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Deficits in social cognition (SC) are significantly related to community functioning in schizophrenia (SZ). Few studies investigated longitudinal changes in SC and its impact on recovery. In the present study, we aimed: (a) to estimate the magnitude and clinical significance of SC change in outpatients with stable SZ who were assessed at baseline and after 4 years, (b) to identify predictors of reliable and clinically significant change (RCSC), and (c) to determine whether changes in SC over 4 years predicted patient recovery at follow-up.
Methods
The reliable change index was used to estimate the proportion of true change in SC, not attributable to measurement error. Stepwise multiple logistic regression models were used to identify the predictors of RCSC in a SC domain (The Awareness of Social Inference Test [TASIT]) and the effect of change in TASIT on recovery at follow-up.
Results
In 548 participants, statistically significant improvements were found for the simple and paradoxical sarcasm of TASIT scale, and for the total score of section 2. The reliable change index was 9.8. A cut-off of 45 identified patients showing clinically significant change. Reliable change was achieved by 12.6% and RCSC by 8% of participants. Lower baseline TASIT sect. 2 score predicted reliable improvement on TASIT sect. 2. Improvement in TASIT sect. 2 scores predicted functional recovery, with a 10-point change predicting 40% increase in the probability of recovery.
Conclusions
The RCSC index provides a conservative way to assess the improvement in the ability to grasp sarcasm in SZ, and is associated with recovery.
Abnormal auditory processing of deviant stimuli, as reflected by mismatch negativity (MMN), is often reported in schizophrenia (SCZ). At present, it is still under debate whether this dysfunctional response is specific to the full-blown SCZ diagnosis or rather a marker of psychosis in general. The present study tested MMN in patients with SCZ, bipolar disorder (BD), first episode of psychosis (FEP), and in people at clinical high risk for psychosis (CHR).
Methods
Source-based MEG activity evoked during a passive auditory oddball task was recorded from 135 patients grouped according to diagnosis (SCZ, BD, FEP, and CHR) and 135 healthy controls also divided into four subgroups, age- and gender-matched with diagnostic subgroups. The magnetic MMN (mMMN) was analyzed as event-related field (ERF), Theta power, and Theta inter-trial phase coherence (ITPC).
Results
The clinical group as a whole showed reduced mMMN ERF amplitude, Theta power, and Theta ITPC, without any statistically significant interaction between diagnosis and mMMN reductions. The mMMN subgroup contrasts showed lower ERF amplitude in all the diagnostic subgroups. In the analysis of Theta frequency, SCZ showed significant power and ITPC reductions, while only indications of diminished ITPC were observed in CHR, but no significant decreases characterized BD and FEP.
Conclusions
Significant mMMN alterations in people experiencing psychosis, also for diagnoses other than SCZ, suggest that this neurophysiological response may be a feature shared across psychotic disorders. Additionally, reduced Theta ITPC may be associated with risk for psychosis.
Resilience is defined as the ability to modify thoughts to cope with stressful events. Patients with schizophrenia (SCZ) having higher resilience (HR) levels show less severe symptoms and better real-life functioning. However, the clinical factors contributing to determine resilience levels in patients remain unclear. Thus, based on psychological, historical, clinical and environmental variables, we built a supervised machine learning algorithm to classify patients with HR or lower resilience (LR).
Methods
SCZ from the Italian Network for Research on Psychoses (N = 598 in the Discovery sample, N = 298 in the Validation sample) underwent historical, clinical, psychological, environmental and resilience assessments. A Support Vector Machine algorithm (based on 85 variables extracted from the above-mentioned assessments) was built in the Discovery sample, and replicated in the Validation sample, to classify between HR and LR patients, within a nested, Leave-Site-Out Cross-Validation framework. We then investigated whether algorithm decision scores were associated with the cognitive and clinical characteristics of patients.
Results
The algorithm classified patients as HR or LR with a Balanced Accuracy of 74.5% (p < 0.0001) in the Discovery sample, and 80.2% in the Validation sample. Higher self-esteem, larger social network and use of adaptive coping strategies were the variables most frequently chosen by the algorithm to generate decisions. Correlations between algorithm decision scores, socio-cognitive abilities, and symptom severity were significant (pFDR < 0.05).
Conclusions
We identified an accurate, meaningful and generalizable clinical-psychological signature associated with resilience in SCZ. This study delivers relevant information regarding psychological and clinical factors that non-pharmacological interventions could target in schizophrenia.
