vital that ED cognitions continue to be assessed and monitored as therapeutic targets and treatment outcomes as well as being examined as constructs in empirical research. This review aimed to systematically identify and evaluate the psychometric properties of existing self-report measures of ED cognitions. METHODS: A systematic review protocol was registered using the international prospective register of systematic reviews (PROSPERO; CRD42023440840). Included studies described the development, validation and/or the psychometric evaluation of a measure (or subscale) that was specifically developed to solely assess ED cognitions (that is thoughts, expectations, assumptions, or beliefs), in English-speaking, adult populations. The search was conducted using three electronic databases: PsycINFO, MedLine, and Embase. Two independent reviewers conducted screening, selection and evaluation of the psychometric properties of relevant measures using a standardised, well-established quality appraisal tool. RESULTS: Of the initial search of 7581 potential studies, 59 met inclusion criteria and described the psychometric evaluation of 31 measures (or subscales) of ED cognitions. The findings from the current review indicate that of the included measures, none currently meet all nine criteria of adequate psychometric properties. The Eating Beliefs Questionnaire (EBQ; and EBQ-18), and the Eating Disorder Inventory Body Dissatisfaction subscale (EDI [BD]) currently possess the most evidence supporting their validity, reliability, and clinical utility. CONCLUSIONS: The findings of the current systematic review provide guidance for future researchers to focus efforts on improving evidence for the validity, reliability and utility of self-report measures of ED cognitions. Overall, the present study has provided a detailed and systematic evaluation to support researchers and clinicians in future selection of measures of ED cognitions dependent on the specific aims of their research and treatment.

Theoretical and empirical research suggests that eating disorder (ED) cognitions (that is, thoughts, expectations, assumptions, and beliefs) are important factors contributing to the development and maintenance of EDs. As such, it is important to continue to assess and monitor these in research and in clinical practice. Valid, reliable and useful assessment tools are critical in this process. This systematic review aimed to identify and evaluate the psychometric properties of existing self-report measures of ED cognitions. Included studies described the development, validation and/or the psychometric evaluation of a measure specifically developed to solely assess ED cognitions. Three electronic databases were searched, and studies screened and selected by two independent reviewers. The included studies and self-report measured were evaluated using a standardised tool to evaluate their psychometric properties. Fifty-nine studies were included, that identified a total of 31 measures (or subscales) assessing ED cognitions. The findings from the current review indicate that none of the included measures currently meet all nine criteria of adequate psychometric properties. The EBQ, EBQ-18, and EDI-III (BD) currently have the most evidence in support of their psychometric properties. This study provides direction for future researchers to focus efforts on improving evidence for the validity, reliability and utility of these self-report measures. Overall, we provided information to support researchers and clinicians in future selection of measures of ED cognitions.

Reduced access to reinforcement drives delay discounting during experienced delays.

Rewards lose value as a function of delay. Previous studies suggest that delays have a bigger effect on reward value when people must wait during the delay. However, whether delays involve waiting or postponing has often been confounded with whether choices are about hypothetical or real rewards. The current study characterized the effects of waiting and postponing in hypothetical and experiential choice contexts separately. In Experiment 1 we observed steeper delay discounting for waiting than for postponing in choices about both hypothetical money and about experienced computer game points. Two factors potentially contributing to steeper discounting in choices about waiting are reduced access to other rewards and direct costs of waiting. In Experiment 2, we adapted the experiential delay-discounting task to manipulate each factor separately. Reduced access to other reinforcers had a bigger effect on delay discounting than direct costs of waiting. These results underscore the importance of considering the unique influence of waiting and associated opportunity costs in both basic delay-discounting research and in applied contexts.

Interpretation of SNP combination effects on schizophrenia etiology based on stepwise deep learning with multi-precision data.

Schizophrenia genome-wide association studies (GWAS) have reported many genomic risk loci, but it is unclear how they affect schizophrenia susceptibility through interactions of multiple SNPs. We propose a stepwise deep learning technique with multi-precision data (SLEM) to explore the SNP combination effects on schizophrenia through intermediate molecular and cellular functions. The SLEM technique utilizes two levels of precision data for learning. It constructs initial backbone networks with more precise but small amount of multilevel assay data. Then, it learns strengths of intermediate interactions with the less precise but massive amount of GWAS data. The learned networks facilitate identifying effective SNP interactions from the intractably large space of all possible SNP combinations. We have shown that the extracted SNP combinations show higher accuracy than any single SNPs and preserve the accuracy in an independent dataset. The learned networks also provide interpretations of molecular and cellular interactions of SNP combinations toward schizophrenia etiology.

