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1.
Neuroinformatics ; 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31902057

RESUMO

Electro- and magneto-encephalography are functional neuroimaging modalities characterised by their ability to quantify dynamic spatiotemporal activity within the brain. However, the visualisation techniques used to illustrate these effects are currently limited to single- or multi-channel time series plots, topographic scalp maps and orthographic cross-sections of the spatiotemporal data structure. Whilst these methods each have their own strength and weaknesses, they are only able to show a subset of the data and are suboptimal at articulating one or both of the space-time components.Here, we propose Porthole and Stormcloud, a set of data visualisation tools which can automatically generate context appropriate graphics for both print and screen with the following graphical capabilities:Animated two-dimensional scalp maps with dynamic timeline annotation and optional user interaction;Three-dimensional construction of discrete clusters within sparse spatiotemporal volumes, rendered with 'cloud-like' appearance and augmented by cross-sectional scalp maps indicating local maxima.These publicly available tools were designed specifically for visualisation of M/EEG spatiotemporal statistical parametric maps, however, we also demonstrate alternate use cases of posterior probability maps and weight maps produced by machine learning classifiers. In principle, the methods employed here are transferrable to visualisation of any spatiotemporal image.

2.
PLoS Biol ; 17(7): e3000368, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31291244

RESUMO

[This corrects the article DOI: 10.1371/journal.pbio.2006812.].

3.
J Matern Fetal Neonatal Med ; : 1-6, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035852

RESUMO

OBJECTIVES: The main objective of this study was to evaluate the accuracy of prenatal ultrasound to diagnose corpus callosum alterations, compared to prenatal magnetic resonance imaging (MRI), postnatal image techniques (ultrasound and/or MRI), and post-mortem examination in terminated pregnancies. METHODS: Retrospective review of 86 cases of prenatal ultrasound diagnosis of corpus callosum anomalies between January 2007 and December 2015 at a third level Maternal Fetal Medicine center. The study reviewed the findings of prenatal ultrasound and MRI, post-mortem examination in cases of termination of pregnancy (TOP) or stillbirths and postnatal ultrasound, and MRI in neonates. The anomalies of corpus callosum (CC) were classified as complete agenesis of the corpus callosum (ACC), partial ACC, or dysgenesis of CC. RESULTS: Fifty-eight (67.4%) cases resulted in TOP, 26 (30.2%) cases opted to continue with the pregnancy and two (2.3%) cases were lost to follow up. Among the 26 cases that continued with the pregnancy, 24 (92.3%) were live births and two (7.7%) were stillborn. All cases in which a third trimester MRI was performed (n = 46) confirmed the prenatal ultrasound diagnosis of CC anomaly. In seven (15.2%) of them, the MRI found additional intracranial findings and in three cases (6.5%) the type of CC anomaly (complete, partial, or dysgenesis) was reclassified (Kappa index: 0.86, 95% CI: 0.71-1.00). CC anomalies were confirmed in 46 (95.8%) of the 48 cases in which a post-mortem examination was available, the type of anomaly being reclassified in three cases (6.3%) (Kappa index: 0.88, 95% CI: 0.75-1.00). Among the 10 cases in which a postnatal ultrasound was performed, the CC anomaly was confirmed in all and the type of anomaly was reclassified in 1 (10%) of them (Kappa index: 0.75, 95% CI: 0.32-1.00). CONCLUSION: Corpus callosum agenesis can be detected on the routine mid-trimester ultrasound scan. Prenatal ultrasound and MRI can accurately classify the type of CC abnormality. Moreover, third trimester MRI can detect additional intracranial anomalies in 15% of cases.

