BACKGROUND: The brain and retina are derived from the neuroectoderm and have structural and functional similarities. Researchers have separately analyzed brain and retinal perfusion in psychosis patients, but few studies have investigated the relationship between them. While the retina can serve as a proxy for brain disorders such as Alzheimer’s or Parkinson’s, less is known for psychosis. Thus, this study aims to examine the connection between retinal and brain perfusion in patients with psychosis. METHODS: A total of 48 participants, 17 healthy control and 31 probands, took part in the Bipolar and Schizophrenia Network on Intermediate Phenotype-2 (BSNIP-2) study at the Boston location at Beth Israel Deaconess Medical Center. Participants underwent arterial spin labeling MRI (magnetic resonance imaging) and retinal OCTA (optical coherence tomography angiography) imaging to determine brain and retinal perfusion, respectively. Whole retinal layer (superficial, deep, and choriocapillaris) and lobe-wise brain perfusion (frontal, temporal, parietal, occipital, and cingulate cortices) was used for analyses. Statistical analysis was performed in R and results were summarized using basic descriptive statistics. RESULTS: In probands, there was a significant positive correlation between vessel diameter index (VDI) and frontal lobe perfusion (r=0.74, p=0.000027) and between vessel diameter (VD) and frontal lobe perfusion (r=0.64, p=0.00077), but not for healthy controls. There was a significant negative correlation between VDI and temporal lobe perfusion (r=-0.56, p=0.0046), but not for healthy controls. There were no significant results for healthy controls or probands between retinal perfusion and occipital lobe perfusion. CONCLUSION: This study demonstrates that retinal perfusion may be a proxy marker for frontal lobe perfusion and could be used for predicting cognitive performance in a psychosis population given that the frontal lobe is primarily involved in executive functioning. There was an absence of a relationship between retinal perfusion and the occipital perfusion which suggests that retinal perfusion does not match visual neuronal pathway connections to the occipital cortex. These findings demonstrate a step towards appreciating how the retina can be leveraged to understand brain dysfunction in psychosis.

Κυριότερος σκοπός είναι η αξιολόγηση των συστημάτων Υπολογιστικής Τομογραφίας και Μαγνητικού Συντονισμού κατά την εφαρμογή της τεχνικής Δυναμικής Αιμάτωσης (Perfusion). Επίσης η δημιουργία και εφαρμογή αναλυτικού και αποτελεσματικού πρωτοκόλλου στην οξεία ισχαιμία με σκοπό την άμεση βοήθεια του ισχαιμικού εγκεφάλου. / Thesis MSc in order to highlight the usefulness of CT Brain Perfusion in acute brain ischemia.

A imagem por ressonância magnética (IRM) tem se tornado uma poderosa ferramenta clínica na avaliação da anatomia cerebral. Recentemente, várias técnicas têm tornado possível a caracterização da função cerebral através da estimativa de alguns parâmetros metabólicos. Uma dessas técnicas é a perfusão cerebral, que descreve a passagem de sangue através da rede vascular cerebral, e permite estimar, não invasivamente, algumas características das funções hemodinâmicas tais como Volume de Sangue Cerebral (CBV), Fluxo de Sangue Cerebral (CBF) e Tempo de Trânsito Médio (MTT). Neste trabalho foi desenvolvido um programa computacional, baseado na plataforma Matlab, que analisa as imagens e cria mapas de perfusão. Primeiro foi comparado o desempenho do método de ajuste de curvas convencional Levenberg-Marquardt (LM) versus o Método que utiliza o Algoritmo Genético (AG). Os resultados mostraram que os AGS são muito mais estáveis, com relação aos seus parâmetros de controle, do que o método usual LM e, portanto, fornece evidencias da eficácia do AG em relação ao método convencional. Como um segundo e principal objetivo nós aplicamos o método para construir e examinar os mapas de perfusão em pacientes com anemia falciforme (sickle cell disease -SCD), particularmente em relação a complicações neurológicas e anormalidades vistas como uma técnica de imagem complementar. Além disso, os mapas de perfusão agregam informação a respeito de aspectos funcionais do sistema vascular, que é complementar a informação anatômica. Os nossos resultados com mostraram que esses mapas são uma ferramenta importante para auxiliar na avaliação clínica dos pacientes com anemia falciforme, como também podem ser aplicados para avaliar áreas em risco tão bem quanto ajudar no tratamento clínico de tais pacientes. / Magnetic Resonance Imaging (MRI) has become a powerful clinical tool for evaluation of brain anatomy. Several recently techniques have made possible the characterization of brain function via assessment of metabolic parameters. One of these techniques is the cerebral perfusion, which describes passage of blood through the brain\'s vascular network, and al- lows estimating, non-invasively, some characteristics of hemodynamic functions such as Cerebral Blood Volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT). In this work a computational program was development, based on Matlab platform, which analyze perfusion images and create perfusion maps. First, the performance of conven- tional Levenberg-Marquardt Method (LM) versus a Genetic Algorithms (GAs) was com- pared. The results showed that the GAs are more stable than usual LM method with rela- tion to their control parameters and therefore provides evidence the effectiveness of the GAs with relation to a conventional method. As a second and principal objective we ap- plied the method to construct and examine perfusion maps of patients with sickle cell dis- ease (SCD), particularly in relation to the neurological complications and to abnormalities seen with complementary imaging techniques. Moreover, perfusion maps aggregate infor- mation about functional aspects of the vascular system, which is complementary to ana- tomical information. Our results show that these maps are an important tool to support clinical evaluation of sickle cell disease patients, as it may be applied to evaluate brain areas at risk as well as a help in the clinical treatment of such patients.

