Visual population receptive fields in people with schizophrenia have reduced inhibitory surrounds

People with schizophrenia (SZ) experience abnormal visual perception on a range of visual tasks, which have been linked to abnormal synaptic transmission and an imbalance between cortical excitation and inhibition. However differences in the underlying architecture of visual cortex neurons, which might explain these visual anomalies, have yet to be reported in vivo. Here, we probe the neural basis of these deficits by using functional MRI (fMRI) and population receptive field (pRF) mapping to infer properties of visually responsive neurons in people with SZ. We employed a Difference-of-Gaussian (DoG) model to capture the centre-surround configuration of the pRF, providing critical information about the spatial scale of the pRFs inhibitory surround. Our analysis reveals that SZ is associated with reduced pRF size in early retinotopic visual cortex as well as a reduction in size and depth of the inhibitory surround in V1, V2 and V4. We consider how reduced inhibition might explain the diverse range of visual deficits reported in SZ. SIGNIFICANCE STATEMENT: People with schizophrenia (SZ) experience abnormal perception on a range of visual tasks, which has been linked to abnormal synaptic transmission and an imbalance between cortical excitation/inhibition. However associated differences in the underlying architecture of visual cortex neurons have yet to be reported in vivo. We used fMRI and population receptive field (pRF) mapping to demonstrate that the fine-grained functional architecture of visual cortex in people with SZ differs from unaffected controls. SZ is associated with reduced pRF size in early retinotopic visual cortex, largely due to reduced inhibitory surrounds. An imbalance between cortical excitation and inhibition could drive such a change in the centre-surround pRF configuration, and ultimately explain the range of visual deficits experienced in SZ

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia

Objective: Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients alt-hough the actual prevalence, phenomenology and risk factors remain unclear. The aim of the pre-sent study was to address the three aforementioned questions. Method: The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. Results: OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p=.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean=5.1; SD=3.6) correlated with length of clozapine treatment (r=.21; p=.026), and obsessing factor (mean=4.8; SD=3.6) correlated with psychosis severity (r=.59; p=.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plas-ma levels, after correcting for psychosis severity. Conclusion: Screening for OCD in clozapine patients, and probably in those treated with structur-ally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.Dr. Fernandez-Egea was supported by 2009 Young investigator award and intramural funding from CPFT/NIHR-CRN supported setting the database. Prof. Bernardo is funded by the Spanish Ministry of Science and Education, the Spanish Ministry of Economy and Competiveness, Centro de Inves-tigación Biomédica en Red de Salud Mental (CIBERSAM), from the Government of Catalonia, Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR441), from the Foundation European Group for Research In Schizophrenia (EGRIS) , and from the 7th Framework Program of the European Union. Dr. Y Worbe is supported by Association Française du syndrome de Gilles de la Tourette, Founda-tion de recherche Medicale and Dystonia Foundation for Medical Research (USA). Prof. TW Robbins' research is funded by a Wellcome Senior Investigator Award (104631/Z/14/Z). Work was completed at the Behavioural and Clinical Neuroscience Institute, which was supported by a joint award from the Medical Research Council and Wellcome Trust (G00001354)

Association of birth weight and the development of antipsychotic induced adiposity in individuals with treatment resistant schizophrenia.

Though weight gain is a common side effect of antipsychotic treatment, there are no useful predictors of which patients are likely to be affected and to what degree. It has been shown that exposure to adverse conditions during intra-uterine life confers a vulnerability to the development of later life metabolic complications and low birth weight for gestational age has been shown to be a robust marker of such prenatal adversity. We hypothesised that patients with schizophrenia with a lower birth weight will have increased vulnerability to the weight inducing effects of antipsychotic treatment. The relationship between birth weight and total and central adiposity, measured as body mass index (BMI) and waist-to-hip ratio (WHR) respectively, was examined in three groups: drug naïve first episode of psychosis (FEP) patients (n=41), treatment resistant schizophrenia (TRS) patients (n=42) and matched healthy volunteers (n=72). All analyses were controlled for age, gender and duration of treatment exposure. We found that a lower birth weight was associated with higher BMI and WHR only in TRS patients but not in FEP or controls, suggesting that prenatal adversity, as indicated by the surrogate marker of a lower birth weight, confers an increased vulnerability to clozapine induced weight gain.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2016.03.00

