Brain network alterations in Attention-Deficit and Hyperactivity Disorder: towards an integrative perspective based on systems neuroscience

Mención Internacional en el título de doctorAttention-Deficit and Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, affecting mainly the school-age population but also having a moderate prevalence rate into adulthood. It is characterized by symptoms of inattention, impulsivity, and hyperactivity improper for the patient’s age. However, this agedependent characterization of ADHD makes the diagnosis such a problematic issue: the maturation rate is different for each child, making the evaluation of what is age-proper a subjective and difficult question. All of this leads to the ubiquitous question of ADHD, namely, whether there is overdiagnosis of the disease or if it even exists. That is why studying the brain is crucial in ADHD, because finding effective biomarkers able to characterize the disease will allow us to diagnose it more accurately. Magnetic Resonance Imaging (MRI) is one of the most powerful and versatile tools for studying the brain, providing information about both its structure and activity. Traditional MRI studies have focused on analyzing properties of specific brain regions in terms of their shape (e.g., the volume of a structure) or their relation with a cognitive function (e.g., if a structure activates during object recognition), finding multiple alterations in ADHD [8]. However, these widespread regions that present abnormalities are connected between them and with other areas forming the brain network, and their alterations may indeed represent different parts of a more global phenomenon [8, 9]. There are four main neurobiological models that explain ADHD: the maturational lag hypothesis, the dual-pathway model, the Default Mode Network (DMN) interference hypothesis, and multinetwork models. The maturational lag hypothesis is based on ADHD diagnostic criteria and posits that the brain of people with this condition will resemble a younger one [10]. The dual-pathway model proposes two different processing streams for the main symptoms of ADHD: inattention is related to alterations in the corticostriatal executive circuits, while impulsivity/hyperactivity is associated with abnormalities in emotional processing [11, 12]. The DMN interference hypothesis posits that this functional network is not properly suppressed during goal-directed tasks, which is translated into intrusion of inner mental activity [13]. Finally, multinetwork models approach the neurobiology of people with ADHD as an alteration of multiple functional networks [14, 15]. All of these models have received substantial support from neuroimaging studies, which suggests that all of them are correct but incomplete descriptions of the brain profile of people with ADHD. The present dissertation aims to determine whether there is an alteration of the global brain organization in people with ADHD that may underlie the features that characterize the different neurobiological models of the disorder. For that, we will apply two different graph-theory methods based on systems science to the restingstate functional Magnetic Resonance Imaging data of adults and children with ADHD. The two proposed metrics are Stepwise Functional Connectivity (SFC) and Local and Distant Functional Connectivity (LFC and DFC). The first one measures the integration of information from sensory cortices to areas related to high-order cognitive functions, and in Study 1 [16], it will be applied to a sample of medication-naïve adults with ADHD. LFC and DFC study topological properties with physical distance restrictions, that is, the level of connectivity of each voxel with those around it or those far away. This method will be applied to a sample of children with ADHD in Study 2 [17] and the same sample of adults used in Study 1 in Study 3 [18]. Our results consist of alterations in widespread regions that overlap with most functional networks [19]. Specifically, in adults with ADHD, we observed a decrease in integration in the DMN that locally affects the Posterior Cingulate Cortex and its functional connectivity with the medial Prefrontal Cortex. Additionally, the integration of sensory information in these areas was also found to be reduced in the same sample. The integration of the DMN and its development into cortical hubs is a crucial process in the maturation of the brain [20], which relates this finding with a maturational lag. In both children and adults with ADHD, we also observed a lack of segregation between the DMN, the Ventral Attentional Network, and the Frontoparietal Network in a frontal area of the brain. The developmental trajectory of this area consists of the differentiation of three regions, each of them pertaining to one of these networks [21], and thus, it is a sign of brain immaturity. Also, overconnectivity (lack of segregation) between these networks underlies the DMN interference hypothesis and is indeed a multinetwork alteration [14, 22]. We also found abnormalities in the Visual Network in the form of increased integration of information in these areas while decreased local functional integration of the region, which reflects a behavior more typical of associative than sensory cortices [23, 24]. Finally, local connectivity of sensorimotor cortices presents different maturation trends between ADHD and controls while predicting ADHD symptomatology in all of them. In conclusion, our results suggest that for understanding ADHD, we cannot focus just on a few areas related to high-order cognitive functions, but the whole brain functional network is compromised. This goes in line with a recent meta-analysis [8] that was unable to find convergence in specific regions abnormalities and proposed an analysis based on network interactions. Altogether, this dissertation reflects the need to approach ADHD from a systems neuroscience perspective that encompasses all the currently available models instead of proposing alternative reductionist ones.Programa de Doctorado en Ciencia y Tecnología Biomédica por la Universidad Carlos III de MadridPresidente: Juan Domingo Gispert López.- Secretario: Carles Soriano Mas.- Vocal: Óscar Esteban Sanz-Drangue

