Investigating the increased risk of schizophrenia and bipolar disorders in relatives of ADHD probands using colocalization analysis of common genetic variants.

BACKGROUND: Relatives of ADHD probands are known to be at increased risk of schizophrenia and bipolar disorder, suggesting shared genetic factors. In this study, we aim to identify shared common risk variants (i.e., Single-Nucleotide Polymorphisms, SNPs) between ADHD and schizophrenia, and between ADHD and bipolar disorder. METHODS: With the summary data from three GWAS, one on ADHD (20,183 cases with ADHD and 35,191 controls), another on schizophrenia (76,755 cases with schizophrenia and 243,649 controls) and another on bipolar disorder (41,917 cases with bipolar disorder and 371,549 controls), we used colocalization analysis to identify SNPs shared by ADHD and schizophrenia, and SNPs shared by ADHD and bipolar disorder. Functional genomic analyses were then conducted on these two sets of shared common genetic variants. RESULTS: We found that three of the 12 SNPs associated with ADHD colocalized with schizophrenia SNPs and one of the 12 SNPs associated with ADHD colocalized with bipolar disorder. Only 0.4% of the SNPs associated with schizophrenia (2 out of 431) and 2.3% of the SNPs associated with bipolar disorder (2 out of 86), colocalized with ADHD SNPs. Some genes mapped to these shared genetic variants (SCN2A and UNC5D) are involved in the development of the nervous system. CONCLUSIONS: Using colocalization analysis, the present study uncovers shared genetic variants associated with ADHD and schizophrenia as well as ADHD and bipolar disorder, and may at least partially explain the increased risk of schizophrenia and bipolar disorder in relatives of ADHD probands.

French validation of the barriers to access to care evaluation (BACE-3) scale.

BACKGROUND: The aim of this study was to develop and evaluate a French version of the Barriers to Access to Care Evaluation (BACE-3) scale that is tailored to the socio-cultural and language setting of the study. METHODS: The translation of the BACE-3 into French and its validation were the two key components of this psychometric investigation. An online survey was created and circulated to French-speaking participants who volunteered to participate in the study. RESULTS: For all translated questions, the reliability analysis key results (Cronbach's alpha and McDonald's Omega) were both>0.95, which is an excellent reliability value. The BACE-3 items were shown to be positively related to one another, implying excellent validity. Results of exploratory and confirmatory factor analyses showed that all stigma-related items were loaded under the same factor. CONCLUSIONS: The BACE-3 has been validated in French, and its psychometric qualities have been thoroughly evaluated and found to be excellent.

Serum immune markers and transition to psychosis in individuals at clinical high risk.

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis. An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood-brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.

Dopamine-induced pruning in monocyte-derived-neuronal-like cells (MDNCs) from patients with schizophrenia.

The long lapse between the presumptive origin of schizophrenia (SCZ) during early development and its diagnosis in late adolescence has hindered the study of crucial neurodevelopmental processes directly in living patients. Dopamine, a neurotransmitter consistently associated with the pathophysiology of SCZ, participates in several aspects of brain development including pruning of neuronal extensions. Excessive pruning is considered the cause of the most consistent finding in SCZ, namely decreased brain volume. It is therefore possible that patients with SCZ carry an increased susceptibility to dopamine's pruning effects and that this susceptibility would be more obvious in the early stages of neuronal development when dopamine pruning effects appear to be more prominent. Obtaining developing neurons from living patients is not feasible. Instead, we used Monocyte-Derived-Neuronal-like Cells (MDNCs) as these cells can be generated in only 20 days and deliver reproducible results. In this study, we expanded the number of individuals in whom we tested the reproducibility of MDNCs. We also deepened the characterization of MDNCs by comparing its neurostructure to that of human developing neurons. Moreover, we studied MDNCs from 12 controls and 13 patients with SCZ. Patients' cells differentiate more efficiently, extend longer secondary neurites and grow more primary neurites. In addition, MDNCs from medicated patients expresses less D1R and prune more primary neurites when exposed to dopamine. Haloperidol did not influence our results but the role of other antipsychotics was not examined and thus, needs to be considered as a confounder.

