• Neuroinformatics

The ability to visualize the perfusion territories of the brain feeding arteries is important for many clinical applications. Recently, selective arterial spin labeling (ASL) MRI has been introduced as the first method capable to visualize the perfusion territories of the brain in-vivo. In this thesis we describe the possibilities of selective ASL MRI and show the importance of perfusion territory information in studying the cerebral circulation in both patients with and without steno-occlusive disease. This most important findings of this thesis are twofold. Firstly, we demonstrate that the perfusion territories of the brain feeding arteries are considerably variable. Secondly, the variation in perfusion territories is mainly caused by anatomical variants of the circle of Willis, large artery steno-occlusive disease, or the combination of both. Thus far, the cerebral vascular territories are generally described as relatively invariant. Numerous standard atlases and textbooks show schematic drawings of the ‘normal’ territorial distribution. Most of these drawings are based on combinations of postmortem studies and assume a symmetrical and negligible variable territorial distribution. In contrast to these post-mortem studies, we demonstrated in-vivo that the variability of the cerebral perfusion territories is significantly greater than was previously assumed. The finding that the configuration of the circle of Willis strongly affects the extent of the cerebral perfusion territories seems relevant since up to 65% of healthy control subjects have an anatomical variant type. In addition to the large variability at the level of the circle of Willis, our results demonstrated that the presence of a severe stenosis or occlusion at the level of the arteries in the neck has major consequences for the distribution of the cerebral perfusion territories. Obstructive arterial disease at the level of the arteries in the neck is found in about 8% in the general healthy population, up to 30% in patients with symptomatic cerebral ischemia. The large variability of the cerebral territorial distribution demonstrated in this thesis has major implications for the clinical diagnosis and treatment of stroke. For example, physicians considering whether to treat acute stroke often use anatomic CT or MR images to assess affected vascular territories, and to determine whether infarction is embolic or hypotensive in nature. However, the results of this thesis demonstrate that neither the territories affected nor the nature of stroke can be accurately diagnosed on the basis of such anatomic studies. Currently used schematic drawings of the cerebral flow territories are based on standard atlases, and therefore give no certainty on the extent of the territories in the individual patient. To know more accurately the location of the perfusion territories, one should visualize them. In conclusion, the interaction of stenosis severity, multi-vessel disease, and vascular anatomy defines the location and the extent of the perfusion territories of the brain feeding arteries. To relate focal brain lesions to underlying perfusion territories in individual cases, knowledge of the territorial distribution is essential

The ability to visualize the perfusion territories of the brain feeding arteries is important for many clinical applications. Recently, selective arterial spin labeling (ASL) MRI has been introduced as the first method capable to visualize the perfusion territories of the brain in-vivo. In this thesis we describe the possibilities of selective ASL MRI and show the importance of perfusion territory information in studying the cerebral circulation in both patients with and without steno-occlusive disease. This most important findings of this thesis are twofold. Firstly, we demonstrate that the perfusion territories of the brain feeding arteries are considerably variable. Secondly, the variation in perfusion territories is mainly caused by anatomical variants of the circle of Willis, large artery steno-occlusive disease, or the combination of both. Thus far, the cerebral vascular territories are generally described as relatively invariant. Numerous standard atlases and textbooks show schematic drawings of the ‘normal’ territorial distribution. Most of these drawings are based on combinations of postmortem studies and assume a symmetrical and negligible variable territorial distribution. In contrast to these post-mortem studies, we demonstrated in-vivo that the variability of the cerebral perfusion territories is significantly greater than was previously assumed. The finding that the configuration of the circle of Willis strongly affects the extent of the cerebral perfusion territories seems relevant since up to 65% of healthy control subjects have an anatomical variant type. In addition to the large variability at the level of the circle of Willis, our results demonstrated that the presence of a severe stenosis or occlusion at the level of the arteries in the neck has major consequences for the distribution of the cerebral perfusion territories. Obstructive arterial disease at the level of the arteries in the neck is found in about 8% in the general healthy population, up to 30% in patients with symptomatic cerebral ischemia. The large variability of the cerebral territorial distribution demonstrated in this thesis has major implications for the clinical diagnosis and treatment of stroke. For example, physicians considering whether to treat acute stroke often use anatomic CT or MR images to assess affected vascular territories, and to determine whether infarction is embolic or hypotensive in nature. However, the results of this thesis demonstrate that neither the territories affected nor the nature of stroke can be accurately diagnosed on the basis of such anatomic studies. Currently used schematic drawings of the cerebral flow territories are based on standard atlases, and therefore give no certainty on the extent of the territories in the individual patient. To know more accurately the location of the perfusion territories, one should visualize them. In conclusion, the interaction of stenosis severity, multi-vessel disease, and vascular anatomy defines the location and the extent of the perfusion territories of the brain feeding arteries. To relate focal brain lesions to underlying perfusion territories in individual cases, knowledge of the territorial distribution is essential