Cytomegalovirus antibodies are associated with mood disorders, suicide, markers of neuroinflammation, and microglia activation in postmortem brain samples.

Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause central nervous system disease. We hypothesize that CMV may contribute to the neuroinflammation that underlies some psychiatric disorders by (1) exacerbating inflammation through the induction of anti-viral immune responses, and (2) translating peripheral inflammation into neuroinflammation. We investigated whether the presence of anti-CMV antibodies in blood were associated with mental illness, suicide, neuroinflammation, and microglial density in the dorsolateral prefrontal cortex (DLPFC) in postmortem samples. Data (n = 114 with schizophrenia; n = 78 with bipolar disorder; n = 87 with depression; n = 85 controls) were obtained from the Stanley Medical Research Institute. DLPFC gene expression data from a subset of 82 samples were categorized into "high" (n = 30), and "low" (n = 52) inflammation groups based on a recursive two-step cluster analysis using expression data for four inflammation-related genes. Measurements of the ratio of non-ramified to ramified microglia, a proxy of microglial activation, were available for a subset of 49 samples. All analyses controlled for age, sex, and ethnicity, as well as postmortem interval, and pH for gene expression and microglial outcomes. CMV seropositivity significantly increased the odds of a mood disorder diagnosis (bipolar disorder: OR = 2.45; major depression: OR = 3.70) and among the psychiatric samples, of suicide (OR = 2.09). Samples in the upper tercile of anti-CMV antibody titers were more likely to be members of the "high" inflammation group (OR = 4.41, an effect driven by schizophrenia and bipolar disorder samples). CMV positive samples also showed an increased ratio of non-ramified to ramified microglia in layer I of the DLPFC (Cohen's d = 0.81) as well as a non-significant increase in this ratio for the DLPFC as a whole (d = 0.56). The results raise the possibility that the reactivation of CMV contributes to the neuroinflammation that underlies some cases of psychiatric disorders.

The impact of psychological treatment on intolerance of uncertainty in generalized anxiety disorder: A systematic review and meta-analysis.

Research has demonstrated a strong link between intolerance of uncertainty and generalized anxiety disorder (GAD). The current systematic review and meta-analysis aimed to evaluate how effective evidence-based psychological treatments are at reducing intolerance of uncertainty for adults with GAD. An extensive literature search identified 26 eligible studies, with a total of 1199 participants with GAD. Psychological treatments (k = 32 treatment groups) yielded large significant within-group effect size from pre- to post-treatment and pre-treatment to follow-up for intolerance of uncertainty (g = 0.88; g = 1.05), as well as related symptoms including worry (g = 1.32; g = 1.45), anxiety (g = 0.94; g = 1.04) and depression (g = 0.96; g = 1.00). Psychological treatment also yielded a large significant between-group effect on intolerance of uncertainty (g = 1.35). Subgroups analysis found that CBT that directly targeted intolerance of uncertainty (CBT-IU) throughout treatment was significantly more effective than general CBT at reducing intolerance of uncertainty (p < 0.01) and worry (p < 0.01) from pre- to post treatment, however, this result was not maintained at follow-up. Meta-regression analyses supported this finding as increases in the amount of time spent directly targeting intolerance of uncertainty, significantly increased the effect size for both intolerance of uncertainty (z = 2.01, p < 0.01) and worry (z = 2.23, p < 0.01). Overall, these findings indicate that psychological treatments are effective at reducing IU, and related symptom measures of GAD.

Increased prefrontal cortical cells positive for macrophage/microglial marker CD163 along blood vessels characterizes a neuropathology of neuroinflammatory schizophrenia.