Neurodevelopmental disorders (NDD) without boundaries: research and interventions beyond classifications.

On June 2022, the 2nd Webinar "Neurodevelopmental Disorders (NDD) without boundaries took place at the Imagine Institute in Paris and was broadcasted live and in replay. The aim of this webinar is to address NDD in a dimensional rather than in a categorical approach. Several speakers were invited to present their researches on the subject. Classifications in NDD were discussed: irritability in NDD, involvement of the immune system in neurodevelopment, nutrition and gut microbiota modulate brain inflammation and neurodevelopment, co-occurring conditions in autistic adolescents and adults without intellectual disability. Classifications in psychiatric disorders were asked: mapping the effect of genes on cognition and autism risk, epigenetics and symptomatic trajectory in neurodevelopmental disorders, the autism-schizophrenia continuum in two examples: minor neurological signs and EEG microstates, the cerebellum in schizophrenia and autism: from imaging to intervention perspectives. Both genetic and environmental factors, along with clinical and imaging features, argue toward a continnum between NDD but also with adult psychiatric presentations. This new paradigm could modify the therapeutic strategy, with the development of large-spectrum treatments or new psychotherapies addressing co-occuring symptoms. The complexity and the heterogeneity of NDD apply well to the next scientific and political challenges: developing international convergence to push back the frontiers of our knowledge. This article is a summary of the 2nd webinar "Neurodevelopmental Disorders (NDD) without boundaries: research and interventions beyond classifications" sponsored by the French National Academy of Medicine, the autism and neurodevelopmental disorders scientific interest group (GIS), the International Research Network Dev-O-Psy and the French Institute of Psychiatry (GDR3557). Oral presentations are available as a replay on the following website (in French): https://autisme-neurodev.org/evenements/2022/04/12/tnd-sans-frontieres-la-recherche-et-les-interventions-au-dela-des-classifications/ .

Caregiving-related experiences associated with depression severity and its symptomatology among caregivers of individuals with a severe mental disorder: an online cross-sectional study.

Caring for a relative with a severe mental disorder puts family caregivers to a great risk of depression. While overall caregiving burden is a strong predictor of depression, the contribution of the various dimensions of burden to caregivers' depression as well as their relationships with depressive symptoms has received little attention. 384 family caregivers completed a cross-sectional online survey including the Center for Epidemiological Studies Depression (CES-D) scale, the Zarit Burden Interview (ZBI), and the Brief Experience of Caregiving Inventory (BECI), measuring caregiving burden and experience. We estimated the structure of the relationships between caregiving experiences (i.e., ZBI and BECI subscales) and CES-D symptoms using a network approach. Negative Emotion/Consequences, (lack of) Positive Personal Experience, and Stigma/Effects on Family were the most connected caregiving dimensions to depression. To untangle the role of the Negative Emotion/Consequences component (by far the most central node in estimated networks), a secondary analysis incorporating its composing items was estimated. Losing control over life, feeling strained around the relative and impaired self-perceived health emerged as central nodes. Interestingly, these caregiving-related dimensions or experiences were differentially connected to depressive symptoms. We discuss how these findings might help future research and inform tailored psychoeducational interventions for family caregivers of people with a severe mental disorder.

Neurophysiological explorations across the spectrum of psychosis, autism, and depression, during wakefulness and sleep: protocol of a prospective case-control transdiagnostic multimodal study (DEMETER).