Psychosis onset typically occurs during adolescence or early adulthood, coinciding with the latest stage of brain maturation. Alterations in brain functional connectivity (FC) accompany the emergence of psychiatric symptoms and cognitive impairments. Thus, age-related FC changes may be informative regarding psychosis onset.
Objectives
We defined neurotypical age-related FC trajectories and hypothesized that FC of individuals at familial and clinical high risk (HR) for psychosis deviates from FC of neurotypical controls (NC).
Methods
We analyzed two independent cohorts, of (a) 356 early adult NC (yNC; age=22±2y, m:f=149:207), and 127 mature adult NC (aNC; age=38±7y, m:f=79:48), and (b) 92 yNC (age=22±2y, m:f=34:58), 33 aNC (age=36±6y, m:f=21:12), 38 early HR adults (age=20±3y, m:f=18:20). We acquired fMRI data from multiple scans (resting-state, working memory, episodic memory, and implicit emotion processing). FC was obtained by computing Pearson’s correlations between time-courses of every independent component (IC) defined by an Independent Component Analysis approach (NeuroMark). Age-varying components of interest (yNC/aNC differences on FC based on linear mixed effect regressions) were tested for differences between HR and yNC through the Wilcoxon rank-sum
test.
Results
showed age-related FC differences (yNC/aNC) in a set of 17 IC pairs (pFDR<0.05). HR showed increased FC within a network including dorsolateral and medial prefrontal cortices, and sensorimotor cortex, while decreased FC between cerebellum and the parietal and visual cortices, compared with yNC (pFDR<0.05). HR showed no significant difference compared with aNC (pFDR>0.05).
Conclusions
This study tested FC alterations associated with the risk for psychosis and highlighted the relationship between psychosis and potentially altered brain functional processes.
Improving real-life functioning is the main goal of the most advanced integrated treatment programs in people with schizophrenia. The Italian Network for Research on Psychoses used network analysis in a four-year follow-up study to test whether the pattern of relationships among illness-related variables, personal resources and context-related factors differed between patients who were classified as recovered at follow-up versus those who did not recover. In a large sample (N=618) of clinically-stable, community-dwelling subjects with schizophrenia, the study demonstrated a considerable stability of the network structure. Functional capacity and everyday life skills had a high betweenness and closeness in the network at both baseline and follow-up, while psychopathological variables remained more peripheral. The network structure and connectivity of non-recovered patients were similar to those observed in the whole sample, but very different from those in recovered subjects, in which we found few connections only. These data strongly suggest that tightly coupled symptoms/dysfunctions tend to maintain each other’s activation, contributing to poor outcome in subjects with schizophrenia. The data suggest that early and integrated treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia.
Disclosure
Honoraria, advisory board, or consulting fees from Angelini, Astra Zeneca, Bristol-Myers Squibb, Gedeon Richter Bulgaria, Innova-Pharma, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer, and Pierre Fabre, for services not related to this abstract
An extensive literature regarding gender differences relevant to several aspects of schizophrenia is nowadays available. It includes some robust findings as well as some inconsistencies. The identification of gender differences and the understanding of their explanations may help to clarify the underlying etiopathogenetic mechanisms of specific aspects of the disorder.
Objectives
The present study aimed at investigating gender differences on premorbid, clinical, cognitive and outcome indices, as well as their impact on recovery, in a large sample of patients with schizophrenia recruited within the multicenter study of the Italian Network for Research on Psychoses.
Methods
State-of-the-art instruments were used to assess the investigated domains. Group comparisons between male and female patients were performed on all considered indices. The associations of premorbid, clinical and cognitive indices with recovery in the two patient groups were investigated by means of multiple regressions.
Results
Males with respect to females had a worse premorbid adjustment – limited to the academic dimension – an earlier age of onset, a higher frequency of history of substance and alcohol abuse, more severe negative symptoms (both avolition and expressive deficit), positive symptoms and impairment of social cognition. No gender difference was observed in neurocognition nor in the rates of recovery.
Conclusions
Although males showed some disadvantages in the clinical picture, this was not translated into a worse outcome. This finding may be related to the complex interplay of several factors acting as predictors or mediators of outcome.
Clinical high-risk states for psychosis (CHR) are associated with functional impairments and depressive disorders. A previous PRONIA study predicted social functioning in CHR and recent-onset depression (ROD) based on structural magnetic resonance imaging (sMRI) and clinical data. However, the combination of these domains did not lead to accurate role functioning prediction, calling for the investigation of additional risk dimensions. Role functioning may be more strongly associated with environmental adverse events than social functioning.