4.
Neuroimage ; 195: 454-462, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30959193

RESUMO

Auditory prediction errors, i.e. the mismatch between predicted, forthcoming auditory sensations and actual sensory input, trigger the detection of surprising auditory events in the environment. Auditory mismatches engage a hierarchical functional network of cortical sources, which are also interconnected by auditory white matter pathways. Hence it is plausible that these structural and functional networks are quantitatively related. The present study set out to investigate whether structural connectivity of auditory white matter pathways enables the effective connectivity underpinning auditory mismatch responses. Participants (N = 89) underwent diffusion weighted magnetic resonance imaging (MRI) and electroencephalographic (EEG) recordings. Anatomically-constrained tractography was used to extract auditory white matter pathways, namely the bilateral arcuate fasciculi, inferior fronto-occipital fasciculi (IFOF), and the auditory interhemispheric pathway, from which Apparent Fibre Density (AFD) was calculated. EEG data were recorded in the same participants during a stochastic oddball paradigm, which was used to elicit auditory prediction error responses. Dynamic causal modelling was used to investigate the effective connectivity underlying auditory mismatch responses generated in brain regions interconnected by the above mentioned auditory white matter pathways. Our results showed that brain areas interconnected by all auditory white matter pathways best explained the dynamics of auditory mismatch responses. Furthermore, AFD in the right arcuate fasciculus was significantly associated with the effective connectivity between the cortical regions that lie within it. Taken together, these findings indicate that auditory prediction errors recruit a fronto-temporal network of brain regions that are effectively and structurally connected by auditory white matter pathways.


Assuntos
Vias Auditivas/fisiologia , Percepção Auditiva/fisiologia , Encéfalo/fisiologia , Substância Branca/fisiologia , Adolescente , Adulto , Imagem de Difusão por Ressonância Magnética/métodos , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
5.
Haematologica ; 104(9): 1822-1829, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30733272

RESUMO

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

6.
Neuroimage Clin ; 22: 101721, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785050

RESUMO

One of the most common copy number variants, the 22q11.2 microdeletion, confers an increased risk for schizophrenia. Since schizophrenia has been associated with an aberrant neural response to repeated stimuli through both reduced adaptation and prediction, we here hypothesized that this may also be the case in nonpsychotic individuals with a 22q11.2 deletion. We recorded high-density EEG from 19 individuals with 22q11.2 deletion syndrome (12-25 years), as well as 27 healthy volunteers with comparable age and sex distribution, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Using posterior probability maps and dynamic causal modelling we tested three different models accounting for repetition dependent changes in cortical responses as well as in effective connectivity; namely an adaptation model, a prediction model, and a model including both adaptation and prediction. Repetition-dependent changes were parametrically modulated by a combination of adaptation and prediction and were apparent in both cortical responses and in the underlying effective connectivity. This effect was reduced in individuals with a 22q11.2 deletion and was negatively correlated with negative symptom severity. Follow-up analysis showed that the reduced effect of the combined adaptation and prediction model seen in individuals with 22q11.2 deletion was driven by reduced adaptation rather than prediction failure. Our findings suggest that adaptation is reduced in individuals with a 22q11.2 deletion, which can be interpreted in light of the framework of predictive coding as a failure to suppress prediction errors.


Assuntos
Síndrome da Deleção 22q11/fisiopatologia , Adaptação Fisiológica/fisiologia , Percepção Auditiva/fisiologia , Encéfalo/fisiopatologia , Estimulação Acústica , Adolescente , Adulto , Teorema de Bayes , Criança , Eletroencefalografia , Feminino , Humanos , Masculino , Adulto Jovem
7.
PLoS Biol ; 17(2): e2006812, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30811381

RESUMO

The encoding of sensory information in the human brain is thought to be optimised by two principal processes: 'prediction' uses stored information to guide the interpretation of forthcoming sensory events, and 'attention' prioritizes these events according to their behavioural relevance. Despite the ubiquitous contributions of attention and prediction to various aspects of perception and cognition, it remains unknown how they interact to modulate information processing in the brain. A recent extension of predictive coding theory suggests that attention optimises the expected precision of predictions by modulating the synaptic gain of prediction error units. Because prediction errors code for the difference between predictions and sensory signals, this model would suggest that attention increases the selectivity for mismatch information in the neural response to a surprising stimulus. Alternative predictive coding models propose that attention increases the activity of prediction (or 'representation') neurons and would therefore suggest that attention and prediction synergistically modulate selectivity for 'feature information' in the brain. Here, we applied forward encoding models to neural activity recorded via electroencephalography (EEG) as human observers performed a simple visual task to test for the effect of attention on both mismatch and feature information in the neural response to surprising stimuli. Participants attended or ignored a periodic stream of gratings, the orientations of which could be either predictable, surprising, or unpredictable. We found that surprising stimuli evoked neural responses that were encoded according to the difference between predicted and observed stimulus features, and that attention facilitated the encoding of this type of information in the brain. These findings advance our understanding of how attention and prediction modulate information processing in the brain, as well as support the theory that attention optimises precision expectations during hierarchical inference by increasing the gain of prediction errors.


