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.

In neuro surgery, the expression awake surgery generally refers to tumour surgery in the brain while the patient is concious. At Akademiska Sjukhuset, Uppsala, it is today standard to perform awake surgery on tumours located in the dominant left hemisphere while awake. However, regarding awake surgery in the non-dominant right hemisphere it is not clear what functions should be tested and how this should be done. A test battery for awake surgery in the right hemisphere should be developed like the test that are used in awake surgery in the left hemisphere. Science recommends awake surgery in the right hemisphere which already being done around Europe. As patients with brain tumours have a good prognosis post operative it is important to retain, or ameliorate, their quality of life. This literature study’s main purpose is to present which functions, important for language and communication, are located in the right hemisphere. The study also intends to account for testing of these functions intraoperatively, after rightsided stroke and on persons with right hemisphere lesions. The functions are many in number, essential for maintaining the quality of life but some are difficult to test. According to the literature study, the functions that appeared most significant are neglect and pragmatic with its functional, social and communicative effects. More research on the right hemispherical functions and how they are organized is necessary. The work intends to be the basis for continued development of awake surgery tests in the right hemisphere in Akademiska Sjukhuset, Uppsala. / Inom neurokirurgin avser uttrycket vakenkirurgi oftast tumörkirurgi i hjärnan samtidigt som patienten är vid fullt medvetande under ingreppet. Vid Akademiska Sjukhuset i Uppsala är det standard att operera tumörer belägna i den språkligt dominanta vänstra hemisfären i vaket tillstånd medan man vid en del andra centra även förespråkar vakenkirurgi i den icke-språkligt dominanta högra hemisfären. Det är emellertid inte klarlagt vilka funktioner som i så fall bör testas och hur detta ska gå till. Ett testbatteri vid vakenkirurgi i höger hemisfär skulle behöva utvecklas likt det test som används vid tumörer i vänster hemisfär. Vakenkirurgi i höger hemisfär genomförs i dag på enstaka center i Europa. Då patienter med hjärntumörer kan ha en god prognos postoperativt är det angeläget att behålla, eller förbättra, deras livskvalitet. Denna litteraturstudies huvudsakliga syfte är att presentera vilka funktioner, viktiga för språk och kommunikation, som är lokaliserade i höger hemisfär. Studien redogör också för testning av dessa funktioner intraoperativt, efter högersidig stroke och på personer med högerhemisfäriska skador. Funktionerna är många till antalet, viktiga för att bibehålla livskvaliteten men en del även svårtestade. Enligt vår litteraturgenomgång är de funktioner som framstått som mest betydelsefulla neglekt och pragmatik med dess funktionella, sociala och kommuniktiva påverkan. Mer forskning om höger hemisfärs funktioner och hur dessa är organiserade behövs. Arbetet ämnar ligga till grund för fortsatt utveckling av vakenkirurgitest i höger hemisfär på Akademiska Sjukhuset i Uppsala.