Aims
We aimed to predict role functioning in CHR, ROD and transdiagnostically, by adding environmental adverse events-related variables to clinical and sMRI data domains within the PRONIA sample.
Method
Baseline clinical, environmental and sMRI data collected in 92 CHR and 95 ROD samples were trained to predict lower versus higher follow-up role functioning, using support vector classification and mixed k-fold/leave-site-out cross-validation. We built separate predictions for each domain, created multimodal predictions and validated them in independent cohorts (74 CHR, 66 ROD).
Results
Models combining clinical and environmental data predicted role outcome in discovery and replication samples of CHR (balanced accuracies: 65.4% and 67.7%, respectively), ROD (balanced accuracies: 58.9% and 62.5%, respectively), and transdiagnostically (balanced accuracies: 62.4% and 68.2%, respectively). The most reliable environmental features for role outcome prediction were adult environmental adjustment, childhood trauma in CHR and childhood environmental adjustment in ROD.
Conclusions
Findings support the hypothesis that environmental variables inform role outcome prediction, highlight the existence of both transdiagnostic and syndrome-specific predictive environmental adverse events, and emphasise the importance of implementing real-world models by measuring multiple risk dimensions.
Personalised prediction of functional outcomes is a promising approach for targeted early intervention in psychiatry. However, generalisability and resource efficiency of such prognostic models represent challenges. In the PRONIA study (German Clinical Trials Register: DRKS00005042), we demonstrate excellent generalisability of prognostic models in individuals at clinical high-risk for psychosis or with recent-onset depression, and substantial contributions of detailed clinical phenotyping, particularly to the prediction of role functioning. These results indicate that it is possible that functioning prediction models based only on clinical data could be effectively applied in diverse healthcare settings, so that neuroimaging data may not be needed at early assessment stages.
The European impact of the clinical high risk for psychosis (CHR-P) paradigm is constrained by the lack of critical mass (detection) to power prognostic and preventive interventions.
Methods
An ITAlian partnership for psychosis prevention (ITAPP) was created across CHR-P centers, which were surveyed to describe: (a) service, catchment area, and outreach; (b) service users; and (c) interventions and outcomes. Descriptive statistics and Kaplan–Meier failure function complemented the analyses.
Results
The ITAPP included five CHR-P clinical academic centers established from 2007 to 2018, serving about 13 million inhabitants, with a recruitment capacity of 277 CHR-P individuals (mean age: 18.7 years, SD: 4.8, range: 12–39 years; 53.1% females; 85.7% meeting attenuated psychotic symptoms; 85.8% without any substance abuse). All centers were multidisciplinary and included adolescents and young adults (transitional) primarily recruited through healthcare services. The comprehensive assessment of at-risk mental state was the most widely used instrument, while the duration of follow-up, type of outreach, and preventive interventions were heterogeneous. Across 205 CHR-P individuals with follow up (663.7 days ± 551.7), the cumulative risk of psychosis increased from 8.7% (95% CI 5.3–14.1) at 1 year to 15.9% (95% CI 10.6–23.3) at 2 years, 21.8% (95% CI 14.9–31.3) at 3 years, 34.8% (95% CI 24.5–47.9) at 4 years, and 51.9% (95% CI 36.3–69.6) at 5 years.
Conclusions
The ITAPP is one of the few CHR-P clinical research partnerships in Europe for fostering detection, prognosis, and preventive care, as well as for translating research innovations into practice.
In a cross-sectional study, the Italian Network for Research on Psychoses (INReP) found that variables relevant to the disease, personal resources and social context explain 53.8% of real-life functioning variance in a large sample of community dwelling people with schizophrenia. In a longitudinal study, the INReP aimed to identify baseline predictors of main domains of real-life functioning, i.e. work skills, interpersonal relationships and everyday life skills, at 4-year follow-up. We assessed psychopathology, social and non-social cognition, functional capacity, personal resources, and context-related factors, as well as real-life functioning as the main outcome. We used structural equation modeling (SEM) and latent change score (LCS) model to identify predictors of real-life functioning domains at follow-up and changes from baseline in the same domains. Six-hundred-eighteen subjects took part in the study. Neurocognition predicted everyday life and work skills; avolition predicted interpersonal relationships; positive symptoms work skills, and social cognition work skills and interpersonal functioning. Higher neurocognitive abilities predicted the improvement of everyday life and work skills, as well as of social cognition and functional capacity; better baseline social cognition predicted the improvement of work skills and interpersonal functioning, and better baseline everyday life skills predicted the improvement of work skills. Several variables which predict important aspects of functional outcome of people with schizophrenia are not routinely assessed and are not systematically targeted by intervention programs in community mental health services. A larger dissemination of practices such as cognitive training and personalized psychosocial interventions should be promoted in mental health care.