BACKGROUND: Quantitative electroencephalography (EEG) analysis offers the opportunity to study high-level cognitive processes across psychiatric disorders. In particular, EEG microstates translate the temporal dynamics of neuronal networks throughout the brain. Their alteration may reflect transdiagnostic anomalies in neurophysiological functions that are impaired in mood, psychosis, and autism spectrum disorders, such as sensorimotor integration, speech, sleep, and sense of self. The main questions this study aims to answer are as follows: 1) Are EEG microstate anomalies associated with clinical and functional prognosis, both in resting conditions and during sleep, across psychiatric disorders? 2) Are EEG microstate anomalies associated with differences in sensorimotor integration, speech, sense of self, and sleep? 3) Can the dynamic of EEG microstates be modulated by a non-drug intervention such as light hypnosis? METHODS: This prospective cohort will include a population of adolescents and young adults, aged 15 to 30 years old, with ultra-high-risk of psychosis (UHR), first-episode psychosis (FEP), schizophrenia (SCZ), autism spectrum disorder (ASD), and major depressive disorder (MDD), as well as healthy controls (CTRL) (N = 21 × 6), who will be assessed at baseline and after one year of follow-up. Participants will undergo deep phenotyping based on psychopathology, neuropsychological assessments, 64-channel EEG recordings, and biological sampling at the two timepoints. At baseline, the EEG recording will also be coupled to a sensorimotor task and a recording of the characteristics of their speech (prosody and turn-taking), a one-night polysomnography, a self-reference effect task in virtual reality (only in UHR, FEP, and CTRL). An interventional ancillary study will involve only healthy controls, in order to assess whether light hypnosis can modify the EEG microstate architecture in a direction opposite to what is seen in disease. DISCUSSION: This transdiagnostic longitudinal case-control study will provide a multimodal neurophysiological assessment of clinical dimensions (sensorimotor integration, speech, sleep, and sense of self) that are disrupted across mood, psychosis, and autism spectrum disorders. It will further test the relevance of EEG microstates as dimensional functional biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06045897.

Asynchronous neural maturation predicts transition to psychosis.

AIM: Neuroimaging-based machine-learning predictions of psychosis onset rely on the hypothesis that structural brain anomalies may reflect the underlying pathophysiology. Yet, current predictors remain difficult to interpret in light of brain structure. Here, we combined an advanced interpretable supervised algorithm and a model of neuroanatomical age to identify the level of brain maturation of the regions most predictive of psychosis. METHODS: We used the voxel-based morphometry of a healthy control dataset (N = 2024) and a prospective longitudinal UHR cohort (N = 82), of which 27 developed psychosis after one year. In UHR, psychosis was predicted at one year using Elastic-Net-Total-Variation (Enet-TV) penalties within a five-fold cross-validation, providing an interpretable map of distinct predictive regions. Using both the whole brain and each predictive region separately, a brain age predictor was then built and validated in 1605 controls, externally tested in 419 controls from an independent cohort, and applied in UHR. Brain age gaps were computed as the difference between chronological and predicted age, providing a proxy of whole-brain and regional brain maturation. RESULTS: Psychosis prediction was performant with 80 ± 4% of area-under-curve and 69 ± 5% of balanced accuracy (P < 0.001), and mainly leveraged volumetric increases in the ventromedial prefrontal cortex and decreases in the left precentral gyrus and the right orbitofrontal cortex. These regions were predicted to have delayed and accelerated maturational patterns, respectively. CONCLUSION: By combining an interpretable supervised model of conversion to psychosis with a brain age predictor, we showed that inter-regional asynchronous brain maturation underlines the predictive signature of psychosis.

Influence of cannabis use on incidence of psychosis in people at clinical high risk.

AIMS: Evidence for case-control studies suggests that cannabis use is a risk factor for the development of psychosis. However, there have been limited prospective studies and the direction of this association remains controversial. The primary aim of the present study was to examine the association between cannabis use and the incidence of psychotic disorders in people at clinical high risk of psychosis. Secondary aims were to assess associations between cannabis use and the persistence of psychotic symptoms, and with functional outcome. METHODS: Current and previous cannabis use were assessed in individuals at clinical high risk of psychosis (n = 334) and healthy controls (n = 67), using a modified version of the Cannabis Experience Questionnaire. Participants were assessed at baseline and followed up for 2 years. Transition to psychosis and persistence of psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental States criteria. Level of functioning at follow up was assessed using the Global Assessment of Functioning disability scale. RESULTS: During follow up, 16.2% of the clinical high-risk sample developed psychosis. Of those who did not become psychotic, 51.4% had persistent symptoms and 48.6% were in remission. There was no significant association between any measure of cannabis use at baseline and either transition to psychosis, the persistence of symptoms, or functional outcome. CONCLUSIONS: These findings contrast with epidemiological data that suggest that cannabis use increases the risk of psychotic disorder.

Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis.

BACKGROUND: Psychosis is associated with a reasoning bias, which manifests as a tendency to 'jump to conclusions'. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes. METHODS: In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A 'beads' task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point. RESULTS: There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, p = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ. CONCLUSIONS: In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.

Non-cell-autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse.

The OTX2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, which projects to limbic structures controlling complex behaviors. OTX2 is also produced in choroid plexus epithelium, from which it is secreted into cerebrospinal fluid and transferred to limbic structure parvalbumin interneurons. Previously, adult male mice subjected to early-life stress were found susceptible to anxiety-like behaviors, with accompanying OTX2 expression changes in ventral tegmental area or choroid plexus. Here, we investigated the consequences of reduced OTX2 levels in Otx2 heterozygote mice, as well as in Otx2+/AA and scFvOtx2tg/0 mouse models for decreasing OTX2 transfer from choroid plexus to parvalbumin interneurons. Both male and female adult mice show anxiolysis-like phenotypes in all three models. In Otx2 heterozygote mice, we observed no changes in dopaminergic neuron numbers and morphology in ventral tegmental area, nor in their metabolic output and projections to target structures. However, we found reduced expression of parvalbumin in medial prefrontal cortex, which could be rescued in part by adult overexpression of Otx2 specifically in choroid plexus, resulting in increased anxiety-like behavior. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of anxiety-related phenotypes in the mouse.

Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis.

Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.

Prevalence and risk factors of self-reported psychotic experiences among high school and college students: A systematic review, meta-analysis, and meta-regression.

BACKGROUND: Adolescents are at high risk of incident psychopathology. Fleeting psychotic experiences (PEs) that emerge in young people in response to stress may be warning signs that are missed by research that fails to study stressed populations, such as late high school and college/university students. Our aim in this systematic review was to conduct a meta-analysis that estimates prevalence rates of PEs in students, and to assess whether these rates differ by gender, age, culture, and COVID-19 exposure. METHOD: We searched nine electronic databases, from their inception until January 31, 2022 for relevant studies. We pooled the estimates using the DerSimonian-Laird technique and random-effects meta-analysis. Our main outcome was the prevalence of self-reported PEs in high school and college/university students. We subsequently analyzed our data by age, gender, population, country, culture, evaluation tool, and COVID-19 exposure. RESULTS: Out of 486 studies retrieved, a total of 59 independent studies met inclusion criteria reporting 210' 024 students from 21 different countries. Nearly one in four students (23.31%; 95% CI 18.41%-29.05%), reported having experienced PEs (heterogeneity [Q = 22,698.23 (62), p = 0.001] τ2  = 1.4418 [1.0415-2.1391], τ = 1.2007 [1.0205-1.4626], I2  = 99.7%, H = 19.13 [18.59-19.69]). The 95% prediction intervals were 04.01%-68.85%. Subgroup analyses showed that the pooled prevalence differed significantly by population, culture, and COVID-19 exposure. CONCLUSION: This meta-analysis revealed high prevalence rates of self-reported PEs among teen and young adult students, which may have significance for mental health screening in school settings. An important realization is that PEs may have very different mental health meaning in different cultures.

A novel tablet-based application for assessment of manual dexterity and its components: a reliability and validity study in healthy subjects.