Introduktion: I dagens intensivvård hålls patienter som vårdas i respirator mer ytligt sederade. Patienterna blir berövade sitt verbala tal och behandlas i en miljö som kan upplevas som skrämmande. Detta ställer högre krav på sjuksköterskan, att bemöta patientens psykosociala behov på ett bra sätt och etablera en vårdande relation. Syfte: Att belysa sjuksköterskors erfarenheter av att skapa en vårdande relation med en vaken eller lätt sederad patient som vårdas i respirator på en intensivvårdsavdelning. Metod: En kvalitativ induktiv design användes och data insamlades med hjälp av fyra fokusgruppsintervjuer, med totalt 14 kvinnliga sjuksköterskor med minst två års yrkeserfarenhet av intensivvård. Studien utgick från tre intensivvårdsenheter i västra Sverige. Den insamlade datan analyserades med hjälp av kvalitativ innehållsanalys. Resultat: Sjuksköterskors erfarenheter av att skapa en vårdande relation med en vaken eller lätt sederad patient som vårdas i respirator, tolkades utifrån följande teman för att belysa olika faktorer som är av vikt: kommunikation i mötet, att lyfta fram personen bakom patienten, det vårdande rummet och när relationen försvåras. Slutsats: Att med hjälp av kommunikation skapa en gemensam förståelse, att lära känna patienten och orientera patienten i nuet, att vårda med respekt och trygghet och slutligen att sträva efter att lösa eventuella hinder som uppstår på vägen, var alla centrala faktorer i skapandet av en vårdande relation. Som blivande intensivvårdssjuksköterskor anser författarna att studien ger viktiga infallsvinklar i problemområdet som kan vara användbara i deras kommande yrkesroll. / Introduction: In today's intensive care, patients who are mechanically ventilated are more often lightly sedated. Patients are deprived of their verbal communication and treated in an environment that they can find frightening. This puts greater demands on the nurse, in order to respond to the patient's psychosocial needs in a positive way and establish a caring relationship. Aim: To illuminate nurses’ experience of creating a caring relationship with an awake or lightly sedated patient undergoing mechanical ventilation in an intensive care unit. Method: A qualitative inductive design was used and data was collected with four focus groups, with a total of 14 female registered nurses with at least two years professional experience of intensive care. The study was conducted at three intensive care units in western Sweden. Data was analysed with a qualitative content analysis.   Result: Nurses' experience of creating a caring relationship with an awake or lightly sedated patient undergoing mechanical ventilation, was interpreted on the basis of the following themes to highlight the various factors that are of importance; communication in the meeting, to highlight the person behind the patient, the room of caring and when the relationship is complicated. Conclusion: Using communication to create a common understanding, to get to know the patient and orient the patient in the present, to provide care with respect and impart a sense of comfort, and finally strive to resolve any challenges that may arise along the way, were all key factors in creating a caring relationship. As future intensive care nurses, the authors consider that the study provides important insights into the problem area that may be useful in their future profession.

Nous avons analysé l'activité de population au sein du cortex visuel primaire en vue de comprendre (i) les mécanismes mis en jeu lors de l'intégration de l'information visuelle suite à un mouvement oculaire, et inversement (ii) de l'influence du traitement effectué au niveau de V1 sur la génération d'un mouvement oculaire.1. Nous avons enregistré des saccades de fixation, et mis en relation, essai par essai, ces mouvements avec la représentation de la position d'un stimulus local dans V1. Après une saccade de fixation, l'activité se déplace de façon cohérente dans V1. Le décours temporel des réponses au niveau des foyers pre- et post-saccadiques montre une dynamique biphasique. La taille du foyer d'activité augmente. Nous proposons que le comportement des populations de neurones s'explique par deux phénomènes principaux : (i) La réponse suppressive précoce attribuable à la décharge corollaire (ii) de connections latérales qui réactiveraient le foyer pre-saccadique.2. Nous avons enregistré l'OFR, et cherché à savoir si la réponse de V1 l'influençait. Les latences VSD précèdent les latences OFR. Il n'existe pas de corrélation à l'essai unique. Nous avons montré que la force et la dynamique des réponses de V1 n'étaient pas prédictives de l'OFR. La distance de la périphérie à un effet sur la réponse VSD, mais pas sur l'OFR. La dynamique de propagation de cette suppression, nous avons montré deux phases : une précoce sur l'ensemble de la carte, et une plus périphérique tardive. Nous proposons que la suppression précoce soit originaire de projections en retour de structures comme MT et MST, alors que la suppression plus lente s'explique par les connections horizontales. / We analyzed population activity in V1 to understand (i) the consequence of eye movements on integration of visual information, and (ii) the influence of the processing performed at the level of V1 on the generation of eye movements.1. We recorded fixational saccades, relating, trial-by-trial, these eye movements with the representation of the position of a local stimulus in V1. After a fixational saccade, activity moves consistently in V1. However, the time-course of responses display a biphasic dynamic. This results in a global increase of the extent of cortical activity representing the local stimulus. We propose that the behavior of populations of neurons studied is explained by the contribution of two main phenomena: (i) an early suppressive response that could be attributed to the corollary discharge and (ii) the lateral connections generating lateral interactions between pre and post-saccadic lci of activity.2. We recorded the ocular following response, determining whether the response of V1 influences the oculomotor response. We studied the contrast response function of the population V1 activity and the OFR. The dynamics of CRF for a local stimulus are similar and shifted in time. We found no correlations between the single trial latencies between V1 and the OFR. At the chosen scale, surround suppression was found to be distance-dependent only in V1. The dynamics of the surround suppression shows two phases: an early suppression present over a wide cortical area, and a later peripheral spread. We propose that the early surround suppression originates from feedback from MT and MST, while the later is explained by the horizontal connections.

