The research performed in this thesis aims to improve our understanding about one of the most malignant tumors of the human brain – glioma. From the early stages of my career I was confronted with the cruel reality of losing patients due to this devastating disease. The studies performed over the last four years involve extensive data analysis in different clinical and laboratory settings. The direct application of different analysis methods and tools in order to investigate the glioma infiltration delineation has potentially lead to direct applications of our results in the clinical setting. The overall approach of the study is based on three primary outcome measures, i.e., neuronal, electrophysiological and genetic/molecular features for distinguishing infiltrated and non-infiltrated zones within specifically peritumoral tissue (PT) and, more extensively, across the radiologically-defined boundaries of healthy, peritumoral and tumoral tissues. As such, we propose for the first time an objective demarcation and characterization of the PT and we detail how the genetic and epigenetic alterations within the tumoral and peritumoral area are linked with macroscopic functional MRI results. We also describe scale-free features (power law exponent) as well as distinct spectral features and reactivity to external stimulus in the tumoral and adjacent tissue of patients and provide novel insights in terms of glioma’s electrophysiology. The insights gained from these empirical studies further improve our understanding about the pathophysiology of this disease at micro- and macroscopic scales allowing us to envisage novel management methods for patients affected by glioma.

A new mathematical model of short-term synaptic plasticity (STP) at the Schaffer collateral is introduced. Like other models of STP, the new model relates short-term synaptic plasticity to an interaction between facilitative and depressive dynamic influences. Unlike previous models, the new model successfully simulates facilitative and depressive dynamics within the framework of the synaptic vesicle cycle. The novelty of the model lies in the description of a competitive interaction between calcium-sensitive proteins for binding sites on the vesicle release machinery. By attributing specific molecular causes to observable presynaptic effects, the new model of STP can predict the effects of specific alterations to the presynaptic neurotransmitter release mechanism. This understanding will guide further experiments into presynaptic functionality, and may contribute insights into the development of pharmaceuticals that target illnesses manifesting aberrant synaptic dynamics, such as Fragile-X syndrome and schizophrenia. The new model of STP will also add realism to brain circuit models that simulate cognitive processes such as attention and memory. The hippocampal processing loop is an example of a brain circuit involved in memory formation. The hippocampus filters and organizes large amounts of spatio-temporal data in real time according to contextual significance. The role of synaptic dynamics in the hippocampal system is speculated to help keep the system close to a region of instability that increases encoding capacity and discriminating capability. In particular, synaptic dynamics at the Schaffer collateral are proposed to coordinate the output of the highly dynamic CA3 region of the hippocampus with the phase-code in the CA1 that modulates communication between the hippocampus and the neocortex.

No description available.

Doctoral thesis assessing the effects of one-week of escitalopram administration on healthy humans during sequence motor learning training. Published in 3 research articles.

