A neurogenetic model for the study of schizophrenia spectrum disorders: The International 22q11.2 Deletion Syndrome Brain Behavior Consortium

Rare copy number variants contribute significantly to the risk for schizophrenia, with the 22q11.2 locus consistently implicated. Individuals with the 22q11.2 deletion syndrome (22q11DS) have an estimated 25-fold increased risk for schizophrenia spectrum disorders, compared to individuals in the general population. The International 22q11DS Brain Behavior Consortium is examining this highly informative neurogenetic syndrome phenotypically and genomically. Here we detail the procedures of the effort to characterize the neuropsychiatric and neurobehavioral phenotypes associated with 22q11DS, focusing on schizophrenia and subthreshold expression of psychosis. The genomic approach includes a combination of whole genome sequencing and genome-wide microarray technologies, allowing the investigation of all possible DNA variation and gene pathways influencing the schizophrenia-relevant phenotypic expression. A phenotypically rich data set provides a psychiatrically well-characterized sample of unprecedented size (n=1,616) that informs the neurobehavioral developmental course of 22q11DS. This combined set of phenotypic and genomic data will enable hypothesis testing to elucidate the mechanisms underlying the pathogenesis of schizophrenia spectrum disorders

Detection of early age-related macular degeneration using novel functional parameters of the focal cone electroretinogram

The focal cone electroretinogram is a sensitive marker for macular disease, but have we unlocked its full potential? Typically assessment of waveform parameters is subjective and focuses on a small number of locations (e.g. the a-wave). This study evaluated the discriminatory and diagnostic potential of 4 conventional and 15 novel, objectively determined, parameters in patients with early Age-related Macular Degeneration. Focal cone electroretinograms were recorded in 54 participants with early Age-related Macular Degeneration (72.9±8.2 years) and 54 healthy controls (69±7.7 years). Conventional a and b wave amplitudes and implicit times were measured and compared to novel parameters derived from both the 1st and 2nd derivatives and the frequency-domain power spectrum of the electroretinogram.Statistically significant differences between groups were shown for all conventional parameters, the majority of 1st and 2nd derivative parameters and the power spectrum at 25 and 30 Hz. Receiver operating characteristics showed that both conventional and 1st and 2nd derivative implicit times had provided the best diagnostic potential. A regression model showed a small improvement over any individual parameter investigated. The non-conventional parameters enhanced the objective evaluation of the focal electroretinogram, especially when the amplitude was low. Furthermore, the novel parameters described here allow the implicit time of the electroretinogram to be probed at points other than the peaks of the a and b waves. Consequently these novel analysis techniques could prove valuable in future electrophysiological investigation, detection and monitoring of Age-related Macular Degeneration

The use of Bayesian latent class cluster models to classify patterns of cognitive performance in healthy ageing

The main focus of this study is to illustrate the applicability of latent class analysis in the assessment of cognitive performance profiles during ageing. Principal component analysis (PCA) was used to detect main cognitive dimensions (based on the neurocognitive test variables) and Bayesian latent class analysis (LCA) models (without constraints) were used to explore patterns of cognitive performance among community-dwelling older individuals. Gender, age and number of school years were explored as variables. Three cognitive dimensions were identified: general cognition (MMSE), memory (MEM) and executive (EXEC) function. Based on these, three latent classes of cognitive performance profiles (LC1 to LC3) were identified among the older adults. These classes corresponded to stronger to weaker performance patterns (LC1>LC2>LC3) across all dimensions; each latent class denoted the same hierarchy in the proportion of males, age and number of school years. Bayesian LCA provided a powerful tool to explore cognitive typologies among healthy cognitive agers.The study is integrated in the "Maintaining health in old age through homeostasis (SWITCHBOX)" collaborative project funded by the European Commission FP7 initiative (grant HEALTH-F2-2010-259772). NS and JAP are main team members of the European consortium SWITCHBOX (http://www.switchbox-online.eu/). NCS is supported by a SwitchBox post-doctoral fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebocontrolled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.TW Weickert, D Weinberg, R Lenroot, SV Catts, R Wells, A Vercammen, M O, Donnell, C Galletly, D Liu, R Balzan, B Short, D Pellen, J Curtis, VJ Carr, J Kulkarni, PR Schofield and CS Weicker

The PHF21B gene is associated with major depression and modulates the stress response

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.M-L Wong, M Arcos-Burgos, S Liu, J I Vélez, C Yu, B T Baune, M C Jawahar, V Arolt, U Dannlowski, A Chuah, G A Huttley, R Fogarty, M D Lewis, S R Bornstein, and J Licini

