MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Social and occupational recovery in early psychosis: a systematic review and meta-analysis of psychosocial interventions.

BACKGROUND: Psychosis, even in its early stages, ranks highly among the causes of disability worldwide, resulting in an increased focus on improved recovery of social and occupational functioning. This study aimed to provide an estimate of the effectiveness of psychosocial interventions for improving functioning in early psychosis. We also sought evidence of superiority between intervention approaches. METHODS: An electronic search was conducted using PubMed and PsycINFO to identify original articles reporting on trials of psychosocial interventions in early-stage psychosis, published up to December 2020 and is reported following PRISMA guidelines. Data were extracted on validated measures of functioning from included studies and pooled standardised mean difference (SMD) was estimated. RESULTS: In total, 31 studies involving 2811 participants were included, focusing on: cognitive behavioural therapy for psychosis (CBTp), family-based therapy, supported employment, cognitive remediation training (CRT) and multi-component psychosocial interventions. Across interventions, improved function was observed (SMD = 0.239; 95% confidence interval 0.115-0.364, p < 0.001). Effect sizes varied by intervention type, stage of illness, length and duration of treatment and outcome measure used. In particular, interventions based on CRT significantly outperformed symptom-focused CBT interventions, while multi-component interventions were associated with largest gains. CONCLUSIONS: Psychosocial interventions, particularly when provided as part of a multi-component intervention model and delivered in community-based settings are associated with significant improvements in social and occupational function. This review underscores the value of sensitively tracking and targeting psychosocial function as part of the standard provided by early intervention services.

Evidence supporting the use of a brief cognitive assessment in routine clinical assessment for psychosis.

Cognitive impairment is a core feature of psychosis. Full cognitive assessments are not often conducted in routine clinical practice as administration is time-consuming. Here, we investigated whether brief tests of cognition could be used to predict broader neurocognitive performance in a manner practical for screening use in mental health services. We carried out a principal component analysis (PCA) to obtain an estimate of general cognitive function (N = 415). We investigated whether brief tests of memory accounted for a significant percentage of variation in the PCA scores. We used discriminant function analysis to determine if measures could predict classification as lower, intermediate or higher level of cognitive function and to what extent these groups overlapped with groups based on normative data. Memory tests correctly classified 65% of cases in the highest scoring group, 35% of cases in the intermediate group, and 77% of cases in the lowest scoring group. These PCA-derived groups and groups based on normative scores for the two tests were significantly associated (χ2 = 164.00, p < 0.001). These measures accurately identified three quarters of the low performing group, the group of greatest interest from the perspective of identifying those likely to need greater supports as part of clinical care. In so doing they suggest a potentially useful approach to screening for cognitive impairment in clinical services, upon which further assessment can be built if required.

Cognitive Remediation and Social Recovery in Early Psychosis (CReSt-R): protocol for a pilot randomised controlled study.

BACKGROUND: Psychosis, even in its early stages, is associated with significant disability, causing it to be ranked ahead of paraplegia and blindness in those aged 18-35 in terms of years lived with disability. Current pharmacological and psychological interventions intervention have focused primarily on the reduction of positive symptoms (hallucinations and delusions), with little benefit to domains of psychosis such as cognitive difficulties and social and occupational functioning. METHODS/DESIGN: The CReSt-R intervention trial is a single center, pilot randomised controlled study based at the National University of Ireland (NUI), Galway. The trial will recruit participants from four clinical sites with assessment and intervention completed by the primary NUI Galway team. The trial will explore the feasibility, acceptability, and effectiveness of a novel psychosocial intervention for early psychosis based on a combined cognitive remediation training and cognitive behavioural therapy approach focused on social recovery. Participants, aged 16-35 within the first 5 years of a diagnosed psychotic disorder, will be recruited from the Children and Adolescent Mental Health Service and the Adult Mental Health Services in the region. DISCUSSION: Cognitive remediation training (for improving cognition) and social recovery focused cognitive behavioural therapy, have both separately demonstrated effectiveness. This trial will evaluate the feasibility, acceptability, and explore the efficacy of a treatment approach that combines both approaches as part of an integrated, multicomponent intervention. TRIAL REGISTRATION: Cognitive Remediation & Social Recovery in Early Psychosis (CReSt-R): ClincialTrials.gov Identifier NCT04273685. Trial registered Feb 18th, 2020. Last updated April 14th, 2021.

Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Cortisol stress response in psychosis from the high-risk to the chronic stage: a systematic review.

