Direct estimation of evoked hemoglobin changes by multimodality fusion imaging

In recent years there has been an emergence of an assortment of imaging modalities for noninvasively studying the brain. Among these, functional magnetic resonance imaging (fMRI)^{1, 2, 3, 4} and diffuse optical tomography (DOT)^{5, 6, 7, 8} are two techniques that have been developed largely in parallel to study cerebral functional hemodynamic responses. While both of these technologies are being applied successfully to a wide range of similar neuroscience and clinical topics, there are intrinsic limitations to each method, which are imposed by the governing physics of each technology (reviewed in Refs. 9, 10). For example, while fMRI techniques such as blood oxygen level dependent (BOLD) can provide a measurement of blood oxygen saturation changes with fairly high spatial resolution (typically $2\text{to}4\mathrm{mm}$ for functional studies), these signals are physiologically ambiguous, owing to the indirect relationship between changes in the transverse relaxation rate of hydrogen nuclei $\left(\Delta R_2^{*}\right)$ and physiological hemodynamic parameters (i.e., deoxyhemoglobin and blood oxygen saturation) (reviewed in Ref. 11). Although such ambiguity does not impede the use of BOLD for mapping the spatial patterns of evoked changes, this does limit the use of BOLD to directly relate physiological parameters between subjects without additional calibration methods. Calibration of the BOLD signal is possible by inducing isometabolic changes in cerebral blood flow using hypercapnia or similar vasoactive agents. ^{12, 13, 14, 15, 16, 17, 18} However, these hypercapnic-calibration methods require the subject to inhale increased levels of carbon dioxide gas for prolonged periods of time (up to several minutes). This procedure is both technically challenging and subject to several possible sources of systematic error¹⁹ that may render the technique difficult to translate to clinical applications. While the use of hypercapnia-calibrated fMRI techniques to provide quantitative measurements of blood oxygen saturation changes has been important in applying MR techniques to study metabolism, an alternative to hypercapnia calibration is needed to make the estimation of functional $\mathrm{CMR}{\mathrm{O}}_2$ changes more routine. As $\mathrm{CMR}{\mathrm{O}}_2$ is more directly related to neural-metabolic coupling, these measurements could have significant impact in better understanding the connections between neural and hemodynamic function in health and disease (reviewed in Ref. 20).