Daniel P. Bulte

A calibration method for quantitative BOLD fMRI based on hyperoxia

The estimation of changes in CMR(O2) using functional MRI involves an essential calibration step using a vasoactive agent to induce an isometabolic change in CBF. This calibration procedure is performed most commonly using hypercapnia as the isometabolic stimulus. However, hypercapnia possesses a number of detrimental side effects. Here, a new method is presented using hyperoxia to perform the same calibration step. This procedure requires independent measurement of Pa(O2), the BOLD signal, and CBF. We demonstrate that this method yields results that are comparable to those derived using other methods. Further, the hyperoxia technique is able to provide an estimate of the calibration constant that has lower overall intersubject and intersession variability compared to the hypercapnia approach.

Cerebral perfusion response to hyperoxia.

Graded levels of supplemental inspired oxygen were investigated for their viability as a noninvasive method of obtaining intravascular magnetic resonance image contrast. Administered hyperoxia has been shown to be effective as a blood oxygenation level-dependent contrast agent for magnetic resonance imaging (MRI); however, it is known that high levels of inspired fraction of oxygen result in regionally decreased perfusion in the brain potentially confounding the possibility of using hyperoxia as a means of measuring blood flow and volume. Although the effects of hypoxia on blood flow have been extensively studied, the hyperoxic regime between normoxia and 100% inspired oxygen has been only intermittently studied. Subjects were studied at four levels of hyperoxia induced during a single session while perfusion was measured using arterial spin labelling MRI. Reductions in regional perfusion of grey matter were found to occur even at moderate levels of hyperoxia; however, perfusion changes at all oxygen levels were relatively mild (less than 10%) supporting the viability of hyperoxia-induced contrast.

Quantitative measurement of cerebral physiology using respiratory-calibrated MRI.

Functional magnetic resonance imaging typically measures signal increases arising from changes in the transverse relaxation rate over small regions of the brain and associates these with local changes in cerebral blood flow, blood volume and oxygen metabolism. Recent developments in pulse sequences and image analysis methods have improved the specificity of the measurements by focussing on changes in blood flow or changes in blood volume alone. However, FMRI is still unable to match the physiological information obtainable from positron emission tomography (PET), which is capable of quantitative measurements of blood flow and volume, and can indirectly measure resting metabolism. The disadvantages of PET are its cost, its availability, its poor spatial resolution and its use of ionising radiation. The MRI techniques introduced here address some of these limitations and provide physiological data comparable with PET measurements. We present an 18-minute MRI protocol that produces multi-slice whole-brain coverage and yields quantitative images of resting cerebral blood flow, cerebral blood volume, oxygen extraction fraction, CMRO(2), arterial arrival time and cerebrovascular reactivity of the human brain in the absence of any specific functional task. The technique uses a combined hyperoxia and hypercapnia paradigm with a modified arterial spin labelling sequence.

Flow-metabolism coupling in human visual, motor, and supplementary motor areas assessed by magnetic resonance imaging.

Combined blood oxygenation level‐dependent (BOLD) and arterial spin labeling (ASL) functional MRI (fMRI) was performed for simultaneous investigation of neurovascular coupling in the primary visual cortex (PVC), primary motor cortex (PMC), and supplementary motor area (SMA). The hypercapnia‐calibrated method was employed to estimate the fractional change in cerebral metabolic rate of oxygen consumption (CMRO2) using both a group‐average and a per‐subject calibration. The group‐averaged calibration showed significantly different CMRO2−CBF coupling ratios in the three regions (PVC: 0.34 ± 0.03; PMC: 0.24 ± 0.03; and SMA: 0.40 ± 0.02). Part of this difference emerges from the calculated values of the hypercapnic calibration constant M in each region (MPVC = 6.6 ± 3.4, MPMC = 4.3 ± 3.5, and MSMA = 7.2 ± 4.1), while a relatively minor part comes from the spread and shape of the sensorimotor BOLD–CBF responses. The averages of the per‐subject calibrated CMRO2−CBF slopes were 0.40 ± 0.04 (PVC), 0.31 ± 0.03 (PMC), and 0.44 ± 0.03 (SMA). These results are 10–30% higher than group‐calibrated values, and are potentially more useful for quantifying individual differences in focal functional responses. The group‐average calibrated motor coupling value is increased to 0.28 ± 0.03 when stimulus‐correlated increases in end‐tidal CO2 are included. Our results support the existence of regional differences in neurovascular coupling, and argue for the importance of achieving optimal accuracy in hypercapnia calibrations to resolve method‐dependent variations in published results. Magn Reson Med 57:538–547, 2007.

Evidence for a vascular contribution to diffusion FMRI at high b value.

