Standard tone stability as a manipulation of precision in the oddball paradigm: Modulation of prediction error responses to fixed-probability deviants

Electrophysiological sensory deviance detection signals, such as the mismatch negativity (MMN), have been interpreted from the predictive coding framework as manifestations of prediction error (PE). From a frequentist perspective of the classic oddball paradigm, deviant stimuli are unexpected because of their low probability. However, the amount of PE elicited by a stimulus can be dissociated from its probability of occurrence: when the observer cannot make confident predictions, any event holds little surprise value, no matter how improbable. Here we tested the hypothesis that the magnitude of the neural response elicited to an improbable sound (D) would scale with the precision of the prediction derived from the repetition of another sound (S), by manipulating repetition stability. We recorded the Electroencephalogram (EEG) from 20 participants while passively listening to 4 types of isochronous pure tone sequences differing in the probability of the S tone (880 Hz) while holding constant the probability of the D tone [1,046 Hz; p(D) = 1/11]: Oddball [p(S) = 10/11]; High confidence (7/11); Low confidence (4/11); and Random (1/11). Tones of 9 different frequencies were equiprobably presented as fillers [p(S) C p(D) C p(F) = 1]. Using a mass-univariate non-parametric, cluster-based correlation analysis controlling for multiple comparisons, we found that the amplitude of the deviant-elicited ERP became more negative with increasing S probability, in a time-electrode window consistent with the MMN (ca. 120- 200 ms; frontal), suggesting that the strength of a PE elicited to an improbable event indeed increases with the precision of the predictive model

Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review

Background: Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning. Methods: We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains. Findings: A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied. Interpretation: mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process. Funding: Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514)

Relação entre funcionamento cognitivo e o perfil sintomático com a qualidade de vida de pacientes com transtornos do espectro da esquizofrenia

Objective: To evaluate the association of psychopathological symptoms and cognitive functioning with the measures of subjective quality of life of a group of patients diagnosed with the schizophrenia spectrum. Methodology: The study included 102 outpatients who met the DSM-IV-TR criteria for the diagnosis of schizophrenia spectrum disorders. The data were obtained by means of the Seville Questionnaire of Quality of Life (CSCV), the scale for the positive and negative schizophrenia syndrome (PANSS), the Beck Depression Inventory (BDI) as well as the state-trait Anxiety Inventory (STAI). Results: The multiple regression analysis showed, on one hand, that favorable aspects of quality of life are affected by cognitive disorganization, positive, depressive and anxiety symptoms. On the other hand, the presence of emotional symptoms is strongly associated with unfavorable aspects, which suggests that this symptomatic dimension impairs the subjective perception of well-being of patients with schizophrenia spectrum disorders. Conclusions: Psychopathological symptoms and cognitive function affect the subjective quality of life in patients with schizophrenia. If the aim of the treatment is to improve the perceived quality of life, the strategies should consider seeking the improvement symptoms of an emotional nature, such as depression / anxiety and emotional distress.Objetivo: evaluar la asociación de los síntomas psicopatológicos y el funcionamiento cognitivo con las medidas de calidad de vida subjetiva en pacientes con diagnósticos del espectro de la esquizofrenia. Metodología: se incluyeron 102 pacientes ambulatorios que cumplían criterios DSM-IVTR para el diagnóstico de alguno de los trastornos del espectro de la esquizofrenia. Los datos se obtuvieron utilizando el Cuestionario Sevilla de Calidad de Vida, la Escala para el síndrome positivo y negativo de la esquizofrenia (PANSS), el Inventario de depresión de Beck y el Inventario de Ansiedad estado/rasgo. Resultados: el análisis de regresión múltiple mostró que los aspectos favorables de la calidad de vida están afectados por la desorganización cognitiva, los síntomas positivos, depresivos y ansiosos. Por otra parte, la presencia de síntomas de carácter emocional está fuertemente asociada a los aspectos desfavorables, lo que hace pensar que esta dimensión sintomática deteriora la percepción subjetiva de bienestar de los pacientes con trastornos del espectro de la esquizofrenia. Conclusiones: los síntomas psicopatológicos y la función cognitiva afectan la calidad de vida subjetiva en pacientes con esquizofrenia. Si el objetivo con el tratamiento es lograr que mejore la calidad de vida percibida, las estrategias deben considerar la búsqueda de la mejoría de los síntomas de carácter emocional, como la depresión, la ansiedad y el malestar emocional.Objetivo: avaliar a associação dos sintomas psicopatológicos e o funcionamento cognitivo com as medidas de qualidade de vida subjetiva em pacientes com diagnósticos do espectro da esquizofrenia. Metodologia: se incluíram 102 pacientes ambulatórios que cumpriam critérios DSMIV-TR para o diagnóstico de algum dos transtornos do espectro da esquizofrenia. Os dados se obtiveram utilizando o Questionário Sevilla de Qualidade de Vida, a Escala para a síndrome positiva e negativa da esquizofrenia (PANSS), o Inventário de depressão de Beck e o Inventário de Ansiedade estado/característica. Resultados: a análise de regressão múltipla mostrou que os aspectos favoráveis da qualidade de vida estão afetados pela desorganização cognitiva, os sintomas positivos, depressivos e ansiosos. Por outra parte, a presença de sintomas de carácter emocional está fortemente associada aos aspectos desfavoráveis, o que se faz pensar que esta dimensão sintomática deteriora a percepção subjetiva de bem-estar dos pacientes com transtornos do espectro da esquizofrenia. Conclusões: os sintomas psicopatológicos e a função cognitiva afetam a qualidade de vida subjetiva em pacientes com esquizofrenia. Se o objetivo com o tratamento é conseguir que melhore a qualidade de vida percebida, as estratégias devem considerar a busca da melhoria dos sintomas de carácter emocional, como a depressão, a ansiedade e o mal-estar emocional

