Quantitative ß mapping for calibrated fMRI.

The metabolic and hemodynamic dependencies of the blood oxygenation level-dependent (BOLD) signal form the basis for calibrated fMRI, where the focus is on oxidative energy demanded by neural activity. An important part of calibrated fMRI is the power-law relationship between the BOLD signal and the deoxyhemoglobin concentration, which in turn is related to the ratio between oxidative demand (CMRO2) and blood flow (CBF). The power-law dependence between BOLD signal and deoxyhemoglobin concentration is signified by a scaling exponent ß. Until recently most studies assumed a ß value of 1.5, which is based on numerical simulations of the extravascular BOLD component. Since the basal value of CMRO2 and CBF can vary from subject-to-subject and/or region-to-region, a method to independently measure ß in vivo should improve the accuracy of calibrated fMRI results. We describe a new method for ß mapping through characterizing R2' - the most sensitive relaxation component of BOLD signal (i.e., the reversible magnetic susceptibility component that is predominantly of extravascular origin at high magnetic field) - as a function of intravascular magnetic susceptibility induced by an FDA-approved superparamagnetic contrast agent. In α-chloralose anesthetized rat brain, at 9.4 T, we measured ß values of ~0.8 uniformly across large neocortical swathes, with lower magnitude and more heterogeneity in subcortical areas. Comparison of ß maps in rats anesthetized with medetomidine and α-chloralose revealed that ß is independent of neural activity levels at these resting states. We anticipate that this method for ß mapping can help facilitate calibrated fMRI for clinical studies.

Brain region and activity-dependent properties of M for calibrated fMRI.

Calibrated fMRI extracts changes in oxidative energy demanded by neural activity based on hemodynamic and metabolic dependencies of the blood oxygenation level-dependent (BOLD) response. This procedure requires the parameter M, which is determined from the dynamic range of the BOLD signal between deoxyhemoglobin (paramagnetic) and oxyhemoglobin (diamagnetic). Since it is unclear if the range of M-values in human calibrated fMRI is due to regional/state differences, we conducted a 9.4T study to measure M-values across brain regions in deep (α-chloralose) and light (medetomidine) anesthetized rats, as verified by electrophysiology. Because BOLD signal is captured differentially by gradient-echo (R2*) and spin-echo (R2) relaxation rates, we measured M-values by the product of the fMRI echo time and R2' (i.e., the reversible magnetic susceptibility component), which is given by the absolute difference between R2* and R2. While R2' mapping was shown to be dependent on the k-space sampling method used, at nominal spatial resolutions achieved at high magnetic field of 9.4T the M-values were quite homogenous across cortical gray matter. However cortical M-values varied in relation to neural activity between brain states. The findings from this study could improve precision of future calibrated fMRI studies by focusing on the global uniformity of M-values in gray matter across different resting activity levels.

High-resolution relaxometry-based calibrated fMRI in murine brain: Metabolic differences between awake and anesthetized states.

Functional magnetic resonance imaging (fMRI) techniques using the blood-oxygen level-dependent (BOLD) signal have shown great potential as clinical biomarkers of disease. Thus, using these techniques in preclinical rodent models is an urgent need. Calibrated fMRI is a promising technique that can provide high-resolution mapping of cerebral oxygen metabolism (CMRO2). However, calibrated fMRI is difficult to use in rodent models for several reasons: rodents are anesthetized, stimulation-induced changes are small, and gas challenges induce noisy CMRO2 predictions. We used, in mice, a relaxometry-based calibrated fMRI method which uses cerebral blood flow (CBF) and the BOLD-sensitive magnetic relaxation component, R2', the same parameter derived in the deoxyhemoglobin-dilution model of calibrated fMRI. This method does not use any gas challenges, which we tested on mice in both awake and anesthetized states. As anesthesia induces a whole-brain change, our protocol allowed us to overcome the former limitations of rodent studies using calibrated fMRI. We revealed 1.5-2 times higher CMRO2, dependent upon brain region, in the awake state versus the anesthetized state. Our results agree with alternative measurements of whole-brain CMRO2 in the same mice and previous human anesthesia studies. The use of calibrated fMRI in rodents has much potential for preclinical fMRI.