A imagem por ressonância magnética (IRM) tem se tornado uma poderosa ferramenta clínica na avaliação da anatomia cerebral. Recentemente, várias técnicas têm tornado possível a caracterização da função cerebral através da estimativa de alguns parâmetros metabólicos. Uma dessas técnicas é a perfusão cerebral, que descreve a passagem de sangue através da rede vascular cerebral, e permite estimar, não invasivamente, algumas características das funções hemodinâmicas tais como Volume de Sangue Cerebral (CBV), Fluxo de Sangue Cerebral (CBF) e Tempo de Trânsito Médio (MTT). Neste trabalho foi desenvolvido um programa computacional, baseado na plataforma Matlab, que analisa as imagens e cria mapas de perfusão. Primeiro foi comparado o desempenho do método de ajuste de curvas convencional Levenberg-Marquardt (LM) versus o Método que utiliza o Algoritmo Genético (AG). Os resultados mostraram que os AGS são muito mais estáveis, com relação aos seus parâmetros de controle, do que o método usual LM e, portanto, fornece evidencias da eficácia do AG em relação ao método convencional. Como um segundo e principal objetivo nós aplicamos o método para construir e examinar os mapas de perfusão em pacientes com anemia falciforme (sickle cell disease -SCD), particularmente em relação a complicações neurológicas e anormalidades vistas como uma técnica de imagem complementar. Além disso, os mapas de perfusão agregam informação a respeito de aspectos funcionais do sistema vascular, que é complementar a informação anatômica. Os nossos resultados com mostraram que esses mapas são uma ferramenta importante para auxiliar na avaliação clínica dos pacientes com anemia falciforme, como também podem ser aplicados para avaliar áreas em risco tão bem quanto ajudar no tratamento clínico de tais pacientes. / Magnetic Resonance Imaging (MRI) has become a powerful clinical tool for evaluation of brain anatomy. Several recently techniques have made possible the characterization of brain function via assessment of metabolic parameters. One of these techniques is the cerebral perfusion, which describes passage of blood through the brain\'s vascular network, and al- lows estimating, non-invasively, some characteristics of hemodynamic functions such as Cerebral Blood Volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT). In this work a computational program was development, based on Matlab platform, which analyze perfusion images and create perfusion maps. First, the performance of conven- tional Levenberg-Marquardt Method (LM) versus a Genetic Algorithms (GAs) was com- pared. The results showed that the GAs are more stable than usual LM method with rela- tion to their control parameters and therefore provides evidence the effectiveness of the GAs with relation to a conventional method. As a second and principal objective we ap- plied the method to construct and examine perfusion maps of patients with sickle cell dis- ease (SCD), particularly in relation to the neurological complications and to abnormalities seen with complementary imaging techniques. Moreover, perfusion maps aggregate infor- mation about functional aspects of the vascular system, which is complementary to ana- tomical information. Our results show that these maps are an important tool to support clinical evaluation of sickle cell disease patients, as it may be applied to evaluate brain areas at risk as well as a help in the clinical treatment of such patients.

No description available.