Assuntos
Atenção/fisiologia , Adolescente , Adulto , Encéfalo/fisiologia , Eletroencefalografia , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa , Fatores de Tempo , Adulto Jovem
8.
Elife ; 82019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30648533

RESUMO

Our ability to rapidly detect threats is thought to be subserved by a subcortical pathway that quickly conveys visual information to the amygdala. This neural shortcut has been demonstrated in animals but has rarely been shown in the human brain. Importantly, it remains unclear whether such a pathway might influence neural activity and behavior. We conducted a multimodal neuroimaging study of 622 participants from the Human Connectome Project. We applied probabilistic tractography to diffusion-weighted images, reconstructing a subcortical pathway to the amygdala from the superior colliculus via the pulvinar. We then computationally modeled the flow of haemodynamic activity during a face-viewing task and found evidence for a functionally afferent pulvinar-amygdala pathway. Critically, individuals with greater fibre density in this pathway also had stronger dynamic coupling and enhanced fearful face recognition. Our findings provide converging evidence for the recruitment of an afferent subcortical pulvinar connection to the amygdala that facilitates fear recognition. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

9.
J Vis ; 19(1): 3, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30630191

RESUMO

Neural processing of sensory input in the brain takes time, and for that reason our awareness of visual events lags behind their actual occurrence. One way the brain might compensate to minimize the impact of the resulting delays is through extrapolation. Extrapolation mechanisms have been argued to underlie perceptual illusions in which moving and static stimuli are mislocalised relative to one another (such as the flash-lag and related effects). However, where in the visual hierarchy such extrapolation processes take place remains unknown. Here, we address this question by identifying monocular and binocular contributions to the flash-grab illusion. In this illusion, a brief target is flashed on a moving background that reverses direction. As a result, the perceived position of the target is shifted in the direction of the reversal. We show that the illusion is attenuated, but not eliminated, when the motion reversal and the target are presented dichoptically to separate eyes. This reveals extrapolation mechanisms at both monocular and binocular processing stages contribute to the illusion. We interpret the results in a hierarchical predictive coding framework, and argue that prediction errors in this framework manifest directly as perceptual illusions.


Assuntos
Percepção de Movimento/fisiologia , Ilusões Ópticas/fisiologia , Visão Binocular/fisiologia , Visão Monocular/fisiologia , Vias Visuais/fisiologia , Adulto , Análise de Variância , Humanos , Estimulação Luminosa/métodos
10.
Hum Brain Mapp ; 40(2): 529-537, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30251761

RESUMO

Widespread white matter connectivity disruptions have commonly been reported in schizophrenia. However, it is questionable whether structural connectivity decline is specifically associated with schizophrenia or whether it extends along a continuum of psychosis into the healthy population. Elucidating brain structure changes associated with psychotic-like experiences in healthy individuals is insofar important as it is a necessary first step towards our understanding of brain pathology preceding florid psychosis. High resolution, multishell diffusion-weighted magnetic resonance images (MRI) were acquired from 89 healthy individuals. Whole-brain white matter fibre tracking was performed to quantify the strength of white matter connections. Network-based statistics were applied to white matter connections in a regression model in order to test for a linear relationship between streamline count and psychotic-like experiences. A significant subnetwork was identified whereby streamline count declined with increasing psychotic-like experiences. This network of structural connectivity reductions affected all cortical lobes, subcortical structures and the cerebellum and spanned along prominent association and commissural white matter pathways. A widespread network of linearly declining connectivity strength with increasing number of psychotic-like experiences was identified in healthy individuals. This finding is in line with white matter connectivity reductions reported from early to chronic stages of schizophrenia and might therefore aid the development of tools to identify individuals at risk of transitioning to psychosis.