BACKGROUND: We developed five tablet-based tasks (applications) to measure multiple components of manual dexterity. AIM: to test reliability and validity of tablet-based dexterity measures in healthy participants. METHODS: Tasks included: (1) Finger recognition to assess mental rotation capacity. The subject taps with the finger indicated on a virtual hand in three orientations (reaction time, correct trials). (2) Rhythm tapping to evaluate timing of finger movements performed with, and subsequently without, an auditory cue (inter-stimulus interval). (3) Multi-finger tapping to assess independent finger movements (reaction time, correct trials, unwanted finger movements). (4) Sequence tapping to assess production and memorization of visually cued finger sequences (successful taps). (5) Line-tracking to assess movement speed and accuracy while tracking an unpredictably moving line on the screen with the fingertip (duration, error). To study inter-rater reliability, 34 healthy subjects (mean age 35 years) performed the tablet tasks twice with two raters. Relative reliability (Intra-class correlation, ICC) and absolute reliability (Standard error of measurement, SEM) were established. Task validity was evaluated in 54 healthy subjects (mean age 49 years, range: 20-78 years) by correlating tablet measures with age, clinical dexterity assessments (time taken to pick-up objects in Box and Block Test, BBT and Moberg Pick Up Test, MPUT) and with measures obtained using a finger force-sensor device. RESULTS: Most timing measures showed excellent reliability. Poor to excellent reliability was found for correct trials across tasks, and reliability was poor for unwanted movements. Inter-session learning occurred in some measures. Age correlated with slower and more variable reaction times in finger recognition, less correct trials in multi-finger tapping, and slower line-tracking. Reaction times correlated with those obtained using a finger force-sensor device. No significant correlations between tablet measures and BBT or MPUT were found. Inter-task correlation among tablet-derived measures was weak. CONCLUSIONS: Most tablet-based dexterity measures showed good-to-excellent reliability (ICC ≥ 0.60) except for unwanted movements during multi-finger tapping. Age-related decline in performance and association with finger force-sensor measures support validity of tablet measures. Tablet-based components of dexterity complement conventional clinical dexterity assessments. Future work is required to establish measurement properties in patients with neurological and psychiatric disorders.

Differential Methylation Pattern of Schizophrenia Candidate Genes in Tetrahydrocannabinol-Consuming Treatment-Resistant Schizophrenic Patients Compared to Non-Consumer Patients and Healthy Controls.

BACKGROUND: Patients suffering from schizophrenic psychosis show reduced synaptic connectivity compared to healthy individuals. Furthermore, the use of cannabis often precedes the onset of schizophrenic psychosis. Therefore, we investigated whether consumption of cannabis has an impact on the methylation pattern of schizophrenia candidate genes concerned with the development and preservation of synapses and synaptic function. METHODS: Fifty blood samples of outpatients affected by treatment-resistant schizophrenic psychosis were collected in the outpatient department of Ch Ste Anne/INSERM (Paris, France). Extracted DNA was sent to the LMN/MHH (Hanover, Germany) where DNA samples were bisulfite converted. The methylation patterns of the promoter region of neuregulin 1 (NRG1), neurexin (NRXN1), disrupted in schizophrenia 1 (DISC1), and microtubule-associated-protein tau (MAPT) were then analysed by sequencing according to Sanger. RESULTS: In NRXN1 the group of non-consumer patients showed a methylation rate slightly lower than controls. In patients with preliminary use of tetrahydrocannabinol (THC) the NRXN1 promoter turned out to be methylated almost two times higher than in non-consumer patients. In MAPT, non-consumer patients showed a significant lower mean methylation rate in comparison to controls. In THC-consuming patients the difference compared with controls became less. NRG1 and DISC1 showed no significant differences between groups, whereas DISC1 appeared to be not methylated at all. CONCLUSION: In MAPT and NRXN1 mean methylation rates were lower in non-consumer patients compared with controls, which seems to be a compensatory mechanism. With consumption of THC, mean methylation rates were increased: in the case of MAPT compared with controls, and in NRXN1 even significantly beyond that. Methylation of NRG1 and DISC1 seems not to be affected by the psychiatric disorder or by consumption of THC.

Impaired attentional modulation of sensorimotor control and cortical excitability in schizophrenia.