Le traitement des gliomes de haut grade représente un réel défi médical. Les techniques de thérapies actuelles sont principalement à visée palliative et leur efficacité est limitée. De nombreuses stratégies thérapeutiques sont explorées pour trouver un traitement curatif. La radiothérapie stéréotaxique par rayonnement synchrotron (SSRT) est une technique innovante dont le principe repose sur l'accumulation sélective d'un élément lourd (Z élevé) dans la tumeur, suivie d'une irradiation stéréotaxique avec un faisceau monochromatique de rayons X, de faible énergie (50-100 keV), issus d'une source synchrotron. Une augmentation de la dose déposée localement dans la tumeur est obtenue grâce au renforcement de l’effet photoélectrique dans ces conditions. Cette thèse s’inscrit dans le cadre des essais cliniques de phase I et II de la SSRT menés sur des métastases cérébrales, au synchrotron européen à Grenoble. Une injection systémique d’un agent de contraste iodé et un faisceau synchrotron de 80 keV sont utilisés lors de ces essais. L’efficacité de la SSRT repose directement sur la concentration de l’agent de contraste iodé accumulé dans la tumeur, sa stabilité au cours du temps et sa reproductibilité chez le même patient. L’objectif principal de ce travail a été d’évaluer et de modéliser les concentrations d'iode moyennes atteintes dans des métastases cérébrales, d’une part, et d’appréhender les impacts dosimétriques, engendrés par les variations spatiales et temporelles de ces concentrations sur le traitement des patients, d’autre part. Un protocole d'imagerie scanner a été conçu spécifiquement pour cette étude afin de permettre le suivi, temporel et spatial, des concentrations d'iode et l’extraction des paramètres de perfusion cérébrale dans une métastase cérébrale. Une méthodologie d'analyse expérimentale et une modélisation théorique de la bio-distribution d'iode dans des métastases cérébrales ont été développées. Un modèle mathématique reliant les concentrations d'iode aux paramètres de perfusion a été établi, dans le but de prédire les concentrations d'iode chez chaque patient et de réduire la durée du protocole de suivi. La reproductibilité de la prise de contraste a été caractérisée chez des patients à dix jours d’intervalle. Les impacts dosimétriques des écarts de concentrations d'iode observés sur les plans de traitement en SSRT ont été analysés. Ces derniers ont été comparés aux plans de traitement obtenus avec différentes techniques de pointe en radiothérapie afin d’évaluer les performances dosimétriques de la SSRT. / Gliomas treatment is still a challenging disease in medicine. Available treatments are mainly palliative and their efficiency is limited. Since years, many therapeutic strategies have been explored to find a cure. Synchrotron stereotactic radiotherapy (SSRT) is an innovative treatment combining the selective accumulation of heavy elements in tumours with stereotactic irradiations using monochromatic medium energy x-rays from a synchrotron source. A localised dose enhancement in brain tumours is obtained due to the reinforced photoelectric absorption in these conditions. This thesis takes part in the framework of phase I/II clinical trials, which are underway at the European Synchrotron Radiation Facility in Grenoble, France. These trials are realised on human brain metastasis using venous infusion of iodinated contrast agents and a 80 keV X-ray beam. The radiation dose enhancement depends on the amount of iodine in the tumour, its time course and its reproducibility for each patient. The aim of this work was to evaluate and model the amounts of iodine concentrations reached in brain metastasis, and to analyse the dosimetric deviations caused by spatial and temporal variations of these concentrations during the treatments. A CT cine scan protocol was designed especially for this study in order to extract quantitative iodine concentrations and associated brain perfusion parameters in human brain metastasis, as key parameters for treatment feasibility and quality. An experimental analysis methodology and a theoretical model of iodine biodistribution were developed. A mathematical relationship between iodine concentrations and perfusion parameters was established in order to estimate these concentrations for each patient in the future and to reduce the imaging dose, associated to the prolonged imaging acquisition time. The reproducibility of iodine uptake between the CT planning scan day and the treatment day was assessed (~10 days interval). The impact of iodine concentration variations on reference SSRT dosimetries was analysed. Finally, SSRT treatment plans were compared to those obtained with different cutting-edge radiotherapy techniques in order to evaluate dosimetric performances of SSRT.