11.
Neuroimage ; 190: 154-171, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30195053

RESUMO

The 22q11.2 deletion is one of the most common copy number variants in humans. Carriers of the deletion have a markedly increased risk for neurodevelopmental brain disorders, including schizophrenia, autism spectrum disorders, and attention deficit hyperactivity disorder. The high risk of psychiatric disorders associated with 22q11.2 deletion syndrome offers a unique possibility to identify the functional abnormalities that precede the emergence of psychosis. Carriers of a 22q11.2 deletion show a broad range of sensory processing and cognitive abnormalities similar as in schizophrenia, such as auditory and visual sensory processing, response inhibition, working memory, social cognition, reward processing and arithmetic processing. All these processes have a significant negative impact on daily life if impaired and have been studied extensively in schizophrenia using task-based functional neuroimaging. Here, we review task-related functional brain mapping studies that have used electroencephalography or functional magnetic resonance imaging to identify functional alterations in carriers with 22q11.2 deletion syndrome within the above mentioned cognitive and sensory domains. We discuss how the identification of functional changes at the brain system level can advance the general understanding of which neurobiological alterations set the frame for the emergence of neurodevelopmental disorders in the human brain. The task-based functional neuroimaging literature shows conflicting results in many domains. Nevertheless, consistent similarities between 22q11.2 deletion syndrome and schizophrenia have been found for sensory processing, social cognition and working memory. We discuss these functional brain alterations in terms of potential biomarkers of increased risk for psychosis in the general population.


Assuntos
Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Síndrome de DiGeorge/fisiopatologia , Potenciais Evocados/fisiologia , Neuroimagem Funcional , Transtornos da Percepção/fisiopatologia , Esquizofrenia/fisiopatologia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Síndrome de DiGeorge/complicações , Síndrome de DiGeorge/diagnóstico por imagem , Suscetibilidade a Doenças/diagnóstico por imagem , Suscetibilidade a Doenças/fisiopatologia , Humanos , Transtornos da Percepção/diagnóstico por imagem , Transtornos da Percepção/etiologia , Esquizofrenia/diagnóstico por imagem
12.
Int J Womens Health ; 10: 783-795, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568515

RESUMO

Introduction: The VEGF family has been identified as abnormal in preeclampsia (PE). Hypertensive disorders of pregnancy (HDP) are major contributors to maternal and neonatal morbidity and mortality worldwide; likewise, umbilical cord anatomical abnormalities (UCAA) are linked to poor neonatal outcomes. Based on the relationship described between PE and UCAA and the role of the VEGF family in PE, this study explored VEGF expression in placental and UC tissued from patients with PE and with UCAA. Methods: We performed an observational, analytical study on placentas, comparing protein and mRNA expression in four groups: patients with PE, patients with UC abnormalities, patients with both, and patients with none of them. Using immunohistochemistry, we studied VEGF A, VEGF R1 (FLT1), MMP1, and PLGF. With quantitative reverse transcription polymerase chain reaction we described mRNA expression of PLGF, VEGF and sFLT1, and sFLT1/PLGF ratio. Results: Forty newborns were included. Sixty-seven percent of mothers and 45% of newborns developed no complications. Immunohistochemistry was performed on UC and placental disc paraffin-embedded tissue; in the latter, the mRNA of the VEGF family was also measured. Statistically significant differences were observed among different expressions in both HDP and UCAA groups. Interestingly, the UCAA group exhibited lower levels of sFLT1 and VEGF-A in comparison with other groups, with significant P-value for sFLT1 (P=0000.1). Conclusion: The origin of UCAA abnormalities and their relation with HDP are still unknown. VEGF family alterations could be involved in both. This study provides the first approach related to molecules linked to UCAA.

