Exploring non-stationarity patterns in schizophrenia: neural reorganization abnormalities in the alpha band

Producción CientíficaObjective. The aim of this paper was to characterize brain non-stationarity during an auditory oddball task in schizophrenia (SCH). The level of non-stationarity was measured in the baseline and response windows of relevant tones in SCH patients and healthy controls. Approach. Event-related potentials were recorded from 28 SCH patients and 51 controls. Non-stationarity was estimated in the conventional electroencephalography frequency bands by means of Kullback-Leibler divergence (KLD). Relative power (RP) was also computed to assess a possible complementarity with KLD. Main results. Results showed a widespread statistically significant increase in the level of non-stationarity from baseline to response in all frequency bands for both groups. Statistically significant differences in non-stationarity were found between SCH patients and controls in beta-2 and especially in the alpha band. SCH patients showed more non-stationarity in the left parieto-occipital region during the baseline window in the beta-2 band. A leave-one-out cross validation classification study with feature selection based on binary stepwise logistic regression to discriminate between SCH patients and controls provided an accuracy of 89.87% and area under ROC of 0.9510. Significance. KLD can characterize transient neural reorganization during an attentional task in response to novelty and relevance. Our findings suggest anomalous reorganization of neural dynamics in SCH during an oddball task. The abnormal frequency-dependent modulation found in SCH patients during relevant tones is in agreement with the hypothesis of aberrant salience detection in SCH. The increase in non-stationarity in the alpha band during the active task supports the notion that this band is involved in top-down processing. The baseline differences in the beta-2 band suggest that hyperactivation of the default mode network during attention tasks may be related to SCH symptoms. Furthermore, the binary stepwise logistic regression procedure selected features from both KLD and RP, supporting the idea that these measures can be complementary.This research project was supported in part by the projects TEC2014-53196-R of ‘Ministerio de Economía y Competitividad’ and FEDER; the project VA037U16 from the “Consejería de Educación de la Junta de Castilla y León”, the “Fondo de Investigaciones Sanitarias (Instituto de Salud Carlos III)” under projects FIS PI11/02203 and PI15/00299; and the “Gerencia Regional de Salud de Castilla y León” under projects GRS 932/A/14 and GRS 1134/A/15. P. Núñez was in receipt of a ‘Promoción de empleo joven e implantación de la Garantía Juvenil en I+D+i’ grant from ‘Ministerio de Economía y Competitividad’ and the University of Valladolid, A. Bachiller and J. Gomez-Pilar were in receipt of a PIF-UVA grant from the University of Valladolid. A. Lubeiro has a predoctoral scholarship from the “Junta de Castilla y León” and European Social Fund

Latest Cretaceous palaeogeographic evolution of northeast Iberia: Insights from the Campanian continental Montalbán subbasin (Spain)

This work characterizes for the first time the 500–700 m-thick uppermost Cretaceous continental sedimentary succession of the Allueva Fm recorded in the northeastern margin of the Iberian basin, in the Montalbán subbasin (Maestrazgo domain, Spain). The middle-upper Campanian age of this unit constrained here by new paleomagnetic and biostratigraphic data involves major revision of previous stratigraphic and palaeogeographic interpretations. The uplift of the northern marginal areas of the Montalbán subbasin onwards from the middle Campanian supplied the coarse terrigenous-clastic sediments common in the alluvial Allueva Fm. Moreover, a sharp increase of the sedimentation rates (from 4 to 19 cm/ky) from the lower to the middle-upper part of the Allueva Fm has been related to further increase of the tectonic activity during the middle part of the late Campanian. Also relevant are the new discovered vertebrate sites mostly found in the marginal areas of a large lacustrine-palustrine carbonate system developed during the latest Campanian. Vertebrate sites include a fossil assemblage with abundance of titanosaur sauropod dinosaurs as well as the presence of ornithopod dinosaurs and crocodylomorphs. A review of the dinosaur fossil sites recorded in other Iberian subbasins shows a similar fossil assembage occurrence during the late Campanian–earliest Maastrichtian timespan, previous to the faunal turnover that took place in the Ibero-Armorican landmass around the onset of the late Maastrichtian. The stratigraphic, sedimentological and paleontological characterization of the successions recorded during the initial stages of development of the Montalbán subbasin have major implication to understand the latest Cretaceous palaeogeographic evolution of northeast Iberia. Comparative review to other latest Cretaceous continental successions deposited in other domains of the Iberian basin indicates a south to north migration of newly developed subsident subbasins: during the Campanian (South Iberian domain), during the middle-late Campanian (northern Maestrazgo domain), and during the Maastrichtian (central Castillian domain)