Transcript levels of cytokines and SERPINA3 have been used to define a substantial subset (40%) of individuals with schizophrenia with elevated inflammation and worse neuropathology in the dorsolateral prefrontal cortex (DLPFC). In this study, we tested if inflammatory proteins are likewise related to high and low inflammatory states in the human DLFPC in people with schizophrenia and controls. Levels of inflammatory cytokines (IL6, IL1ß, IL18, IL8) and a macrophage marker (CD163 protein) were measured in brains obtained from the National Institute of Mental Health (NIMH) (N = 92). First, we tested for diagnostic differences in protein levels overall, then we determined the percentage of individuals that could be defined as "high" inflammation using protein levels. IL-18 was the only cytokine to show increased expression in schizophrenia compared to controls overall. Interestingly, two-step recursive clustering analysis showed that IL6, IL18, and CD163 protein levels could be used as predictors of "high and low" inflammatory subgroups. By this model, a significantly greater proportion of schizophrenia cases (18/32; 56.25%; SCZ) were identified as belonging to the high inflammatory (HI) subgroup compared to control cases (18/60; 30%; CTRL) [χ2(1) = 6.038, p = 0.014]. When comparing across inflammatory subgroups, IL6, IL1ß, IL18, IL8, and CD163 protein levels were elevated in both SCZ-HI and CTRL-HI compared to both low inflammatory subgroups (all p < 0.05). Surprisingly, TNFα levels were significantly decreased (-32.2%) in schizophrenia compared to controls (p < 0.001), and were most diminished in the SCZ-HI subgroup compared to both CTRL-LI and CTRL-HI subgroups (p < 0.05). Next, we asked if the anatomical distribution and density of CD163+ macrophages differed in those with schizophrenia and high inflammation status. Macrophages were localized to perivascular sites and found surrounding small, medium and large blood vessels in both gray matter and white matter, with macrophage density highest at the pial surface in all schizophrenia cases examined. A higher density of CD163+ macrophages, that were also larger and more darkly stained, was found in the SCZ-HI subgroup (+154% p < 0.05). We also confirmed the rare existence of parenchymal CD163+ macrophages in both high inflammation subgroups (schizophrenia and controls). Brain CD163+ cell density around blood vessels positively correlated with CD163 protein levels. In conclusion, we find a link between elevated interleukin cytokine protein levels, decreased TNFα protein levels, and elevated CD163+ macrophage densities especially along small blood vessels in those with neuroinflammatory schizophrenia.

Changes in cytokine and cytokine receptor levels during postnatal development of the human dorsolateral prefrontal cortex.

In addition to their traditional roles in immune cell communication, cytokines regulate brain development. Cytokines are known to influence neural cell generation, differentiation, maturation, and survival. However, most work on the role of cytokines in brain development investigates rodents or focuses on prenatal events. Here, we investigate how mRNA and protein levels of key cytokines and cytokine receptors change during postnatal development of the human prefrontal cortex. We find that most cytokine transcripts investigated (IL1B, IL18, IL6, TNF, IL13) are lowest at birth and increase between 1.5 and 5 years old. After 5 years old, transcriptional patterns proceeded in one of two directions: decreased expression in teens and young adults (IL1B, p = 0.002; and IL18, p = 0.004) or increased mean expression with maturation, particularly in teenagers (IL6, p = 0.004; TNF, p = 0.002; IL13, p < 0.001). In contrast, cytokine proteins tended to remain elevated after peaking significantly around 3 years of age (IL1B, p = 0.012; IL18, p = 0.026; IL6, p = 0.039; TNF, p < 0.001), with TNF protein being highest in teenagers. An mRNA-only analysis of cytokine receptor transcripts found that early developmental increases in cytokines were paralleled by increases in their ligand-binding receptor subunits, such as IL1R1 (p = 0.033) and IL6R (p < 0.001) transcripts. In contrast, cytokine receptor-associated signaling subunits, IL1RAP and IL6ST, did not change significantly between age groups. Of the two TNF receptors, the 'pro-death' TNFRSF1A and 'pro-survival' TNFRSF1B, only TNFRSF1B was significantly changed (p = 0.028), increasing first in toddlers and again in young adults. Finally, the cytokine inhibitor, IL13, was elevated first in toddlers (p = 0.006) and again in young adults (p = 0.053). While the mean expression of interleukin-1 receptor antagonist (IL1RN) was highest in toddlers, this increase was not statistically significant. The fluctuations in cytokine expression reported here support a role for increases in specific cytokines at two different stages of human cortical development. The first is during the toddler/preschool period (IL1B, IL18, and IL13), and the other occurs at adolescence/young adult maturation (IL6, TNF and IL13).

An exploratory investigation of schema modes in social anxiety disorder: Empirical findings and case conceptualization.

BACKGROUND: Current "gold standard" treatments for social anxiety disorder (SAD) are limited by the limited emphasis of key etiological factors in conceptualization, and many individuals with SAD experience residual symptoms posttreatment. Hence, the novel application of the Schema Therapy Mode Model may provide a helpful framework for extending clinical understanding and treatment options for SAD. This exploratory study aimed to investigate the presence and pattern of schema modes among SAD individuals. METHOD: Forty individuals with SAD completed questionnaire measures of symptomatology, social anxiety-relevant cognitions, schema modes, childhood trauma, and parental style. RESULTS: Key maladaptive schema modes identified in SAD were Vulnerable Child, Punitive Critic, Demanding Critic, Compliant Surrender, and Detached Self-Soother. CONCLUSION: Outcomes provide the basis for a proposed schema mode case conceptualization for SAD and are hoped to provide a rationale for testing the applicability of Schema Therapy as a novel treatment for SAD. Key limitations are discussed.

