Associations between aerobic fitness, negative symptoms, cognitive deficits and brain structure in schizophrenia - a cross-sectional study

Negative symptoms and cognitive deficits are common in individuals with schizophrenia, greatly affect their outcome, and have been associated with alterations in cerebral gray and white matter volume (GMV, WMV). In the last decade, aerobic endurance training has emerged as a promising intervention to alleviate these symptoms and improved aerobic fitness has been suggested as a key moderator variable. In the present study, we investigated, whether aerobic fitness is associated with fewer cognitive deficits and negative symptoms and with GMVs and WMVs in individuals with schizophrenia in a cross-sectional design. In the largest study to date on the implications of fitness in individuals with schizophrenia, 111 participants at two centers underwent assessments of negative symptoms, cognitive functioning, and aerobic fitness and 69 underwent additional structural magnetic resonance imaging. Multilevel Bayesian partial correlations were computed to quantify relationships between the variables of interest. The main finding was a positive association of aerobic fitness with right hippocampal GMV and WMVs in parahippocampal and several cerebellar regions. We found limited evidence for an association of aerobic fitness with cognitive functioning and negative symptoms. In summary, our results strengthen the notion that aerobic fitness and hippocampal plasticity are interrelated which holds implications for the design of exercise interventions in individuals with schizophrenia

Association between aerobic fitness and the functional connectome in patients with schizophrenia

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-022-01411-x

Exercise as an add-on treatment in individuals with schizophrenia: results from a large multicenter randomized controlled trial

Current treatment methods do not achieve recovery for most individuals with schizophrenia, and symptoms such as negative symptoms and cognitive deficits often persist. Aerobic endurance training has been suggested as a potential add-on treatment targeting both physical and mental health. We performed a large-scale multicenter, rater-blind, parallel-group randomized controlled clinical trial in individuals with stable schizophrenia. Participants underwent a professionally supervised six-month training comprising either aerobic endurance training (AET) or flexibility, strengthening, and balance training (FSBT, control group), follow-up was another six months. The primary endpoint was all-cause discontinuation (ACD); secondary endpoints included effects on psychopathology, cognition, functioning, and cardiovascular risk. In total, 180 participants were randomized. AET was not superior to FSBT in ACD and most secondary outcomes, with dropout rates of 59.55% and 57.14% in the six-month active phase, respectively. However, both groups showed significant improvements in positive, general, and total symptoms, levels of functioning and in cognitive performance. A higher training frequency additionally promoted further memory domains. Participants with higher baseline cognitive abilities were more likely to respond to the interventions. Our results support integrating exercise into schizophrenia treatment, while future studies should aim to develop personalized training recommendations to maximize exercise-induced benefits

Evolutionary and Experimental Assessment of Novel Markers for Detection of Xanthomonas euvesicatoria in Plant Samples

BACKGROUND: Bacterial spot-causing xanthomonads (BSX) are quarantine phytopathogenic bacteria responsible for heavy losses in tomato and pepper production. Despite the research on improved plant spraying methods and resistant cultivars, the use of healthy plant material is still considered as the most effective bacterial spot control measure. Therefore, rapid and efficient detection methods are crucial for an early detection of these phytopathogens. METHODOLOGY: In this work, we selected and validated novel DNA markers for reliable detection of the BSX Xanthomonas euvesicatoria (Xeu). Xeu-specific DNA regions were selected using two online applications, CUPID and Insignia. Furthermore, to facilitate the selection of putative DNA markers, a customized C program was designed to retrieve the regions outputted by both databases. The in silico validation was further extended in order to provide an insight on the origin of these Xeu-specific regions by assessing chromosomal location, GC content, codon usage and synteny analyses. Primer-pairs were designed for amplification of those regions and the PCR validation assays showed that most primers allowed for positive amplification with different Xeu strains. The obtained amplicons were labeled and used as probes in dot blot assays, which allowed testing the probes against a collection of 12 non-BSX Xanthomonas and 23 other phytopathogenic bacteria. These assays confirmed the specificity of the selected DNA markers. Finally, we designed and tested a duplex PCR assay and an inverted dot blot platform for culture-independent detection of Xeu in infected plants. SIGNIFICANCE: This study details a selection strategy able to provide a large number of Xeu-specific DNA markers. As demonstrated, the selected markers can detect Xeu in infected plants both by PCR and by hybridization-based assays coupled with automatic data analysis. Furthermore, this work is a contribution to implement more efficient DNA-based methods of bacterial diagnostics

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Effects of a psychoeducational program for chronic pain management Efectos de un programa psicoeducativo en el control del dolor crónico Efeitos de um programa psicoeducativo no controle da dor crônica