Novel Measure of the Weigh Distribution Balance on the Brain Network: Graph Complexity Applied to Schizophrenia

Producción CientíficaThe aim of this study was to assess brain complexity dynamics in schizophrenia (SCH) patients during an auditory oddball task. For that task, we applied a novel graph measure based on the balance of the node weighs distribution. Previous studies applied complexity parameters that were strongly dependent on network topology. This fact could bias the results besides being necessary correction techniques as surrogating process. In the present study, we applied a novel graph complexity measure from the information theory: Shannon Graph Complexity (SGC). Complexity patterns form electroencephalographic recordings of 20 healthy controls and 20 SCH patients during an auditory oddball task were analyzed. Results showed a significantly more pronounced decrease of SGC for controls than for SCH patients during the cognitive task. These findings suggest an important change in the brain configuration towards more balanced networks, mainly in the connections related to long-range interactions. Since these changes are significantly more pronounced in controls, it implies a deficit in the neural network reorganization in SCH patients. In addition, SGC showed a suitable discrimination ability using a leave-one-out cross-validation: 0.725 accuracy and 0.752 area under receiver operating characteristics curve. The novel complexity measure proposed in this study demonstrated to be independent of network topology and, therefore, it complements traditional graph measures to characterize brain networks.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

Analysis of Functional Connectivity during an Auditory Oddball Task in Schizophrenia

Producción CientíficaThe aim of this study was to evaluate neural coupling patterns in schizophrenia (SCH) patients and healthy controls during an auditory oddball task. Two measures of functional connectivity were applied to 28 SCH patients and 51 healthy controls to characterize electroencephalographic (EEG) activity. Specifically, magnitude squared coherence (MSC) and the imaginary part of coherency (ICOH) were computed for five frequency bands: theta, alpha, beta-1, beta-2 and gamma. The results showed a statistically significant modulation increase in MSC and ICOH for controls with respect to SCH in the theta band, and a decrease in ICOH for the beta-2 band. Furthermore, controls showed more significant changes from the baseline and active task windows than SCH patients. Our findings suggest that SCH patients show coupling abnormalities during an auditory oddball task compared to healthy controls.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

Analysis of the Non-stationarity of Neural Activity during an Auditory Oddball Task in Schizophrenia

Producción CientíficaThe aim of this study was to characterize brain dynamics during an auditory oddball task. For this purpose, a measure of the non-stationarity of a given time-frequency representation (TFR) was applied to electroencephalographic (EEG) signals. EEG activity was acquired from 20 schizophrenic (SCH) patients and 20 healthy controls while they underwent a three-stimulus auditory oddball task. The Degree of Stationarity (DS), a measure of the non-stationarity of the TFR, was computed using the continuous wavelet transform. DS was calculated for both the baseline [-300 0] ms and active task [150 550] ms windows of a P300 auditory oddball task. Results showed a statistically significant increase (p<0.05) in non-stationarity for controls during the cognitive task in the central region, while less widespread statistically significant differences were obtained for SCH patients, especially in the beta-2 and gamma bands. Our findings support the relevance of DS as a means to study cerebral processing in SCH. Furthermore, the lack of statistically significant changes in DS for SCH patients suggests an abnormal reorganization of neural dynamics during an oddball task.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (VA059U13

Relations between structural and EEG-based graph metrics in healthy controls and schizophrenia patients

