Comprehensive review:Computational modelling of Schizophrenia

Computational modelling has been used to address: (1) the variety of symptoms observed in schizophrenia using abstract models of behavior (e.g. Bayesian models - top-down descriptive models of psychopathology); (2) the causes of these symptoms using biologically realistic models involving abnormal neuromodulation and/or receptor imbalance (e.g. connectionist and neural networks - bottom-up realistic models of neural processes). These different levels of analysis have been used to answer different questions (i.e. understanding behavioral vs. neurobiological anomalies) about the nature of the disorder. As such, these computational studies have mostly supported diverging hypotheses of schizophrenia's pathophysiology, resulting in a literature that is not always expanding coherently. Some of these hypotheses are however ripe for revision using novel empirical evidence.Here we present a review that first synthesizes the literature of computational modelling for schizophrenia and psychotic symptoms into categories supporting the dopamine, glutamate, GABA, dysconnection and Bayesian inference hypotheses respectively. Secondly, we compare model predictions against the accumulated empirical evidence and finally we identify specific hypotheses that have been left relatively under-investigated

Are language and social communication intact in children with congenital visual impairment at school age?

Background:  Development of children with congenital visual impairment (VI) has been associated with vulnerable socio-communicative outcomes often bearing striking similarities to those of sighted children with autism.1 To date, very little is known about language and social communication in children with VI of normal intelligence. Methods:  We examined the presentation of language and social communication of 15 children with VI and normal-range verbal intelligence, age 6–12 years, using a standardised language assessment and parental reports of everyday social and communicative behaviours. Their profiles were compared to those of typically developing sighted children of similar age and verbal ability. Results:  Compared to their sighted peers, and relative to their own good and potentially superior structural language skills, children with VI showed significantly poorer use of language for social purposes. Pragmatic language weaknesses were a part of a broader socio-communicative profile of difficulties, present in a substantial proportion of these children and consistent with the pattern found in sighted children with autism. Conclusions:  There are ongoing socio-communicative and pragmatic language difficulties in children with congenital VI at school age, despite their good intellectual abilities and advanced linguistic skills. Further research is required to unpack the underlying causes and factors maintaining this vulnerability in such children

Resting State Default-Mode Network Connectivity in Early Depression Using a Seed Region-of-Interest Analysis: Decreased Connectivity With Caudate Nucleus

Aim: Reports on resting brain activity in healthy controls have described a default-mode network (DMN) and important differences in DMN connectivity have emerged for several psychiatric conditions. No study to date, however, has investigated resting-state DMN in relatively early depression before years of medication treatment. The objective of the present study was, therefore, to investigate the DMN in patients seeking help from specialized mental health services for the first time for symptoms of depression. Methods: Fourteen depressed subjects and 15 matched controls were scanned using 4-T functional magnetic resonance imaging while resting with eyes closed. All but one subject was medication free. A precuneus/posterior cingulate cortex (P/PCC) seed-region connectivity analysis was used to identify the DMN and compare study groups in regions of relevance to depression. Results: The P/PCC analysis identified the DMN well in both study groups, consistent with prior literature. Direct comparison showed significantly reduced correlation between the P/PCC and the bilateral caudate in depression compared with controls and no areas of increased connectivity in the depressed group. Conclusions: The present study is the first to investigate resting-state DMN in the early stages of treatment-seeking for depression. Depressed subjects had decreased connectivity between the P/PCC and the bilateral caudate, regions known to be involved in motivation and reward processing. Deficits in DMN connectivity with the caudate may be an early manifestation of major depressive disorder

3′-5′ Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo

pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity

Impaired Design Fluency Is a Marker of Pathological Cognitive Aging; Results from the Korean Longitudinal Study on Health and Aging

ObjectiveaaWe investigated neuropsychological markers that can be used to discriminate pathological cognitive aging from normal cognitive aging. MethodsaaWe administered frontal lobe function tests including the Wisconsin Card Sorting Test (WCST), digit span test, lexical fluency test, fixed condition design fluency test, and Trail Making Test B (TMT-B) to 92 individuals with pathological cognitive aging (PCA) and 222 individuals with normal cognitive aging (NCA). We examined the main effects of participants ’ diagnoses (PCA, NCA) and age (65-69 years old, 70-74 years old and 75 years old or over) on their test performance using multivariate analysis of variance. ResultsaaThe main effects of both the diagnosis (F=2.860, p=0.002) and the age group (F=2.484, p<0.001) were significant. The PCA group showed lower performance on the backward digit span test (F=14.306, p<0.001), fixed condition design fluency test (F=8.347, p=0.004) and also exhibited perseverative errors in the WCST (F=4.19, p=0.042) compared with the NCA group. The main effect of the diagnosis on the backward digit span test and the fixed condition design fluency test remained significant after Bonferroni correction

Delirium risk screening and haloperidol prophylaxis program in hip fracture patients is a helpful tool in identifying high-risk patients, but does not reduce the incidence of delirium