13.
Front Neurosci ; 12: 598, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356864

RESUMO

Predictive coding postulates that we make (top-down) predictions about the world and that we continuously compare incoming (bottom-up) sensory information with these predictions, in order to update our models and perception so as to better reflect reality. That is, our so-called "Bayesian brains" continuously create and update generative models of the world, inferring (hidden) causes from (sensory) consequences. Neuroimaging datasets enable the detailed investigation of such modeling and updating processes, and these datasets can themselves be analyzed with Bayesian approaches. These offer methodological advantages over classical statistics. Specifically, any number of models can be compared, the models need not be nested, and the "null model" can be accepted (rather than only failing to be rejected as in frequentist inference). This methodological paper explains how to construct posterior probability maps (PPMs) for Bayesian Model Selection (BMS) at the group level using electroencephalography (EEG) or magnetoencephalography (MEG) data. The method has only recently been used for EEG data, after originally being developed and applied in the context of functional magnetic resonance imaging (fMRI) analysis. Here, we describe how this method can be adapted for EEG using the Statistical Parametric Mapping (SPM) software package for MATLAB. The method enables the comparison of an arbitrary number of hypotheses (or explanations for observed responses), at each and every voxel in the brain (source level) and/or in the scalp-time volume (scalp level), both within participants and at the group level. The method is illustrated here using mismatch negativity (MMN) data from a group of participants performing an audio-spatial oddball attention task. All data and code are provided in keeping with the Open Science movement. In doing so, we hope to enable others in the field of M/EEG to implement our methods so as to address their own questions of interest.

14.
Front Neural Circuits ; 12: 43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875638

RESUMO

Predictive coding postulates that the brain continually predicts forthcoming sensory events based on past experiences in order to process sensory information and respond to unexpected events in a fast and efficient manner. Predictive coding models in the context of overt speech are believed to operate along auditory white matter pathways such as the arcuate fasciculus and the frontal aslant. The aim of this study was to investigate whether brain regions that are structurally connected via these white matter pathways are also effectively engaged when listening to externally-generated, temporally-predicable speech sounds. Using Electroencephalography (EEG) and Dynamic Causal Modeling (DCM) we investigated network models that are structurally connected via the arcuate fasciculus from primary auditory cortex to Wernicke's and via Geschwind's territory to Broca's area. Connections between Broca's and supplementary motor area, which are structurally connected by the frontal aslant, were also included. The results revealed that bilateral areas interconnected by indirect and direct pathways of the arcuate fasciculus, in addition to regions interconnected by the frontal aslant best explain the EEG responses to speech that is externally-generated but temporally predictable. These findings indicate that structurally connected brain regions involved in the production and processing of auditory stimuli are also effectively connected.


Assuntos
Córtex Auditivo/fisiologia , Mapeamento Encefálico , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Fala/fisiologia , Adolescente , Adulto , Eletroencefalografia/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino , Adulto Jovem
15.
Leukemia ; 32(10): 2211-2223, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29511289

RESUMO

Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and ß-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex. Blocking PP1 activity, both pharmacologically and genetically, resulted in TAK1 hyperphosphorylation at residues T344, S389, T444, and T511, which have functional impact on canonical NF-κB signaling. Inhibition of TAK1 precluded NF-κB and ß-catenin signaling and induced apoptosis of CTCL cell lines and primary Sézary syndrome cells both in vitro and in vivo. Detection of phosphorylated TAK1 at T444 and T344 is associated with the presence of lymphoma in a set of 60 primary human samples correlating with NF-κB and ß-catenin activation. These results identified TAK1 as a potential biomarker and therapeutic target for CTCL therapy.


Assuntos
Linfoma Cutâneo de Células T/metabolismo , MAP Quinase Quinase Quinases/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Neoplasias Cutâneas/metabolismo , beta Catenina/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Humanos , Camundongos , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosforilação/fisiologia , Receptores de Neuropeptídeo Y/metabolismo , Síndrome de Sézary/metabolismo
16.
Schizophr Res ; 197: 328-336, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29395612

