Understanding the ageing process is of increasing importance to an ageing society and one aspect of this is investigating what role the brain has in this process. Cognitive ability declines as we age and it is one of the most distressing aspects of getting older. Brain tissue deterioration is a significant contributor to lower cognitive ability in late life but the underlying biological mechanisms in the brain are not yet fully understood. One reason for this is the difficulty in obtaining accurate measures of potential ageing-related brain biomarkers. The chapters in this thesis explore the difficulties of quantifying brain changes in the ageing brain from Magnetic Resonance Imaging (MRI), and how the changes identified are related to cognition in later life. The data was acquired as part of the second wave of the longitudinal Lothian Birth Cohort 1936 study in which 866 people aged 73 years, returned for cognitive and medical assessment. At this stage of the study 702 underwent MR imaging resulting in 627 complete datasets across all testing. The entire data, a randomly chosen subset of 150 and 416 freely available data were used to investigate global and regional measurement methods in older brains and how the resultant measurements related to cognitive performance. Furthermore the presence of early life cognitive data in the form of a general intelligence test sat at age 11, served as an indicator of cognitive ability prior to the potential influence of the ageing process. The chapters concerning global measures at first establish, that a measure of intracranial volume (ICV) serves as both a way of correcting for individual differences in brain size between participants and as a proxy premorbid measure of brain size. The analysis, utilising freely available cross-sectional MRI data (http://www.oasis-brains.org) revealed that ICV differed very little between 18-28 year olds and 84-96 year olds where as total brain tissue volume (TBV) differed by 14.1% between the two groups, which was more than twice the standard deviation across the entire age range (18-96 years). Second a validated, reliable method for measuring ICV was investigated using 150 people randomly chosen from the LBC1936 study. Automated and semi-automated methods were validated against reference measurements the results of which showed that common ageing features make automated and semi-automated methods that do not have an additional manual editing step, ineffective at producing accurate ICV measurements. This analysis also highlighted the need to employ additional spatial overlap assessment to volumetric comparison of measurement methods to reduce the effect of false-positives and false-negatives skewing apparent discrepancies between methods. Using the information gained here ICV and TBV from the entire LBC1936 cohort were analysed in a structural equation model, alongside cognitive ability measures at both age 11 and age 73. We found that TBV was a stronger predictor of later life cognitive ability, after accounting for early life ability, but that a modest association remained between ICV and late life cognition. This suggests that early life factors pay a role in how well we age, though the relationship is complex. The regional measures chapters look at two brain regions commonly associated with ageing, the hippocampus and the frontal lobes. Measuring either of these brain regions in large samples of healthy older adults is challenging for many reasons. The hippocampus is small and as with all brain regions shows greater variation in older age, this makes employing automated methods that have the advantage of being fast and reproducible difficult. Following the results of our systematic review of automated methods for measuring the hippocampus, the two most commonly used and available automated methods were validated against reference standard measurements. The results indicated that although automated methods present an attractive alternative to laborious manual measurements they still require manual editing to produce accurate measurements in older adults. The modified strategy employed across the LBC1936 was to use an automated method and then manually edit the output; these segmentations were used to investigate the potential of multimodal image analysis in clarifying associations between the hippocampus and cognitive ability in old age. The analysis focused on associations between longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and general factors of fluid intelligence, cognitive processing speed and memory. The findings show that multi-modal MRI assessments were more sensitive than volumetric measurements at detecting associations with cognitive measures. The difficulty with producing a relevant frontal lobe measure was made apparent when the result of a large systematic review looking at the manual protocols used revealed 19 methods and 15 different landmarks had been employed. This resulted in an analysis that took the 5 most common boundaries reported and applied them to 10 randomly selected participants from the LBC1936. The results showed significant differences between the resultant volumes, with the smallest measurement when using the genu as the posterior marker representing only 35% of the measurement acquired using the central sulcus. The results from the studies presented in this thesis strongly highlight the need to develop age specific methods when using brain MRI to study ageing. Furthermore the implications of using unstandardised protocols, making assumptions about a methods performance based on validation in younger samples and the need to account for early life factors in this area of research have been made clearer. Studies building on these findings will be beneficial in elucidating the role of the brain in ageing.