Background: Delirium in patients with hip fractures lead to higher morbidity and mortality. Prevention in high-risk patients by prescribing low dose haloperidol is currently under investigation. Methods. This prospective cohort surveillance assessed hip fracture patients for risk of developing a delirium with the Risk Model for Delirium (RD) score. High-risk patients (score ≥5 points) were treated with a prophylactic low-dose of haloperidol according to hospital protocol. Primary outcome was delirium incidence. Secondary outcomes were differences between high- and low-risk patients in delirium, length of stay (LOS), return to pre-fracture living situation and mortality. Logistic regression analysis was performed with age, ASA-classification, known dementia, having a partner, type of fracture, institutional residence and psychotropic drug use as possible confounders. Results: 445 hip fracture patients aged 65 years and older were admitted from January 2008 to December 2009. The RD-score was completed in 378 patients, 173 (45.8%) high-risk patients were treated with prophylactic medication. Sensitivity was 71.6%, specificity 63.8% and the negative predictive value (NPV) of a score < 5 was 85.9%. Delirium incidence (27.0%) was not significantly different compared to 2007 (27.8%) 2006 (23.9%) and 2005 (29.0%) prior to implementation of the RD- protocol. Logistic regression analysis showed that high-risk patients did have a significant higher delirium incidence (42.2% vs. 14.1%, OR 4.1, CI 2.43-7.02). They were more likely to be residing at an alternative living situation after 3 months (62.3% vs. 17.0%, OR 6.57, CI 3.23-13.37) and less likely to be discharged from hospital before 10 days (34.9% vs. 55.9%, OR 1.63, CI 1.03-2.59). Significant independent risk factors for a delirium were a RD-score 5 (OR 4.13, CI 2.43-7.02), male gender (OR 1.93, CI 0.99-1.07) and age (OR 1.03, CI 0.99-1.07). Conclusions: Introducing the delirium prevention protocol did not reduce delirium incidence. The RD-score did identify patients with a high risk to develop a delirium. This high-risk group had a longer LOS and returned to pre-fracture living situation less often. The NPV of a score < 5 was high, as it should be for a screening instrument. Concluding, the RD-score is a useful tool to identify patients with poorer outcome

Increased Immune Complexes of Hypocretin Autoantibodies in Narcolepsy

International audienceBACKGROUND: Hypocretin peptides participate in the regulation of sleep-wake cycle while deficiency in hypocretin signaling and loss of hypocretin neurons are causative for narcolepsy-cataplexy. However, the mechanism responsible for alteration of the hypocretin system in narcolepsy-cataplexy and its relevance to other central hypersomnias remain unknown. Here we studied whether central hypersomnias can be associated with autoantibodies reacting with hypocretin-1 peptide present as immune complexes. METHODOLOGY: Serum levels of free and dissociated (total) autoantibodies reacting with hypocretin-1 peptide were measured by enzyme-linked immunosorbent assay and analyzed with regard to clinical parameters in 82 subjects with narcolepsy-cataplexy, narcolepsy without cataplexy or idiopathic hypersomnia and were compared to 25 healthy controls. PRINCIPAL FINDINGS: Serum levels of total but not free IgG autoantibodies against hypocretin-1 were increased in narcolepsy-cataplexy. Increased levels of complexed IgG autoantibodies against hypocretin-1 were found in all patients groups with a further increase in narcolepsy-cataplexy. Levels of total IgM hypocretin-1 autoantibodies were also elevated in all groups of patients. Increased levels of anti-idiotypic IgM autoantibodies reacting with hypocretin-1 IgG autoantibodies affinity purified from sera of subjects with narcolepsy-cataplexy were found in all three groups of patients. Disease duration correlated negatively with serum levels of hypocretin-1 IgG and IgM autoantibodies and with anti-idiotypic IgM autoantibodies. CONCLUSION: Central hypersomnias and particularly narcolepsy-cataplexy are characterized by higher serum levels of autoantibodies directed against hypocretin-1 which are present as immune complexes most likely with anti-idiotypic autoantibodies suggesting their relevance to the mechanism of sleep-wake cycle regulation

Establishing the reliability and validity of the Zagazig Depression Scale in a UK student population: an online pilot study

Background: It is thought that depressive disorders will be the second leading cause of disability worldwide by 2020. Recently, there is a steady increase in the number of university students diagnosed and treated as depression patients. It can be assumed that depression is a serious mental health problem for university students because it affects all age groups of the students either younger or older equally. The current study aims to establish the reliability and validity of the Zagazig Depression scale in a UK sample. Methods: The study was a cross-sectional online survey. A sample of 133 out of 275 undergraduate students from a range of UK Universities in the academic year 2008-2009, aged 20.3 ± 6.3 years old were recruited. A modified back translated version of Zagazig Depression scale was used. In order to validate the Zagazig Depression scale, participants were asked to complete the Patient Health Questionnaire. Statistical analysis includes Kappa analysis, Cronbach's alpha, Spearman's correlation analysis, and Confirmatory Factor analysis. Results: Using the recommended cut-off of Zagazig Depression scale for possible minor depression it was found that 30.3% of the students have depression and higher percentage was identified according to the Patient Health Questionnaire (37.4%). Females were more depressed. The mean ZDS score was 8.3 ± 4.2. Rates of depression increase as students get older. The reliability of The ZDS was satisfactory (Cronbach's alpha was .894). For validity, ZDS score was strongly associated with PHQ, with no significant difference (p-value > 0.05), with strong positive correlation (r = +.8, p-value < 0.01). Conclusion: The strong, significant correlation between the PHQ and ZDS, along with high internal consistency of the ZDS as a whole provides evidence that ZDS is a reliable measure of depressive symptoms and is promising for the use of the translated ZDS in a large-scale cross-culture study