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Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O 2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO 2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O 2 sensitivity increased. By contrast, O 2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO 2 but different mechanisms of O 2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO 2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O 2 sensitivity in the two systems.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: Individuals susceptible to high altitude pulmonary edema show altered pulmonary vascular responses within minutes of exposure to hypoxia. We hypothesized that a similar acute-phase vulnerability to hypoxia may exist in the brain of individuals susceptible to acute mountain sickness (AMS). In established AMS and high altitude cerebral edema, there is a propensity for vasogenic white matter edema. We therefore hypothesized that increased cerebral blood flow (CBF) during acute hypoxia would also be disproportionately greater in white matter (WM) than grey matter (GM) in AMS-susceptible subjects. We quantified regional CBF using arterial spin labeling MRI during 30 min hypoxia (F(I)O(2) = 0.125) in two groups: AMS-susceptible (AMS-S, n = 6) who invariably experienced AMS at altitude, and AMS-resistant (AMS-R, n = 6) who never experienced AMS despite multiple rapid ascents to high altitude. SaO(2) during hypoxia did not differ between groups (AMS-S = 87+/-4%, AMS-R = 89+/-3%, p = 0.3). Steady-state whole-brain CBF increased in hypoxia (p<0.005), but did not differ between groups (normoxia: AMS-S = 42.7+/-14.0 ml/(100 g min), AMS-R = 41.7+/-10.1 ml/(100 g min); hypoxia: AMS-S = 47.8+/-19.5 ml/(100 g min), AMS-R = 48.2+/-10.1 ml/(100 g min), p = 0.65), and cerebral oxygen delivery remained constant. The percent change in CBF did not differ between brain regions or between groups (although absolute CBF change was greater in GM): (GM: AMS-S = 6.1+/-7.7 ml/(100 g min) (10+/-11%), AMS-R = 8.3+/-5.7 ml/(100 g min) (17+/-11%), p = 0.57; WM: AMS-S = 4.3+/-5.1 ml/(100 g min) (12+/-15%), AMS-R = 4.8+/-2.9 ml/(100 g min) (16+/-9%), p = 0.82)., Conclusion: CBF increases in acute hypoxia, but is not different between WM and GM, irrespective of AMS susceptibility. Acute phase differences in regional CBF during acute hypoxia are not a primary feature of susceptibility to AMS.

Neural activity in the brain is accompanied by changes in cerebral blood flow (CBF) and blood oxygenation that are detectable with functional magnetic resonance imaging (fMRI) techniques. In this paper, recent mathematical models of this hemodynamic response are reviewed and integrated. Models are described for: (1) the blood oxygenation level dependent (BOLD) signal as a function of changes in cerebral oxygen extraction fraction (E) and cerebral blood volume (CBV); (2) the balloon model, proposed to describe the transient dynamics of CBV and deoxy-hemoglobin (Hb) and how they affect the BOLD signal; (3) neurovascular coupling, relating the responses in CBF and cerebral metabolic rate of oxygen (CMRO(2)) to the neural activity response; and (4) a simple model for the temporal nonlinearity of the neural response itself. These models are integrated into a mathematical framework describing the steps linking a stimulus to the measured BOLD and CBF responses. Experimental results examining transient features of the BOLD response (post-stimulus undershoot and initial dip), nonlinearities of the hemodynamic response, and the role of the physiologic baseline state in altering the BOLD signal are discussed in the context of the proposed models. Quantitative modeling of the hemodynamic response, when combined with experimental data measuring both the BOLD and CBF responses, makes possible a more specific and quantitative assessment of brain physiology than is possible with standard BOLD imaging alone. This approach has the potential to enhance numerous studies of brain function in development, health, and disease.

Cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) signal measurements make it possible to estimate steady-state changes in the cerebral metabolic rate of oxygen (CMRO2) with a calibrated BOLD method. However, extending this approach to measure the dynamics of CMRO2 requires an additional assumption: that deoxygenated cerebral blood volume (CBVdHb) follows CBF in a predictable way. A test-case for this assumption is the BOLD post-stimulus undershoot, for which one proposed explanation is a strong uncoupling of flow and blood volume with an elevated level of CBVdHb during the post-stimulus period compared to baseline due to slow blood volume recovery (Balloon Model). A challenge in testing this model is that CBVdHb differs from total blood volume, which can be measured with other techniques. In this study, the basic hypothesis of elevated CBVdHb during the undershoot was tested, based on the idea that the BOLD signal change when a subject switches from breathing a normoxic gas to breathing a hyperoxic gas is proportional to the absolute CBVdHb. In 19 subjects (8F), dual-echo BOLD responses were measured in primary visual cortex during a flickering radial checkerboard stimulus in normoxia, and the identical experiment was repeated in hyperoxia (50% O2/balance N2). The BOLD signal differences between normoxia and hyperoxia for the pre-stimulus baseline, stimulus, and post-stimulus periods were compared using an equivalent BOLD signal calculated from measured R2* changes to eliminate signal drifts. Relative to the pre-stimulus baseline, the average BOLD signal change from normoxia to hyperoxia was negative during the undershoot period (p = 0.0251), consistent with a reduction of CBVdHb and contrary to the prediction of the Balloon Model. Based on these results, the BOLD post-stimulus undershoot does not represent a case of strong uncoupling of CBVdHb and CBF, supporting the extension of current calibrated BOLD methods to estimate the dynamics of CMRO2.

Calibrated blood oxygenation level dependent (BOLD) imaging is a multimodal functional MRI technique designed to estimate changes in cerebral oxygen metabolism from measured changes in cerebral blood flow and the BOLD signal. This technique addresses fundamental ambiguities associated with quantitative BOLD signal analysis; however, its dependence on biophysical modeling creates uncertainty in the resulting oxygen metabolism estimates. In this work, we developed a Bayesian approach to estimating the oxygen metabolism response to a neural stimulus and used it to examine the uncertainty that arises in calibrated BOLD estimation due to the presence of unmeasured model parameters. We applied our approach to estimate the CMRO2 response to a visual task using the traditional hypercapnia calibration experiment as well as to estimate the metabolic response to both a visual task and hypercapnia using the measurement of baseline apparent R2' as a calibration technique. Further, in order to examine the effects of cerebral spinal fluid (CSF) signal contamination on the measurement of apparent R2', we examined the effects of measuring this parameter with and without CSF-nulling. We found that the two calibration techniques provided consistent estimates of the metabolic response on average, with a median R2'-based estimate of the metabolic response to CO2 of 1.4%, and R2'- and hypercapnia-calibrated estimates of the visual response of 27% and 24%, respectively. However, these estimates were sensitive to different sources of estimation uncertainty. The R2'-calibrated estimate was highly sensitive to CSF contamination and to uncertainty in unmeasured model parameters describing flow-volume coupling, capillary bed characteristics, and the iso-susceptibility saturation of blood. The hypercapnia-calibrated estimate was relatively insensitive to these parameters but highly sensitive to the assumed metabolic response to CO2.

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.