Central to recovery-oriented approaches in schizophrenia are treatment integration and personalization, targeting key variables beyond symptom reduction. The Italian network for research on psychoses conducted a study demonstrating, using network analysis, the central role of community activities in bridging the effects of symptoms, cognition, functional capacity and service engagement on real-word functioning. A 4-year follow-up study was recently completed and the presentation will illustrate the findings. Network analysis was used to test whether relationships among all variables at baseline were similar at follow-up. In addition, the network structure was compared between subjects classified as recovered or non-recovered at follow-up. Six hundred eighteen subjects were assessed at both baseline and 4-year follow-up. Results showed that the network structure was stable from baseline to follow-up, and the overall strength of the connections among variables did not significantly change. Functional capacity and everyday life skills were the most central variables in the network at both baseline and follow-up, while psychopathological variables were more peripheral. The network structure of non-recovered patients was similar to the one observed in the whole sample, but very different from that of recovered subjects, showing few connections among the different nodes. These data strongly suggest that connections among symptoms/dysfunctions tend to maintain over time, contributing to poor outcome in schizophrenia. Early treatment plans, targeting variables with high centrality, might prevent the emergence of self-reinforcing networks of symptoms and dysfunctions in people with schizophrenia.
Disclosure
Armida Mucci has been a consultant and/or advisor to or has received honoraria from Gedeon Richter Bulgaria, Janssen Pharmaceuticals, Lundbeck, Otsuka, Pfizer and Pierre Fabre. None of these has any impact on this abstract and on the presented study.
This work presents the results of the physical characterization of palygorskite and its adsorptive behaviour for three solvatochromic dyes (Nile blue chloride (NBC), methylene blue (MTB) and dithizone (DTZ)). Adsorption isotherms were used to determine the maximum adsorption of the solvatochromic dyes on the palygorskite. The characterization of palygorskite was carried out via mineralogical and chemical analysis with X-ray diffraction, X-ray fluorescence, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy, surface-charge measurement (ζ-potential), thermogravimetric analysis, textural analysis and cation-exchange capacity analysis. The material consists of palygorskite and quartz and its chemistry is dominated by SiO2, MgO and Fe2O3. The specific surface area and cation-exchange capacity of the palygorskite are 142 m2 g–1 and 41 cmol(+) kg–1, respectively. The SEM and TEM analyses showed a fibrous structure with fibres 20–100 nm long. The thermogravimetric analysis showed three endothermic events at 57.3°C, 171.8°C and 439.6°C. The adsorption capacities of the palygorskite for NBC (basic pH), MTB (basic pH) and DTZ (neutral pH) were 0.082, 0.013 and 0.102 g g–1, respectively. The adsorptions of NBC and MTB were fitted with the Langmuir isotherm model and the adsorption of DTZ was fitted with the Sips model.
Genome-Wide Association Studies (GWASs) have identified several genes associated with Schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. In addition, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, fragile X mental retardation syndrome-related 1 (FXR1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by glycogen synthase kinase-3β (GSK3β), which has been implicated in pathophysiology of SCZ and response to antipsychotics (APs). rs496250 and rs12630592, two eQTLs (Expression Quantitative Trait Loci) of FXR1 and GSK3β, respectively, interact on emotion stability and amygdala/prefrontal cortex activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NSs) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication.
Methods
To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and FXR1 expression, as already reported for GSK3β expression.
Results
We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex.
Discussion
Our findings suggest that, like GSK3β, FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3β pathway for NSs of SCZ.
