Arterial Spin Labeling methods for quantitative brain perfusion mapping

Cerebral blood flow (CBF) is one of the most important physiological parameters, in particular it is crucial for proper maintenance of normal metabolic rates in animals and humans and informs on the homeostastis of the brain. CBF, which is tightly coupled to glucose metabolism, is also a well-established correlate of brain function and therefore an essential marker for evaluating the complex brain mechanisms at both normal and diseased states. The scientific and technological revolution of Magnetic Resonance Imaging (MRI) in the last decades allowed the development of new imaging techniques for the in vivo measurement of brain perfusion without using ionizing radiation, unlike techniques as Computed Tomography (CT) or Positron Emission Tomography (PET). Among these different MRI sequences, Arterial Spin Labeling (ASL) was created for non-invasively measuring the perfusion parameters by using magnetically labeled arterial blood water as an endogenous tracer. Therefore, this method eliminates all the potential risks connected to external contrast agents, allowing repeated and longitudinal studies in patients for monitoring the disease progression as well as easily studying the physiological brain mechanisms in healthy subjects thanks to its non invasiveness. The development of ASL techniques is currently an active research area and applications of ASL both in clinics and neuroscience are steadily growing. The main focus of this thesis is on the development and evaluation of ASL methods ultimately with applications for functional brain imaging and quantitative mapping in resting-state conditions. Different aspects of ASL sequences, from acquisition to post-processing analysis, will be assessed in the context of this thesis as well as possible solutions for solving some open problems in this field. In Chapter I, the general context of our studies is introduced. In particular, it presents a brief introduction to perfusion imaging techniques and basic physical principles of the main ASL sequences. In the last part of the chapter, different models for perfusion quantification from ASL data are described along with the general pipeline employed for ASL data analysis. The next two chapters are devoted to introduce some of the main limitations encountered when ASL sequences are implemented and acquired in the MRI scanners. Indeed, a series of preliminary steps were performed on the product ASL sequences available in two different MRI scanners in order to increase the data quality and obtain more reliable perfusion estimates (Chapter II). An improved framework for minimising severe artefacts shown by the use of ASL with a 3D readout module is then introduced in Chapter III. This is a more complete approach which combines both the acquisition phase, involving the use of a new strategy for acquiring 3D ASL data, and post-processing analysis phase, with an ad-hoc algorithm for further reducing these artefacts which can seriously compromise the final results. In Chapter IV the ASL suitability for functional imaging studies is investigated by using different types of motor tasks and comparing the results to those obtained with the Blood Oxygenation Level Dependent (BOLD) functional MRI technique, which is still considered to be the gold-standard in this type of studies. In particular, the results from two techniques will be compared in terms of activation, localisation, sensitivity and spatial accuracy. The motor protocol includes active and passive hand movements, in order to evaluate from a more physiological point of view the different haemodynamic changes induced by these tasks. Chapter V introduces two main questions that need to be addressed in order to confidently apply ASL sequence in clinical settings, especially when single patients have to be evaluated. Therefore, patient-specific analyses are described. In the first part, a novel approach for assessing the reliability of perfusion estimates is proposed, in order to provide complementary information that can help for a more precise interpretation of the results. In the second part, an automatic criterion for identifying on single patients areas of altered (increased/decreased) perfusion is introduced. This approach in particular will be extensively used in the following chapter. In Chapter VI, the experimental design and clinical applications on a group of patients are described. In particular, the chapter focuses on the evaluation of ASL results in comparison to those derived from other techniques as electrical source localization and PET in a group of twelve epileptic patients. The scope is to apply a multimodal approach combining noninvasive techniques of acquisition and analysis for the presurgical evaluation of drug-resistant epilepsy. Two subsequent ASL studies are described. In the first study, the main focus was on the assessment of the ASL suitability for detecting perfusion changes correlated to the epileptic focus in comparison to the results given by PET, which has shown during the last decades to have a high sensitivity and specificity in localising the focus in epileptic patients. In the second study, we sought to perform the ASL analysis at patient level and automatically identify the altered areas that might be connected to the focus by using the proposed approach introduced in Chapter V. In both cases, electrophysiological data and electrical source imaging were used as correlates and references for critically evaluating the ASL findings. In a subgroup of patients, the post-operative MRI scans and the clinical outcome information were also available and used as ground truth for assessing ASL and source imaging pre-operative results. The combination of multimodal techniques and their respectively methods of analysis are useful tools in the presurgical workup of epilepsy providing different methods of localization of the same epileptic foci and complementary information for a more complete picture of the disease. Furthermore, ASL represents a novel tool to the study of epilepsy and may play an increasingly important role in the evaluation of patients with refractory focal epilepsy.