Hintergrund: Im Rahmen intrakranieller Operationen kann die intraoperative Darstellung der Gehirndurchblutung die intraoperative Entscheidungsfindung unterstützen. Eine Alternative zu den etablierten Methoden der fluoreszenzgestützten Techniken und der Duplex-Sonographie stellt die intraoperative Perfusionsbildgebung auf Grundlage der Thermographie dar. Hiermit wird die temperaturabhängige, infrarote Strahlung des Gehirns gemessen, die annehmbar abhängig von der zerebralen Perfusion ist. Das Verfahren vereint die Vorteile des nebenwirkungsarmen, kontaktlosen, wiederholten und ökonomischen Einsatzes mit einem verhältnismäßig geringen apparativen Aufwand. Fragestellung/Hypothese: In der vorliegenden Arbeit sollen die intraoperativen Temperaturvariationen des Kortex thermographisch untersucht werden. Durch die intravenöse Applikation eines kalten Flüssigkeitsbolus kann ein systemischer Kältereiz erzeugt werden, der als thermographisches Kontrastmittel agiert. Die Untersuchung der Sensitivität der kortikalen Kältesignalerfassung in Abhängigkeit der Injektionsparameter des Flüssigkeitsbolus und anderer intraoperativer Variablen soll für die Etablierung eines robusten und klinisch nutzbaren Messaufbaus genutzt werden. Die gewonnenen Informationen sollen darüber hinaus zur Entwicklung eines Auswertungsalgorithmus für die automatisierte, thermographische Erfassung des kortikalen Kältesignals dienen. Abschließend werden potenzielle, klinische Anwendungsszenarien beschrieben. Material und Methoden: Die thermographischen Aufnahmen wurden mit ungekühlten Focal-Plane-Array-Kameras mit einer thermischen Auflösung von bis zu 20 mK durchgeführt. Es wurden 97 Patienten intraoperativ untersucht und insgesamt 210 Kältebolusinjektionen appliziert. Die zugrundeliegenden Pathologien waren größtenteils Glioblastome und zerebrale Metastasen sowie Gliome II°/III°, Hirninfarkte, arteriovenöse Malformationen und Aneurysmen. Nach chirurgischer Exposition des zerebralen Kortex wurde die thermographische Messung des Kortex gestartet. Es folgte die intravenöse Injektion der Kälteboli mit einer Temperatur von etwa 4°C aus physiologischer Kochsalzlösung und einem Volumen von 20 ml (59 % der Fälle) oder 50 ml (41 % der Fälle) über einen peripheren (76 % der Fälle) oder zentralen Venenkatheter (24 % der Fälle). Es wurden die Injektionsgeschwindigkeit und Vitalparameter registriert. Nachfolgend wurden die thermographischen Sequenzen einer Datenvorverarbeitung unterzogen, um das Signal-Rausch-Verhältnis zu verbessern. Es folgte die Auswertung der resultierenden Temperatur-Zeit-Reihen zur Kältesignaldetektion mit der Hauptkomponentenanalyse nach Steiner et al., dem Bigauss-Algorithmus nach Hollmach und einer manuellen Analyse (Steiner et al., 2011; Hollmach, 2016). Die Qualität der Auswertungsalgorithmen wurden auf Basis von 10 parallelen Kältebolus-ICG-Injektionen überprüft. Die ICG-Signale wurden als Referenz für die Kältesignaldetektionen genutzt. Die Beschreibung der Kältesignale erfolgte anhand der Parameter twash-in, tmin(T), trise, ttransit und ΔT. Ergebnisse: Die Thermographie kann kleinste Temperaturvariation des Kortex von bis zu 20 mK aufzeichnen. Periodische Temperaturänderungen können zum Teil durch physiologische Prozesse wie Atmung und Herzaktion erklärt werden, während andere spontane Temperaturschwankungen bisher keinen pathophysiologischen Äquivalenten zugewiesen werden können. Das systemische Kältesignal in Form des intravenösen Kältebolus kann bei der kortikalen Passage thermographisch als Temperatursenke registriert werden. Die Sensitivität der Kältesignalerfassung wird wesentlich durch die Injektionsparameter Bolusvolumen, Applikationsort und -geschwindigkeit bestimmt und lässt sich durch eine periphervenöse, 50 ml umfassende Bolusinjektion mit einer Geschwindigkeit von ≥ 5,4 ml/s auf über 70 % steigern. Die Vitalparameter beeinflussen die Kältesignaldetektion nicht. Die Validierung der Kältesignaldetektionen mittels paralleler Kältebolus-ICG-Injektionen offenbarte, dass die präexistenten Auswertungsalgorithmen der Hauptkomponentenanalyse und des Bigauss-Algorithmus eine hohe Sensitivität von 90 % hinsichtlich anteilig richtig-positiver Kältesignaldetektionen erzielen. Jedoch wurden in 90 % der Referenzfälle falsch-positive Kältesignale erkannt, sodass eine geringe Spezifität und ein geringer positiv-prädiktiver Wert resultiert. Beide Algorithmen weisen eine hohe Fehleranfälligkeit auf und sind ungeeignet, um intraoperativ das systemische Kältesignal zuverlässig zu erfassen. Aus den gewonnenen Erkenntnissen der manuellen Analyse der ICG-Kältebolus-Referenzfälle konnte der optimierte AKE-Auswertungsalgorithmus (Automatisierte Kältesignaldetektion nach Empirischem Vorwissen) entwickelt werden. Der AKE-Algorithmus besitzt in den Referenzfällen eine Sensitivität von 100 % und eine qualitativ deutlich verbesserte Spezifität. Der AKE-Algorithmus ist in der Lage, im intraoperativen Einsatz die Kältesignale innerhalb weniger Minuten nach der Kältebolusinjektion zuverlässig in Form zweidimensionaler Parameterkarten zu visualisieren. Auf Basis des AKE-Algorithmus wurden die Kältesignalerfassungen in verschiedenen intrakraniellen Pathologien untersucht. Die Kältesignalparameter in Glioblastomen präsentieren neben einer großen Heterogenität eine durchschnittlich erhöhte Perfusion im Vergleich zum peritumoralen Gewebe in Form einer verminderten twash-in und einer erhöhten ttransit. Jedoch ist eine Identifizierung der Tumorgrenzen anhand der Kältesignaldetektionen nicht möglich, weil die