Halloysite is a 1:1 dioctahedral clay mineral that has been studied widely for applications in nanotechnology and as a mineral exploration guide for recognizing regolith-hosted heavy rare earth element (HREE) deposits. In Brazil, pegmatites from the state of Rio de Janeiro have been catalogued, but their potential to host halloysite deposits has never been studied. After a mineral exploration programme, one pegmatite with considerable halloysite contents and economic potential was discovered. This study reports the mineralogical and chemical characterization of the halloysite of this pegmatite and evaluates the possibility of clay-adsorbed HREE deposits, like that in the Zudong (China) regolith-hosted HREE deposit. Seven samples were collected in horizontal channels. Bulk samples and clay fractions (<2 μm) were analysed by quantitative mineral analysis (X-ray diffraction/Rietveld method), chemical analysis (major elements by X-ray fluorescence and Y, U, Th and rare earth elements by inductively coupled plasma mass spectrometry), scanning electron microscopy, Fourier-transform infrared spectroscopy, particle-size analysis, nitrogen physisorption and cation-exchange capacity. Mixed polygonal/cylindrical halloysite-7Å in concentrations between 6.3 and 35.4 wt.% in bulk samples and between 58.0 and 89.8 wt.% in the clay fractions were identified in the pegmatite. The clay fractions presented an average chemical composition of 45.46 wt.% SiO2, 36.10 wt.% Al2O3, 14.62 wt.% loss on ignition and 1.04 wt.% Fe2O3, as well as technological properties close to those observed in world-class halloysite deposits such as Dragon Mine (USA) and Matauri Bay (New Zealand). The clay minerals did not present significant HREE contents.
Autism spectrum disorders (ASDs) and schizophrenia spectrum disorders (SSDs), although conceptualized as separate entities, may share some clinical and neurobiological features. ASD symptoms may have a relevant role in determining a more severe clinical presentation of schizophrenic disorder but their relationships with cognitive aspects and functional outcomes of the disease remain to be addressed in large samples of individuals.
Aims
To investigate the clinical, cognitive, and functional correlates of ASD symptoms in a large sample of people diagnosed with schizophrenia.
Methods
The severity of ASD symptoms was measured with the PANSS Autism Severity Scale (PAUSS) in 921 individuals recruited for the Italian Network for Research on Psychoses multicenter study. Based on the PAUSS scores, three groups of subjects were compared on a wide array of cognitive and functional measures.
Results
Subjects with more severe ASD symptoms showed a poorer performance in the processing speed (p = 0.010), attention (p = 0.011), verbal memory (p = 0.035), and social cognition (p = 0.001) domains, and an overall lower global cognitive composite score (p = 0.010). Subjects with more severe ASD symptoms also showed poorer functional capacity (p = 0.004), real-world interpersonal relationships (p < 0.001), and participation in community-living activities (p < 0.001).
Conclusions
These findings strengthen the notion that ASD symptoms may have a relevant impact on different aspects of the disease, crucial to the life of people with schizophrenia. Prominent ASD symptoms may characterize a specific subpopulation of individuals with SSD.
Rasd2 is a striatal GTP-binding protein that modulates Akt and mTOR signaling cascades, well known to be highly vulnerable pathways in psychiatric disorders.
Aims
We investigated the association of Rasd2 and its genetic variation with a series of prefronto-striatal phenotypes related to psychosis in rodents and humans.
Objectives
We want to provide evidence that Rasd2 controls the vulnerability to schizophrenia-related behavior induced by psychothomimetic drugs in mice. Moreover, we aim to find genetic variations within the Rasd2 gene that influence a series of brain schizophrenia-related phenotypes in human.
Methods
Rasd2 knockout mice were employed to evaluate schizophrenia-like behaviors induced by psychotomimetic drugs like amphetamine and phencyclidine. Furthermore, we investigated if RASD2genetic variations in humans are associated with mRNA expression in post-mortem prefrontal cortex, as well as prefrontal and striatal grey matter volume and physiology during working memory as measured with MRI in healthy subjects. Finally, we assessed RASD2mRNA expression levels in post-mortem brains of patients with schizophrenia and bipolar disorder.
Results
We found that both psychotomimetics triggered greater vulnerability to motor stimulation and to prepulse inhibition deficits in Rasd2 mutants. In humans, we found that a genetic variation (rs6518956) within RASD2 predicts prefrontal mRNA expression as well as prefrontal grey matter volume and prefronto-striatal activity during working memory. Finally, we reported that RASD2 mRNA expression is slightly reduced in post-mortem prefrontal cortex of patients with schizophrenia.
Conclusions
Collectively, our data suggests that RASD2represents a gene of potential interest in psychiatric disorders for its ability to modulate prefronto-striatal phenotypes related to schizophrenia.
Negative symptoms have been associated with functional outcome of patients with schizophrenia by a large body of literature. However, in previous studies negative symptoms were regarded as a unitary construct, while recent literature data suggest that they include at least two factors, ‘Avolition” and ‘Poor Emotional Expression” (EE), that might show different relationships to functional outcome; moreover, the inter-relationships of negative symptoms, neurocognition, social cognition and real-life functioning are poorly understood.