Conformidad estructural de arquitecturas combinado con análisis de impacto de cambios

La conformidad de arquitecturas de software es una práctica que permite mantener la estructura arquitectónica alineada y consistente con su implementación en código. Entre otros beneficios, este alineamiento permite a los arquitectos y desarrolladores realizar distintos análisis de la solución desde etapas tempranas (por ej., de performance, o de modificabilidad, entre otros). Para esto, deben verificarse periódicamente las relaciones entre los elementos arquitectónicos y sus contrapartes en el código fuente, a fin de detectar posibles violaciones de la arquitectura. Las técnicas y herramientas existentes para conformidad arquitectónica proveen un buen soporte para verificar relaciones de tipo estructural. Sin embargo, ciertos análisis que son útiles a nivel arquitectónico, como es el caso del impacto de cambios (CIA, Change Impact Analysis), son difíciles de verificar en relación al código fuente, lo cuál genera una brecha entre las suposiciones y conclusiones que se hacen a nivel arquitectónica y la implementacioón actual del sistema. Este trabajo presenta un enfoque que extiende las reglas básicas de conformidad estructural con reglas que permiten contemplar suposiciones de CIA con el fin de validarlas en la implementación de la arquitectura. En particular, se propone una herramienta que integra un CIA en base a escenarios de modificabilidad con el modelo de reflexión de Murphy & Notkin. Los resultados, si bien son preliminares, indican que este enfoque permite identificar distintos tipos de violaciones arquitectónicas.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Conformidad estructural de arquitecturas combinado con análisis de impacto de cambios

La conformidad de arquitecturas de software es una práctica que permite mantener la estructura arquitectónica alineada y consistente con su implementación en código. Entre otros beneficios, este alineamiento permite a los arquitectos y desarrolladores realizar distintos análisis de la solución desde etapas tempranas (por ej., de performance, o de modificabilidad, entre otros). Para esto, deben verificarse periódicamente las relaciones entre los elementos arquitectónicos y sus contrapartes en el código fuente, a fin de detectar posibles violaciones de la arquitectura. Las técnicas y herramientas existentes para conformidad arquitectónica proveen un buen soporte para verificar relaciones de tipo estructural. Sin embargo, ciertos análisis que son útiles a nivel arquitectónico, como es el caso del impacto de cambios (CIA, Change Impact Analysis), son difíciles de verificar en relación al código fuente, lo cuál genera una brecha entre las suposiciones y conclusiones que se hacen a nivel arquitectónica y la implementacioón actual del sistema. Este trabajo presenta un enfoque que extiende las reglas básicas de conformidad estructural con reglas que permiten contemplar suposiciones de CIA con el fin de validarlas en la implementación de la arquitectura. En particular, se propone una herramienta que integra un CIA en base a escenarios de modificabilidad con el modelo de reflexión de Murphy & Notkin. Los resultados, si bien son preliminares, indican que este enfoque permite identificar distintos tipos de violaciones arquitectónicas.Sociedad Argentina de Informática e Investigación Operativa (SADIO

Epidemiología y pronóstico de los pacientes con VIH ingresados en la UCI en la era de tratamiento antirretroviral de gran actividad actual