Impairments in attentional, working memory and sensorimotor processing have been consistently reported in schizophrenia. However, the interaction between cognitive and sensorimotor impairments and the underlying neural mechanisms remains largely uncharted. We hypothesized that altered attentional processing in patients with schizophrenia, probed through saccadic inhibition, would partly explain impaired sensorimotor control and would be reflected as altered task-dependent modulation of cortical excitability and inhibition. Twenty-five stabilized patients with schizophrenia, 17 unaffected siblings and 25 healthy control subjects were recruited. Subjects performed visuomotor grip force-tracking alone (single-task condition) and with increased cognitive load (dual-task condition). In the dual-task condition, two types of trials were randomly presented: trials with visual distractors (requiring inhibition of saccades) or trials with addition of numbers (requiring saccades and addition). Both dual-task trial types required divided visual attention to the force-tracking target and to the distractor or number. Gaze was measured during force-tracking tasks, and task-dependent modulation of cortical excitability and inhibition were assessed using transcranial magnetic stimulation. In the single-task, patients with schizophrenia showed increased force-tracking error. In dual-task distraction trials, force-tracking error increased further in patients, but not in the other two groups. Patients inhibited fewer saccades to distractors, and the capacity to inhibit saccades explained group differences in force-tracking performance. Cortical excitability at rest was not different between groups and increased for all groups during single-task force-tracking, although, to a greater extent in patients (80%) compared to controls (40%). Compared to single-task force-tracking, the dual-task increased cortical excitability in control subjects, whereas patients showed decreased excitability. Again, the group differences in cortical excitability were no longer significant when failure to inhibit saccades was included as a covariate. Cortical inhibition was reduced in patients in all conditions, and only healthy controls increased inhibition in the dual-task. Siblings had similar force-tracking and gaze performance as controls but showed altered task-related modulation of cortical excitability and inhibition in dual-task conditions. In patients, neuropsychological scores of attention correlated with visuomotor performance and with task-dependant modulation of cortical excitability. Disorganization symptoms were greatest in patients with weakest task-dependent modulation of cortical excitability. This study provides insights into neurobiological mechanisms of impaired sensorimotor control in schizophrenia showing that deficient divided visual attention contributes to impaired visuomotor performance and is reflected in impaired modulation of cortical excitability and inhibition. In siblings, altered modulation of cortical excitability and inhibition is consistent with a genetic risk for cortical abnormality.

Predicting the individual risk of psychosis conversion in at-risk mental state (ARMS): a multivariate model reveals the influence of nonpsychotic prodromal symptoms.

To improve the prediction of the individual risk of conversion to psychosis in UHR subjects, by considering all CAARMS' symptoms at first presentation and using a multivariate machine learning method known as logistic regression with Elastic-net shrinkage. 46 young individuals who sought help from the specialized outpatient unit at Sainte-Anne hospital and who met CAARMS criteria for UHR were assessed, among whom 27 were reassessed at follow-up (22.4 ± 6.54 months) and included in the analysis. Elastic net logistic regression was trained, using CAARMS items at baseline to predict individual evolution between converters (UHR-P) and non-converters (UHR-NP). Elastic-net was used to select the few CAARMS items that best predict the clinical evolution. All validations and significances of predictive models were computed with non-parametric re-sampling strategies that provide robust estimators even when the distributional assumption cannot be guaranteed. Among the 25 CAARMS items, the Elastic net selected 'obsessive-compulsive symptoms' and 'aggression/dangerous behavior' as risk factors for conversion while 'anhedonia' and 'mood swings/lability' were associated with non-conversion at follow-up. In the ten-fold stratified cross-validation, the classification achieved 81.8% of sensitivity (P = 0.035) and 93.7% of specificity (P = 0.0016). Non-psychotic prodromal symptoms bring valuable information to improve the prediction of conversion to psychosis. Elastic net logistic regression applied to clinical data is a promising way to switch from group prediction to an individualized prediction.

Exploring and visualizing multidimensional data in translational research platforms.