In this thesis I have described the introduction and validation of a new spatially non-selective arterial spin labeling (SNS-ASL) method in healthy subjects. Acceleration selective ASL (AccASL) was compared with pseudo continuous ASL (pCASL), a traditional ASL method, as well as other spatially non-selective ASL methods (velocity selective ASL, as introduced by Wong et al with two velocity-selective blocks, and using only a single labeling module), and with [15O]-H2O PET as the gold standard for brain perfusion imaging. By combining an AccASL with VSASL labeling module, the location of label origin in the vascular tree was assessed. Furthermore, time-encoded pCASL was explored in combination with SNS-ASL labeling modules to obtain insight into labeling at multiple post labeling delays (PLD). Finally, te-pCASL was combined with T2-Relaxation-under-Spin-Tagging (TRUST) to provide a time efficient method to distinguish spin compartments based on their T2-values.

Image-quality assessment is a fundamental step before clinical evaluation of magnetic resonance images. The aim of this study was to introduce a visual scoring system that provides a quality control standard for arterial spin labeling (ASL) and that can be applied to cerebral blood flow (CBF) maps, as well as to ancillary ASL images. The proposed image quality control (QC) system had two components: (1) contrast-based QC (cQC), describing the visual contrast between anatomical structures; and (2) artifact-based QC (aQC), evaluating image quality of the CBF map for the presence of common types of artifacts. Three raters evaluated cQC and aQC for 158 quantitative signal targeting with alternating radiofrequency labelling of arterial regions (QUASAR) ASL scans (CBF, T1 relaxation rate, arterial blood volume, and arterial transient time). Spearman correlation coefficient (r), intraclass correlation coefficients (ICC), and receiver operating characteristic analysis were used. Intra/inter-rater agreement ranged from moderate to excellent; inter-rater ICC was 0.72 for cQC, 0.60 for aQC, and 0.74 for the combined QC (cQC + aQC). Intra-rater ICC was 0.90 for cQC; 0.80 for aQC, and 0.90 for the combined QC. Strong correlations were found between aQC and CBF maps quality (r = 0.75), and between aQC and cQC (r = 0.70). A QC score of 18 was optimal to discriminate between high and low quality clinical scans. The proposed QC system provided high reproducibility and a reliable threshold for discarding low quality scans. Future research should compare this visual QC system with an automatic QC system.

The brainstem (BS) is involved in critical physiologic processes, including control of cardiovascular and respiratory functions. This study implements a multi-inversion time pulsed arterial spin labelling (MTI PASL) imaging sequence that addresses the challenges of BS imaging and aims to measure normal and elevated BS perfusion in healthy volunteers. An initial experiment was performed to obtain the kinetic curve of the label in the BS and consequently to estimate the label arrival times and tissue perfusion in seven participants. A second experiment estimated the BS cerebral vascular reactivity (CVR) to hypercapnia in 10 participants. Images were acquired with a gradient-echo sequence with two spiral interleaves and short echo time (TE=2.7 ms). Data were analyzed with a two-compartment model, including a tissue and arterial component. In both experiments, perfusion in the BS was significantly lower than in cortical gray matter (repeated measures analysis of variance (RM-ANOVA), P<0.05), which is as expected since the BS consists of gray and white matter, the latter typically showing lower perfusion. The BS CVR found here is comparable to previous reports obtained with positron emission tomography (PET) imaging. Multi-inversion time pulsed ASL in combination with a two-compartment signal model can be used to assess BS perfusion and CVR.

Arterial spin labeling (ASL) is a magnetic resonance imaging technique for measuring tissue perfusion using a freely diffusible intrinsic tracer. As compared with other perfusion techniques, ASL offers several advantages and is now available for routine clinical practice in many institutions. Its noninvasive nature and ability to quantitatively measure tissue perfusion make ASL ideal for research and clinical studies. Recent technical advances have increased its sensitivity and also extended its potential applications. This review focuses on some basic knowledge of ASL perfusion, emerging techniques and clinical applications in neuroimaging.