Dans mes travaux de thèse, je me suis intéressé à la fonction de la barrière hémato-encéphalique (BHE) et son impact dans le développement de médicaments à visée du système nerveux central (SNC). Cependant, plusieurs obstacles limitant le processus de développement de nouveaux médicaments ont été identifiés. Parmi eux, une faible biodisponibilité cérébrale est reconnue pour être un facteur limitant majeur. Malgré ce constat, la biodisponibilité et la pharmacodynamie cérébrales sont souvent inconnues ou globalement négligées durant le processus de développement des médicaments. Actuellement, 3 méthodes permettent d'explorer la pharmacocinétique cérébrale in vivo, à savoir l'analyse du liquide céphalorachidien, la tomographie par émission de positron et la microdialyse cérébrale. Chaque approche présente certaines contraintes, la première fournit des informations restreintes, la seconde est coûteuse et limitée à une utilisation principalement académique, la troisième est souvent réalisée sur des modèles rongeurs rendant la transposabilité des données à l’homme complexe. Le projet de recherche réalisé s’est articulé autour de cette problématique et a suivi deux axes de développement. Le premier s’est orienté sur l’étude du passage dans le contexte particulier de la maladie de Parkinson. Le second aborde le manque de modèles pertinents utilisables lors du développement d’un nouveau médicament et présente une solution possible, la microdialyse intracérébrale sur macaque vigile. Les études en lien avec la maladie de Parkinson ont mis en évidence que premièrement, les statines sont inefficace dans le traitement des dyskinésies lévodopa induites chez les patients parkinsoniens. Cet échec peut être en partie explicable par une biodisponibilité cérébrale insuffisante du principe actif. Deuxièmement, la fonction de BHE est modifiée sur le modèle de référence de la maladie de Parkinson, le macaque traité au 1-méthyle 4-phényl 1,2,3,6-tétrahydro pyridine (MPTP). Le travail réalisé selon le second axe démontre la faisabilité de l’échantillonnage du liquide extracellulaire cérébral sur macaque vigile par microdialyse. / While working on my thesis, I focused on the function of the blood-brain barrier (BBB) and its impact in drug development to target the central nervous system (CNS). However, several obstacles that slow down the process of developing new successful drugs have been identified. Among several factors, the poor brain bioavailability is acknowledged as a primary limiting factor. Despite this statement, both brain bioavailability and brain pharmacodynamic are either unknown or globally overlooked during the drug development process. Currently, 3 methods allow exploring in vivo brain pharmacokinetic: cerebral spinal fluid sampling analysis, Positron Emission Tomography imaging and brain microdialysis. Each approach has its own constraints, the first provides restricted information, the second is expensive and limited to a mainly academic use, and the third is often carried out on rodent models making the transferability of data in complex man. The research project is focused on this issue and followed two paths of development. The first is focused on the study of the crossing in the particular context of Parkinson's disease. The second addresses the lack of appropriate model used in the development of a new drug and presents a possible solution, intracerebral microdialysis in awake macaque. Studies linked with Parkinson's disease show that statins has proved ineffective in the treatment of levodopa-induced dyskinesia in parkinsonian patients. This failure can be explained in part by insufficient brain bioavailability of the active compound. Secondly, in macaques treated with 1-methyl 4-phenyl 1,2,3,6-tetrahydro pyridine (MPTP), the gold standard model of Parkinson's disease, the BBB is modified. The work done along the second axis shows the feasibility of sampling brain extracellular fluid by microdialysis in awake macaque.