The unprecedented advances in technology and scientific research over the past few years have provided the scientific community with new and more complex forms of data. Large data sets collected from single groups or cross-institution consortiums containing hundreds of omic and clinical variables corresponding to thousands of patients are becoming increasingly commonplace in the research setting. Before any core analyses are performed, visualization often plays a key role in the initial phases of research, especially for projects where no initial hypotheses are dominant. Proper visualization of data at a high level facilitates researcher's abilities to find trends, identify outliers and perform quality checks. In addition, research has uncovered the important role of visualization in data analysis and its implied benefits facilitating our understanding of disease and ultimately improving patient care. In this work, we present a review of the current landscape of existing tools designed to facilitate the visualization of multidimensional data in translational research platforms. Specifically, we reviewed the biomedical literature for translational platforms allowing the visualization and exploration of clinical and omics data, and identified 11 platforms: cBioPortal, interactive genomics patient stratification explorer, Igloo-Plot, The Georgetown Database of Cancer Plus, tranSMART, an unnamed data-cube-based model supporting heterogeneous data, Papilio, Caleydo Domino, Qlucore Omics, Oracle Health Sciences Translational Research Center and OmicsOffice® powered by TIBCO Spotfire. In a health sector continuously witnessing an increase in data from multifarious sources, visualization tools used to better grasp these data will grow in their importance, and we believe our work will be useful in guiding investigators in similar situations.

Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review.

Scaffolding proteins represent an evolutionary solution to controlling the specificity of information transfer in intracellular networks. They are highly concentrated in complexes located in specific subcellular locations. One of these complexes is the postsynaptic density of the excitatory synapses. There, scaffolding proteins regulate various processes related to synaptic plasticity, such as glutamate receptor trafficking and signalling, and dendritic structure and function. Most scaffolding proteins can be grouped into 4 main families: discs large (DLG), discs-large-associated protein (DLGAP), Shank and Homer. Owing to the importance of scaffolding proteins in postsynaptic density architecture, it is not surprising that variants in the genes that code for these proteins have been associated with neuropsychiatric diagnoses, including schizophrenia and autism-spectrum disorders. Such evidence, together with the clinical, neurobiological and genetic overlap described between schizophrenia and autism-spectrum disorders, suggest that alteration of scaffolding protein dynamics could be part of the pathophysiology of both. However, despite the potential importance of scaffolding proteins in these psychiatric conditions, no systematic review has integrated the genetic and molecular data from studies conducted in the last decade. This review has the following goals: to systematically analyze the literature in which common and/or rare genetic variants (single nucleotide polymorphisms, single nucleotide variants and copy number variants) in the scaffolding family genes are associated with the risk for either schizophrenia or autism-spectrum disorders; to explore the implications of the reported genetic variants for gene expression and/or protein function; and to discuss the relationship of these genetic variants to the shared genetic, clinical and cognitive traits of schizophrenia and autism-spectrum disorders.

Health-related quality of life in outpatients with schizophrenia: factors that determine changes over time.

PURPOSE: The objective of this study was to analyze the clinical factors associated with changes in HRQoL in outpatients with schizophrenia using both generic and condition-specific HRQoL scales. METHODS: Adult outpatients with schizophrenia at least 18 years of age who did not have an acute psychotic exacerbation in the 3 months prior to baseline were recruited. PANSS dimensions were calculated based on Lindenmayer et al.'s five factors. HRQoL data were assessed by patients using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D) questionnaires. RESULTS: Out of the 1345 patients included at baseline, 1196 (89%) were evaluated at 12 months. Regression models showed that the factor most consistently associated with HRQoL at endpoint was change in the PANSS negative symptoms score. A decrease in the PANSS negative symptoms score from baseline to 1 year was associated with a decrease in HRQoL during the same period. There were also significant associations of the change in PANSS excitatory factor with all the HRQoL scales except the SF-36 PCS. Female gender was associated with a decrease in all HRQoL ratings. There was also a relationship between years since onset and HRQoL. The longer the time since illness onset, the larger the decrease in HRQoL. CONCLUSIONS: This study has found that, in outpatients with schizophrenia, changes in negative and excitement symptoms may have a greater an association with HRQoL than changes in positive, cognitive and depressive symptoms.