The blood oxygenation level-dependent (BOLD) contrast is widely used in functional magnetic resonance imaging (fMRI) studies aimed at investigating neuronal activity. However, the BOLD signal reflects changes in blood volume and oxygenation rather than neuronal activity per se. Therefore, understanding the transformation of microscopic vascular behavior into macroscopic BOLD signals is at the foundation of physiologically informed noninvasive neuroimaging. Here, we use oxygen-sensitive two-photon microscopy to measure the BOLD-relevant microvascular physiology occurring within a typical rodent fMRI voxel and predict the BOLD signal from first principles using those measurements. The predictive power of the approach is illustrated by quantifying variations in the BOLD signal induced by the morphological folding of the human cortex. This framework is then used to quantify the contribution of individual vascular compartments and other factors to the BOLD signal for different magnet strengths and pulse sequences.

What is the organization of cerebral microvascular oxygenation and morphology that allows adequate tissue oxygenation at different activity levels? We address this question in the mouse cerebral cortex using microscopic imaging of intravascular O₂ partial pressure and blood flow combined with numerical modelling. Here we show that parenchymal arterioles are responsible for 50% of the extracted O₂ at baseline activity, and the majority of the remaining O₂ exchange takes place within the first few capillary branches. Most capillaries release little O₂ at baseline acting as an O₂ reserve that is recruited during increased neuronal activity or decreased blood flow. Our results challenge the common perception that capillaries are the major site of O₂ delivery to cerebral tissue. The understanding of oxygenation distribution along arterio-capillary paths may have profound implications for the interpretation of blood-oxygen-level dependent (BOLD) contrast in functional magnetic resonance imaging and for evaluating microvascular O₂ delivery capacity to support cerebral tissue in disease.

An automated massive histology setup combined with an optical coherence tomography (OCT) microscope was used to image a total of $n=5$ whole mouse brains. Each acquisition generated a dataset of thousands of OCT volumetric tiles at a sampling resolution of $4.9×4.9×6.5μm$. This paper describes techniques for reconstruction and segmentation of the sliced brains. In addition to the measured OCT optical reflectivity, a single scattering photon model was used to compute the attenuation coefficients within each tissue slice. Average mouse brain templates were generated for both the OCT reflectivity and attenuation contrasts and were used with an $n$-tissue segmentation algorithm. To better understand the brain tissue OCT contrast origin, one of the mouse brains was acquired using dMRI and coregistered to its corresponding assembled brain. Our results indicate that the optical reflectivity in a fiber bundle varies with its orientation, its fiber density, and the number of fiber orientations it contains. The OCT mouse brain template generation and coregistration to dMRI data demonstrate the potential of this massive histology technique to pursue cross-sectional, multimodal, and multisubject investigations of small animal brains.

The Journal of Biomedical Optics (JBO) publishes peer-reviewed papers on the use of novel optical systems and techniques for improved health care and biomedical research.

Optical coherence tomography (OCT) has recently been used to produce 3D angiography of microvasculature and blood flow maps of large vessels in the rodent brain in-vivo. However, use of this optical method for the study of cerebrovascular disease has not been fully explored. Recent developments in neurodegenerative diseases has linked common cardiovascular risk factors to neurodegenerative risk factors hinting at a vascular hypothesis for the development of the latter. Tools for studying cerebral blood flow and the myogenic tone of cerebral vasculature have thus far been either highly invasive or required ex-vivo preparations therefore not preserving the delicate in-vivo conditions. We propose a novel technique for reconstructing the flow profile over a single cardiac cycle in order to evaluate flow pulsatility and vessel compliance. A vascular model is used to simulate changes in vascular compliance and interpret OCT results. Comparison between atherosclerotic and wild type mice show a trend towards increased compliance in the smaller arterioles of the brain (diameter < 80μm) in the disease model. These results are consistent with previously published ex-vivo work confirming the ability of OCT to investigate vascular dysfunction.