[ES] La Animación como Arte alquímico y práctica contemplativa mindfulness, es un potenciador de la transformación del "ser" y su consciencia, desarrollando la comunicación consciente y la autorregulación hacia el bienestar. A través del proceso creativo y alquímico de las películas animadas, se puede cultivar la atención plena y una visión holística, fomentando con ello el pensamiento crítico, reflexivo y creativo en busca de la coherencia en las historias que vivimos y las que recreamos. El objetivo principal de esta Tesis Doctoral, es mostrar a la comunidad, la animación como un lenguaje alternativo y práctica mediadora y preventiva, tanto para los individuos como para la sociedad, desde las Artes y la Educación, frente a la desinformación, desorientación y manipulación mediática que actualmente vivimos. La animación así concebida, favorece una mente despierta, atenta, sensible y equilibrada, con un corazón sabio y el animador, se convierte en un un artista chamánico consciente, en un alquimista, cuyo arte será mediador desde el individuo a la comunidad, estableciendo un diálogo abierto para el cuidado emocional y la autorreflexión. Nuestra perspectiva plantea un cambio, pasando de usar la animación como forma de entretenimiento, a utilizarla como una herramienta de aprendizaje neuro artístico, introduciendo aspectos de la Neurociencia en el proceso creativo y transformándola así en un arte neuro plástico, que promueve la neuroplasticidad autodirigida y la inteligencia emocional. Con esta metodología se estimulan valores como la compasión, la empatía y la resiliencia, donde el proceso alquímico de transformación individual, invita a realizar un viaje introspectivo y purificador, conectando la mente y el cuerpo, el individuo con el grupo y la comunidad con el mundo, a través de las historias animadas. Narrativas que pueden idear nuevos héroes y heroínas, independientes y compasivos, que nos ofrezcan otros modos de enfrentar los desafíos de la vida con humor y sabiduría. En el campo del arte en general y dentro de la industria del cine en particular, por el poder que el audiovisual tiene hoy en día sobre la población, es vital cultivar artistas conscientes de los contenidos que producen, por el impacto e influencia que ejercen en ellos mismos/as, y en la sociedad que los consume y cultura a la que los dirigen. La animación es un lenguaje ancestral y fuente de sabiduría que ofrece un espacio sagrado desde el yo para la comunicación e intercambio de información con el otro; puente entre la ciencia y el arte, lo visible y lo oculto, lo espiritual y lo terrenal, lo análogo y tecnológico, donde el límite lo pone solo la imaginación. Entrar en el mundo animado, es entrar en el mundo de los sueños y la Alquimia espiritual, donde todo es posible. / [CA] L'Animació com a Art alquímico i pràctica contemplativa mindfulness, és un potenciador de la transformació de el "ser" i la seua consciència, desenrollant la comunicació conscient i la autorregulación cap al benestar. A través del procés creatiu i alquímico de les películes animades, es pot cultivar l'atenció plena i una visió holística, fomentant en això el pensament crític, reflexiu i creatiu en busca de la coherència en les històries que vivim i les que recreem. L'objectiu principal d'esta Tesis Doctoral, és mostrar a la comunitat, l'animació com un llenguage alternatiu i pràctica mediadora i preventiva, tant per als individus com per a la societat, des de les Arts i l'Educació, front a la desinformació, desorientación i manipulació mediàtica que actualment vivim. L'animació aixina concebuda, favorix una ment desperta, atenta, sensible i equilibrada, en un cor sapient i l'animador, es convertix en un un artiste chamánico conscient, en un alquimiste, l'art del qual serà mediador des del individuo a la comunitat, establint un diàlec obert per al conte emocional i la autorreflexión. La nostra perspectiva planteja un canvi, passant d'usar l'animació com a forma d'entreteniment, a utilisar-la com una ferramenta d'aprenentage neuro artístic, introduint aspectes de la Neurociencia en el procés creatiu i transformant la aixina en un art neuro plàstic, que promou la