Developement of a procedure to calculate intracranial pressure by means of arterial blood pressure and blood flow velocity in a big cerebral artery. Methods of systems theory are used. / Entwicklung eines Verfahrens zur Berechnung des Hirndrucks aus dem Bludrucksignal und der Blutströmungsgeschwindigkeit in einer großen Hirnarterie. Es werden Methoden der Systemtheorie verwendet.

The origin and development of human cerebral asymmetries is yet a debated issue. One prominent manifestation of cerebral asymmetry is handedness with humans showing a dextral population bias. Handedness in humans is not fully established before the age of six. However, head turning preference in newborns is thought to be an important factor in the development of later handedness. If this head turning preference did not disappear completely during development but would prevail into adulthood it might, thus, be associated with handedness. Therefore, this study aimed to assess head turning preference in adults and to relate a possibly emerging bias to handedness. Forty-two adults (6 females, aged 23- 63, mean age = 35) participated in the study. Head turning preference was assessed by means of a move during Ju Jutsu martial arts training, which requires the trainee to move the head to either left or right. The direction of head movement is not specified for this move, leaving the choice to the trainee. Handedness was measured by the Edinburgh Handedness Inventory. Results did not reveal a profound head turning bias in adults. Contrary to the dextral bias in handedness, in this study a leftward bias in head turning emerged from those participants who showed a head turning preference. Head turning bias did not depend on handedness. The finding of a nearly absent and predominantly leftward head turning bias in this sample is discussed in the context of the Ju Jutsu task, training experience and trainer bias. It is concluded that the Ju Jutsu move is not a sufficient task to assess head turning preference in humans. Thus, to further illuminate the relation between head turning preference and handedness, studies are needed which assess head turning preference in adults in an un-trainable and unbiased situation.

Frontal EEG alpha asymmetry and its relation to depression / Die frontale EEG Alphaasymmetrie und Beziehungen zu Depression/Depressivität

Zur langfristigen Markierung von hämatogenen Zellen wurde Knochenmark mit dem Gen für das grüne fluoreszierende Protein (GFP) transduziert und in bestrahlte Empfängermäuse transplantiert. Die GFP-Expression im peripheren Blut dieser Tiere war über den untersuchten Zeitraum von vier Monaten stabil. Die Hirne der Empfängertiere wurden zu den Zeitpunkten zwei, vier, acht und fünfzehn Wochen nach Knochenmarktransplantation auf die Präsenz von GFP-exprimierenden Zellen untersucht. Es fand sich eine im Zeitverlauf zunehmende Einwanderung und Differenzierung von GFP-exprimierenden hämatogenen Zellen zu ramifizierten Mikrogliazellen in der grauen und weißen Substanz. Nach vier Monaten stammten bis zu ein Viertel aller regionalen Mikrogliazellen aus dem transplantierten Knochenmark. Nach fokaler cerebraler Ischämie wanderten deutlich mehr GFP-positive Zellen aus dem Blut in das ischämische Areal ein und differenzierten zu ramifizierten Mikrogliazellen. Diese Ergebnisse implizieren einen Weg für den Transfer des humanen Immunodefizienzvirus in das Zentralnervensystem und offerieren einen nichtinvasiven Weg, genetisch manipulierte Zellen in das adulte Hirnparenchym einzuschleusen. / In order to stably label hematogenous cells, bone marrow was transduced with the gene for the green fluorescent protein (GFP) and transplanted into irradiated recipient mice. The GFP- expression in peripheral blood cells of these animals was stable within the examined time frame of four months. Brains of recipient animals were examined for the presence of GFP- expressing cells at two, four, eight and fifteen weeks after bone marrow transplantation. An increasing migration and differentiation of hematogenous GFP-expressing cells into ramified parenchymal microglia within the white and grey matter was found. After four months, up to quarter of regional microglia were bone-marrow derived. Following focal cerebral ischemia, an increased influx of GFP-positive blood-borne cells differentiating into ramified microglia was observed. These results imply a route for the human immunodeficiency virus into the central nervous system, and they offer a noninvasive approach for the transfer of genetically manipulated cells into the adult brain parenchyma.

