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We present a method allowing determination of resting cerebral oxygen metabolism (CMRO2) from MRI and end-tidal O2 measurements acquired during a pair of respiratory manipulations producing different combinations of hypercapnia and hyperoxia. The approach is based on a recently introduced generalization of calibrated MRI signal models that is valid for arbitrary combinations of blood flow and oxygenation change. Application of this model to MRI and respiratory data during a predominantly hyperoxic gas manipulation yields a specific functional relationship between the resting BOLD signal M and the resting oxygen extraction fraction OEF0. Repeating the procedure using a second, primarily hypercapnic, manipulation provides a different functional form of M vs. OEF0. These two equations can be readily solved for the two unknowns M and OEF0. The procedure also yields the resting arterial O2 content, which when multiplied by resting cerebral blood flow provides the total oxygen delivery in absolute physical units. The resultant map of oxygen delivery can be multiplied by the map of OEF0 to obtain a map of the resting cerebral metabolic rate of oxygen consumption (CMRO2) in absolute physical units. Application of this procedure in a group of seven human subjects provided average values of 0.35±0.04 and 6.0±0.7% for OEF0 and M, respectively in gray-matter (M valid for 30ms echo-time at 3T). Multiplying OEF0 estimates by the individual values of resting gray-matter CBF (mean 52±5ml/100g/min) and the measured arterial O2 content gave a group average resting CMRO2 value of 145±30μmol/100g/min. The method also allowed the generation of maps depicting resting OEF, BOLD signal, and CMRO2.

Functional magnetic resonance imaging with blood oxygenation level-dependent (BOLD) contrast has had a tremendous influence on human neuroscience in the last twenty years, providing a non-invasive means of mapping human brain function with often exquisite sensitivity and detail. However the BOLD method remains a largely qualitative approach. While the same can be said of anatomic MRI techniques, whose clinical and research impact has not been diminished in the slightest by the lack of a quantitative interpretation of their image intensity, the quantitative expression of BOLD responses as a percent of the baseline T2*- weighted signal has been viewed as necessary since the earliest days of fMRI. Calibrated MRI attempts to dissociate changes in oxygen metabolism from changes in blood flow and volume, the latter three quantities contributing jointly to determine the physiologically ambiguous percent BOLD change. This dissociation is typically performed using a “calibration” procedure in which subjects inhale a gas mixture containing small amounts of carbon dioxide or enriched oxygen to produce changes in blood flow and BOLD signal which can be measured under well-defined hemodynamic conditions. The outcome is a calibration parameter M which can then be substituted into an expression providing the fractional change in oxygen metabolism given changes in blood flow and BOLD signal during a task. The latest generation of calibrated MRI methods goes beyond fractional changes to provide absolute quantification of resting-state oxygen consumption in micromolar units, in addition to absolute measures of evoked metabolic response. This review discusses the history, challenges, and advances in calibrated MRI, from the personal perspective of the author.

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ΔEtCO2 in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ΔEtCO2, P < 0.01). The OEF was 41±8% and 38±6%, and the CMRO2 was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ΔEtCO2, P < 0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.

Altered resting cerebral blood flow (CBF 0 ) in the acute phase post-concussion may contribute to neurobehavioral deficiencies, often reported weeks after the injury. However, in addition to changes in CBF 0 , little is known about other physiological mechanisms that may be disturbed within the cerebrovasculature. The aim of this study was to assess whether changes in baseline perfusion following sport-related concussion (SRC) were co-localized with changes in cerebral metabolic demand. Forty-two subjects (15 SRC patients 8.0 ± 4.6 days post-injury and 27 age-matched healthy control athletes) were studied cross-sectionally. CBF 0 , cerebrovascular reactivity (CVR), resting oxygen extraction (OEF 0 ) and cerebral metabolic rate of oxygen consumption (CMRO 2|0 ) were measured using a combination of hypercapnic and hyperoxic breathing protocols, and the biophysical model developed in calibrated MRI. Blood oxygenation level dependent and perfusion data were acquired simultaneously using a dual-echo arterial spin labelling sequence. SRC patients showed significant decreases in CBF 0 spread across the grey-matter ( P  < 0.05, corrected), and these differences were also confounded by the effects of baseline end-tidal CO 2 ( P  < 0.0001). Lower perfusion was co-localized with reductions in regional CMRO 2|0 ( P  = 0.006) post-SRC, despite finding no group-differences in OEF 0 ( P  = 0.800). Higher CVR within voxels showing differences in CBF was also observed in the SRC group ( P  = 0.001), compared to controls. Reductions in metabolic demand despite no significant changes in OEF 0 suggests that hypoperfusion post-SRC may reflect compromised metabolic function after the injury. These results provide novel insight about the possible pathophysiological mechanisms underlying concussion that may affect the clinical recovery of athletes after sport-related head injuries.

