Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

MRI Characterization of Radiation Necrosis in an Animal Model: Time to Onset, Progression, and Therapeutic Response

Radiation necrosis is a severe, but late occurring type of injury to normal tissue, within and surrounding a radiation treatment field, which can lead to significant complications for neurooncology patients. Radiation necrosis is difficult to distinguish from recurrent tumor by either neurologic examination or clinical imaging protocols. Concerns for the development of radiation necrosis often limit therapeutic radiation doses. Current treatment options for radiation necrosis are limited. The development of solutions to these clinical challenges has been hampered by an appropriate animal model of radiation necrosis. With a novel mouse model of radiation necrosis developed in our lab employing a Gamma Knife, which enables high-dose, fractionated, hemispherical irradiation in the mouse brain, the objectives were to i) optimise radiation dosing schemes: total dose, fractionation) for this Gamma-Knife mouse-model of radiation necrosis; ii) determine the efficacy of bevacizumab: Avastin) and its murine analog B20-4.1.1, both vascular endothelial growth factor: VEGF) inhibitors, as mitigators of radiation necrosis in mice; iii) validate the neuroprotective effect of SB 415286, an inhibitor of glycogen synthase kinase 3β;: GSK-3β), in mouse brain following high-dose radiation treatment; and iv) identify and validate the quantitative blood oxygen level dependent: qBOLD) method as an imaging marker of radiation necrosis. For these purposes, a series of experiments were performed, including monitoring the onset and progression of radiation necrosis in mice receiving different dose schedules, comparing the development of radiation necrosis in irradiated mice with or without treatments, and mapping the irradiated and non-irradiated mouse brains using qBOLD method. It was found that i) radiation dose schedules affect the onset and progression of radiation necrosis; ii) anti-VEGF antibodies slow the progression of radiation necrosis in irradiated brain tissue; iii) SB 415286 protects against and mitigates radiation necrosis in irradiated brain tissue; and iv) a high SNR: 400 at least) is required to decouple oxygen extraction fraction: OEF) and deoxyhemoglombin cerebral blood volume: dCBV) in mouse brain using qBOLD method. In qBOLD, the voxel spread function: VSF) reduces the effect of macroscopic magnetic field inhomogeneities. However, with current shimming methods, imaging parameters, and post-processing algorithms, the resulting OEF and dCBV maps in the mouse brain are not reliable. These results demonstrated that the development of radiation necrosis in this Gamma Knife mouse model can be characterized by both anatomic MR imaging and histology. Both anti-VEGF therapy and GSK-3β inhibition could be potential therapeutic managements for radiation necrosis, but further studies are needed to optimize dosing schemes and treatment periods and elucidate mechanisms of action. Characterizing radiation necrosis in mouse brain using qBOLD remains a challenge due to the imperfect correction for macro magnetic field inhomogeneities

Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities

Study of the Term Neonatal Brain Injury with combined Diffuse Optical Tomography and Electroencephalography

This thesis describes the application of combined diffuse optical tomography (DOT) and electroencephalography (EEG) in the investigation of neonatal term brain injury. With hypoxic ischaemic encephalopathy (HIE) and perinatal stroke being the most frequent contributors to brain injury in the term neonatal population, the first part of the thesis focuses on the description and ongoing requirement for their further investigation. In continuation to that, the characteristics and unique properties of both DOT and EEG are described and explored. The combination of these two modalities was utilised in elucidating the relationship between neuronal activity and cerebral haemodynamics both in physiological processes as well as in disease, by the infant’s cot side. This work differs to previous studies using near-infrared technologies and EEG, as a denser whole head array was used, offering the potential of 3-dimensional image reconstruction of the cortical haemodynamic events in relation to electro-cortical activity. These methods were applied in the study of critically ill infants presenting with seizures in the first few days of life. The relevant results are presented in three separate chapters of the thesis. Distinct neurophysiological phenomena such as seizures and burst suppression were detected and studied in association to underlying HIE. On the grounds of a pre-existing pilot study of our research group, distinct prolonged de-oxygenated cortical areas were identified following electrical seizure activity. Further exploration of infants with seizures provided limited supporting evidence. The investigation of burst suppression in HIE led to the first ever identification of repeated, waveform, cortical haemodynamic events in response to bursts of electrical activity with some spatial correlation to regions of brain injury. Further analysis of the low frequencies within the diffuse optical signal in cases of perinatal stroke, showed a consistent interhemispheric difference between the healthy and stroke-affected brain regions. The limitations, prospects and conclusions are presented in the final chapter. The use of simultaneous DOT and EEG offers a unique neuro-monitoring and neuro-investigating tool in the neonatal intensive care environment, which is safe, portable, and cost-effective, Ongoing research is required for the exploration and development of the methodology and its potential diagnostic properties

Functional Imaging of Malignant Gliomas with CT Perfusion

The overall survival of patients with malignant gliomas remains dismal despite multimodality treatments. Computed tomography (CT) perfusion is a functional imaging tool for assessing tumour hemodynamics. The goals of this thesis are to 1) improve measurements of various CT perfusion parameters and 2) assess treatment outcomes in a rat glioma model and in patients with malignant gliomas. Chapter 2 addressed the effect of scan duration on the measurements of blood flow (BF), blood volume (BV), and permeability-surface area product (PS). Measurement errors of these parameters increased with shorter scan duration. A minimum scan duration of 90 s is recommended. Chapter 3 evaluated the improvement in the measurements of these parameters by filtering the CT perfusion images with principal component analysis (PCA). From computer simulation, measurement errors of BF, BV, and PS were found to be reduced. Experiments showed that CT perfusion image contrast-to-noise ratio was improved. Chapter 4 investigated the efficacy of CT perfusion as an early imaging biomarker of response to stereotactic radiosurgery (SRS). Using the C6 glioma model, we showed that responders to SRS (surviving \u3e 15 days) had lower relative BV and PS on day 7 post-SRS when compared to controls and non-responders (P \u3c 0.05). Relative BV and PS on day 7 post-SRS were predictive of survival with 92% accuracy. Chapter 5 examined the use of multiparametric imaging with CT perfusion and 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) to identify tumour sites that are likely to correlate with the eventual location of tumour progression. We developed a method to generate probability maps of tumour progression based on these imaging data. Chapter 6 investigated serial changes in tumour volumetric and CT perfusion parameters and their predictive ability in stratifying patients by overall survival. Pre-surgery BF in the non-enhancing lesion and BV in the contrast-enhancing lesion three months after radiotherapy had the highest combination of sensitivities and specificities of ≥ 80% in predicting 24 months overall survival. iv Optimization and standardization of CT perfusion scans were proposed. This thesis also provided corroborating evidence to support the use of CT perfusion as a biomarker of outcomes in patients with malignant gliomas