Claudine Gauthier

Magnetic resonance imaging of resting OEF and CMRO₂ using a generalized calibration model for hypercapnia and hyperoxia

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 30 ms echo-time at 3T). Multiplying OEF₀ estimates by the individual values of resting gray-matter CBF (mean 52 ± 5 ml/100 g/min) and the measured arterial O₂ content gave a group average resting CMRO₂ value of 145 ± 30 μmol/100 g/min. The method also allowed the generation of maps depicting resting OEF, BOLD signal, and CMRO₂.

Cortical lamina-dependent blood volume changes in human brain at 7 T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8-1.6mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans.

Age dependence of hemodynamic response characteristics in human functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) studies of cognitive aging have generally compared the amplitude and extent of blood oxygen level-dependent (BOLD) signal increases evoked by a task in older and younger groups. BOLD is thus used as a direct index of neuronal activation and it is assumed that the relationship between neuronal activity and the hemodynamic response is unchanged across the lifespan. However, even in healthy aging, differences in vascular and metabolic function have been observed that could affect the coupling between neuronal activity and the BOLD signal. Here we use a calibrated fMRI method to explore vascular and metabolic changes that might bias such BOLD comparisons. Though BOLD signal changes evoked by a cognitive task were found to be similar between a group of younger and older adults (e.g., 0.50 ± 0.04% vs. 0.50 ± 0.05% in right frontal areas), comparison of BOLD and arterial spin labelling (ASL) responses elicited in the same set of structures by a controlled global hypercapnic manipulation revealed significant differences between the 2 groups. Older adults were found to have lower responses in BOLD and flow responses to hypercapnia (e.g., 1.48 ± 0.07% vs. 1.01 ± 0.06% over gray matter for BOLD and 24.92 ± 1.37% vs. 20.67 ± 2.58% for blood flow), and a generally lower maximal BOLD response M (5.76 ± 0.2% vs. 5.00 ± 0.3%). This suggests that a given BOLD response in the elderly might represent a larger change in neuronal activity than the same BOLD response in a younger cohort. The results of this study highlight the importance of ancillary measures such as ASL for the correct interpretation of BOLD responses when fMRI responses are compared across populations who might exhibit differences in vascular physiology.

A generalized procedure for calibrated MRI incorporating hyperoxia and hypercapnia

Calibrated MRI techniques use the changes in cerebral blood flow (CBF) and blood oxygenation level‐dependent (BOLD) signal evoked by a respiratory manipulation to extrapolate the total BOLD signal attributable to deoxyhemoglobin at rest (M). This parameter can then be used to estimate changes in the cerebral metabolic rate of oxygen consumption (CMRO2) based on task‐induced BOLD and CBF signals. Different approaches have been described previously, including addition of inspired CO2 (hypercapnia) or supplemental O2 (hyperoxia). We present here a generalized BOLD signal model that reduces under appropriate conditions to previous models derived for hypercapnia or hyperoxia alone, and is suitable for use during hybrid breathing manipulations including simultaneous hypercapnia and hyperoxia. This new approach yields robust and accurate M maps, in turn allowing more reliable estimation of CMRO2 changes evoked during a visual task. The generalized model is valid for arbitrary flow changes during hyperoxia, thus benefiting from the larger total oxygenation changes produced by increased blood O2 content from hyperoxia combined with increases in flow from hypercapnia. This in turn reduces the degree of extrapolation required to estimate M. The new procedure yielded M estimates that were generally higher (7.6 ± 2.6) than those obtained through hypercapnia (5.6 ± 1.8) or hyperoxia alone (4.5 ± 1.5) in visual areas. These M values and their spatial distribution represent a more accurate and robust depiction of the underlying distribution of tissue deoxyhemoglobin at rest, resulting in more accurate estimates of evoked CMRO2 changes. Hum Brain Mapp, 2013.

Elimination of visually evoked BOLD responses during carbogen inhalation: Implications for calibrated MRI

Breathing a mixture of 10% CO(2) with 90% O(2) (referred to here as carbogen-10) increases blood flow due to the vasodilatory effect of CO(2), and raises blood O(2) 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 O(2) 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%.

Absolute quantification of resting oxygen metabolism and metabolic reactivity during functional activation using QUO2 MRI

We have recently described an extension of calibrated MRI, which we term QUO2 (for QUantitative O(2) imaging), providing absolute quantification of resting oxidative metabolism (CMRO(2)) and oxygen extraction fraction (OEF(0)). By combining BOLD, arterial spin labeling (ASL) and end-tidal O(2) measurements in response to hypercapnia, hyperoxia and combined hyperoxia/hypercapnia manipulations, and the same MRI measurements during a task, a comprehensive set of vascular and metabolic measurements can be obtained using a generalized calibration model (GCM). These include the baseline absolute CBF in units of ml/100g/min, cerebrovascular reactivity (CVR) in units of %Δ CBF/mm Hg, M in units of percent, OEF(0) and CMRO(2) at rest in units of μmol/100g/min, percent evoked CMRO(2) during the task and n, the value for flow-metabolic coupling associated with the task. The M parameter is a calibration constant corresponding to the maximal BOLD signal that would occur upon removal of all deoxyhemoglobin. We have previously shown that the GCM provides estimates of the above resting parameters in grey matter that are in excellent agreement with literature. Here we demonstrate the method using functionally-defined regions-of-interest in the context of an activation study. We applied the method under high and low signal-to-noise conditions, corresponding respectively to a robust visual stimulus and a modified Stroop task. The estimates fall within the physiological range of literature values, showing the general validity of the GCM approach to yield non-invasively an extensive array of relevant vascular and metabolic parameters.