neuroplasticidad autodirigida i l'inteligència emocional. En esta metodologia s'estimulen valors com la compassió, l'empatia i la resiliencia, a on el procés alquímico de transformació individual, invita a realisar un viage introspectivo i purificador, conectant la ment i el cos, l'individu en el grup i la comunitat en el món, a través de les històries animades. Narrativa que poden idear nous héroes i heroïnes, independents i compassius, que nos oferixquen atres modos d'enfrontar els desafius de la vida en humor i saber. En el camp de l'art en general i dins de l'indústria del cine en particular, pel poder que l'audiovisual té hui en dia sobre la població, és vital cultivar artistes conscients dels continguts que produïxen, per l'impacte i influència que eixercixen en ells mateixos/as, i en la societat que els consumix i cultura a la que els dirigixen. L'animació és un llenguage ancestral i font de saber que oferix un espai sagrat des del yo per a la comunicació i intercanvi d'informació en l'atre; pont entre la ciència i l'art, lo visible i lo amagat, lo espiritual i lo terrenal, lo anàlec i tecnològic, a on el llímit ho posa solament l'imaginació. Entrar en el món animat, és entrar en el món dels somis i l'Alquímia espiritual, a on tot és possible. / [EN] Animation as an alchemical art and mindfulness contemplative practice, is an enhancer of the transformation of the "self" and its consciousness, developing conscious communication and self-regulation towards well-being. Through the creative and alchemical process of animated films, mindfulness and a holistic vision can be cultivated, thereby fostering critical, reflective and creative thinking in search of coherence in the stories we live and those we recreate. The main objective of this Doctoral Thesis is to show the community, animation as an alternative language and mediating and preventive practice, both for individuals and for society, from the Arts and Education, against misinformation, disorientation and the media manipulation that we currently live. The animation thus conceived, favors an awake, attentive, sensitive and balanced mind, with a wise heart and the animator, becomes a conscious shamanic artist, an alchemist, whose art will mediate from the individual to the community, establishing an open dialogue for emotional care and self-reflection. Our perspective proposes a change, going from using animation as a form of entertainment, to using it as a neuro-artistic learning tool, introducing aspects of Neuroscience in the creative process and thus transforming it into a neuroplastic art, which promotes self-directed neuroplasticity and emotional intelligence. With this methodology, values such as compassion, empathy and resilience are stimulated, where the alchemical process of individual transformation invites us to go on an introspective and purifying journey, connecting the mind and the body, the individual with the group and the community with the world, through animated stories. Narratives that can create new heroes and heroines, independent and compassionate, that offer us other ways to face life's challenges with humor and wisdom. In the field of art in general and within the film industry in particular, due to the power that the audiovisual has today over the population, it is vital to cultivate artists who are aware of the content they produce, due to the impact and influence they exert on themselves, and in the society that consumes them and the culture to which they are directed. Animation is an ancient language and source of wisdom that offers a sacred space from the self for communication and exchange of information with the other; bridge between science and art, the visible and the hidden, the spiritual and the earthly, the analogous and technological, where the limit is set only by the imagination. Entering the animated world is entering the world of dreams and spiritual Alchemy, where everything is possible. / Carpe Pérez, IC. (2023). La animación, proceso alquímico y práctica contemplativa para la transformación y la comunicación consciente: Neuro Animáticas [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/193686