Functional near-infrared spectroscopy (fNIRS) and functional MRI (fMRI) are non-invasive techniques used to relate activity in different brain regions to certain tasks. Respiratory calibration of the blood oxygen level dependent (BOLD) signal, and combined fNIRS–fMRI approaches have been used to quantify physiological subcomponents giving rise to the BOLD signal. A comparison of absolute oxygen metabolism parameters between MRI and NIRS, using spatially resolved (SRS) NIRS and respiratory calibrated MRI, could yield additional insight in the physiology underlying activation. Changes in the BOLD signal, cerebral blood flow (CBF), and oxygen saturation (SO2) were derived from a single MRI sequence during a respiratory challenge in healthy volunteers. These changes were compared to SO2 obtained by a single probe SRS NIRS setup. In addition, concentration changes in oxygenated (O2Hb), deoxygenated (HHb), and total haemoglobin (tHb), obtained by NIRS, were compared to the parameters obtained by MRI. NIRS SO2 correlated with end-tidal CO2 (0.83, p<0.0001), the BOLD signal (0.82, p<0.0001), CBF (0.85, p<0.0001), and also MRI SO2 (0.82, p<0.0001). The BOLD signal correlated with NIRS HHb (−0.76, p<0.0001), O2Hb (0.41, p=0.001), and tHb (r=0.32, p=0.01). Good correlations show that changes in cerebral physiology, following a respiratory challenge, go hand in hand with changes in the BOLD signal, CBF, O2Hb, HHb, NIRS SO2, and MRI SO2. Out of all NIRS derived parameters, the SO2 showed the best correlation with the BOLD signal. •A setup to simultaneously quantify oxygen saturation with MRI and NIRS is presented.•Healthy adults were subjected to two episodes of hypercapnia breathing.•NIRS oxygen saturation had a good correlation with fMRI/BOLD oxygen saturation.•NIRS oxygen saturation had the best correlation with the fMRI BOLD signal.•Deoxygenated haemoglobin had the second best correlation with the fMRI BOLD signal.

Breathing a mixture of 10% CO2 with 90% O2 (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO2, and raises blood O2 saturation due to the enriched oxygen level. These effects both tend to reduce the level of deoxygenated hemoglobin in brain tissues, thereby reducing the potential for further increases in BOLD contrast. In the present study, blocks of intense visual stimulation (60s) were presented amid longer blocks (180s) during which subjects breathed various fractional concentrations (0–100%) of carbogen-10 diluted with medical air. When breathing undiluted carbogen-10, the BOLD response to visual stimulation was reduced below the level of noise against the background of the carbogen-10 response. At these concentrations, the total (visual+carbogen) BOLD response amplitude (7.5±1.0%, n=6) converged toward that seen with carbogen alone (7.5±1.0%, n=6). In spite of the almost complete elimination of the visual BOLD response, pseudo-continuous arterial spin-labeling on a separate cohort indicated a largely preserved perfusion response (89±34%, n=5) to the visual stimulus during inhalation of carbogen-10. The previously discussed observations suggest that venous saturation can be driven to very high levels during carbogen inhalation, a finding which has significant implications for calibrated MRI techniques. The latter methods involve estimation of the relative change in venous O2 saturation by expressing activation-induced BOLD signal increases as a fraction of the maximal BOLD signal M that would be observed as venous saturation approaches 100%. While the value of M has generally been extrapolated from much smaller BOLD responses induced using hypercapnia or hyperoxia, our results suggest that these effects could be combined through carbogen inhalation to obtain estimates of M based on larger BOLD increases. Using a hybrid BOLD calibration model taking into account changes in both blood flow and arterial oxygenation, we estimated that inhalation of carbogen-10 led to an average venous saturation of 91%, allowing us to compute an estimated M value of 9.5%. ► Almost complete elimination of the visual BOLD response during carbogen-10 breathing. ► Venous saturation can be driven to very high levels during carbogen inhalation. ► Lower bound on M of 7.5% BOLD signal change. ► Preserved perfusion response to visual stimulus despite elimination of BOLD contrast. ► Estimated M value of 9.5% using a hybrid BOLD calibration model.

Disentangling neural activity at different cortical depths during a functional task has recently generated growing interest, since this would allow to separate feedforward and feedback activity. The majority of layer-dependent studies have, so far, relied on gradient-recalled echo (GRE) blood-oxygenation-level dependent (BOLD) acquisitions, which are weighted towards the large draining veins at the cortical surface. The current study aims to obtain quantitative brain activity responses in the primary motor cortex on a laminar scale without the contamination due to accompanying secondary vascular effects. Evoked oxidative metabolism was evaluated using the Davis model, to investigate its applicability, advantages, and limits in lamina-dependent fMRI. Average values for the calibration parameter, M, and for changes in the cerebral metabolic rate of oxygen consumption (CMRO2) during a unilateral finger-tapping task were (11±2)% and (30±7)%, respectively, with distinct variation features across the cortical depth. The results presented here showed an uncoupling between BOLD-based functional magnetic resonance imaging (fMRI) and metabolic changes across cortical depth, while the tight coupling between CMRO2 and CBV was conserved across cortical layers. We conclude that the Davis model can help to obtain estimates of lamina-dependent metabolic changes without contamination from large draining veins, with high consistency and reproducibility across participants.