The molecular genetic landscape of human brain size variation

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease

Lack of cortico-limbic coupling in bipolar disorder and schizophrenia during emotion regulation

Bipolar disorder (BD) and schizophrenia (Sz) share dysfunction in prefrontal inhibitory brain systems, yet exhibit distinct forms of affective disturbance. We aimed to distinguish these disorders on the basis of differential activation in cortico-limbic pathways during voluntary emotion regulation. Patients with DSM-IV diagnosed Sz (12) or BD-I (13) and 15 healthy control (HC) participants performed a well-established emotion regulation task while undergoing functional magnetic resonance imaging. The task required participants to voluntarily upregulate or downregulate their subjective affect while viewing emotionally negative images or maintain their affective response as a comparison condition. In BD, abnormal overactivity (hyperactivation) occurred in the right ventrolateral prefrontal cortex (VLPFC) during up- and downregulation of negative affect, relative to HC. Among Sz, prefrontal hypoactivation of the right VLPFC occurred during downregulation (opposite to BD), whereas upregulation elicited hyperactivity in the right VLPFC similar to BD. Amygdala activity was significantly related to subjective negative affect in HC and BD, but not Sz. Furthermore, amygdala activity was inversely coupled with the activity in the left PFC during downregulation in HC (r=−0.76), while such coupling did not occur in BD or Sz. These preliminary results indicate that differential cortico-limbic activation can distinguish the clinical groups in line with affective disturbance: BD is characterized by ineffective cortical control over limbic regions during emotion regulation, while Sz is characterized by an apparent failure to engage cortical (hypofrontality) and limbic regions during downregulation

Comorbid substance abuse and brain morphology in recent-onset psychosis

The aim of the presented study was to compare schizophrenia and schizoaffective patients early in the course of the disease with and without comorbid substance abuse disorder (SUD vs. NSUD) with regard to brain morphology. In a prospective design 41 patients (20 SUD vs. 21 NSUD) diagnosed as recent-onset schizophrenia or schizoaffective disorder consecutively admitted to hospital received standardized psychopathological evaluation (BPRS, SANS, MADRS, CGI, GAF) and MRI scanning with volumetric measurement of superior temporal gyrus (STG), amygdala-hippocampal complex, and cingulum. Patients with SUD (primarily cannabis) were significantly younger, predominantly male and had a lower socioeconomic status. Despite less attentional impairment (SANS subscore) and elevated anxiety/depression (BPRS subscore) in patients with SUD compared to NSUD, no other psychopathological differences could be detected. There were no differences in the assessed temporolimbic brain morphology between the two subgroups. In conclusion, in this study substance abuse in recent-onset psychosis had no effect on brain morphology and the earlier onset of psychosis in patients with comorbid SUD could not be explained by supposed accentuated brain abnormalities in temporolimbic regions

Disordered semantic representation in schizophrenic temporal cortex revealed by neuromagnetic response patterns

BACKGROUND: Loosening of associations and thought disruption are key features of schizophrenic psychopathology. Alterations in neural networks underlying this basic abnormality have not yet been sufficiently identified. Previously, we demonstrated that spatio-temporal clustering of magnetic brain responses to pictorial stimuli map categorical representations in temporal cortex. This result has opened the possibility to quantify associative strength within and across semantic categories in schizophrenic patients. We hypothesized that in contrast to controls, schizophrenic patients exhibit disordered representations of semantic categories. METHODS: The spatio-temporal clusters of brain magnetic activities elicited by object pictures related to super-ordinate (flowers, animals, furniture, clothes) and base-level (e.g. tulip, rose, orchid, sunflower) categories were analysed in the source space for the time epochs 170–210 and 210–450 ms following stimulus onset and were compared between 10 schizophrenic patients and 10 control subjects. RESULTS: Spatio-temporal correlations of responses elicited by base-level concepts and the difference of within vs. across super-ordinate categories were distinctly lower in patients than in controls. Additionally, in contrast to the well-defined categorical representation in control subjects, unsupervised clustering indicated poorly defined representation of semantic categories in patients. Within the patient group, distinctiveness of categorical representation in the temporal cortex was positively related to negative symptoms and tended to be inversely related to positive symptoms. CONCLUSION: Schizophrenic patients show a less organized representation of semantic categories in clusters of magnetic brain responses than healthy adults. This atypical neural network architecture may be a correlate of loosening of associations, promoting positive symptoms