L'objectif de cette thèse est d'étudier le traitement des expressions faciales de douleur d'un point de vue psychophysique et neurophysiologique. Contrairement aux autres émotions dites de base, la douleur est à la fois une expérience sensorielle et émotionnelle, composantes qui se retrouvent sur l'expression faciale de douleur qui accompagne cette expérience. En ce sens, l'expression faciale de douleur semble être plus riche et complexe que l'expression faciale d'autres émotions, la rendant particulière. Dans une première partie de notre travail, nous avons montré, chez des sujets sains, que l'expression faciale de douleur engendrait un plus haut niveau d'empathie que l'expression faciale d'autres émotions. De plus, une présentation de ces visages masqués à 100 ms était suffisante pour permettre de détecter la douleur sur un visage de façon subliminale alors même que la reconnaissance du genre était impossible dans ces conditions. Dans une seconde partie, nous avons étudié le traitement implicite des expressions faciales de douleur chez des patients souffrant d'épilepsie réfractaire et explorés en stéréotaxie par des électrodes intracérébrales. Pour cela, nous avons détourné leur attention du caractère émotionnel des visages et enregistré des réponses évoquées aux visages expressifs. Les résultats montrent une activation précoce de l'insula antérieure (début de réponse à 131 ms ; pic à 180 ms post-stimulus) suivie d'une activation de l'amygdale (début à 273 ms ; pic à 363 ms). Cependant, ces activations antéro-insulaire et amygdalienne ne sont pas spécifiques de la douleur. L'insula postérieure semble également répondre à la présentation de visages exprimant la douleur mais l'amplitude de cette réponse ne diffère pas de celle de la réponse aux visages neutres. Ainsi, malgré les nombreuses informations que véhicule un visage de douleur, l'être humain est capable de le détecter très rapidement et d'être suffisamment empathique pour prodiguer l'aide appropriée à son prochain. Cette capacité serait permise grâce à l'insula antérieure, relai entre nociception et douleur / The aim of this work is to study painful facial expression processing through psychophysical and neurophysiological approaches. Contrary to the basic emotions, pain is both a sensory and an emotional experience and these two aspects are encoded in the facial expression of pain. In that sense, painful facial expressions are richer and more complex than the facial expression of others emotions. In a first phase, we showed that painful facial expressions trigger more empathy than other emotional facial expressions in healthy subjects. Moreover, a 100ms-masked presentation of faces is enough to subliminally detect pain but not gender. In a second phase, we studied pre-conscious processing of painful facial expressions in patients suffering from refractory epilepsy having intracranial electrodes implanted in the insular cortex and amygdala for stereotaxic exploration of epilepsy. To this purpose, we diverted the patients' attention from the emotional aspects of the faces by asking them to focus on the gender and we recorded evoked potentials to pain and other emotional faces. Results showed an early activation in the anterior part of the insula (onset latency around 131ms, peak latency 180ms post stimulus) followed by an amygdala response (onset latency around 273ms, peak latency 363ms post stimulus). Response to pain faces is larger than that to other emotional faces in anterior insula but anterior-insula and amygdala activations are not pain specific. Posterior part of the insula also responds to painful faces but the amplitude of the evoked potentials do not differ from that of potentials evoked by neutral faces. In this way, even if the pain face contains a great amount of information, the human- being is able to rapidly detect it and to be empathic enough to provide the help needed for others in pain. This ability would be possible through anterior insula activation, thought to be a relay between nociception and emotional reaction to pain

Patients with mechanical heart valves who present with intracranial haemorrhage are initially treated by reversing their coagulopathy. However, these patients will ultimately require that their oral anticoagulant be restarted. The time at which oral anticoagulants are restarted is critical since restarting too early may increase the risk of recurrent bleeding, while withholding anticoagulants increases the patient’s risk of thromboembolic events. The ideal time to restart patients on their oral anticoagulant medication is defined as the time at which all these risks are minimized. This thesis includes a systematic review and meta-analysis of the literature. The main outcomes were recurrent haematoma, valve thrombosis, stroke and peripheral emboli. Results were stratified by types of intracranial haemorrhage. We also conducted a survey to gain insight into current practices of neurosurgeons and thrombosis experts in Canada and USA when they are faced with deciding on anticoagulant restart times in patients with ICH. Results were stratified by type of intracranial bleed and participants’ characteristics and demographics. The systematic review identified that the ideal time for restarting anticoagulant therapy in patients following an ICH is unknown. Meta-analysis was limited by the heterogeneity of the studies. The survey results indicated that physicians had a wide range of practice and that their practice was dependent on the patient’s clinical features, but many physicians would restart oral anticoagulants between 4 and 14 days after the haemorrhage. For this reason we have proposed a multi centre cohort study to investigate the safety and efficacy of restarting patients on anticoagulation therapy between day 5 and 9 post haemorrhage. A full study protocol is presented in this thesis.

L’expression faciale de peur constitue un important vecteur d’information sociale mais aussi environnementale. En condition naturelle, les visages apeurés apparaissent principalement dans notre champ visuel périphérique. Cependant, les mécanismes cérébraux qui sous-tendent la perception de l’expression faciale de peur en périphérie restent largement méconnus. Nous avons démontré, grâce à des études comportementales, des enregistrements magnétoencéphalographiques et intracrâniens, que la perception de l’expression faciale de peur est efficace en grande périphérie. La perception de la peur en périphérie génère une réponse rapide de l’amygdale et du cortex frontal, mais également une réponse plus tardive dans les aires visuelles occipitales et temporales ventrales. Le contrôle attentionnel est capable d’inhiber la réponse précoce à l’expression de peur, mais également d’augmenter les activités postérieures plus tardives liées à la perception des visages. Nos résultats montrent non seulement que les réseaux impliqués dans la perception de la peur sont adaptés à la vision périphérique, mais ils mettent également en avant une nouvelle forme d’investigation des mécanismes de traitement de l’expression faciale, pouvant conduire à une meilleure compréhension des mécanismes de traitement des messages sociaux dans des situations plus écologiques. / Facial expression of fear is an important vector of social and environmental information. In natural conditions, the frightened faces appear mainly in our peripheral visual field. However, the brain mechanisms underlying perception of fear in the periphery remain largely unknown. We have demonstrated, through behavioral, magnetoencephalographic and intracranial studies that the perception of fear facial expression is efficient in large peripheral visual field. Fear perception in the periphery produces an early response in the amygdala and the frontal cortex, and a later response in the occipital and infero-temporal visual areas. Attentional control is able to inhibit the early response to fear expression and to increase the later temporo-occipital activities linked to face perception. Our results show that networks involved in fear perception are adapted to the peripheral vision. Moreover, they validate a new form of investigation of facial expression processing, which may lead to a better understanding of how we process social messages in more ecological situations.