Kältesignalparameter intra- und peritumoralen Gewebes nicht signifikant differieren. Bei der thermographischen Untersuchung maligner Hirninfarkte können die Infarktkerne bereits als hypotherme Kortexregionen und durch eine negative Kältesignaldetektion erfasst werden. Kollateralkreisläufe werden registriert und die Kältesignalparameter korrelieren mit dem postoperativen NIHSS. Die Kältesignalerfassung gelingt zunehmend im Übergang von CT-morphologisch demarkierten zu nicht-demarkierten Hirnarealen und zeigt begleitend eine kürzere twash-in. Damit besteht potenziell die Möglichkeit, in weiteren Untersuchungen die Penumbra zu untersuchen und prognostische Informationen zu gewinnen. Die Kältesignalerkennung bei AVMs konnte sicher erfolgen und die Perfusion der pathologischen Gefäßanteile nachweisen. Somit kann die Thermographie die vollständige Ausschaltung oberflächlicher AVMs unterstützen und ist des Weiteren in der Lage, die Perfusion des umgebenden Parenchyms zu beurteilen. Ebenso kann die Kältesignaldetektion bei der Operation von Aneurysmen zur Erfolgskontrolle und zur Erfassung Clip-bedingter kortikaler Minderperfusionen dienen. Schlussfolgerungen: Die thermographische Detektion eines systemischen Kältereizes ist möglich und kann intraoperativ zusätzliche Informationen generieren, die in operative Entscheidungen oder wissenschaftliche Untersuchungen einfließen können. Um einen robusten und zuverlässigen, intraoperativen Einsatz der thermographischen Kältesignaldetektion zu ermöglichen, sollten zukünftig ausschließlich 50 ml Boli, periphervenöse Injektionen und eine Injektionsgeschwindigkeit ≥ 5,4 ml/s verwendet werden. Für eine schnelle und zuverlässige, intraoperative Ergebnisgenerierung und -darstellung sollte der AKE-Algorithmus bevorzugt werden. Die thermographische Kältesignaldetektion eignet sich insbesondere für die Untersuchung primär vaskulärer Pathologien, wie Hirninfarkte, AVMs oder Aneurysmen.:Inhaltsverzeichnis A Abbildungsverzeichnis B Tabellenverzeichnis C Abkürzungsverzeichnis 1 Einleitung 2 Medizinische Grundlagen 2.1 Präoperative Bildgebung in der Neurochirurgie 2.1.1 Konventionelles MRT, CT und Angiographie 2.1.1 Dynamisch-funktionelle MRT-Sequenzen 2.1.2 Neuronavigation 2.2 Intraoperative Bildgebung zur zerebralen Perfusionsvisualisierung 2.2.1 Fluoreszenzgestützte Techniken 2.2.2 Ultraschall 3 Thermographie 3.1 Physikalische Grundlagen 3.2 Anwendung der Thermographie in der Medizin 4 Zielstellung 5 Material und Methoden 5.1 Thermographische Messung 5.1.1 Messaufbau 5.1.2 Messinstrumentarium 5.1.3 Ablauf der Kältebolus-Messung 5.1.4 Simultane Erfassung des Infrarot- und ICG-Signals 5.2 Methoden der Datenverarbeitung 5.2.1 Vorverarbeitung der Daten 5.2.2 Hauptkomponentenanalyse 5.2.3 Bigauss-Algorithmus 5.3 Auswahl des Patientenkollektivs 6 Ergebnisse 6.1 Patientenkollektiv 6.2 Ergebnisse der Hauptkomponentenanalyse 6.3 Ergebnisse des Bigauss-Algorithmus 6.4 Manuelle Analyse und ICG-Fälle 6.4.1 Schlussfolgerungen der manuell analysierten ICG-Kälteboli 6.4.2 Ergebnisse aller manuell analysierten Kälteboli 6.5 Entwicklung des AKE-Algorithmus 6.6 Ergebnisse des AKE-Algorithmus 6.6.1 Allgemeine Kälteboluscharakteristik 6.6.2 Kältesignalparameter in Abhängigkeit der Injektionsparameter 6.6.3 Kältesignaldetektion als interpathologischer Vergleich 6.6.4 Kältesignaldetektion als intrapathologische Analyse 7 Diskussion 7.1 Vergleich der Verfahren der Kältesignaldetektion 7.2 Einflussfaktoren 7.2.1 Vitalparameter 7.2.2 Injektionsparameter 7.3 Bedeutung der Kältesignalparameter 7.4 Potential der Kältebolusdetektion in Pathologien mittels AKE-Algorithmus 7.4.1 Glioblastom 7.4.2 Maligner Hirninfarkt 7.4.3 Neurovaskuläre Pathologien 7.5 Thesen 8 Zusammenfassung / Summary 9 Literaturverzeichnis 10 Danksagung 11 Anlage 1 12 Anlage 2 / Background: In intracranial surgery, intraoperative imaging of cerebral blood flow can support intraoperative decision making. An alternative to established methods of fluorescence-based techniques and duplex sonography is intraoperative perfusion imaging based on thermography. It receives temperature-dependent, infrared radiation, which depends on cerebral perfusion. Thermography combines the advantages of low-side-effects, contactless, repeated and economical use with a relatively low outlay on equipment. Objective/Hypothesis: In the present work the intraoperative temperature variations of the cortex are to be examined thermographically. The intravenous application of a cold fluid bolus creates a systemic cold stimulus that acts as a thermographic contrast agent. By examining the sensitivity of the cortical cold signal acquisition depending on the injection parameters of the fluid bolus and other intraoperative variables, a robust and clinically usable measurement setup is to be established. The information obtained should also be used to develop an evaluation algorithm for the automated, thermographic detection of the cortical cold signal. Finally, potential clinical application scenarios are described. Material and Methods: The thermographic recordings were made with uncooled focal plane array cameras with a thermal resolution of up to 20 mK. 97 