AIMS: to evaluate the impact of an eight-week psychoeducational program focused on pain intensity, disability and depressive symptoms of patients with chronic pain. METHOD: 79 patients with chronic pain of different etiologies composed the sample. Patients were assessed before, at the end of the intervention and six months after the intervention. The program was developed by a nurse using cognitive-behavioral strategies and was conducted by a multidisciplinary team. The Wilcoxon test was used to compare repeated measures. RESULTS: the participants' mean age was 53 years old, most were female (91%), with an average of 9.5 years of schooling and an average pain duration of 9.9 years. Significant reduction in pain intensity (p<0.001), disability (p<0.001) and depressive symptoms (p<0.001) was found at the end of the program. CONCLUSIONS: the psychoeducational program was effective in reducing pain intensity, reducing disability and in controlling depressive symptoms in this sample.<br>OBJETIVOS: evaluar el impacto de un Programa psicoeducativo de ocho semanas en la intensidad del dolor, incapacidad y síntomas depresivos de pacientes con dolor crónico. MÉTODO: 79 pacientes con dolor crónico de diferentes etiologías compusieron la muestra. Los participantes fueron evaluados antes y al final del Programa y seis meses después. El Programa fue desarrollado por una enfermera, utilizó estrategias cognoscitivo-comportamentales y fue aplicado por un equipo multidisciplinar. La prueba no paramétrico de Wilcoxon fue utilizado para comparar medidas repetidas. RESULTADOS: la mayoría de los participantes eran del sexo femenino (91%), con edad media de 53 años, escolaridad media de 9,5 años y duración media del dolor de 9,9 años. Al final del Programa se observó reducción significativa en la intensidad del dolor (p<0.001), incapacidad (p<0.001) y síntomas depresivos (p<0.001). CONCLUSIONES:el Programa psicoeducativo fue efectivo en el control del dolor, en la reducción de la incapacidad y en el control de los síntomas depresivos en la muestra estudiada.<br>OBJETIVOS: avaliar o impacto de um programa programa psicoeducativo de oito semanas na intensidade da dor, incapacidade e sintomas depressivos de pacientes com dor crônica. MÉTODO: 79 setenta e nove pacientes com dor crônica de diferentes etiologias compuseram a amostra. Os participantes foram avaliados antes e ao final do pPrograma e seis meses após. O pPrograma foi desenvolvido por uma enfermeira, utilizou utilizaram-se estratégias cognitivo-comportamentais, e foi aplicadaso por equipe multidisciplinar. O teste não paramétrico de Wilcoxon foi utilizado para comparar medidas repetidas. RESULTADOS: as maioria doas participantes eram do sexo feminino (91%), com idade média de 53 anos, escolaridade média de 9,5 anos e duração média da dor de 9,9 anos. Ao final do Programa, se observou-se redução significativa na intensidade da dor (p<0,001), incapacidade (p<0,001) e sintomas depressivos (p<0,001). CONCLUSÕES: o pPrograma psicoeducativo foi efetivo no controle da dor, na redução da incapacidade e no controle dos sintomas depressivos na amostra estudada

Cannabis users show enhanced expression of CB1-5HT2A receptor heteromers in olfactory neuroepithelium cells

Cannabinoid CB1 receptors (CB1R) and serotonergic 2A receptors (5HT2AR) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB1R-5HT2AR heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na+ currents in patch clamp recordings. Interestingly, CB1R-5HT2AR heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB1R-5HT2AR heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.This work was supported by grants from DIUE de la Generalitat de Catalunya (2014-SGR-680 and 2014-SGR-1236 to RTF), Instituto de Salud Carlos III, (P14/00210 to P.R.) FIS-FEDER Funds, Spanish Ministry of Economy and Competitiveness (MINECO/FEDER; grant SAF-2014-54840-R to E.I.C. and V.C., grant SAF-2015-69762-R to J.M.F-F., grant MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to Department of Experimental and Health Sciences), and the following networks of Instituto de Salud Carlos III: Red de Trastornos Adictivos, CIBER de Salud Mental, CIBER de Fisiopatología de la Obesidad y Nutrición and CIBER de Enfermedades Neurodegenerativas. M.I.-S. holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness. We would like to thank Dr. María Inmaculada Hernández Muñoz for providing the primers in our gene expression studies and for her invaluable comments and suggestions, Klaus Langohr for his help with the statistical analyses, and Jordi García and Mitona Pujadas for excellent technical assistance. Laura Xicota is currently at ICM Institut du Cerveau et de la Moelle épinière (CNRS UMR7225, INSERM U1127, UPMC) Hôpital de la PitiéSalpêtrière, Paris, France