BOLD signal responses to controlled hypercapnia in human spinal cord.

Functional MRI of the spinal cord is challenging due to the small cross section of the cord and high level of physiological noise. Though blood oxygenation level-dependent (BOLD) contrast has been used to study specific responses of the spinal cord to various stimuli, it has not been demonstrated using a controlled stimulus. In this paper, we use hypercapnic manipulation to study the sensitivity and specificity of functional MRI in the human cervical spinal cord. Simultaneous MR imaging in the brain and spinal cord was performed for direct comparison with the brain, in which responses to hypercapnia have been more extensively characterized. Original contributions include: (i) prospectively controlled hypercapnic changes in end-tidal PCO(2), (ii) simultaneous recording of BOLD responses in the brain and spinal cord, and (iii) generation of statistical maps of BOLD responses throughout the brain and spinal cord, taking into account physiological noise sources. Results showed significant responses in all subjects both in the brain and the spinal cord. In anatomically-defined regions of interest, mean percent changes were 0.6% in the spinal cord and 1% in the brain. Analysis of residual variance demonstrated significantly larger contribution of physiological noise in the spinal cord (P<0.005). To obtain more reliable results from fMRI in the spinal cord, it will be necessary to improve sensitivity through the use of highly parallelized coil arrays and better modeling of physiological noise. Finely, we believe that the use of controlled global stimuli, such as hypercapnia, will help assess the effectiveness of new acquisition techniques.

Hearts and minds: linking vascular rigidity and aerobic fitness with cognitive aging

Human aging is accompanied by both vascular and cognitive changes. Although arteries throughout the body are known to become stiffer with age, this vessel hardening is believed to start at the level of the aorta and progress to other organs, including the brain. Progression of this vascular impairment may contribute to cognitive changes that arise with a similar time course during aging. Conversely, it has been proposed that regular exercise plays a protective role, attenuating the impact of age on vascular and metabolic physiology. Here, the impact of vascular degradation in the absence of disease was investigated within 2 groups of healthy younger and older adults. Age-related changes in executive function, elasticity of the aortic arch, cardiorespiratory fitness, and cerebrovascular reactivity were quantified, as well as the association between these parameters within the older group. In the cohort studied, older adults exhibited a decline in executive functions, measured as a slower performance in a modified Stroop task (1247.90 ± 204.50 vs. 898.20 ± 211.10 ms on the inhibition and/or switching component, respectively) than younger adults. Older participants also showed higher aortic pulse wave velocity (8.98 ± 3.56 vs. 3.95 ± 0.82 m/s, respectively) and lower VO₂ max (29.04 ± 6.92 vs. 42.32 ± 7.31 mL O2/kg/min, respectively) than younger adults. Within the older group, faster performance of the modified Stroop task was associated with preserved aortic elasticity (lower aortic pulse wave velocity; p = 0.046) and higher cardiorespiratory fitness (VO₂ max; p = 0.036). Furthermore, VO₂ max was found to be negatively associated with blood oxygenation level dependent cerebrovascular reactivity to CO₂ in frontal regions involved in the task (p = 0.038) but positively associated with cerebrovascular reactivity in periventricular watershed regions and within the postcentral gyrus. Overall, the results of this study support the hypothesis that cognitive status in aging is linked to vascular health, and that preservation of vessel elasticity may be one of the key mechanisms by which physical exercise helps to alleviate cognitive aging.

Higher levels of cardiovascular fitness are associated with better executive function and prefrontal oxygenation in younger and older women

Aim: Many studies have suggested that physical exercise training improves cognition and more selectively executive functions. There is a growing interest to clarify the neurophysiological mechanisms that underlie this effect. The aim of the current study was to evaluate the neurophysiological changes in cerebral oxygenation associated with physical fitness level and executive functions. Method: In this study, 22 younger and 36 older women underwent a maximal graded continuous test (i.e., V˙O2max) in order to classify them into a fitness group (higher vs. lower fit). All participants completed neuropsychological paper and pencil testing and a computerized Stroop task (which contained executive and non-executive conditions) in which the change in prefrontal cortex oxygenation was evaluated with near infrared spectroscopy (NIRS). Results: Our findings revealed a Fitness × Condition interaction (p < 0.05) such that higher fit women scored better on measures of executive functions than lower fit women. In comparison to lower fit women, higher fit women had faster reaction times in the Executive condition of the computerized Stroop task. No significant effect was observed in the non-executive condition of the test and no interactions were found with age. In measures of cerebral oxygenation (ΔHbT and ΔHbO2), we found a main effect of fitness on cerebral oxygenation during the Stroop task such that only high fit women demonstrated a significant increase in the right inferior frontal gyrus. Discussion/Conclusion: Higher fit individuals who demonstrate better cardiorespiratory functions (as measured by V˙O2max) show faster reaction times and greater cerebral oxygenation in the right inferior frontal gyrus than women with lower fitness levels. The lack of interaction with age, suggests that good cardiorespiratory functions can have a positive impact on cognition, regardless of age.

Comparison of pulsed and pseudocontinuous arterial spin-labeling for measuring CO2-induced cerebrovascular reactivity

To compare the performance of pulsed and pseudocontinuous arterial spin‐labeling (PASL and pCASL) methods in measuring CO2‐induced cerebrovascular reactivity (CVR).