Since 1997, when Bohning and colleagues demonstrated for the first time the feasibility of interleaving transcranial magnetic stimulation (TMS) with blood oxygenation level dependency functional magnetic resonance imaging (BOLD fMRI), this combination became a very promising techniques to study brain connectivity. However, the implementation of a reliable setup for interleaved TMS/fMRI is still technically challenging. In this thesis, I intended to further explore and develop methodological improvements in combining TMS and fMRI and to apply them in order to better understand the neural underpinnings of the behavioral TMS effects and to study brain connectivity. First, I developed and validated a new hardware/software coil positioning method for interleaved TMS/fMRI and demonstrated the feasibility of our overall setup. Second, a setup for combining TMS with continuous arterial spin labeling (CASL) was implemented and I tested the feasibility of this novel combination. Third, I demonstrated that this combination is sensitive enough to reliably measure rCBF changes induced by TMS, and that interleaved TMS/CASL can detect differences between the effects on regional cerebral flow (rCBF) of two different stimulation protocols. Fourth, it was shown that interleaved TMS/CASL is suitable to target questions from cognitive neuroscience. It was demonstrated that TMS applied over left dorsal premotor cortex (PMd) has different effects on the remote rCBF activation depending on the motor task. Overall, the results presented in this thesis suggest that interleaved TMS/CASL can become an interesting complement to interleaving TMS with normal BOLD fMRI, and that this combination can be considered for studying the impact of fully-fledged repetitive TMS protocols. Seit 1997, als Bohning und Kollegen zum ersten Mal die Möglichkeit einer Integration von TMS (Transkranieller Magnetstimulation) mit BOLD-fMRT (Blood Oxygenation Level Dependency Magnetresonanztomographie) demonstrierten, wurde diese Kombination rasch eine verheissungsvolle Methode, um die Konnektivität des Gehirns zu untersuchen. Die Implementierung eines zuverlässigen Setups für die Kombination von TMS/fMRT ist technisch nach wie vor eine grosse Herausforderung. Diese Dissertation beabsichtigt methodologische Verbesserungen für die Kombination von TMS mit fMRT weiter zu entwickeln und anzuwenden. Zuerst wird eine neue Hardware/Software TMS Spulenpositionierungsmethode für TMS kombiniert mit fMRT entwickelt, validiert sowohl die Realisierbarkeit des entwickelten, allgemeinen Setups untersucht. Zweitens wurde ein Setup für die Kombination von TMS mit CASL (Continuous Arterial Spin Labeling) eingeführt und ebenso die Realisierbarkeit dieser neuartigen Kombination geprüft. Drittens wird gezeigt, dass diese Kombination sensitiv genug ist für eine zuverlässige Messung der rCBF (Regional Cerebral Flow) Änderungen, verursacht durch TMS. Es wird ebenso demonstriert, dass die Kombination von TMS mit CASL Unterschiede in den Effekten auf den regionalen rCBF messen kann, hervorgerufen durch zwei verschieden Anregungsprotokolle. Viertens wird nachgewiesen, dass die Kombination von TMS mit CASL geeignet ist, Fragen der kognitiven Neurowissenschaft experimentell zu untersuchen. Es wird zum Beispiel gezeigt, dass TMS Stimulation über den linken dorsalen Premotor Cortex (PMd) verschiedene Effekte auf die rCBF Aktivierung hat, in Abhängigkeit von unterschiedlichen Bewegungszuständen. In Summe schlagen die Ergebnisse, die in dieser Dissertation dargestellt werden, vor, dass die Kombination von TMS mit CASL eine vielversprechende Ergänzung zur herkömmlichen Kombination von TMS mit BOLD-fMRT ist und dass diese Kombination als Auswirkung zur Erforschung neuer TMS Protokolle betrachtet werden kann.

Purpose : The purpose of this study was to describe arterial spin labeling MR image findings of status epilepticus. Materials and Methods: A retrospective chart review within our institute revealed six patients who had been clinically diagnosed as status epilepticus and had also undergone MR imaging that included ASL in addition to routine sequences. Results: Six patients with status epilepticus were studied by conventional MR and arterial spin labeling imaging. All patients showed increased regional CBF correlating with EEG pathology. Notably, in two patients, conventional MRI and DWI showed no abnormal findings whereas pCASL demonstrated regional increased CBF in both patients. Conclusion: Arterial spin labeling might offer additional diagnostic capabilities in the evaluation of patients with status epilepticus.

Cerebral blood flow is an important parameter in many diseases and functional studies that can be accurately measured in humans using arterial spin labelling (ASL) MRI. However, although rat models are frequently used for preclinical studies of both human disease and brain function, rat CBF measurements show poor consistency between studies. This lack of reproducibility is due, partly, to the smaller size and differing head geometry of rats compared to humans, as well as the differing analysis methodologies employed and higher field strengths used for preclinical MRI. To address these issues, we have implemented, optimised and validated a multiphase pseudo-continuous ASL technique, which overcomes many of the limitations of rat CBF measurement. Three rat strains (Wistar, Sprague Dawley and Berlin Druckrey IX) were used, and CBF values validated against gold-standard autoradiography measurements. Label positioning was found to be optimal at 45°, while post-label delay was optimised to 0.55 s. Whole brain CBF measures were 109 ± 22, 111 ± 18 and 100 ± 15 mL/100 g/min by multiphase pCASL, and 108 ± 12, 116 ± 14 and 122 ± 16 mL/100 g/min by autoradiography in Wistar, SD and BDIX cohorts, respectively. Tumour model analysis shows that the developed methods also apply in disease states. Thus, optimised multiphase pCASL provides robust, reproducible and non-invasive measurement of CBF in rats.