Recent work has suggested that diffusion-weighted functional magnetic resonance imaging (FMRI) with strong diffusion weighting (high b value) detects neuronal swelling that is directly related to neuronal firing. This would constitute a much more direct measure of brain activity than current methods and represent a major advance in neuroimaging. However, it has not been firmly established that the observed signal changes do not reflect residual vascular effects, which are known to exist at low b value. This study measures the vascular component of diffusion FMRI directly by using hypercapnia, which induces blood flow changes in the absence of a change in neuronal firing. Hypercapnia elicits a similar diffusion FMRI response to a visual stimulus including a rise in percent signal change with increasing b value, which was reported for visual activation. Analysis of the response timing found no evidence for an early response at high b value, which has been reported as evidence for a nonhemodynamic response. These results suggest that a large component of the diffusion FMRI signal at high b value is vascular rather than neuronal.

Sources of systematic bias in hypercapnia-calibrated functional MRI estimation of oxygen metabolism.

The change in cerebral rate of oxidative metabolism (CMR(O(2))) during neural activation may be estimated from blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and arterial spin-labeling (ASL) fMRI measurements. The established method relies on an epoch of iso-metabolic blood flow increase, typically induced by CO2 breathing, to calibrate the BOLD-CBF relationship at resting-state CMR(O2). Here, we discuss the systematic bias in CMR(O2)-CBF data that can be introduced depending on the value derived for the calibration constant (M) from the CO2 breathing epoch. We demonstrate that the fidelity of BOLD-CBF data acquired during the neural activation task have low impact on the tightness of CMR(O2)-CBF coupling, as well as the coupling slope, when the derived calibration value is of a relatively moderate amplitude (M in the range of, or greater than, 10-15 at 1.5 T). Via the standard reformulation of a grid in BOLD-CBF space into the CMR(O2)-CBF plane, we demonstrate the non-linear transformation that takes place and the sources of systematic bias that result. We find that the outcome of a neurovascular coupling study may be predicted to a large extent purely from the value of the calibration constant, M, that is used. Our results suggest that the accurate determination of M is of greater importance than thought previously and indicate that BOLD-CBF data must always be supplied when considering CMR(O2)-CBF behavior in a particular brain region.

Measurement of cerebral blood volume in humans using hyperoxic MRI contrast.

To develop a new method of measuring quantitative regional cerebral blood volume (CBV) using epochs of hyperoxia as an intravenous contrast agent with T2*‐weighted MRI.

Comparison of hypercapnia-based calibration techniques for measurement of cerebral oxygen metabolism with MRI.

MRI may be used to measure fractional changes in cerebral oxygen metabolism via a metabolic model. One step commonly used in this measurement is calibration with image data acquired during hypercapnia, which is a state of increased CO2 content of the blood. In this study some commonly used hypercapnia‐inducing stimuli were compared to assess their suitability for the calibration step. The following stimuli were investigated: (a) inspiration of a mixture of 4% CO2, 21% O2 and balance N2; (b) 30‐s breath holding; and (c) inspiration of a mixture of 4% CO2 and 96% O2 (i.e., carbogen). Measurements of BOLD and cerebral blood flow made on nine subjects during the different hypercapnia‐inducing stimuli showed that each stimulus leads to a different calibration of the model. We argue that of the aforementioned stimuli, inspiration of 4% CO2, 21% O2 and balance N2 should be preferred for the calibration as the other stimuli produce responses that violate assumptions of the metabolic model. Magn Reson Med 61:391–398, 2009.

Reduced cerebrovascular reactivity in young adults carrying the APOE ε4 allele

Functional magnetic resonance imaging (MRI) studies have shown that APOE ε2‐ and ε4‐carriers have similar patterns of blood‐oxygenation‐level‐dependent (BOLD) activation suggesting that we need to look beyond the BOLD signal to link APOEs effect on the brain to Alzheimers disease (AD)‐risk.

Comparison of CO2 in air versus carbogen for the measurement of cerebrovascular reactivity with magnetic resonance imaging.

Measurement of cerebrovascular reactivity (CVR) can give valuable information about existing pathology and the risk of adverse events, such as stroke. A common method of obtaining regional CVR values is by measuring the blood flow response to carbon dioxide (CO2)-enriched air using arterial spin labeling (ASL) or blood oxygen level-dependent (BOLD) imaging. Recently, several studies have used carbogen gas (containing only CO2 and oxygen) as an alternative stimulus. A direct comparison was performed between CVR values acquired by ASL and BOLD imaging using stimuli of (1) 5% CO2 in air and (2) 5% CO2 in oxygen (carbogen-5). Although BOLD and ASL CVR values are shown to be correlated for CO2 in air (mean response 0.11 ± 0.03% BOLD, 4.46 ± 1.80% ASL, n = 16 hemispheres), this correlation disappears during a carbogen stimulus (0.36 ± 0.06% BOLD, 4.97 ± 1.30% ASL). It is concluded that BOLD imaging should generally not be used in conjunction with a carbogen stimulus when measuring CVR, and that care must be taken when interpreting CVR as measured by ASL, as values obtained from different stimuli (CO2 in air versus carbogen) are not directly comparable.