Functional magnetic resonance imaging (fMRI) techniques in which the blood oxygenation level dependent (BOLD) and cerebral blood flow (CBF) response to a neural stimulus are measured, can be used to estimate the fractional increase in the cerebral metabolic rate of oxygen consumption (CMRO2) that accompanies evoked neural activity. A measure of neurovascular coupling is obtained from the ratio of fractional CBF and CMRO2 responses, defined as n, with the implicit assumption that relative rather than absolute changes in CBF and CMRO2 adequately characterise the flow-metabolism response to neural activity. The coupling parameter n is important in terms of its effect on the BOLD response, and as potential insight into the flow-metabolism relationship in both normal and pathological brain function. In 10 healthy human subjects, BOLD and CBF responses were measured to test the effect of baseline perfusion (modulated by a hypercapnia challenge) on the coupling parameter n during graded visual stimulation. A dual-echo pulsed arterial spin labelling (PASL) sequence provided absolute quantification of CBF in baseline and active states as well as relative BOLD signal changes, which were used to estimate CMRO2 responses to the graded visual stimulus. The absolute CBF response to the visual stimuli were constant across different baseline CBF levels, meaning the fractional CBF responses were reduced at the hyperperfused baseline state. For the graded visual stimuli, values of n were significantly reduced during hypercapnia induced hyperperfusion. Assuming the evoked neural responses to the visual stimuli are the same for both baseline CBF states, this result has implications for fMRI studies that aim to measure neurovascular coupling using relative changes in CBF. The coupling parameter n is sensitive to baseline CBF, which would confound its interpretation in fMRI studies where there may be significant differences in baseline perfusion between groups. The absolute change in CBF, as opposed to the change relative to baseline, may more closely match the underlying increase in neural activity in response to a stimulus.

The calibrated BOLD (blood oxygen level dependent) technique was developed to quantify the BOLD signal in terms of changes in oxygen metabolism. In order to achieve this a calibration experiment must be performed, which typically requires a hypercapnic gas mixture to be administered to the participant. However, an emerging technique seeks to perform this calibration without administering gases using a refocussing based calibration. Whilst hypercapnia calibration seeks to emulate the physical removal of deoxyhaemoglobin from the blood, the aim of refocussing based calibration is to refocus the dephasing effect of deoxyhaemoglobin on the MR signal using a spin echo. However, it is not possible to refocus all of the effects that contribute to the BOLD signal and a scale factor is required to estimate the BOLD scaling parameter M. In this study the feasibility of a refocussing based calibration was investigated. The scale factor relating the refocussing calibration to M was predicted by simulations to be approximately linear and empirically measured to be 0.88±0.36 for the visual cortex and 0.93±0.32 for a grey matter region of interest (mean±standard deviation). Refocussing based calibration is a promising approach for greatly simplifying the calibrated BOLD methodology by eliminating the need for the subject to breathe special gas mixtures, and potentially provides the basis for a wider implementation of quantitative functional MRI. •The feasibility of calibrated BOLD without gas administration was investigated.•The BOLD scaling parameter M was measured using a refocussing based calibration.•Similar to hypercapnia calibration, a scale factor is required to estimate M.•The scale factor was predicted by simulations to be approximately linear.•The scale factor was empirically measured with reference to hypercapnia calibration.

Several techniques have been proposed to estimate relative changes in cerebral metabolic rate of oxygen consumption (CMRO2) by exploiting combined BOLD fMRI and cerebral blood flow data in conjunction with hypercapnic or hyperoxic respiratory challenges. More recently, methods based on respiratory challenges that include both hypercapnia and hyperoxia have been developed to assess absolute CMRO2, an important parameter for understanding brain energetics. In this paper, we empirically optimize a previously presented “original calibration model” relating BOLD and blood flow signals specifically for the estimation of oxygen extraction fraction (OEF) and absolute CMRO2. To do so, we have created a set of synthetic BOLD signals using a detailed BOLD signal model to reproduce experiments incorporating hypercapnic and hyperoxic respiratory challenges at 3T. A wide range of physiological conditions was simulated by varying input parameter values (baseline cerebral blood volume (CBV0), baseline cerebral blood flow (CBF0), baseline oxygen extraction fraction (OEF0) and hematocrit (Hct)). From the optimization of the calibration model for estimation of OEF and practical considerations of hypercapnic and hyperoxic respiratory challenges, a new “simplified calibration model” is established which reduces the complexity of the original calibration model by substituting the standard parameters α and β with a single parameter θ. The optimal value of θ is determined (θ=0.06) across a range of experimental respiratory challenges. The simplified calibration model gives estimates of OEF0 and absolute CMRO2 closer to the true values used to simulate the experimental data compared to those estimated using the original model incorporating literature values of α and β. Finally, an error propagation analysis demonstrates the susceptibility of the original and simplified calibration models to measurement errors and potential violations in the underlying assumptions of isometabolism. We conclude that using the simplified calibration model results in a reduced bias in OEF0 estimates across a wide range of potential respiratory challenge experimental designs. •Analysis of a calibration model of the BOLD signal through a simulation study•Optimization of the calibration model based on the accuracy of OEF0 estimates•New simplified calibration model proposed and shown to improve results accuracy•Error propagation analysis performed on both original and simplified model