Syftet med denna studie är att undersöka förskollärares upplevelser av vaken-vila. Kvalitativaintervjuer med tio förskollärare har genomförts och resultatet har analyserats med IPA. Tvåhuvudteman har framtolkats. Konceptet vaken-vila visar hur förskollärarna uttrycker att vaken-vilaska vara en stund för lugn och återhämtning samtidigt som deras upplevelser skiftar, den upplevs bådesom bra och trevlig men också som svår och stressframkallande. Organisation av vaken-vila handlarom förskollärarnas upplevelser av möjligheter och begränsningar för aktiviteten i relation tillbarngruppsstorlek, personaltäthet, lokal och material. Studiens slutsatser är att vaken-vilan upplevssom en aktivitet med många dimensioner. Strukturella svårigheter såsom brist på personal i relationtill antal barn i förskolan skapar organisatoriska begränsningar för vad aktiviteten vaken-vila kaninnehålla. Detta leder till att några av förskollärarna upplever stress i samband med aktiviteten. Vi kangenom tolkning av vårt resultat se att vaken-vilan verkligen är det vår rubrik påstår: en svår nöt attknäcka. / The purpose of this study is to examine preschool teachers experiences of awake-rest. Qualitativeinterviews with ten preschool teachers have been conducted and the results have been analyzed withIPA. Two main themes have been interpreted: The concept of awake-rest and The organization ofawake-rest. Our interviews revealed that the concept of awake-rest is a moment where preschoolteachers wants there to be calm while allowing for mental recovery. But their experiences of awakerestis of different character. Feeling the activity as both good and enjoyable but also as difficult andstress related. The organization of awake-rest regards preschool teachers experiences about therestrains and opportunities of the activity in relation to child group size, number of staff, environmentand materials. The study concludes that the awake-rest is experienced as an activity with manydimensions. Structural difficulties such as lack of staff in relation to the number of children createsorganizational limitations on what the activity awake-rest may contain. This leads to some of thepreschool teachers experiencing stress in connection with the activity. We can, by interpreting ourresults, see that the awake-rest is really what our headline claims: a hard nut to crack.

The purpose of this study is to analyze and seek for a possible meaning and suggestion behind the soundscape in the first episode of True Detectives fourth season; Night Country. Four individual elements have been selected for deeper analysis and based upon those, six scenes where those elements are present were selected for the study. Each auditory element that was selected was then analyzed  in depth looking at the more technical aspects of identifying and categorizing sound but also how it impacts the audience on an emotional and narrative level to explore, not only how the soundscape is established early on, but what effects this has on the viewers expectations and predictions for how the narrative could unfold.  The results of this study points towards there being, for the first time in the series history, something paranormal happening in the world of the characters. Despite there being hints and suggestions that paranormal activity is part of the cinematic world of True Detective in the past, this has never been the case once the mysteries unfold but the soundscape in Night Country, as early as episode one, and the results of this study suggests that this is about to change. / The purpose of this media production is to be used as a base for discussion during seminars regarding honor related violence and oppression. The mateiral is the be used during education for proffesionals in the field of social work.