Producción CientíficaObjective: To assess using graph-theory properties of both structural and functional networks in schizophrenia patients, as well as the possible prediction of the latter based on the former. Abnormal structural and functional network parameters have been found in schizophrenia, but the dependence of functional network properties on structural alterations has not been described yet in this syndrome. Experimental design: We applied averaged path-length (PL), clustering coefficient (CLC) and density (D) measurements to structural data derived from diffusion magnetic resonance and functional data derived from electroencephalography in 39 schizophrenia patients and 79 controls. Functional data were collected for the global and theta frequency bands with subjects performing an odd-ball task, both prior to stimulus delivery and at the corresponding processing window. Connectivity matrices were constructed respectively from (i) tractography and registered cortical segmentations (structural) and (ii) phase-locking values (functional). Principal observations: In both groups, we observed a significant EEG task-related modulation (change between pre-stimulus and response windows) in the global and theta bands. Patients showed larger structural PL and pre-stimulus density in the global and theta bands, and lower PL task-related modulation in the theta band. Structural network values predicted pre-stimulus global band values in controls and global band task-related modulation in patients. Abnormal functional values found in patients (pre-stimulus density in the global and theta bands and task-related modulation in the theta band) were not predicted by structural data in this group. Structural and functional network abnormalities respectively predicted cognitive performance and positive symptoms in patients. Conclusions: Taken together, the alterations in the structural and functional theta networks in the patients and the lack of significant relations between these alterations, suggest that these types of network abnormalities exist in different groups of schizophrenia patients.This research project was supported in part by grants from Instituto de Salud Carlos III under project PI15/00299, “Gerencia Regional de Salud de Castilla y León” under projects GRS 1263/A/16 and GRS 1485/A/17, and “Ministerio de Economía y Competitividad” and FEDER under grants TEC2014-53196-R and TEC2013-44194-P; by ‘European Commission’ and FEDER under project 'Análisis y correlación entre el genoma completo y la actividad cerebral para la ayuda en el diagnóstico de la enfermedad de Alzheimer' ('Cooperation Programme Interreg V-A Spain-Portugal POCTEP 2014-2020'), and by ‘Consejería de Educación de la Junta de Castilla y León’ and FEDER under project VA037U16. J. Gomez-Pilar was in receipt of a grant from University of Valladolid and A. Lubeiro was in receipt of a grant from Consejería de Educación de la Junta de Castilla y León

A review of recent and future marine extinctions

Between 20 and 24 marine extinctions, ranging from algal to mammal species, have occurred over the past 500 years. These relatively low numbers question whether the sixth mass extinction that is underway on land is also occurring in the ocean. There is, however, increasing evidence of worldwide losses of marine populations that may foretell a wave of oncoming marine extinctions. A review of current methods being used to determine the loss of biodiversity from the world’s oceans reveals the need to develop and apply new assessment methodologies that incorporate standardized metrics that allow comparisons to be made among different regions and taxonomic groups, and between current extinctions and past mass extinction events. Such efforts will contribute to a better understanding of extinction risk facing marine flora and fauna, as well as the ways in which it can be mitigated

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

peer reviewed[en] BACKGROUND: The synchronized activity of distributed neural assemblies — reflected in the electroencephalogram (EEG) — underpins mental function. In schizophrenia, modulation deficits of EEG spectral content during a P300 task have been replicated. The effects of treatment, chronicity and specificity in these deficits and their possible relationship with anatomic connectivity remain to be explored. METHODS: We assessed spectral entropy modulation of the EEG during a P300 task in 79 patients with schizophrenia (of those, 31 werein their first episode), 29 patients with bipolar disorder and 48 healthy controls. Spectral entropy values summarize EEG characteristics by quantifying the irregularity of spectral content. In a subsample, we calculated the network architecture of structural connectivity using diffusion tensor imaging and graph-theory parameters. RESULTS: We found significant spectral entropy modulation deficits with task performance in patients with chronic or first-episode schizophrenia and in patients with bipolar disorder, without significant pre-stimulus spectral entropy differences. The deficits were unrelated to treatment doses, and spectral entropy modulation did not differ between patients taking or not taking antipsychotics, lithium, benzodiazepines or antidepressants. Structural connectivity values were unrelated to spectral entropy modulation. In patients with schizophrenia, spectral entropy modulation was inversely related to negative symptoms and directly related to verbal memory. LIMITATIONS: All patients were taking medication. Patients with bipolar disorder were euthymic and chronic. The cross-sectional nature of this study prevented a more thorough analysis of state versus trait criteria for spectral entropy changes. CONCLUSION: Spectral entropy modulation with task performance is decreased in patients with schizophrenia and bipolar disorder. This deficit was not an effect of psychopharmacological treatment or structural connectivity and might reflect a deficit in the synchronization of the neural assemblies that underlie cognitive activity

