Investigating the pathophysiological BOLD fMRI response to hypercapnia in patients with steno-occlusive disease

Abstract

The blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal constitutes a complex interplay between different neurophysiological parameters, primarily cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2). This represents a major drawback of BOLD fMRI, while the unknown extent of this interplay limits its clinical applicability. For instance, the BOLD fMRI response to hypercapnia is used to measure cerebrovascular reactivity (CVR). CVR is a measurement of the change in CBF in response to a vasoactive stimulus and represents a surrogate marker of the remaining vasodilatory capacity, which is an important clinical parameter of cerebrovascular health. However, it remains unclear whether BOLD-CVR can be considered a clinical imaging marker for stroke risk since it does not measure CBF directly. It is particularly unclear whether paradoxical (i.e. negative) perfusion reserve found with Diamox-challenged (15O)H2O Positron Emission Tomography (PET) --representing hemodynamic failure and increased stroke risk--, also reflects paradoxical BOLD-CVR. With a computer-controlled CO2 targeting machine using a pre-programmed sequence and a novel post-processing analysis method (Chapter 1), the underlying vascular and metabolic features of the BOLD fMRI signal to a controlled hypercapnic stimulus have been investigated. This research has demonstrated that BOLD-CVR in general shows a good agreement with PET perfusion reserve measurements (Chapter 2). To explore the discrepancy between BOLD-CVR and PET perfusion reserve, a remote indirect stroke effect known as diaschisis has been investigated, which causes a cerebral metabolic depression locally. (Chapter 3). In two different projects studying cerebellar and thalamic diaschisis, we observed a clear correlation of decreased BOLD-CVR with reduction of PET CBF, whilst the PET perfusion reserve remained intact. This implies the influence of a change in underlying metabolism to be the primary cause of the reduction of BOLD-CVR (Chapter 4). Finally, the interaction between BOLD-CVR and task-based BOLD fMRI response, in healthy subjects with known intact BOLD fMRI response neuronal activation has been researched. Hereby, a decrease in BOLD-CVR has been provoked by inducing a hypercapnic state at rest. This has shown that task-based BOLD fMRI response similarly decreased (Chapter 5). In summary, in this thesis I investigated the BOLD fMRI response to hypercapnia. The results provide compelling insights into the importance of distinguishing underlying vascular and metabolic components, which can influence the BOLD fMRI response to hypercapnia. These findings may open up new research avenues to study BOLD fMRI applications.