patients were examined intraoperatively and a total of 210 cold bolus injections were administered. The underlying pathologies were mostly glioblastomas and cerebral metastases as well as gliomas II° / III°, brain infarctions, arteriovenous malformations and aneurysms. After surgical exposure of the cerebral cortex, the thermographic measurement of the cortex was started. This was followed by intravenous injection of the cold 0,9% saline boluses with a temperature of about 4 °C and a volume of 20 ml (59% of cases) or 50 ml (41% of cases) via a peripheral (76% of cases) or central venous line (24% of cases). The injection rate and vital parameters were registered. The thermographic sequences were subsequently subjected to data preprocessing in order to improve the signal-to-noise ratio. The resulting temperature-time series are evaluated to find cold signals using the principal component analysis according to Steiner et al., the Bigauss algorithm according to Hollmach and a manual analysis (Steiner et al., 2011; Hollmach, 2016). The results were checked based on 10 parallel cold bolus ICG injections. The ICG signals were used as a reference for the cold signal detection. The cold signals were described by the parameters twash-in, tmin(T), trise, ttransit and ΔT. Results: Thermography can record smallest temperature variations of the cortex up to 20 mK. Periodic changes in temperature can be explained in part by physiological processes such as breathing and heart rate, while other spontaneous temperature fluctuations cannot yet be assigned to any pathophysiological equivalents. The systemic cold signal in the form of the intravenous cold bolus can be thermographically registered as a temperature drop during the cortical passage. The sensitivity of the cold signal detection is essentially determined by the injection parameters bolus volume, injection site and injection rate. It can be increased to more than 70% with a peripheral venous line, 50 ml bolus volume and an injection rate of ≥ 5.4 ml/s. The vital parameters do not influence the cold signal detection. The validation of the cold signal detection using parallel cold bolus and ICG injections revealed that the pre-existent evaluation algorithms of the principal component analysis and the Bigauss algorithm achieve a high sensitivity of 90 % with regard to proportionally correct-positive cold signal detection. However, false-positive cold signals were detected in 90% of the reference cases, resulting in low specificity and low positive-predictive value. Both algorithms are highly susceptible to errors and are unsuitable for reliably detection of the systemic cold signal intraoperatively. From the knowledge obtained from the manual analysis of the ICG - cold bolus reference cases, the optimized AKE evaluation algorithm (Automated Cold signal detection based on Empirical prior knowledge) was developed. In the reference cases, the AKE algorithm has a sensitivity of 100% and a qualitatively significantly improved specificity. The AKE algorithm is able to reliably visualize the cold signals in two-dimensional parameter maps within a few minutes after the cold bolus injection during intraoperative use. Based on the AKE algorithm, the cold signal recordings in various intracranial pathologies were examined. The cold signal parameters of glioblastomas showed a high degree of heterogeneity and on average an increased cerebral perfusion by reduced twash-in and increased ttransit compared to peritumoral tissue. However, an identification of the tumour borders based on the cold signal detection is not possible because the cold signal parameters of intra- and peritumoral tissue do not differ significantly. In the thermographic examination of malignant brain infarctions, the infarct cores can be detected as hypothermic cortex regions and by negative cold signal detection. Collateral circuits are registered thermographically and the cold signal parameters correlate with the postoperative NIHSS. The cold signal acquisition succeeds increasingly in the transition from CT-morphologically infarcted to non-infarcted brain areas and shows a smaller twash-in. Therefore, the cold bolus detection has the potential to investigate the penumbra and to obtain prognostic information. Cold signal detection in AVMs was carried out safely and the perfusion of the pathological vessels were demonstrated. Thus, thermography can support the complete elimination of superficial AVMs and is also able to assess the perfusion of the surrounding parenchyma. Cold signal detection can also be used in the operation of aneurysms to monitor complete elimination and clipping-related cerebral perfusion changes. Conclusions: The thermographic detection of the systemic cold stimulus is possible and can generate additional information intraoperatively, which can be incorporated into intraoperative decision making or scientific studies. In order to enable robust and reliable, intraoperative use of thermographic cold signal detection, further cold bolus examinations should be standardized with intravenous injection of 50 ml boluses via peripheral venous line and an injection rate ≥ 5.4 ml/s. The