Die Kopplung zwischen neuronaler Aktivität und cerebralem Blutfluss ist ein fundamentaler Prozess, der alle cerebralen Funktionen begleitet. Das Thema meiner Habilitation ist die Entdeckung einer neuen Ischämievariante, bei der neuronale Aktivierung eine cerebrale Ischämie auslöst, indem sich die Kopplung zwischen neuronaler Aktivierung und cerebralem Blutfluss umkehrt. Diese Umkehrung wird durch Produkte roter Blutkörperchen im Subarachnoidalraum hervorgerufen. Die eigentümlichste Eigenschaft dieser Ischämievariante ist ihre Wanderung im cerebralen Cortex gemeinsam mit der Welle neuronaler Aktivierung. Deshalb habe ich das Phänomen cortical spreading ischaemia genannt. Das vorgestellte tierexperimentelle Modell könnte für die verzögerten ischämischen neurologischen Defizite nach Subarachnoidalblutung Implikationen besitzen. Die Verbindung mit diesem klinischen Syndrom basiert auf: (a) der Induktion der cortical spreading ischaemia durch Produkte roter Blutkörperchen im Subarachnoidalraum, (b) der Übereinstimmung im Läsionsmuster mit corticalen ischämischen Infarkten, und (c) den therapeutischen Effekten von Nimodipin und mässiger hypervolämischer Hämodilution im klinischen Syndrom und im Tiermodell. Mit Hilfe dieses Modells ist es zum ersten Mal gelungen, experimentell die Hypothese zu bestätigen, dass Produkte roter Blutkörperchen eine cerebrale Ischämie induzieren können. Ich hoffe, dass das Modell dazu beitragen wird, neue Strategien bei der Behandlung von Patienten mit Subarachnoidalblutung zu entwickeln. / The coupling between neuronal activity and cerebral blood flow is a fundamental process, which underpins all cerebral functions. The topic of my Habilitation is the discovery of a new variant of ischaemia in which neuronal activation triggers a cerebral ischaemic event through the inversion of the coupling between neuronal activation and cerebral blood flow. This inversion occurs when red blood cell products are present in the subarachnoid space. The most distinct feature of this variant of ischaemia is its propagation in the cerebral cortex together with the wave of neuronal activation. Therefore, I named the phenomenon cortical spreading ischaemia . The presented animal model may have implications for the delayed ischaemic neurological deficits after subarachnoid haemorrhage. The link with this clinical syndrome has been based: (a) on the induction of cortical spreading ischaemia by red blood cell products in the subarachnoid space, (b) the correspondence between the characteristic patterns of the cortical ischaemic lesions, and (c) the therapeutic effects of nimodipine and moderate hypervolaemic haemodilution in clinical syndrome and animal model. With the aid of this model, it was possible to experimentally confirm the hypothesis that red blood cell products can induce cerebral ischaemia. I hope that the model will contribute to develop new strategies for the treatment of patients with subarachnoid haemorrhage.