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is one of the most common copy number variants and confers a markedly increased risk for schizophrenia. As such, 22q11.2DS is a homogeneous genetic liability model which enables studies to delineate functional abnormalities that may precede disease onset. Mismatch negativity (MMN), a brain marker of change detection, is reduced in people with schizophrenia compared to healthy controls. Using dynamic causal modelling (DCM), previous studies showed that top-down effective connectivity linking the frontal and temporal cortex is reduced in schizophrenia relative to healthy controls in MMN tasks. In the search for early risk-markers for schizophrenia we investigated the neural basis of change detection in a group with 22q11.2DS. We recorded high-density EEG from 19 young non-psychotic 22q11.2 deletion carriers, as well as from 27 healthy non-carriers with comparable age distribution and sex ratio, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Despite finding no significant reduction in the MMN responses, whole-scalp spatiotemporal analysis of responses to the tones revealed a greater fronto-temporal N1 component in the 22q11.2 deletion carriers. DCM showed reduced intrinsic connection within right primary auditory cortex as well as in the top-down, connection from the right inferior frontal gyrus to right superior temporal gyrus for 22q11.2 deletion carriers although not surviving correction for multiple comparison. We discuss these findings in terms of reduced adaptation and a general increased sensitivity to tones in 22q11.2DS.


Assuntos
Percepção Auditiva/fisiologia , Síndrome de DiGeorge/fisiopatologia , Potenciais Evocados Auditivos/fisiologia , Córtex Pré-Frontal/fisiopatologia , Lobo Temporal/fisiopatologia , Adolescente , Adulto , Córtex Auditivo/fisiopatologia , Criança , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Masculino , Modelos Teóricos , Análise Espaço-Temporal , Adulto Jovem
17.
FASEB J ; 32(7): 3878-3891, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29465313

RESUMO

CD5-like (CD5L) is a soluble scavenger cysteine-rich protein that modulates inflammatory responses. We studied the involvement of CD5L in liver cancer. Immunohistochemistry (IHC) of CD5L in 60 hepatocellular carcinomas and 34 adjacent nontumor livers, showed that CD5L staining was higher in tumor than in nontumor tissue (Mann-Whitney test; P = 0.0039). High CD5L correlated with elevated proliferation (Ki67, linear regression; P < 0.0001) and lower patient event-free survival (log-rank; P = 0.0185). Accordingly, CD5L expression was detected in the liver cancer cell lines Huh7, HepG2, and SNU-398. In vitro technologies using these cell lines, including small interfering RNA (siRNA) and cDNA transfection, showed that CD5L promoted colony formation and cell proliferation and protected against cisplatin-induced apoptosis. To find a molecular explanation for these roles, novel CD5L-interacting protein ligands in liver cancer cells were identified by immunoprecipitation followed by mass spectrometry. Among these, the molecular chaperone of the unfolded protein response (UPR), heat shock protein (HSP)-A5, was selected for validation. The interaction was confirmed by confocal microscopy in the Huh7 and HepG2 cell lines. Furthermore, functional experiments revealed that CD5L activates the UPR and autophagy mechanisms in Huh7 cells, thereby providing a novel molecular link between the UPR and autophagy in liver cancer.-Aran, G., Sanjurjo, L., Bárcena, C., Simon-Coma, M., Téllez, É., Vázquez-Vitali, M., Garrido, M., Guerra, L., Díaz, E., Ojanguren, I., Elortza, F., Planas, R., Sala, M., Armengol, C., Sarrias, M.-R. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).


Assuntos
Apoptose , Carcinoma Hepatocelular/metabolismo , Proliferação de Células , Neoplasias Hepáticas/metabolismo , Receptores Depuradores Classe B/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Proteínas de Choque Térmico/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Receptores Depuradores Classe B/genética , Resposta a Proteínas não Dobradas , Regulação para Cima
18.
Cereb Cortex ; 28(5): 1771-1782, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28402428

RESUMO

Predictive coding posits that the human brain continually monitors the environment for regularities and detects inconsistencies. It is unclear, however, what effect attention has on expectation processes, as there have been relatively few studies and the results of these have yielded contradictory findings. Here, we employed Bayesian model comparison to adjudicate between 2 alternative computational models. The "Opposition" model states that attention boosts neural responses equally to predicted and unpredicted stimuli, whereas the "Interaction" model assumes that attentional boosting of neural signals depends on the level of predictability. We designed a novel, audiospatial attention task that orthogonally manipulated attention and prediction by playing oddball sequences in either the attended or unattended ear. We observed sensory prediction error responses, with electroencephalography, across all attentional manipulations. Crucially, posterior probability maps revealed that, overall, the Opposition model better explained scalp and source data, suggesting that attention boosts responses to predicted and unpredicted stimuli equally. Furthermore, Dynamic Causal Modeling showed that these Opposition effects were expressed in plastic changes within the mismatch negativity network. Our findings provide empirical evidence for a computational model of the opposing interplay of attention and expectation in the brain.