Observational study[Abstract] Purpose: To describe the epidemiology of critical disease in HIV-infected patients during the current highly active antiretroviral therapy (HAART) era and to identify hospital mortality predictors. Methods: A longitudinal, retrospective observational study was made of HIV-infected adults admitted to the ICU in two Spanish hospitals between 1 January 2000 and 31 December 2014. Demographic and HIV-related variables were analyzed, together with comorbidities, severity scores, reasons for admission and need for organ support. The chi-squared test was used to compare categorical variables, while continuous variables were contrasted with the Student's t-test, Mann-Whitney U-test or Kruskal-Wallis test, assuming an alpha level=0.05. Multivariate logistic regression analysis was used to calculate odds ratios for assessing correlations to mortality during hospital stay. Joinpoint regression analysis was used to study mortality trends over time. Results: A total of 283 episodes were included for analyses. Hospital mortality was 32.9% (95%CI: 21.2-38.5). Only admission from a site other than the Emergency Care Department (OR 3.64, 95%CI: 1.30-10.20; p=0.01), moderate-severe liver disease (OR 5.65, 95%CI: 1.11-28.87; p=0.04) and the APACHE II score (OR 1.14, 95%CI: 1.04-1.26; p<0.01) and SOFA score at 72h (OR 1.19, 95%CI: 1.02-1.40; p=0.03) maintained a statistically significant relationship with hospital mortality. Conclusions: Delayed ICU admission, comorbidities and the severity of critical illness determine the prognosis of HIV-infected patients admitted to the ICU. Based on these data, HIV-infected patients should receive the same level of care as non-HIV-infected patients, regardless of their immunological or nutritional condition.[Resumen] Objetivos. Describir la epidemiología de la patología crítica en el paciente infectado por VIH durante la era de tratamiento antirretroviral de gran actividad actual y encontrar predictores de mortalidad hospitalaria. Métodos. Estudio observacional, retrospectivo y longitudinal que incluye pacientes infectados por VIH adultos ingresados en las UCI de hospitales de Galicia, entre el 1 de enero de 2000 y el 31 de diciembre de 2014. Analizamos variables demográficas y relacionadas con la infección por el VIH, comorbilidades, puntuaciones de gravedad, motivo de ingreso y necesidad de soporte de órganos. Empleamos la prueba de la Chi-cuadrado para comparar las variables categóricas y las pruebas de la T-Student, U de Mann-Whitney o H de Kruskal-Wallis para las variables continuas, asumiendo un error α = 0,05. Utilizamos la regresión logística multivariante para calcular la OR de la asociación con la mortalidad hospitalaria. Aplicamos análisis de regresión de joinpoint para estudiar la tendencia temporal de mortalidad. Resultados. Incluimos 283 episodios. La mortalidad hospitalaria fue del 32,9% (IC 95% = 21,2-38,5%). El ingreso no procedente de Urgencias (OR 3,64; IC 95% = 1,30-10,20; p = 0,01), la enfermedad hepática moderada-grave (OR 5,65; IC 95% = 1,11-28,87; p = 0,04), el APACHE II (OR 1,14; IC 95% = 1,04-1,26; p < 0,01) y el SOFA a las 72 h (OR 1,19; IC 95% = 1,02-1,40; p = 0,03) se relacionan con la mortalidad hospitalaria en el análisis multivariante. Conclusiones. El retraso en el ingreso en UCI, las comorbilidades y la gravedad del episodio determinan el pronóstico del paciente infectado por VIH ingresado en UCI. Los pacientes con VIH deberían recibir el mismo nivel de cuidados que los pacientes no infectados por VIH, independientemente de su estado inmunológico o nutricional

A label-free optical system with a nanohole array biosensor for discriminating live single cancer cells from normal cells

Developing a simple, fast, and label-free method for discrimination between live cancer cells and normal cells in biological samples still remains a challenge. Here, a system is described that fulfills these features to analyze individual living cells. The system consists of a gold nanohole array biosensor plus a microscope optical design to isolate the spectral response of a single cell. It is demonstrated that differences in the spectral behavior between tumor (colorectal cancer cell lines and primary cells from colorectal cancer tissue) and non-tumor cells (peripheral blood mononuclear cells, skin fibroblasts and colon epithelial cells) are influenced by the actin cortex, which lies within the short penetration depth of the surface plasmon electromagnetic field. The efficacy of this system was assessed by the analysis of about one thousand single cells showing the highest discrimination capacity between normal colon epithelial cells and colorectal cancer cells from surgical specimens, with values of sensitivity and specificity ranging 80-100% and 87-100%, respectively. It is also demonstrated that cell discrimination capacity of the system is highly reduced by disrupting the formation of actin cortex. This plasmonic system may find wide applications in biomedicine and to study key cellular processes that involve the actin cortex, including proliferation, differentiation, and migration.This work was supported by the Instituto de Salud Carlos III through grant DTS18/00141, co-funded by European Regional Development Fund/ European Social Fund “A way to make Europe/Investing in your future” and Instituto de Investigación Valdecilla (IDIVAL) (APG/03)