Die Arbeit stellt die optische Methode der Nahinfraotspektroskopie (NIRS) in der Anwendung zur Messung von Oxygenierungsänderungen am Kopf des Erwachsenen dar. Dabei werden zunächst methodische Aspekte behandelt. Dies schließt (i) die Frage ein ob Änderungen des Redox-Status der Cytochromoxidase mit der NIRS bestimmt werden können; (ii) diskutiert die Ergebnisse zur Darstellbarkeit schneller optischer Signale, wie sie in invasiven Studien als Korrelat der elektrophysiologisch messbaren neuronalen Prozesse bekannt sind und (iii) richtet sich auf die bessere Definition des Messvolumens, sowohl im Sinne einer zweidimensionalen Bildgebung der Oxygenierungs-änderungen an der Hirnoberfläche als auch die Möglichkeiten zu einer Tiefenauflösung. Bezüglich der grundlegenden physiologischen Fragestellungen thematisiert die Arbeit im zweiten Teil Fragestellungen der neuro-vaskulären Kopplung. Dies ist die Frage, wie sich die neuronale, elektrophysiologisch meßbare Aktivität von Neuronen in eine hämodynamische Antwort übersetzt. Hier sind die Einordnung der NIRS-Befunde in ein Modell der vaskulären Antwort aber auch gleichzeitige Messungen mit elektrophysiologischen Methoden und weiteren vaskulär-basierten Methoden, insbesondere der funktionellen Kernspintomographie, Fokus. Schließlich stellt die Arbeit die klinischen Perspektiven in der Neurologie dar, wie sie sich besonders für die vaskulären Erkrankungen des Gehirns aber auch für Fragestellungen bei Epilepsie und Migräne ergeben. / We here present a optical method, near-infrared spectroscopy (NIRS), and its application for non-invasive measurement of oxygenation changes in the adult head. The first part deals with methodological aspects of NIRS. This includes (i) the question whether changes of cytochrome-oxidase redox state can be monitored by NIRS; (ii) the discussion of study results investigating the non-invasive detectability of fast optical signals , known to reflect electrophysiological changes in invasive animal preparations; (iii) and finally the issue how the sampling volume can be better defined, and with respect to a two-dimensional imaging approach of cortical oxygenation changes and the methodological options to achieve a depth resolution. In a second chapter we then focus on the underlying physiological issues mainly raising questions concerning neuro-vascular coupling. Neuro-vascular coupling means the translation of neuronal activity, as can be measured by electrophysiological methods, into the haemodynamic response. Here the focus is on how the results of functional NIRS studies can be interpreted in the light of a model of the vascular response. Also the simultaneous assessment of electrophysiological parameters or the parameters of other methods based on the vascular response, especially fMRI, are dealt with in this chapter. Finally the here presented work gives perspectives of potential clinical applications of the method. This primarily means the application in stroke and other vascularly diseases in neurology, but also includes questions in the clinical fields of epilepsy and migraine.

Cette these traite de la modelisation statistique de formes en imagerie<br />cerebrale.<br /><br />Dans une premiere partie, nous proposons un modele statistique de la forme des sillons corticaux. Le modele est bati par apprentissage a partir de sillons extraits d'images IRM et dotes d'une representation parametrique. La definition d'un repere intrinseque a la forme sillon permet d'aligner l'ensemble des formes extraites et de construire une population d'apprentissage coherente sur laquelle appliquer une analyse en composantes principales afin de deriver le modele. Ce modele statistique est ensuite etendu a un graphe de sillons afin de decrire non plus seulement les caracteristiques morphologiques d'un sillon, mais aussi les relations de position et d'orientation entre sillons principaux.<br />L'analyse presentee ici porte sur un sous-graphe defini par un couple de sillons. <br /><br />Dans une seconde partie, trois applications de la modelisation proposee sont envisagees. D'une part, nous l'utilisons dans un cadre d'evaluation de methodes de recalage global inter-sujets. Pratiquee sur des amers locaux, l'analyse statistique fournit un indicateur de la similarite des formes au sein des populations recalees, et produit un critere de comparaison entre les methodes. D'autre part, nous exploitons la connaissance statistique apportee par le modele sur les sillons dans le contexte de la construction d'atlas anatomiques et fonctionnels. Nous proposons une methode locale et non-lineaire de recalage inter-sujets de donnees fonctionnelles, exprimees sous forme de dipoles MEG (localisations d'activations fonctionnelles), base sur la modelisation des amers anatomiques que sont les sillons corticaux. Exprimentee sur une population de 18 sujets, cette methode s'est averee apte a reduire la variabilite fonctionnelle inter-individuelle observee. Enfin, nous appliquons la methodologie proposee dans le cas des sillons a la modelisation statistique de la forme de frontieres fonctionnelles delimitant des aires visuelles de bas-niveau.