OBJECTIVES: We review studies of whether cortisol levels following psychosocial stress exposure differ between patients with psychosis and healthy control subjects. METHODS: Original research published between 1993 and February 2019 was included in the literature search. Studies that used experimentally induced psychosocial stress and reported stress response measures of plasma or saliva cortisol levels in patients at any stage of illness (i.e. high risk, first episode and chronic phase) were included. RESULTS: A total of 17 studies were included. Although there was evidence of inconsistencies in measures, we observed moderate evidence of an association with stress-induced cortisol blunting response across studies. CONCLUSIONS: This review highlights recent evidence of blunting of cortisol response following experimentally induced psychosocial stress. While there was some evidence of this blunted response across illness types and stages, the strongest evidence was observed for those with chronic schizophrenia. Due to the low number of studies, in particular in bipolar disorder, much work is still needed to accurately characterise the biological effects of stress in psychosis.

Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation.

BACKGROUND: The longstanding association between the major histocompatibility complex (MHC) locus and schizophrenia (SZ) risk has recently been accounted for, partially, by structural variation at the complement component 4 (C4) gene. This structural variation generates varying levels of C4 RNA expression, and genetic information from the MHC region can now be used to predict C4 RNA expression in the brain. Increased predicted C4A RNA expression is associated with the risk of SZ, and C4 is reported to influence synaptic pruning in animal models. METHODS: Based on our previous studies associating MHC SZ risk variants with poorer memory performance, we tested whether increased predicted C4A RNA expression was associated with reduced memory function in a large (n = 1238) dataset of psychosis cases and healthy participants, and with altered task-dependent cortical activation in a subset of these samples. RESULTS: We observed that increased predicted C4A RNA expression predicted poorer performance on measures of memory recall (p = 0.016, corrected). Furthermore, in healthy participants, we found that increased predicted C4A RNA expression was associated with a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing (p < 0.05, corrected). CONCLUSIONS: These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4's developmental role.

Effectiveness of a low support, remotely accessible, cognitive remediation training programme for chronic psychosis: cognitive, functional and cortical outcomes from a single blind randomised controlled trial.

BACKGROUND: Cognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis. METHODS: Ninety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3-6 months post-treatment. RESULTS: Patients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3-6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition. CONCLUSIONS: CR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.

Prefrontal cortical thinning links to negative symptoms in schizophrenia via the ENIGMA consortium.

BACKGROUND: Our understanding of the complex relationship between schizophrenia symptomatology and etiological factors can be improved by studying brain-based correlates of schizophrenia. Research showed that impairments in value processing and executive functioning, which have been associated with prefrontal brain areas [particularly the medial orbitofrontal cortex (MOFC)], are linked to negative symptoms. Here we tested the hypothesis that MOFC thickness is associated with negative symptom severity. METHODS: This study included 1985 individuals with schizophrenia from 17 research groups around the world contributing to the ENIGMA Schizophrenia Working Group. Cortical thickness values were obtained from T1-weighted structural brain scans using FreeSurfer. A meta-analysis across sites was conducted over effect sizes from a model predicting cortical thickness by negative symptom score (harmonized Scale for the Assessment of Negative Symptoms or Positive and Negative Syndrome Scale scores). RESULTS: Meta-analytical results showed that left, but not right, MOFC thickness was significantly associated with negative symptom severity (ß std = -0.075; p = 0.019) after accounting for age, gender, and site. This effect remained significant (p = 0.036) in a model including overall illness severity. Covarying for duration of illness, age of onset, antipsychotic medication or handedness weakened the association of negative symptoms with left MOFC thickness. As part of a secondary analysis including 10 other prefrontal regions further associations in the left lateral orbitofrontal gyrus and pars opercularis emerged. CONCLUSIONS: Using an unusually large cohort and a meta-analytical approach, our findings point towards a link between prefrontal thinning and negative symptom severity in schizophrenia. This finding provides further insight into the relationship between structural brain abnormalities and negative symptoms in schizophrenia.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

Positive symptoms associate with cortical thinning in the superior temporal gyrus via the ENIGMA Schizophrenia consortium.

OBJECTIVE: Based on the role of the superior temporal gyrus (STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. METHOD: This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. RESULTS: Positive symptom severity was negatively related to STG thickness in both hemispheres (left: ßstd = -0.052; P = 0.021; right: ßstd = -0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. CONCLUSION: Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

MiR-137-derived polygenic risk: effects on cognitive performance in patients with schizophrenia and controls.