Change Patterns During Family-Based Treatment for Pediatric Obsessive Compulsive Disorder.

Cognitive behavior therapy (CBT) for young people with obsessive compulsive disorder (OCD) has recently been enhanced to target family environment factors. However, the process of change for OCD symptoms and family factors during treatment is not well understood. Uniquely, we explored patterns of change for OCD symptoms and a range of family variables throughout Baseline, Early, Mid, and Late treatment phases of family-based CBT (FCBT) for 15 young people with OCD using multiple informants. We predicted a linear reduction in OCD symptom severity and family accommodation (FA) across treatment phases, however the investigation into other family factor change patterns was exploratory. OCD symptom severity, FA, parental distress tolerance (DT), and conflict all showed significant linear change patterns across treatment phases according to multiple informants. In addition, the largest proportion of change for these variables typically occurred during the first third of treatment, highlighting the importance of identifying participants with and without early gains in future research. Blame also showed a significant linear change pattern, although with small reductions between treatment phases. Preliminary bivariate analyses sought to better understand whether family factor change predicted subsequent OCD severity change or vice versa. Similar patterns emerged across informants, including identification of OCD severity as a significant predictor of change for Blame at subsequent treatment phases. Analyses also showed bi-directional effects for DT and OCD symptoms across informants, where DT predicted OCD severity at subsequent treatment phases and vice versa. These outcomes support further research aimed at understanding the role of family factors in pediatric OCD symptom change.

Overexpression of transmembrane TNFα in brain endothelial cells induces schizophrenia-relevant behaviors.

Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.

Infections, Inflammation, and Psychiatric Illness: Review of Postmortem Evidence.

While there is an abundance of epidemiological evidence implicating infectious agents in the etiology of severe mental illnesses, postmortem studies have not yet detected an increased incidence of microbial nucleic acid or proteins in the brains of people with mental illness. Nevertheless, abnormally expressed immune and inflammatory markers have consistently been found in the postmortem brain of patients with schizophrenia and mood disorders. Some of these abnormalities may be the result of an infection in utero or early in life that not only impacted the developing immune system but also the developing neurons of the brain. Some of the immune markers that are consistently found to be upregulated in schizophrenia implicate a possible viral infection and the blood brain barrier in the etiology and neuropathology of the disorder.

Psychometric properties of the state Probability and Consequences Questionnaire for social anxiety disorder.

Cognitive models of social anxiety propose that overestimation of the probability and cost of negative evaluation plays a central role in maintaining the disorder. However, there are currently no self-report state-based measures of probability and cost appraisals. The current paper examines the psychometric properties of the Probability and Consequences Questionnaire for social anxiety (PCQ-SA), which measures probability and consequence appraisals both in anticipation of, and in response to, an impromptu speech task. A total of 532 participants were recruited for the present study, consisting of 409 participants with a principal diagnosis of Social Anxiety Disorder (SAD), and 123 non-clinical controls. Results of exploratory and confirmatory factor analyses supported a two-factor solution for the PCQ-SA. The PCQ-SA demonstrated excellent internal consistency, excellent test-retest reliability, good convergent validity at both time points (i.e., pre and post speech task), and sensitivity to treatment. Finally, using Receiver Operating Characteristic Curve Analysis, clinical cut-off scores were calculated for probability and consequences at both time points, with the PCQ-SA scales showing good sensitivity, specificity, and positive and negative predictive values. Overall, the results provide evidence that the PCQ-SA possesses excellent psychometric properties. The PCQ-SA is suitable for use in clinical and research settings to assess key cognitive maintaining factors for SAD.

Single-nucleus RNA sequencing of midbrain blood-brain barrier cells in schizophrenia reveals subtle transcriptional changes with overall preservation of cellular proportions and phenotypes.

The midbrain is an extensively studied brain region in schizophrenia, in view of its reported dopamine pathophysiology and neuroimmune changes associated with this disease. Besides the dopaminergic system, the midbrain contains other cell types that may be involved in schizophrenia pathophysiology. The neurovascular hypothesis of schizophrenia postulates that both the neurovasculature structure and the functioning of the blood-brain barrier (BBB) are compromised in schizophrenia. In the present study, potential alteration in the BBB of patients with schizophrenia was investigated by single-nucleus RNA sequencing of post-mortem midbrain tissue (15 schizophrenia cases and 14 matched controls). We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes were limited to the ependymal cells and pericytes, suggesting that the cells of the BBB are not broadly affected in schizophrenia.