[pt] A experiência de tornar-se mãe e de tornar-se pai de uma criança, mesmo quando ocorre de acordo com as expectativas, exige dos pais um intenso trabalho psíquico de reorganização de suas representações acerca do bebê imaginado e deles próprios. Quando esse bebê é diagnosticado com paralisia cerebral, uma enfermidade decorrente de uma lesão neurológica precoce, que interfere no desenvolvimento infantil de maneira ampla, esse trabalho de reorganização psíquica dos pais sofre uma ruptura. Nosso objetivo nesta tese é investigar o processo de construção da parentalidade quando o bebê é diagnosticado com paralisia cerebral, indagando as condições para que o investimento parental na criança seja mantido. Trata-se de uma pesquisa teórico-clínica com referencial psicanalítico, que articula a investigação teórica a fragmentos de experiências clínicas com pais de crianças portadoras de paralisia cerebral. Nosso estudo se inicia pela discussão da paralisia cerebral do ponto de vista médico, buscando compreender como as características dessa enfermidade afetam as interações precoces entre o bebê e seu cuidador primário. As representações dos pais acerca do filho são investigadas desde a pré-história da parentalidade até as transformações sofridas ao longo da gestação e em torno do nascimento, para situar os efeitos traumáticos do diagnóstico de paralisia cerebral sobre elas. A possibilidade de que os pais realizem um trabalho de luto da criança esperada e invistam na criança real com paralisia cerebral é discutida, levando-se em consideração desde as situações de impasse, que vão do desinvestimento às formas de investimento fusionais, até as situações em que o investimento se sustenta. Nestes casos, destacamos a existência de fantasias e representações paradoxais criadas pelos pais, que parecem, ao mesmo tempo, compreender as consequências da paralisia cerebral para a criança, e projetar expectativas de um desenvolvimento de acordo com os referenciais conhecidos. Argumentamos que essas construções parentais possuem uma função transicional de recomposição da experiência de ilusão necessária ao investimento parental e de descoberta da realidade de uma maneira gradual e tolerável para os pais. Discutimos, finalmente, o papel do psicanalista de sustentação desse paradoxo maturacional. / [fr] L expérience de devenir mère et de devenir père pour un enfant, même lorsqu elle se déroule selon les attentes, demande aux parents un travail psychique intense pour réorganiser leurs représentations du bébé imaginé et d eux-mêmes. Lorsque ce bébé est diagnostiqué avec une paralysie cérébrale, une maladie résultant d une lésion neurologique précoce, qui interfère de manière large avec le développement de l enfant, ce travail de réorganisation psychique subit une rupture. Notre objectif dans cette thèse est d étudier le processus de construction de la parentalité lorsque le bébé est diagnostiqué avec une paralysie cérébrale, en demandant les conditions de maintien de l investissement parental dans l enfant. Il s agit d une recherche théorico-clinique avec un cadre psychanalytique, qui articule l enquête théorique avec des fragments d expériences cliniques avec des parents d enfants atteints de paralysie cérébrale. Notre étude commence par une discussion sur la paralysie cérébrale d un point de vue médical, cherchant à comprendre comment les caractéristiques de cette maladie affectent les interactions précoces entre le bébé et son principal soignant. Les représentations des parents sur l enfant sont étudiées depuis la préhistoire de la parentalité jusqu aux transformations subies pendant la grossesse et autour de la naissance, pour situer sur eux les effets traumatiques du diagnostic de paralysie cérébrale. La possibilité que les parents effectuent un travail de deuil de l enfant attendu et investissent dans l enfant réel atteint de paralysie cérébrale est discutée, en tenant compte des situations d impasse, allant du désinvestissement à des formes d investissement fusionnel, aux situations dans lesquelles l investissement est soutenu. Dans ces cas, nous mettons en évidence l existence de fantasmes et de représentations paradoxales créés par les parents, qui semblent, à la fois, comprendre les conséquences de la paralysie cérébrale pour l enfant, et projeter des attentes de développement selon les références connues. Nous soutenons que ces constructions parentales ont une fonction transitionnelle de recomposer l expérience d illusion nécessaire à l investissement parental et de découverte de la réalité d une manière graduelle et tolérable pour les parents. Enfin, nous discutons du rôle du psychanalyste dans le soutien de ce paradoxe maturationnel.

