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.

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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.

We offer a new method for characterizing the magnitude and dynamics of the vascular response to changes in arterial gas tensions using noninvasive blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI) and paradigms appropriate for clinical settings. A novel respiratory task, “Cued Deep Breathing” (CDB), consisting of two consecutive cycles of cued breaths, has been developed to cause transient hypocapnia, and consequently a strong, short-lived BOLD signal decrease. Data from CDB hypocapnia paradigms and traditional breath-holding hypercapnia paradigms were analyzed on a voxelwise basis to map regional heterogeneity in magnitude and timing parameters. The tasks caused comparable absolute BOLD percent signal changes (~0.5-3.0% in gray matter) and both datasets suggested consistent regional heterogeneity in the response timing: parts of the basal ganglia, particularly the putamen, and bilateral areas of medial cortex reached their maximum signal change several seconds earlier than remaining cortical gray matter voxels. This phenomenon and a slightly delayed response in posterior cortical regions were present in group-maps of ten healthy subjects. An auxiliary experiment in different subjects measured end-tidal CO2 changes associated with the new CDB task and quantitatively compared the resulting reactivity maps with those acquired using a traditional hypercapnia challenge of 4% CO2 gas inspiration. The CDB task caused average end-tidal CO2 decreases between 6.0±1.1 and 10.5±2.6 mmHg, with levels returning to baseline after approximately three breaths, giving evidence that the task indeed causes transient mild hypocapnia. Similarity between resulting reactivity maps suggest CDB offers an alternative method for mapping cerebrovascular reactivity.

Investigations into the blood oxygenation level-dependent (BOLD) functional MRI signal have used respiratory challenges with the aim of probing cerebrovascular physiology. Such challenges have altered the inspired partial pressures of either carbon dioxide or oxygen, typically to a fixed and constant level (fixed inspired challenge (FIC)). The resulting end-tidal gas partial pressures then depend on the subject's metabolism and ventilatory responses. In contrast, dynamic end-tidal forcing (DEF) rapidly and independently sets end-tidal oxygen and carbon dioxide to desired levels by altering the inspired gas partial pressures on a breath-by-breath basis using computer-controlled feedback. This study implements DEF in the MRI environment to map BOLD signal reactivity to CO(2). We performed BOLD (T2(*)) contrast FMRI in four healthy male volunteers, while using DEF to provide a cyclic normocapnic-hypercapnic challenge, with each cycle lasting 4 mins (PET(CO(2)) mean+/-s.d., from 40.9+/-1.8 to 46.4+/-1.6 mm Hg). This was compared with a traditional fixed-inspired (FI(CO(2))=5%) hypercapnic challenge (PET(CO(2)) mean+/-s.d., from 38.2+/-2.1 to 45.6+/-1.4 mm Hg). Dynamic end-tidal forcing achieved the desired target PET(CO(2)) for each subject while maintaining PET(O(2)) constant. As a result of CO(2)-induced increases in ventilation, the FIC showed a greater cyclic fluctuation in PET(O(2)). These were associated with spatially widespread fluctuations in BOLD signal that were eliminated largely by the control of PET(O(2)) during DEF. The DEF system can provide flexible, convenient, and physiologically well-controlled respiratory challenges in the MRI environment for mapping dynamic responses of the cerebrovasculature.

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 (CMR O2 ) using both a group-average and a per-subject calibration. The groupaveraged calibration showed significantly different CMR O2

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.brain activation ͉ diffusion MRI ͉ functional MRI ͉ neuronal swelling F unctional neuroimaging has enabled major advances in the study of normal and pathological brain function. However, the methods that provide the greatest coverage and spatial resolution, including positron emission tomography (1, 2) and magnetic resonance imaging (MRI) (3, 4), are indirect measures of neuronal activity based on metabolically driven changes in blood flow. These hemodynamic measures suffer from spatial and temporal confounds (5, 6), are nonlinearly related to neuronal firing (7,8), and depend on baseline hemodynamics that are uncoupled from the activity of interest (9, 10). An imaging method that detects neuronal activity more directly while achieving whole-brain coverage would therefore represent a significant advance for neuroscience.One alternative method is diffusion-weighted functional MRI (DFMRI), which attenuates the MRI signal in a manner that depends on the amount of motion (diffusion and flow) in the underlying tissue. In general, this attenuation is described by a factor exp(ϪbD), where D is the apparent diffusion coefficient of the local tissue, and b is an acquisition parameter that describes the strength of diffusion contrast. At low b value, true diffusive motion is more difficult to detect, and the ''apparent diffusion'' is dominated by local blood flow (11)(12)(13)(14). In general, diffusion weighting is directional, so that attenuation depends on the diffusion and flow parameters along the applied direction. Different signal sources have been proposed in DFMRI depending on the b value. Early work used low b value, which is thought to reflect tissue perfusion (11-16). Recent work suggested that DFMRI at high b value detects cellular swelling that is a direct consequence of neural firing (17, 18), which would constitute a more direct measure of neuronal activity.A recent study at high b valu...

Cerebrovascular reactivity (CVR) is defined as the ability of vessels to alter their caliber in response to vasoactive factors, by means of dilating or constricting, in order to increase or decrease regional cerebral blood flow (CBF). Importantly, CVR may provide a sensitive biomarker for pathologies where vasculature is compromised. Furthermore, the spatiotemporal dynamics of CVR observed in healthy subjects, reflecting regional differences in cerebral vascular tone and response, may also be important in functional MRI studies based on neurovascular coupling mechanisms. Assessment of CVR is usually based on the use of a vasoactive stimulus combined with a CBF measurement technique. Although transcranial Doppler ultrasound has been frequently used to obtain global flow velocity measurements, MRI techniques are being increasingly employed for obtaining CBF maps. For the vasoactive stimulus, vasodilatory hypercapnia is usually induced through the manipulation of respiratory gases, including the inhalation of increased concentrations of carbon dioxide. However, most of these methods require an additional apparatus and complex setups, which not only may not be well-tolerated by some populations but are also not widely available. For these reasons, strategies based on voluntary breathing fluctuations without the need for external gas challenges have been proposed. These include the task-based methodologies of breath holding and paced deep breathing, as well as a new generation of methods based on spontaneous breathing fluctuations during resting-state. Despite the multitude of alternatives to gas challenges, existing literature lacks definitive conclusions regarding the best practices for the vasoactive modulation and associated analysis protocols. In this work, we perform an extensive review of CVR mapping techniques based on MRI and CO2 variations without gas challenges, focusing on the methodological aspects of the breathing protocols and corresponding data analysis. Finally, we outline a set of practical guidelines based on generally accepted practices and available data, extending previous reports and encouraging the wider application of CVR mapping methodologies in both clinical and academic MRI settings.