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

Bibliographic identification CHASÁKOVÁ, Ludmila. Utility of the "mirror therapy" in the treatment complex regional pain syndrome (type I). Prague: Charles University, 2nd Faculty of Medicine, Department of Rehabilitation and Sports Medicine, 2014. 105 s. Supervisor Mgr. Stanislav Machač. Annotation Objectives: Introduction of "mirror therapy" (MT) principles in patients with Type 1 complex regional pain syndrome (CRPS). Verification of the effectiveness of the MT in terms of sensory, functional and morphological changes. Participants: Sixteen patients (14 women and 2 men, age 55.3±10.5 years) and 10 controls (7 women and 3 men, age 54.9±7.6 years) were included in this study. All of them were diagnosed as patients with Type I CRPS. Methods and measure: The intervention group underwent 6 weeks of MT. Both groups recorded numerical scale pain for 6 weeks. At the beginning and end of the period, all probands underwent examination including: range of motion of wrist flexion and extension, thenar temperature side-to-side difference, volume of the hand and forearm, dynamometry, PegBoard, ability to close the fist, Wind-Up, referred sensations and EQ-5D-3L questionnaire. Results: A statistically significant reduction in pain at rest and during movement was found in the intervention group, not in the control group....

Cette thèse a comme objectif l’étude des processus de plasticité du réseau bulbo-spinal respiratoire après une lésion spinale cervicale unilatérale en C2, qui induit une interruption de la majorité des fibres respiratoires. Cette étude est réalisée par une approche de traçage de voies, couplée à une approche immunohistochimique, biochimique et électrophysiologique.La lésion latérale chronique induit dans la région sus-lésionnelle C1/C2 une diminution du nombre de fibres bulbo-spinales marquées et de la surface de la substance blanche. Nous observons cependant une augmentation du nombre de fibres repoussant dans la substance grise, y compris de terminaisons axonales, ainsi qu’une augmentation du nombre de neurones respiratoires se projetant vers les noyaux phréniques en C3/C4. Suite à la lésion, une sous-population de neurones respiratoires axotomisés exprime des marqueurs de réponse post-lésionnelle.Ces processus de plasticité pourraient contribuer à la récupération fonctionnelle. / The aim of this thesis was to study the anatomical and cellular plasticity processes of bulbospinal respiratory pathways after a unilateral cervical spinal injury C2, which leads to an interruption of the respiratory fibers. This study used an approach of anterograde and retrograde labeling, coupled with immunohistochemical, biochemical and electrophysiological methods.The chronic lateral lesion induced in sus-lesional area C1/C2 a decreased of number of bulbospinal fibers and a decreased white matter, but an increased number fibers sprouting in the gray matter, including axon terminals, and an increased number of respiratory neurons projecting to the phrenic nuclei in C3/C4. Following the lesion, a sub-population of axotomized respiratory neurons express markers of cell body post-lesion response. These processes of plasticity could contribute to functional recovery.

Une altération du métabolisme de l'homocystéine constitue un facteur de risque pour la survenue des maladies neurodégénératives. Par ailleurs, alors que les effets délétères d'une hypoxie néonatale sévère sont bien connus, il a été récemment montré qu'un épisode hypoxique modéré exerçait une neuroprotection via une stimulation de la neurogenèse. Notre objectif fut l'étude des conséquences cérébrales d'une carence précoce en donneurs de méthyles (folates, vitamine B12) combinée ou non à une stimulation hypoxie modérée. Un modèle in vivo de rats nés de mères carencées en donneurs de méthyles fut utilisé. Il a été étudié les mécanismes impliqués dans un modèle de progéniteurs neuronaux carencés. Les résultats ont montré des atteintes de l'intégrité tissulaire et fonctionnelle de l'hippocampe et du cervelet associée à des déficits comportementaux, à différents stades de la vie chez les animaux carencés malgré le retour à une alimentation standard au sevrage. Ces perturbations sont liées aux processus épigénétiques et à l'homocystéinylation de protéines neuronales. De plus, un dimorphisme sexuel est apparu en lien avec le récepteur nucléaire ER alpha. La neurogenèse issue de l'hypoxie a engendré des conséquences bénéfiques à long terme sur le vieillissement cérébral des rats mâles, avec un maintien de l'intégrité hippocampique. Enfin, la combinaison de la carence et de l'hypoxie, a montré que le conditionnement hypoxique améliorait le devenir tissulaire et fonctionnel du cerveau des animaux carencés. Les mécanismes clés surviendraient au cours de périodes critiques de maturation des différentes structures cérébrales, soulignant l'importance des processus de la programmation foetale / The alteration of homocysteine metabolism has been shown to constitute a risk factor for neurodegenerative diseases. Furthermore, whereas deleterious effects of severe neonatal hypoxia have been well documented, it was shown that a moderate episode of hypoxia can exert a neuroprotection with neurogenesis stimulation. Our main goal was to study the consequences on the brain of an early deficiency of methyl donors (folate, vitamin B12) with or without a hypoxia-related stimulation of neurogenesis. The effects of deficiency were investigated in rats born from dams fed a deficient diet until weaning. In vitro neuroprogenitors were additionally used for the study of cell mechanisms involved. Data showed alterations of tissue integrity in the hippocampus and the cerebellum, with associated behavioural deficits at various ages, despite a return to normal diet at weaning. Brain alterations were shown to be mainly related to epigenetic mechanisms and to homocysteinylation of specific neuronal proteins. Moreover, a sexual dimorphism was depicted, with the participation of ER alpha receptor. Neurogenesis induced in germinative zones by a brief neonatal hypoxia led to long term beneficial effects on brain aging in male rats, with preserved hippocampus integrity, in terms of cell density, synaptic plasticity, and related cognitive functions. Finally, the combination of deficiency and hypoxia revealed that brain conditioning by brief neonatal hypoxia was able to improve tissular and functional brain outcome in deficient rats. The key mechanisms involved would occur at critical periods during the maturation of the various brain structures, thus highlighting the role of fetal programming.