Vaken hjärnkirurgi med testning av tal- och språkfunktioner ger viktiga fördelar vid operation av lågmaligna gliom. Denna metod ökar möjligheten för radikal resektion av tumören samtidigt som viktiga funktioner som till exempel språk bevaras. Optimering av det intraoperativa språktestningsförfarandet ökar möjligheten för mer sensitiv språktestning. Det finns idag ingen konsensus, varken internationellt eller nationellt, kring hur man bör testa språkliga funktioner intraoperativt. Syftet med föreliggande arbete är att undersöka om det är möjligt att vidareutveckla de metoder som idag används för elicitering av spontantal och testning av läsning under vakenkirurgi av lågmaligna gliom på Akademiska sjukhuset i Uppsala. För att undersöka detta genomfördes en litteraturgenomgång vilken tillsammans med auskultationer vid operation och intervjuer med yrkesverksamma logopeder och neurokirurger har utmynnat i ett förslag på ett intraoperativt högläsningstest innehållande meningar med nonord, meningar utan nonord samt enskilda ord. Nivåindelningen av testmaterialet möjliggör för testledaren att individuellt anpassa språktestning utifrån patientens förmåga. I samband med färdigställandet av testet genomfördes en pilottestning av materialet. Det föreslagna lästestet förväntas vara mer heltäckande än det som används idag då det möjliggör testning av flera läsfunktioner så som de beskrivs i ”dual route-modellen”, en psykolingvistisk teori om läsning. Dessutom har ett förslag på riktlinjer kring intraoperativt elicitering av spontantal formulerats. / Awake surgery is the gold standard for treatment of low-grade gliomas nearby eloquent language areas in the brain. This method increases the possibility of radical resection while cognitive functions such as language are preserved, as the method allows for online testing of cognitive functions. Improvement of the intraoperative language tests could increase the possibility of more sensitive testing and thereby decrease the risk of postoperative language impairments. There is no international or national agreement on how intraoperative language testing should be performed. The aim of this study is to explore the possibility of developing the methods of language testing which are used today at Akademiska sjukhuset in Uppsala, focusing on reading and spontaneous speech. Therefore the authors have conducted a review of current literature. The literature review, observations of surgery and interviews with speech pathologists and neurosurgeons resulted in the development of an intraoperative reading aloud test with three tasks consisting of sentences with nonwords, sentences without nonwords and single words. The classification of the test material into different levels will allow clinicians to adapt the reading test based on each individual case. A pilot trial of the reading test was preformed. The proposed test is expected to be more comprehensive in comparison to the tests that are currently used, as it enables testing of the different reading routes described in the dual route model, a psycholinguistic reading model. Additionally, guidelines for eliciting spontaneous speech have been defined.

La "chirurgie éveillée du cerveau" consiste à retirer des tumeurs cérébrales infiltrantes (gliomes de bas grade, GIBG) à progression lente chez un patient éveillé. Une cartographie anatomo-fonctionnelle du cerveau est réalisée par stimulation électrique directe (SED) des zones proches de la tumeur afin de discriminer les aires cérébrales fonctionnelles de celles qui ne le sont plus. Les effets inhibiteurs de la stimulation sont mis en évidence par les tests neuropsychologiques réalisés par le patient lors de la chirurgie. Cependant, la SED est paramétrée de manière totalement empirique bien qu’utilisée de façon standardisée. De plus, si ses effets comportementaux sont mis en avant, ses effets électrophysiologiques restent plus méconnus. La conservation de la relation entre électrophysiologie (potentiel évoqué, PE) et comportement (fonction) est cruciale lors de chirurgies des GIBG : l’analyse des PE en temps réel permettrait une identification de ces relations au cours même de la chirurgie.Pour cela, nous avons réalisé des enregistrements peropératoires de l’activité électro-corticographique (ECoG) du cortex (CPP, n° ID-RCB : 2015-A00056-43). L’étude de ces enregistrements a permis de mesurer les effets electrophysiologiques de la SED corticale et sous-corticale, en évaluant la réponse du cerveau à la stimulation au travers des PE. Une chaine d'acquisition spécifique à la mesure de l'ECoG a été développée afin de pouvoir à terme mesurer et visualiser les PE en temps réel. De plus, un algorithme de post-traitement a été implémenté afin de réduire la contamination du signal par l’artefact de stimulation.Mieux comprendre les mécanismes sous-jacents à la SED, notamment au travers de la mesure des réponses électrophysiologiques, doit permettre de proposer des protocoles peropératoires plus objectifs afin d'améliorer la planification chirurgicale et la qualité de vie des patients. / The ‘Awake brain surgery’ consists in removing some slow-growing infiltrative brain tumor (low grade glioma, LGG) in a patient, to delay its development while preserving the functions. An anatomo-functional mapping of the brain is performed by electrically stimulating brain areas near the tumor to discriminate functional versus nonfunctional areas. The inhibitory effects of this direct electrical stimulation (DES) are evidenced by the neuropsychological tests undergone by the patient during the tumor resection. However, the DES parameters are empirically set even though its use is standardised. Moreover, even if its behavioural effects are well known, its electrophysiological effects have been partially depicted.Preserving the relationship between electrophysiology (evoked potential, EP) and behaviour (function) is crucial in LGG surgery.Intra-operative electrocorticographic recordings (ECoG) of the brain activity were thus performed (CPP, n° ID-RCB : 2015-A00056-43). The electrophysiological effects of cortical and subcortical DES on brain activity have been highlighted, by assessing the response of the brain to the stimulation through EP recordings analysis. A new acquisition set-up has also been specifically developed for ECoG recordings in order to measure and eventually visualise the EP in real-time. Furthermore, a post-processing algorithm has been implemented to reduce the signal disturbances induced by the stimulation artefact.A better understanding of the underlying DES mechanisms, in particular through the measurement of electrophysiological responses, should enable designing more perfected protocols in order to improve the surgical planning, and quality of life of the patients.