AKE algorithm should be preferred for fast and reliable, intraoperative result generation. Thermographic cold signal detection is particularly suitable for the investigation of primarily vascular pathologies such as brain infarctions, AVMs or aneurysms.:Inhaltsverzeichnis A Abbildungsverzeichnis B Tabellenverzeichnis C Abkürzungsverzeichnis 1 Einleitung 2 Medizinische Grundlagen 2.1 Präoperative Bildgebung in der Neurochirurgie 2.1.1 Konventionelles MRT, CT und Angiographie 2.1.1 Dynamisch-funktionelle MRT-Sequenzen 2.1.2 Neuronavigation 2.2 Intraoperative Bildgebung zur zerebralen Perfusionsvisualisierung 2.2.1 Fluoreszenzgestützte Techniken 2.2.2 Ultraschall 3 Thermographie 3.1 Physikalische Grundlagen 3.2 Anwendung der Thermographie in der Medizin 4 Zielstellung 5 Material und Methoden 5.1 Thermographische Messung 5.1.1 Messaufbau 5.1.2 Messinstrumentarium 5.1.3 Ablauf der Kältebolus-Messung 5.1.4 Simultane Erfassung des Infrarot- und ICG-Signals 5.2 Methoden der Datenverarbeitung 5.2.1 Vorverarbeitung der Daten 5.2.2 Hauptkomponentenanalyse 5.2.3 Bigauss-Algorithmus 5.3 Auswahl des Patientenkollektivs 6 Ergebnisse 6.1 Patientenkollektiv 6.2 Ergebnisse der Hauptkomponentenanalyse 6.3 Ergebnisse des Bigauss-Algorithmus 6.4 Manuelle Analyse und ICG-Fälle 6.4.1 Schlussfolgerungen der manuell analysierten ICG-Kälteboli 6.4.2 Ergebnisse aller manuell analysierten Kälteboli 6.5 Entwicklung des AKE-Algorithmus 6.6 Ergebnisse des AKE-Algorithmus 6.6.1 Allgemeine Kälteboluscharakteristik 6.6.2 Kältesignalparameter in Abhängigkeit der Injektionsparameter 6.6.3 Kältesignaldetektion als interpathologischer Vergleich 6.6.4 Kältesignaldetektion als intrapathologische Analyse 7 Diskussion 7.1 Vergleich der Verfahren der Kältesignaldetektion 7.2 Einflussfaktoren 7.2.1 Vitalparameter 7.2.2 Injektionsparameter 7.3 Bedeutung der Kältesignalparameter 7.4 Potential der Kältebolusdetektion in Pathologien mittels AKE-Algorithmus 7.4.1 Glioblastom 7.4.2 Maligner Hirninfarkt 7.4.3 Neurovaskuläre Pathologien 7.5 Thesen 8 Zusammenfassung / Summary 9 Literaturverzeichnis 10 Danksagung 11 Anlage 1 12 Anlage 2

L’imagerie IRM de perfusion par Arterial Spin Labeling (ASL) ou marquage des spin artériels a pour principal avantage d’être une méthode d’imagerie non invasive (non irradiante et sans injection de produit de contraste exogène), particulièrement adaptée à l'imagerie cérébrale pédiatrique. Sa facilité de mise en œuvre explique l’engouement pour cette séquence et de nombreuses applications cliniques émergentes. Cette technique initialement développée chez l’adulte nécessite une adaptation à la population pédiatrique, aussi bien des paramètres d’acquisition et de quantification que des algorithmes de traitement d’images. La perfusion cérébrale globale et régionale évolue physiologiquement, parallèlement à l’âge et au développement neurocognitif. Il existe plusieurs méthodes d’étude de la perfusion cérébrale pédiatrique. Dans ce contexte, deux revues de littérature ont été réalisées et publiées : l’une portant sur les différentes techniques d’imagerie de la perfusion cérébrale chez les nouveau-nés, l’autre se focalisant sur la technique d’ASL en pédiatrie et ses applications cliniques. Puis la chaîne de traitement des images morphologiques et de perfusion ASL, développée chez l’adulte au sein de notre unité, a été adaptée aux enfants puis aux nouveau-nés. Ces deux populations ont effectivement des problématiques différentes, en particulier le rapport signal sur bruit de l’ASL est très bon chez les enfants, mais nettement moins bon chez les nouveau-nés, et les images morphologiques ont un contraste différent en raison d’une myélinisation incomplète à la naissance. Grace à l’adaptation de la chaîne de traitement, des travaux de recherche clinique ont pu être finalisés (2 publiés, 1 soumis) illustrant l’intérêt de l’étude de la perfusion cérébrale dans 3 situations : l’étude de l’évolution de la perfusion cérébrale normale chez l’enfant entre 6 mois et 15 ans ; l’étude de la perfusion cérébrale chez les enfants souffrant d’une première crise de migraine avec aura ; et enfin l’étude de l’évolution de la perfusion cérébrale entre le 3ieme et le 10ieme jour de vie chez les enfants souffrant d’asphyxie périnatale et traités par hypothermie. Plusieurs projets restent en cours sur le sujet, avec d’autres challenges de traitement et d’analyse d’image (enfants de neurochirurgie avec modifications morphologiques du cerveau, ou enfants prématurés par exemple), dans la continuité ce qui a été fait au cours de cette thèse. / Physiological changes in overall and regional cerebral perfusion are related to age and neurocognitive development. Brain perfusion in the pediatric population can be assessed using a number of imaging techniques. Two literature reviews were undertaken and published on this topic: one based on brain perfusion imaging techniques in neonates, and the other based on the ASL technique in the pediatric population and its clinical applications. The Arterial Spin Labeling (ASL) MRI perfusion sequence is one of the most suitable imaging techniques for children given that the procedure is non-irradiating and