Reality monitoring impairment in schizophrenia reflects specific prefrontal cortex dysfunction

Reality monitoring impairment is often reported in schizophrenia but the neural basis of this deficit is poorly understood. Difficulties with reality monitoring could be attributable to the same pattern of neural dysfunction as other cognitive deficits that characterize schizophrenia, or might instead represent a separable and dissociable impairment. This question was addressed through direct comparison of behavioral performance and neural activity associated with reality monitoring and working memory in patients with schizophrenia and matched healthy controls. Participants performed a word-pair reality monitoring task and a Sternberg working memory task while undergoing fMRI scanning. Distinct behavioral deficits were observed in the patients during performance of each task, which were associated with separable task- and region-specific dysfunction in the medial anterior prefrontal cortex for reality monitoring and dorsolateral prefrontal cortex for working memory. The results suggest that reality monitoring impairment is a distinct neurocognitive deficit in schizophrenia. The findings are consistent with the presence of a range of dissociable cognitive deficits in schizophrenia which may be associated with variable functional and structural dysconnectivity in underlying processing networks.JRG was supported by a University of Cambridge Behavioural and Clinical Neuroscience Institute studentship, funded by a joint award from the UK Medical Research Council and the Wellcome Trust. JSS was supported by a James S. McDonnell Foundation Scholar award

A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome.

Metabolic complications are commonly found in people treated with clozapine. Reviews on the management of this problem have generally drawn conclusions by grouping different types of studies involving patients treated with various different antipsychotics. We carried out a systematic review and meta-analysis of pharmacological and non-pharmacological treatments for clozapine-induced obesity or metabolic syndrome. Two researchers independently searched PubMed and Embase for randomised controlled trials (RCTs) of treatments for clozapine-induced obesity or metabolic syndrome. All other types of studies were excluded. We only included RCTs where more than 50% of participants were taking clozapine. We identified 15 RCTs. Effective pharmacological treatments for clozapine-induced obesity and metabolic syndrome include metformin, aripiprazole, and Orlistat (in men only). Meta-analysis of three studies showed a robust effect of metformin in reducing body mass index and waist circumference but no effects on blood glucose, triglyceride levels, or HDL levels. In addition, there is limited evidence for combined calorie restriction and exercise as a non-pharmacological alternative for the treatment of clozapine-induced obesity, but only in an in-patient setting. Rosiglitazone, topiramate, sibutramine, phenylpropanolamine, modafinil, and atomoxetine have not shown to be beneficial, despite reports of efficacy in other populations treated with different antipsychotics. We conclude that randomised-controlled trial data support the use of metformin, aripiprazole, and Orlistat (in men only) for treating clozapine-induced obesity. Calorie restriction in combination with an exercise programme may be effective as a non-pharmacological alternative. Findings from trials in different populations should not be extrapolated to people being treated with clozapine.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euroneuro.2016.07.01

Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia.

BACKGROUND: Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. METHODS: We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. RESULTS: Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. CONCLUSIONS: Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients

Inverse association between negative symptoms and body mass index in chronic schizophrenia.

BACKGROUND: We investigated whether negative symptoms, such as poor motivation or anhedonia, were associated with higher body mass index (BMI) in stable patients with schizophrenia chronically treated with antipsychotic medication. METHODS: 62 olanzapine- or clozapine-treated patients with illness duration of at least four years were selected from an international multicenter study on the characterization of negative symptoms. All participants completed the Brief Negative Symptom Scale (BNSS) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between BMI and negative symptoms (BNSS) were explored, as well as multiple regression analyses. We further explored the association of two principal component factors of the BNSS and BMI. Subsidiary analyses re-modeled the above using the negative symptoms subscale of the PANSS and the EMSLEY factor for negative symptoms for convergent validity. RESULTS: Lower negative symptoms (BNSS score) were associated with higher BMI (r=-0.31; p=0.015). A multiple regression analysis showed that negative symptoms (BNSS score) and age were significant predictors of BMI (p=0.037). This was mostly driven by the motivation/pleasure factor of the BNSS. Within this second factor, BMI was negatively associated with anhedonia (r=-0.254; p=0.046) and asociality (r=-0.253; p=0.048), but not avolition (r=-0.169; p=0.188). EMSLEY score was positively associated with BNSS (r=0.873, p<0.001), but negatively associated with BMI (r=-0.308; p=0.015). The association between PANSS and BMI did not reach significance (r=-224, p=0.080). CONCLUSIONS: We conclude that lower negative symptoms were associated with higher BMI (assessed using both the BNSS and EMSLEY) in chronic stable schizophrenia patients, mostly due to lower anhedonia and asociality levels