Objectives
A large multicenter study was carried out by the Italian Network for Research on Psychoses to model relationship between the negative symptom domains and real-life functioning, taking into account the role of other psychopathological dimensions including depression, neurocognition, functional capacity and social cognition.
Methods
A structural equation model was used to investigate direct and indirect effects of the 2 negative symptoms domains, other psychopathological dimensions, including depression, and neurocognition on real-life functioning. Social cognition and functional capacity were modeled as mediators.
Results
In 921 patients with schizophrenia we found that the considered variables explained about 50% of real-life functioning variance. Avolition and functional capacity were the strongest independent predictors, followed by positive and disorganization dimensions, neurocognition and social cognition. EE had only a modest indirect effect on functioning. Neurocognition strongly predicted functional capacity and social cognition, which mediated its effects on functioning.
Conclusion
Our results support the heterogeneity of the two negative symptom domains. Only avolition is a strong predictor of functioning in real-life of patients with schizophrenia independent of social cognition, neurocognition and functional capacity.
Acknowledgements
The study was carried out within the project ‘Multicenter study on factors influencing real-life social functioning of people with a diagnosis of schizophrenia” of the Italian Network for Research on Psychoses.
D-aspartate (D-Asp) is an atypical amino acid that binds to and activates NMDARs. D-Asp occurs abundantly in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-Aspartate Oxidase (DDO). The agonistic activity of D-Asp on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for NMDAR-related alterations observed in schizophrenia. Consistently, substantial reduction of D-Asp was observed in post-mortem schizophrenia brains.
Aims
We evaluated the potential contribution of D-Asp as neurodevelopmental modulator of brain circuits and behaviors relevant to schizophrenia.
Objectives
We analyzed DDO mRNA expression in the post-mortem prefrontal cortex of schizophrenic patients. Moreover, we treated knockout mice for Ddo gene (Ddo-/-) with the NMDAR antagonist phencyclidine to evaluate their schizophrenia-relevant behaviors and circuits. Finally, we assessed cortico-hippocampal connectivity of these mice.
Methods
DDO mRNA detection was performed by quantitative PCR. Phencyclidine-induced schizophrenia-like behaviours were assessed through motor activity and prepulse inhibition paradigms. Resting-state and pharmacological fMRI were used to evaluate functional circuits and connectivity.
Results
DDO mRNA expression is increased in frontal samples of schizophrenic patients. In mice, the absence of Ddo gene produces a significant reduction in phencyclidine-induced motor hyper-activity and prepulse inhibition deficit. Furthermore, increased levels of D-Asp in Ddo-/- animals significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia.
Conclusions
Our data suggest that D-Asp, through the regulation exerted by DDO, may have a role in the pathophysiology of schizophrenia.
The genetic architecture of schizophrenia is based on polygenic trajectories. Indeed, genes converge on molecular co-expression pathways, which may be associated with heritable characteristics of patients and their siblings, called intermediate phenotypes, such as prefrontal anomalies and thalamic dysconnectivity during attentional control [2].
Objectives
Here, we investigated in healthy humans association between co-expression of genes with coordinated thalamo-prefrontal (THA-PFC) expression and functional connectivity during attentional control.
Methods
We used Brainspan dataset to characterize a coordinated THA-PFC expression gene list by correlating post-mortem gene expression in both areas (Kendall's Tau>.76, Bonferroni P < .05). Then, we identified a PFC co-expression network1 and tested all gene sets for THA-PFC and PGC loci [3] enrichments (P < .05). SNPs associated with the first principal component of the resulting enriched gene set were combined in a Polygenic Co-Expression Index (PCI) [1]. We conducted Independent Component Analysis (ICA) on attentional control fMRI data (n = 265) and selected Independent Components (ICs) including the thalamus and being highly correlated with an attentional control network2. Multiple regressions were conducted (predictor: PCI) using a thalamic cluster previously associated with familial risk for schizophrenia [2] as ROI (FWE P < .05).
Results
In one of the 8 ICs of interest there was a positive effect of PCI on thalamic connectivity strength in a cluster overlapping with our ROI (Z = 4.3).
Conclusion
Decreased co-expression of genes included in PCI predicts thalamic dysconnectivity during attentional control, suggesting a novel co-regulated molecular pathway potentially implicated in genetic risk for schizophrenia.
Disclosure of interest
The authors have not supplied their declaration of competing interest.