MUTLI-SCALE FUNCTIONAL IMAGING OF CEREBROVASCULAR DYNAMICS WITH APPLICATION TO BRAIN TUMORS

To meet cerebral metabolic demands, a sophisticated neurovascular mechanism is responsible for coupling neuronal activation with modulation of vascular tone and local cerebral blood flow (CBF). Due to this coupling, imaging techniques such as functional magnetic resonance imaging (fMRI) and optical imaging can characterize cerebrovascular dynamics as a surrogate to neural activation, making them useful tools for investigating brain functionality. These techniques have sparked widespread research into approaches capable of early detection of brain tumor-induced alterations in brain function, a consequence that often preordains cognitive decline. However, the complex interplay between abnormal brain tumor vasculature and disease-induced neurovascular uncoupling (NVU) can confound the interpretation of optical and MRI-derived functional imaging data. Therefore, in this thesis we sought to elucidate the effects of brain tumor progression on neuronal function through multi-scale analysis of resting state cerebrovascular dynamics. We first quantified brain tumor-induced changes on the resting state fMRI (rsfMRI) signal relative to that from healthy murine brains. We observed that brain tumors induced brain-wide reorganization of resting state networks extending to the contralateral hemisphere, accompanied by global attenuation of blood-oxygen-level-dependent (BOLD) signal fluctuations. Histological validation suggested that these connectivity alterations may be attributable to NVU. Next, we employed laser speckle contrast imaging (LSCI) and optical intrinsic signal (OIS) imaging to acquire multi-contrast hemodynamic maps of the entire murine cortical surface during both, the resting state and in response to a vasodilatory challenge. By exploiting the high temporal resolution and microvascular-scale spatial resolution, we characterized these changes at a level not possible with conventional fMRI techniques. Finally, we examined stimulus-induced changes in neurovascular dynamics using multi-contrast optical imaging. Using the neuronal and hemodynamic information acquired from the murine auditory cortex in response to auditory stimulation, we utilized two mathematical models to isolate regions exhibiting a frequency specific vascular response. Collectively, our findings on brain tumor induced alterations in resting state connectivity using multi-scale functional imaging methods lay the foundation for developing a novel biomarker for brain cancer progression. Furthermore, our multimodality research brings to the forefront the growing importance of functional imaging in neuroscience and beyond

Brain tumors disrupt the resting-state connectome

Brain tumor patients often experience functional deficits that extend beyond the tumor site. While resting-state functional MRI (rsfMRI) has been used to map such functional connectivity changes in brain tumor patients, the interplay between abnormal tumor vasculature and the rsfMRI signal is still not well understood. Therefore, there is an exigent need for new tools to elucidate how the blood‑oxygenation-level-dependent (BOLD) rsfMRI signal is modulated in brain cancer. In this initial study, we explore the utility of a preclinical model for quantifying brain tumor-induced changes on the rsfMRI signal and resting-state brain connectivity. We demonstrate that brain tumors induce brain-wide alterations of resting-state networks that extend to the contralateral hemisphere, accompanied by global attenuation of the rsfMRI signal. Preliminary histology suggests that some of these alterations in brain connectivity may be attributable to tumor-related remodeling of the neurovasculature. Moreover, this work recapitulates clinical rsfMRI findings from brain tumor patients in terms of the effects of tumor size on the neurovascular microenvironment. Collectively, these results lay the foundation of a preclinical platform for exploring the usefulness of rsfMRI as a potential new biomarker in patients with brain cancer. Keywords: Brain tumor, fMRI, Neurovascular uncoupling, Resting-state, Connectivit