Les chromophores classiques ne sont pas toujours efficaces en absorption à deux photons. Leur faible efficacité nécessite l'utilisation de fortes puissances laser et de grandes concentrations en colorants. Dans ce sens, la microscopie à deux photons in vivo requière le développement de nouvelles stratégies de marquage utilisant des chromophores spécialement dédiés à la microscopie à deux photons. Dans le cadre de collaborations avec des chimistes spécialisés dans la synthèse de molécules à forte section efficace d'absorption à deux photons, différents chromophores ont été synthétisés. Ces molécules organiques sont souvent hydrophobes et ne sont pas utilisables directement pour les applications en biologie. Le travail effectuer ici a consisté à encapsuler ces molécules dans des micelles de copolymères biocompatibles, les Pluronic. Les Pluronic sont des matériaux pouvant s'auto assembler en milieu aqueux sous forme de micelles et permettent de solubiliser des composés hydrophobes. Cette stratégie est déjà utilisé pour permettre de transporter différents composés hydrophobes dans les organismes vivants et a été utilisée ici pour transporter des chromophores ultrasensibles à deux photons dans le sang de manière à imager la vascularisation in vivo. / Classic fluorescent dyes are not necessary efficient in two-photon absorption. Their low two-photon absorption efficiency often requires high laser power and important dye concentrations. Therefore, new dyes and other administration strategies need to be developed specifically for intravital two-photon microscopy. In collaboration with chemists, specialized in the synthesis of molecules with a high two-photon absorption cross-section, different dyes have been synthesized. Most of these dyes are hydrophobic and not directly suitable for biological applications. The work presented in this thesis consisted of encapsulating hydrophobic molecules in biocompatible Pluronic block copolymers. In water, Pluronic unimers with hydrophobic and hydrophilic blocks self-assembled in hydrophilic micelles forming a hydrophobic core around the molecules. This strategy has been used already for the transport and delivery of different hydrophobic molecules in living organism. In the present study, this strategy has been transposed to transport ultra sensitive two-photon dyes in the blood plasma for deep vascular imaging in vivo.

Le immagini mentali sono un analogo della percezione? Studiando i pazienti con danni cerebrali, abbiamo visto che le menomazioni percettive sono spesso associate a limitazioni nella capacità di creare immagini (Farah 1988, 2000). Nella recente letteratura tuttavia sono riportati casi di doppia dissociazione, in cui funzioni percettive sono preservate e quelle immaginative danneggiate, o viceversa, funzioni percettive danneggiate ma intatta capacità immaginativa. Nel seguente studio l’obiettivo è indagare i rapporti tra la percezione e immaginazione in pazienti con danno cerebrale, in 5 diversi domini: forme, colori, volti, materiale ortografico e relazioni spaziali. Nel primo studio l'obiettivo era di esplorare le immagini mentali e la capacità di percezione visiva in pazienti con lesioni cerebrali attraverso una batteria di test sviluppata da Bachoud Levi, Bartolomeo, Chokron nel 2001 e adattata per il campione italiano da Antonietti, Oliveri, Incorpora et al. (2008). In un secondo studio abbiamo indagato le relazioni tra imagery e stile cognitivo visualizzatore/verbalizzatore, proponendo 2 questionari (VVQ e QSVV). Infine in un terzo studio, attraverso indagini strumentali (DTI, TAC, RMN) in un gruppo di pazienti con danno focale e deficit specifici di imagery, abbiamo individuato le correlazioni tra deficit nei diversi domini dell’imagery e della percezione con i danni corrispondenti a livello neurale. / Is imagery an analogous of perception? By studying patients with brain damage we saw that perceptual impairments are often associated to limitations in the ability to create images (Farah 1988, 2000). In recent literature we found cases of double dissociation, in which perceptual functions are preserved and those imaginative impaired or, vice versa, there are damaged perception functions but intact imaginative capacity. We aim to investigate the relationships between perception and imagery in patients with brain damage, in 5 different domains: shapes, colour, faces, orthographic material and spatial relationships. In the first study the aim was to explore mental imagery and visual perception skills in patients with brain injury through a battery of tests developed by Bachoud-Lèvi, Bartolomeo, Chokron in 2001, and readapted for the Italian sample by Antonietti, Oliveri, Incorpora et aal (2008). In a second study we investigated the relationships between imagery test performance and visualizer/verbalizer cognitive style, detected by proposing 2 questionnaires (VVQ and QSVV). Finally in a third study, through instrumental investigations (DTI, TAC, MRI) in a group of patient with focal damage and specific imagery deficit, we aimed to correlate imagery and perception deficits to corresponding impairment in neural correlates.