ABLE: Automated Brain Lines Extraction Based on Laplacian Surface Collapse.

The archetypical folded shape of the human cortex has been a long-standing topic for neuroscientific research. Nevertheless, the accurate neuroanatomical segmentation of sulci remains a challenge. Part of the problem is the uncertainty of where a sulcus transitions into a gyrus and vice versa. This problem can be avoided by focusing on sulcal fundi and gyral crowns, which represent the topological opposites of cortical folding. We present Automated Brain Lines Extraction (ABLE), a method based on Laplacian surface collapse to reliably segment sulcal fundi and gyral crown lines. ABLE is built to work on standard FreeSurfer outputs and eludes the delineation of anastomotic sulci while maintaining sulcal fundi lines that traverse the regions with the highest depth and curvature. First, it segments the cortex into gyral and sulcal surfaces; then, each surface is spatially filtered. A Laplacian-collapse-based algorithm is applied to obtain a thinned representation of the surfaces. This surface is then used for careful detection of the endpoints of the lines. Finally, sulcal fundi and gyral crown lines are obtained by eroding the surfaces while preserving the connectivity between the endpoints. The method is validated by comparing ABLE with three other sulcal extraction methods using the Human Connectome Project (HCP) test-retest database to assess the reproducibility of the different tools. The results confirm ABLE as a reliable method for obtaining sulcal lines with an accurate representation of the sulcal topology while ignoring anastomotic branches and the overestimation of the sulcal fundi lines. ABLE is publicly available via https://github.com/HGGM-LIM/ABLE .This work was supported by the project exAScale ProgramIng models for extreme Data procEssing (ASPIDE), that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 801091. This work has received funding from “la Caixa” Foundation under the project code LCF/PR/HR19/52160001. Susanna Carmona funded by Instituto de Salud Carlos III, co-funded by European Social Fund “Investing in your future” (Miguel Servet Type I research contract CP16/00096). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Yasser Alemán-Gómez is supported by the Swiss National Science Foundation (185897) and the National Center of Competence in Research (NCCR) SYNAPSY - The Synaptic Bases of Mental Diseases, funded as well by the Swiss National Science Foundation (51AU40-1257).S

Introducción de la gammificación como herramienta docente en la asignatura de Farmacología dentro del Grado de Odontología

Fac. de OdontologíaFALSEsubmitte

Liquid biopsy: a non-invasive approach for Hodgkin lymphoma genotyping

The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an alternative tool for non-invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1–23) with a median variant allele frequency of 4·2% (0·84–28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B-symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010)”, the Health Council of the Junta de Castilla y León (GRS2037/A/19) (GRS1845/A/18) and private Gilead (GLD/18/00063). MGA is supported with a grant from the Accelerator consortia (Cancer Research UK; C355/A26819). CJ and AM are supported by the ISCII (CD19/00030 and FI19/00320). MES is supported by Contrato Miguel Servet tipo II (CPII18/00028). MA is financed by CIBER-CB16/12/00233. All Spanish funding is co-sponsored by the European Union FEDER program

Bypass and hyperbole in soil science:A perspective from the next generation of soil scientists

International audienceWe, the co‐authors of this letter, are an international group of soil scientists at early career stages, from PhD students to postdoctoral researchers, lecturers, and research fellows with permanent positions. Here, we present our collective musings on soil research challenges and opportunities and, in particular, the points raised by Philippe Baveye (Baveye, 2020a, 2020b) and Johan Bouma (Bouma, 2020) on bypass and hyperbole in soil science. Raising awareness about these issues is a first and necessary step. To this end, we would like to thank Philippe Baveye and Johan Bouma for initiating this debate.......