STI epidemic re-emergence, socio-epidemiological clusters characterisation and HIV coinfection in Catalonia, Spain, during 2017-2019 : A retrospective population-based cohort study

Objectives To describe the epidemiology of sexually transmitted infections (STIs), identify and characterise socio-epidemiological clusters and determine factors associated with HIV coinfection. Design Retrospective population-based cohort. Setting Catalonia, Spain. Participants 42 283 confirmed syphilis, gonorrhoea, chlamydia and lymphogranuloma venereum cases, among 34 600 individuals, reported to the Catalan HIV/STI Registry in 2017-2019. Primary and secondary outcomes Descriptive analysis of confirmed STI cases and incidence rates. Factors associated with HIV coinfection were determined using logistic regression. We identified and characterized socio-epidemiological STI clusters by Basic Health Area (BHA) using K-means clustering. Results The incidence rate of STIs increased by 91.3% from 128.2 to 248.9 cases per 100 000 population between 2017 and 2019 (p<0.001), primarily driven by increase among women (132%) and individuals below 30 years old (125%). During 2017-2019, 50.1% of STIs were chlamydia and 31.6% gonorrhoea. Reinfections accounted for 10.8% of all cases and 6% of cases affected HIV-positive individuals. Factors associated with the greatest likelihood of HIV coinfection were male sex (adjusted OR (aOR) 23.69; 95% CI 16.67 to 35.13), age 30-39 years (versus <20 years, aOR 18.58; 95% CI 8.56 to 52.13), having 5-7 STI episodes (vs 1 episode, aOR 5.96; 95% CI 4.26 to 8.24) and living in urban areas (aOR 1.32; 95% CI 1.04 to 1.69). Living in the most deprived BHAs (aOR 0.60; 95% CI 0.50 to 0.72) was associated with the least likelihood of HIV coinfection. K-means clustering identified three distinct clusters, showing that young women in rural and more deprived areas were more affected by chlamydia, while men who have sex with men in urban and less deprived areas showed higher rates of STI incidence, multiple STI episodes and HIV coinfection. Conclusions We recommend socio-epidemiological identification and characterisation of STI clusters and factors associated with HIV coinfection to identify at-risk populations at a small health area level to design effective interventions

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

An iterative identification procedure for dynamic modeling of biochemical networks

<p>Abstract</p> <p>Background</p> <p>Mathematical models provide abstract representations of the information gained from experimental observations on the structure and function of a particular biological system. Conferring a predictive character on a given mathematical formulation often relies on determining a number of non-measurable parameters that largely condition the model's response. These parameters can be identified by fitting the model to experimental data. However, this fit can only be accomplished when identifiability can be guaranteed.</p> <p>Results</p> <p>We propose a novel iterative identification procedure for detecting and dealing with the lack of identifiability. The procedure involves the following steps: 1) performing a structural identifiability analysis to detect identifiable parameters; 2) globally ranking the parameters to assist in the selection of the most relevant parameters; 3) calibrating the model using global optimization methods; 4) conducting a practical identifiability analysis consisting of two (<it>a priori </it>and <it>a posteriori</it>) phases aimed at evaluating the quality of given experimental designs and of the parameter estimates, respectively and 5) optimal experimental design so as to compute the scheme of experiments that maximizes the quality and quantity of information for fitting the model.</p> <p>Conclusions</p> <p>The presented procedure was used to iteratively identify a mathematical model that describes the NF-<it>κ</it>B regulatory module involving several unknown parameters. We demonstrated the lack of identifiability of the model under typical experimental conditions and computed optimal dynamic experiments that largely improved identifiability properties.</p