Industrial By-Products As a Novel Circular Source of Biocompatible Extracellular Vesicles

Extracellular vesicles (EVs) constitute an intricate system of molecular exchange that has recently gained tremendous interest. However, sustainable sources of safe biological EVs remain scarce and elusive. This study explores and defines the use of food industry by-products (BP) as a circular source of safe biocompatible EVs. Averaged diameter and molecular compositions indicate a large yield of exosomes and high abundancy of membrane lipids with signaling capacity in these vesicles. Complex proteomes mimicking those circulating in human blood plasma are also identified. Furthermore, BP-EVs do not show relevant cytotoxicity and display excellent oral and intravenous bioavailability together with specific organ targeting capacity. Collectively, it is believed that the novel findings reported here will open substantial venues for the use of BP as an optimal source of biocompatible nanovesicles in manifold applications of the biotechnological and biomedical fields.The authors sincerely thank Gemma Plaza, oenologist at the Castell del Remei winery in Penelles, Lleida, Spain and Juan Carlos Blanco, production manager at Mahou San Miguel in Alovera, Madrid, Spain for their kind and altruistic help on the obtention of their respective industry by-product samples. The authors also thank Dr. Hector Peinado and his research group at the National Center for Oncology Research (CNIO) in Madrid (Spain) for their support on the morphometric characterization of BP-EVs. Support for this work was provided by the Research and Education Council of the Community of Madrid, Spain (2018-T1/ BIO-10633), Ministry of Science and Innovation, Spain (PID2020- 114885RB-C21) and a FIS project by Carlos III Institute of Health (ISCIII), Spain (PI20/00623). A.S. acknowledges a grant from the Talento Program 2018 of the Community of Madrid. X.G.-P. acknowledges grants from Sara Borrell postdoctoral program (CD19/00243) and Miguel Servet tenure track program (CP21/00096) of the Instituto de Salud Carlos III (ISCIII, Spain), respectively awarded on the 2019 and 2021 calls under ISCIII-Health Strategy Actions [These grants are cofunded with European Union Funds (ISCIII Miguel Servet Program 2021 is cofunded by Fondo Social Europeo Plus, FSE+)]. M.V.C. acknowledges a Miguel Servet program contract (CPII20/00007). C.L.’s Ph.D. was funded by the Regional Ministry of Science, Universities and Innovation of the Community of Madrid and the European Social Fund for the recruitment of predoctoral researchers (PEJD-2019-PRE/BIO-16475). IRBLLEIDA and X.G.-P. are co-funded by CERCA Program/Generalitat de Catalunya

Risk factors for metabolic syndrome in individuals with recent-onset psychosis at disease onset and after 1-year follow-up

Metabolic syndrome (MetS) is a cluster of parameters encompassing the most dangerous heart attack risk factors, associated with increased morbidity and mortality. It is highly prevalent in recent-onset psychosis (ROP) patients. In this pilot study, we evaluated MetS parameters (fasting glucose, high-density lipoprotein (HDL) cholesterol (HDL-c), fasting triglycerides, waist circumference, and systolic and diastolic blood pressure), clinical symptoms, pharmacological treatment, lifestyle, and inflammatory markers in 69 patients with ROP and 61 healthy controls (HCs). At baseline, waist circumference (p = 0.005) and fasting triglycerides (p = 0.007) were higher in patients with ROP than in HCs. At the 1-year follow-up, patients showed clinical improvement, with a reduction in the positive and negative syndrome scale (PANSS) score (p < 0.001), dietary intake (p = 0.001), and antipsychotic medication dose (p < 0.001); however, fasting glucose (p = 0.011), HDL-c (p = 0.013) and waist circumference worsened (p < 0.001). We identified sex, age, BMI, dietary intake, physical activity, daily tobacco use, daily cannabis use, and antipsychotic doses as risk factors contributing to baseline MetS parameters. After 1-year follow-up, those factors plus the PANSS and Calgary Depression Scale for Schizophrenia (CDSS) scores were associated with MetS parameters. Further studies are needed to understand the contributions of the studied risk factors in patients with ROP at onset and during disease progression

Multivariate brain functional connectivity through regularized estimators

Functional connectivity analyses are typically based on matrices containing bivariate measures of covariability, such as correlations. Although this has been a fruitful approach, it may not be the optimal strategy to fully explore the complex associations underlying brain activity. Here, we propose extending connectivity to multivariate functions relating to the temporal dynamics of a region with the rest of the brain. The main technical challenges of such an approach are multidimensionality and its associated risk of overfitting or even the non-uniqueness of model solutions. To minimize these risks, and as an alternative to the more common dimensionality reduction methods, we propose using two regularized multivariate connectivity models. On the one hand, simple linear functions of all brain nodes were fitted with ridge regression. On the other hand, a more flexible approach to avoid linearity and additivity assumptions was implemented through random forest regression. Similarities and differences between both methods and with simple averages of bivariate correlations (i.e., weighted global brain connectivity) were evaluated on a resting state sample of N = 173 healthy subjects. Results revealed distinct connectivity patterns from the two proposed methods, which were especially relevant in the age-related analyses where both ridge and random forest regressions showed significant patterns of age-related disconnection, almost completely absent from the much less sensitive global brain connectivity maps. On the other hand, the greater flexibility provided by the random forest algorithm allowed detecting sex-specific differences. The generic framework of multivariate connectivity implemented here may be easily extended to other types of regularized models

High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders

Altres ajuts: Financial support was received from "Fundació Parc Taulí Institut d'Investigació i Innovació Parc Taulí I3PT" (Grant Nos. CIR2009/33, CIR2010/034) and "Fundació Barnola-Vallribera 2011".A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services