Biologic Therapy in Refractory Non-Multiple Sclerosis Optic Neuritis Isolated or Associated to Immune Mediated Inflammatory Diseases. A Multicenter Study

We aimed to assess the e cacy of biologic therapy in refractory non-Multiple Sclerosis (MS) Optic Neuritis (ON), a condition more infrequent, chronic and severe than MS ON. This was an open-label multicenter study of patients with non-MS ON refractory to systemic corticosteroids and at least one conventional immunosuppressive drug. The main outcomes were Best Corrected Visual Acuity (BCVA) and both Macular Thickness (MT) and Retinal Nerve Fiber Layer (RNFL) using Optical Coherence Tomography (OCT). These outcome variables were assessed at baseline, 1 week, and 1, 3, 6 and 12 months after biologic therapy initiation. Remission was defined as the absence of ON symptoms and signs that lasted longer than 24 h, with or without an associated new lesion on magnetic resonance imaging with gadolinium contrast agents for at least 3 months. We studied 19 patients (11 women/8 men; mean age, 34.8 13.9 years). The underlying diseases were Bechet?s disease (n = 5), neuromyelitis optica (n = 3), systemic lupus erythematosus (n = 2), sarcoidosis (n = 1), relapsing polychondritis (n = 1) and anti-neutrophil cytoplasmic antibody -associated vasculitis (n = 1). It was idiopathic in 6 patients. The first biologic agent used in each patient was: adalimumab (n = 6), rituximab (n = 6), infliximab (n = 5) and tocilizumab (n = 2). A second immunosuppressive drug was simultaneously used in 11 patients: methotrexate (n = 11), azathioprine (n = 2), mycophenolate mofetil (n = 1) and hydroxychloroquine (n = 1). Improvement of the main outcomes was observed after 1 year of therapy when compared with baseline data: mean SD BCVA (0.8 0.3 LogMAR vs. 0.6 0.3 LogMAR; p = 0.03), mean SD RNFL (190.5 175.4 m vs. 183.4 139.5 m; p = 0.02), mean SD MT (270.7 23.2 m vs. 369.6 137.4 m; p = 0.03). Besides, the median (IQR) prednisone-dose was also reduced from 40 (10?61.5) mg/day at baseline to. 2.5 (0?5) mg/day after one year of follow-up; p = 0.001. After a mean SD follow-up of 35 months, 15 patients (78.9%) achieved ocular remission, and 2 (10.5%) experienced severe adverse events. Biologic therapy is e ective in patients with refractory non-MS ON

Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology

Mutations in the GBA gene that encodes the lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated a set of differentiated and stable human dopaminergic cell lines that express the two most prevalent GBA mutations as well as GBA knockout cell lines as a in vitro disease modeling system to study the relationship between mutant GBA and the abnormal accumulation of α-synuclein. We performed a deep analysis of the consequences triggered by the presence of mutant GBA protein and the loss of GCase activity in different cellular compartments, focusing primarily on the lysosomal compartment, and analyzed in detail the lysosomal activity, composition, and integrity. The loss of GCase activity generates extensive lysosomal dysfunction, promoting the loss of activity of other lysosomal enzymes, affecting lysosomal membrane stability, promoting intralysosomal pH changes, and favoring the intralysosomal accumulation of sphingolipids and cholesterol. These local events, occurring only at a subcellular level, lead to an impairment of autophagy pathways, particularly chaperone-mediated autophagy, the main α-synuclein degradative pathway. The findings of this study highlighted the role of lysosomal function and lipid metabolism in PD and allowed us to describe a molecular mechanism to understand how mutations in GBA can contribute to an abnormal accumulation of different α-synuclein neurotoxic species in PD pathology.The authors wish to thank Dr. Arango (VHIR) for the PX461 vector and all the Vila lab members for their support. This work was supported by the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (Spain)-FEDER (PI17/00496 and PI20/00728), the Michael J. Fox Foundation, the Silverstein Foundation (MJFF 16182), and the BBVA Foundation (NanoERT). M.M. was supported by an FPU doctoral fellowship (FPU18/05595) from MINECO (Spain); J.R. was supported by a PERIS fellowship (Generalitat de Catalunya); E.P. was supported by a VHIR doctoral fellowship (VHIR, Barcelona).Peer reviewe