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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.

Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2, or PtiO2. During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml−1·min−1 (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml−1·min−1, P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml−1·min−1 (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml−1·min−1 (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia. [ABSTRACT FROM AUTHOR]

Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T2) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T2 relaxation was estimated from a T2 index of T2-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T2,index decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T2,index initially increased after 2 days, but decreased after 7 days. T2,index changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia subjects demonstrate difficulties on tasks requiring saccadic inhibition, despite normal refixation saccade performance. Saccadic inhibition is ostensibly mediated via prefrontal cortex and associated cortical/subcortical circuitry. The current study tests hypotheses about the neural substrates of normal and abnormal saccadic performance among subjects with schizophrenia.Methods: Using functional magnetic resonance imaging, blood oxygenation level-dependent (BOLD) data were recorded while 13 normal and 14 schizophrenia subjects were engaged in refixation and antisaccade tasks.Results: Schizophrenia subjects did not demonstrate the increased prefrontal cortex BOLD contrast during antisaccade performance that was apparent in the normal subjects. Schizophrenia subjects did, however, demonstrate normal BOLD contrast associated with refixation saccade performance in the frontal and supplementary eye fields, and posterior parietal cortex.Conclusions: Results from the current study support hypotheses of dysfunctional prefrontal cortex circuitry among schizophrenia subjects. Furthermore, this abnormality existed despite normal BOLD contrast observed during refixation saccade generation in the schizophrenia group. [ABSTRACT FROM AUTHOR]