Variants at microRNA-137 (MIR137), one of the most strongly associated schizophrenia risk loci identified to date, have been associated with poorer cognitive performance. As microRNA-137 is known to regulate the expression of ~1900 other genes, including several that are independently associated with schizophrenia, we tested whether this gene set was also associated with variation in cognitive performance. Our analysis was based on an empirically derived list of genes whose expression was altered by manipulation of MIR137 expression. This list was cross-referenced with genome-wide schizophrenia association data to construct individual polygenic scores. We then tested, in a sample of 808 patients and 192 controls, whether these risk scores were associated with altered performance on cognitive functions known to be affected in schizophrenia. A subgroup of healthy participants also underwent functional imaging during memory (n=108) and face processing tasks (n=83). Increased polygenic risk within the empirically derived miR-137 regulated gene score was associated with significantly lower performance on intelligence quotient, working memory and episodic memory. These effects were observed most clearly at a polygenic threshold of P=0.05, although significant results were observed at all three thresholds analyzed. This association was found independently for the gene set as a whole, excluding the schizophrenia-associated MIR137 SNP itself. Analysis of the spatial working memory fMRI task further suggested that increased risk score (thresholded at P=10-5) was significantly associated with increased activation of the right inferior occipital gyrus. In conclusion, these data are consistent with emerging evidence that MIR137 associated risk for schizophrenia may relate to its broader downstream genetic effects.

Detecting facial emotion recognition deficits in schizophrenia using dynamic stimuli of varying intensities.

BACKGROUND: Deficits in facial emotion recognition have been associated with functional impairments in patients with Schizophrenia (SZ). Whilst a strong ecological argument has been made for the use of both dynamic facial expressions and varied emotion intensities in research, SZ emotion recognition studies to date have primarily used static stimuli of a singular, 100%, intensity of emotion. To address this issue, the present study aimed to investigate accuracy of emotion recognition amongst patients with SZ and healthy subjects using dynamic facial emotion stimuli of varying intensities. To this end an emotion recognition task (ERT) designed by Montagne (2007) was adapted and employed. METHODS: 47 patients with a DSM-IV diagnosis of SZ and 51 healthy participants were assessed for emotion recognition. Results of the ERT were tested for correlation with performance in areas of cognitive ability typically found to be impaired in psychosis, including IQ, memory, attention and social cognition. RESULTS: Patients were found to perform less well than healthy participants at recognising each of the 6 emotions analysed. Surprisingly, however, groups did not differ in terms of impact of emotion intensity on recognition accuracy; for both groups higher intensity levels predicted greater accuracy, but no significant interaction between diagnosis and emotional intensity was found for any of the 6 emotions. Accuracy of emotion recognition was, however, more strongly correlated with cognition in the patient cohort. DISCUSSION: Whilst this study demonstrates the feasibility of using ecologically valid dynamic stimuli in the study of emotion recognition accuracy, varying the intensity of the emotion displayed was not demonstrated to impact patients and healthy participants differentially, and thus may not be a necessary variable to include in emotion recognition research.

Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: a 3-year prospective cohort study.

BACKGROUND: Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown. METHOD: Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by -0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for. CONCLUSIONS: Anticholinergic burden has a significant impact on patients' ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.

Neural effects of social environmental stress - an activation likelihood estimation meta-analysis.

BACKGROUND: Social environmental stress, including childhood abuse and deprivation, is associated with increased rates of psychiatric disorders such as schizophrenia and depression. However, the neural mechanisms mediating risk are not completely understood. Functional magnetic resonance imaging (MRI) studies have reported effects of social environmental stress on a variety of brain regions, but interpretation of results is complicated by the variety of environmental risk factors examined and different methods employed. METHOD: We examined brain regions consistently showing differences in blood oxygen level-dependent (BOLD) response in individuals exposed to higher levels of environmental stress by performing a coordinate-based meta-analysis on 54 functional MRI studies using activation likelihood estimation (ALE), including an overall sample of 3044 participants. We performed separate ALE analyses on studies examining adults (mean age ⩾18 years) and children/adolescents (mean age <18 years) and a contrast analysis comparing the two types of study. RESULTS: Across both adult and children/adolescent studies, ALE meta-analysis revealed several clusters in which differences in BOLD response were associated with social environmental stress across multiple studies. These clusters incorporated several brain regions, among which the right amygdala was most frequently implicated. CONCLUSIONS: These findings suggest that a variety of social environmental stressors is associated with differences in the BOLD response of specific brain regions such as the right amygdala in both children/adolescents and adults. What remains unknown is whether these environmental stressors have differential effects on treatment response in these brain regions.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.