No description available.

This semestral thesis deals with visualization of intracranial EEG. In the first part, theoretical basics of EEG is mentioned. After that, image registration, as a needed tool for visualization is described followed by research of methods of visualization of high frequency oscilations from intracranial EEG. Finally, method for visualization of high frequency oscilations from EEG in real MRI patient scans is designed and implemented.

Epileptic disease is connected with change in activity of neuronal clusters. Brain connectivity analysis deals with statistic interdependencies between different neuronal centres. Earlier studies show that changes in connectivity can be seen near primary epileptic site. What is changing connectivity and its characteristic in interictal recordings are yet to be fully known. In this thesis are analyzed data from intracranial EEG electrodes, positioned in and neighboring areas of epileptic site. Changes in connectivity of epileptic site and its surroundings are observed by nonlinear correlation method. Decrease in connectivity of epileptic site during slow wave sleep was detected on frequencies above 80 Hz. Reduced connectivity was measured on the border of epileptic zone and normal tissue. Observed features are accentuated during sleep. It was also found out that connectivity at the border of epileptic zone apears to have nonlinear property. The results show that physiological processes during sleep are influencing connectivity near epileptic site and decrease in connectivity may be related to nonlinear dependence of neuronal activity at the border of epileptic zone. This study confirms hypothesis of the earlier studies and reveals new facts about connectivity of epileptic site from the perspective of nonlinear processes. Consequent study based on this findings might lead to more precise delineation of epileptic site and to better understanding of processes, which are causing epileptic fits.

This thesis describes selected methods of brain connectivity analysis. It was created an application, as a part of this thesis - plugin for evaluating relationships and dependencies between signals calculated as Pearson correlation coefficients. Computation of these coefficients is accelerated by GPU.

The Human brain consists of mutually connected neuronal populations that build anatomically and functionally separated structures. To understand human brain activity and connectivity, it is crucial to describe how these structures are connected and how information is spread. Commonly used methods often work with data from scalp EEG, with a limited number of contacts, and are incapable of observing dynamic changes during cognitive processes or different behavioural states. In addition, connectivity studies almost never analyse pathological parts of the brain, which can have a crucial impact on pathology research and treatment. The aim of this work is connectivity analysis and its evolution in time during cognitive tasks using data from intracranial EEG. Physiological processes in cognitive stimulation and the local connectivity of pathology in the epileptic brain during wake and sleep were analysed. The results provide new insight into human brain physiology research. This was achieved by an innovative approach which combines connectivity methods with EEG spectral power calculation. The second part of this work focuses on seizure onset zone (SOZ) connectivity in the epileptic brain. The results describe the functional isolation of the SOZ from the surrounding tissue, which may contribute to clinical research and epilepsy treatment.

Background: Impaired homocysteine metabolism is associated with a number of vasculopathies including extracranial aneurysms. We analyzed the possible association of nine genetic variants of homocysteine metabolism with the occurrence of intracranial aneurysms. Methods: Caucasian patients (n = 255) treated at two German hospitals for intracranial aneurysms and local controls (n = 348) were genotyped for the following polymorphisms: methionine synthase (MTR) c.2756A→G, methylenetetrahydrofolate reductase (MTHFR) c.677C→T, MTHFR c.1298A→C, cystathionine β-synthase (CBS) c.844_855ins68, CBS c.833T→C, dihydrofolate reductase (DHFR) c.594 + 59del19bp, glutathione S-transferase Ω-1 (GSTO1) c.428C→A, reduced folate carrier 1 (RFC1) c.80G→A and transcobalamin 2 (Tc2) c.776C→G. Results: The G-allele of the missense polymorphism Tc2 c.777C→G was found to be underrepresented in patients, suggesting that this variant may protect from the formation of cerebral aneurysms [odds ratio per two risk alleles (OR) 0.48; 95% confidence interval (CI) 0.30–0.77; p = 0.002]. We obtained borderline results for the G-allele of RFC1 c.80G→A (OR 1.64; 95% CI 1.01–2.65; p = 0.051) and the insertion allele of DHFR c.594 + 59del19bp (OR 1.61; 95% CI 1.00–2.60; p = 0.059), which were found to be overrepresented in patients. Conclusion: Polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.