non-invasive (without exogenous contrast agent injection). There are many emerging cerebral perfusion imaging applications for children due to the highly convenient implementation of the ASL sequence, which can be easily incorporated into standard brain MRI protocols following acquisition of morphological images. Certain technical adjustments to the imaging parameters are required to account for the fundamental differences between the pediatric and adult populations. Measuring cerebral blood flow (CBF) in neonates and children using ASL therefore requires a number of adaptations to acquisition and related parameters.The processing of ASL data also requires specific adaptations, in particular regarding the automated segmentation of brain tissues, and the parameters used for CBF quantification models. The processing pipeline for both anatomical and perfusion images that had been previously developed by our team for adult data was adapted firstly for children and secondly for neonates. These two populations notably have specific age-related concerns; in particular the signal-to-noise ratio of ASL is very good in children, but much less so in neonates, and the morphological images have inverted contrast due to incomplete myelination at birth. Following adaptation of the processing pipeline, several studies were completed (2 original articles published and 1 under review), showing the clinical benefits of studying cerebral perfusion in three situations: first physiological changes in cerebral perfusion in children between 6 months and 15 years; secondly changes in cerebral perfusion in children with a first attack of migraine with aura; and lastly changes in brain perfusion between day of life 3 and day of life 10 in asphyxiated neonates. Following adaptation of the processing pipeline, several studies were completed (2 original articles published and 1 under review), showing the clinical benefits of studying cerebral perfusion in three situations: first physiological changes in cerebral perfusion in children between 6 months and 15 years; secondly changes in cerebral perfusion in children with a first attack of migraine with aura; and lastly changes in brain perfusion between day of life 3 and day of life 10 in asphyxiated neonates. Several studies are still in progress, and these present new image processing challenges, involving, for example, children with neurosurgical conditions and morphological changes in the brain, or premature babies, in line with the work undertaken for this thesis.

<p>    </p> <p>Cerebrovascular diseases, such as stroke, constitute the most common life-threatening neurological disease in the United States. To support normal brain function, maintaining adequate brain perfusion (i.e., cerebral blood flow (CBF)) is important. Therefore, it is crucial to assess the brain perfusion so that early intervention in cerebrovascular diseases can be applied if abnormal perfusion is observed. The goal of my study is to develop metrics to measure the brain perfusion through modeling brain physiology using resting-state and task-based blood-oxygenation-level- dependent (BOLD) functional MRI (fMRI). My first and second chapters focused on deriving the blood arrival time using the resting-state BOLD signal. In the first chapters, we extracted the systemic low-frequency oscillations (sLFOs) in the fMRI signal from the internal carotid arteries (ICA) and the superior sagittal sinus (SSS). Consistent and robust results were obtained across 400 scans showing the ICA signals leading the SSS signals by about 5 seconds. This delay time could be considered as an effective perfusion biomarker that is associate with the cerebral circulation time (CCT). To further explore sLFOs in assessing dynamic blood flow changes during the scan, in my second chapter, a “carpet plot” (a 2-dimensional plot time vs. voxel) of scaled fMRI signal intensity was reconstructed and paired with a developed slope-detection algorithm. Tilted vertical edges across which a sudden signal intensity change took place were successfully detected by the algorithm and the averaged propagation time derived from the carpet plot matches the cerebral circulation time. Given that CO₂ is a vasodilator, controlling of inhaled CO₂ is able to modulate the BOLD signal, therefore, as a follow-up study, we focused on investigating the feasibility of using a CO₂ modulated sLFO signal as a “natural” bolus to track CBF with the tool developed from the second chapter. Meaningful transit times were derived from the CO₂-MRI carpet plots. Not only the timing, the BOLD signal deformation (the waveform change) under CO₂ challenge also reveals very useful perfusion information, representing how the brain react to stimulus. Therefore, my fourth chapter focused on characterizing the brain reaction to the CO₂ stimulus to better measure the brain health using BOLD fMRI. Overall, these studies deepen our understanding of fMRI signal and the derived perfusion parameters can potentially be used to assess some cerebrovascular diseases, such as stroke, ischemic brain damage, and steno-occlusive arterial disease in addition to functional activations. </p>