Mes travaux de thèse portent sur l’application de l’imagerie fUS (functional ultrasound imaging) à l’imagerie cérébrale préclinique chez le petit animal. Le but était de transformer cette technique d’imagerie cérébrale récente en un véritable outil de quantification de l’état cérébral. Les objectifs principaux ont été de démontrer la faisabilité de l’imagerie fUS chez le petit animal non anesthésié ainsi que de passer du modèle rat au modèle souris - modèle de choix en imagerie préclinique en neurosciences - de surcroît de façon non invasive. J’ai tout d’abord mis au point une nouvelle séquence d’imagerie ultrasonore ultrarapide (Multiplane Wave imaging), permettant d’améliorer le rapport signal-à-bruit des images grâce à l’augmentation virtuelle de l’amplitude du signal émis, sans diminuer la cadence ultrarapide d’acquisition. Dans un deuxième temps j’ai démontré la possibilité d’imager le cerveau de la souris et du jeune rat anesthésiés par échographie Doppler ultrarapide, de manière transcrânienne et complètement non invasive, sans chirurgie ni injection d’agents de contraste. J’ai ensuite mis au point un montage expérimental, une séquence ultrasonore et un protocole expérimental permettant de réaliser de l’imagerie fUS de manière minimalement invasive chez des souris éveillées et libres de leurs mouvements. Enfin, j’ai démontré la possibilité d’utiliser le fUS pour étudier la connectivité fonctionnelle du cerveau au repos (sans stimulus) chez des souris éveillées ou sédatées. L’imagerie fUS et la combinaison « modèle souris » + « minimalement invasif » + « animal éveillé » + « connectivité fonctionnelle » constituent un outil précieux pour la communauté des neuroscientifiques travaillant sur des modèles animaux pathologiques ou de nouvelles molécules pharmacologiques / My work focuses on the application of fUS (functional ultrasound) imaging to preclinical brain imaging in small animals. The goal of my thesis was to turn this recent vascular brain imaging technique into a quantifying tool for cerebral state. The main objectives were to demonstrate the feasibility of fUS imaging in the non-anaesthetized small rodents and to move from rat model imaging to mouse model imaging –most used model for preclinical studies in neuroscience-, while developing the least invasive imaging protocols. First, I have developed a new ultrafast ultrasonic imaging sequence (Multiplane Wave imaging), improving the image signal-to-noise ratio by virtually increasing emitted signal amplitude, without reducing the ultrafast framerate. Then, I have demonstrated the possibility to use ultrafast Doppler ultrasound imaging to image both the mouse brain and the young rat brain, non-invasively and through the intact skull, without surgery or contrast agents injection. Next, I have developed an experimental setup, an ultrasound sequence and an experimental protocol to perform minimally invasive fUS imaging in awake and freely-moving mice. Finally, I have demonstrated the possibility to use fUS imaging to study the functional connectivity of the brain in a resting state in awake or sedated mice, still in a transcranial and minimally invasive way. fUS imaging and the combination of "mouse model" + "minimally invasive" + "awake animal" + "functional connectivity" represent a very promising tool for the neuroscientist community working on pathological animal models or new pharmacological molecules