Assuntos
Atenção/fisiologia , Teorema de Bayes , Mapeamento Encefálico , Encéfalo/fisiologia , Modelos Neurológicos , Estimulação Acústica , Adulto , Percepção Auditiva/fisiologia , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Valor Preditivo dos Testes , Psicoacústica , Adulto Jovem
19.
Oncotarget ; 8(59): 99261-99273, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245899

RESUMO

Cyclin O (encoded by CCNO) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous CCNO mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of Ccno in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus. To further investigate the functions of Ccno in vivo, we have generated a new mouse model characterized by the constitutive loss of Ccno in all tissues and followed a cohort during ageing. Ccno-/- mice were growth impaired and developed hydrocephalus with high penetrance. In addition, some Ccno+/- mice also developed hydrocephalus and affected Ccno-/- and Ccno+/- mice exhibited additional CNS defects including cortical thinning and hippocampal abnormalities. In addition to the CNS defects, both male and female Ccno-/- mice were infertile and female mice exhibited few motile cilia in the oviduct. Our results further establish CCNO as an important gene for normal development and suggest that heterozygous CCNO mutations could underlie hydrocephalus or diminished fertility in some human patients.

20.
Biol Psychiatry ; 82(6): 447-454, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28838469

RESUMO

BACKGROUND: Anxious hypervigilance is marked by sensitized sensory-perceptual processes and attentional biases to potential danger cues in the environment. How this is realized at the neurocomputational level is unknown but could clarify the brain mechanisms disrupted in psychiatric conditions such as posttraumatic stress disorder. Predictive coding, instantiated by dynamic causal models, provides a promising framework to ground these state-related changes in the dynamic interactions of reciprocally connected brain areas. METHODS: Anxiety states were elicited in healthy participants (n = 19) by exposure to the threat of unpredictable, aversive shocks while undergoing magnetoencephalography. An auditory oddball sequence was presented to measure cortical responses related to deviance detection, and dynamic causal models quantified deviance-related changes in effective connectivity. Participants were also administered alprazolam (double-blinded, placebo-controlled crossover) to determine whether the cortical effects of threat-induced anxiety are reversed by acute anxiolytic treatment. RESULTS: Deviant tones elicited increased auditory cortical responses under threat. Bayesian analyses revealed that hypervigilant responding was best explained by increased postsynaptic gain in primary auditory cortex activity as well as modulation of feedforward, but not feedback, coupling within a temporofrontal cortical network. Increasing inhibitory gamma-aminobutyric acidergic action with alprazolam reduced anxiety and restored feedback modulation within the network. CONCLUSIONS: Threat-induced anxiety produced unbalanced feedforward signaling in response to deviations in predicable sensory input. Amplifying ascending sensory prediction error signals may optimize stimulus detection in the face of impending threats. At the same time, diminished descending sensory prediction signals impede perceptual learning and may, therefore, underpin some of the deleterious effects of anxiety on higher-order cognition.


Assuntos
Ansiedade/fisiopatologia , Percepção Auditiva/fisiologia , Encéfalo/fisiopatologia , Medo/fisiologia , Adulto , Alprazolam/farmacologia , Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Percepção Auditiva/efeitos dos fármacos , Teorema de Bayes , Encéfalo/efeitos dos fármacos , Medo/efeitos dos fármacos , Feminino , Moduladores GABAérgicos/farmacologia , Humanos , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Modelos Neurológicos , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Processamento de Sinais Assistido por Computador , Ácido gama-Aminobutírico/metabolismo
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