J. Jean Chen

Age-associated reductions in cerebral blood flow are independent from regional atrophy

Prior studies have demonstrated decreasing cerebral blood flow (CBF) in normal aging, but the full spatial pattern and potential mechanism of changes in CBF remain to be elucidated. Specifically, existing data have not been entirely consistent regarding the spatial distribution of such changes, potentially a result of neglecting the effect of age-related tissue atrophy in CBF measurements. In this work, we use pulsed arterial-spin labelling to quantify regional CBF in 86 cognitively and physically healthy adults, aged 23 to 88 years. Surface-based analyses were utilized to map regional decline in CBF and cortical thickness with advancing age, and to examine the spatial associations and dissociations between these metrics. Our results demonstrate regionally selective age-related reductions in cortical perfusion, involving the superior-frontal, orbito-frontal, superior-parietal, middle-inferior temporal, insular, precuneus, supramarginal, lateral-occipital and cingulate regions, while subcortical CBF was relatively preserved in aging. Regional effects of age on CBF differed from that of grey-matter atrophy. In addition, the pattern of CBF associations with age displays an interesting similarity with the default-mode network. These findings demonstrate the dissociation between regional CBF and structural alterations specific to normal aging, and augment our understanding of mechanisms of pathology in older adults.

Global Cerebral Oxidative Metabolism during Hypercapnia and Hypocapnia in Humans: Implications for BOLD fMRI:

The effect of carbon dioxide (CO2) on cerebral metabolism is of tremendous interest to functional imaging. In particular, mild-to-moderate hypercapnia is routinely used in calibrated blood oxygen-level dependent (BOLD)-functional magnetic resonance imaging (fMRI)-based quantification of cerebral oxidative metabolism changes (ΔCMRO2), and relies on the assumption of a stable CMRO2 during CO2 challenges. However, this assumption has been challenged by certain animal studies, necessitating its verification in humans and under conditions customary to fMRI. We report, for the first time, on global ΔCMRO2 measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO2 modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO2 is expected at the levels of end-tidal CO2 changes customary to calibrated BOLD.

BOLD-specific cerebral blood volume and blood flow changes during neuronal activation in humans.

To understand and predict the blood‐oxygenation level‐dependent (BOLD) fMRI signal, an accurate knowledge of the relationship between cerebral blood flow (ΔCBF) and volume (ΔCBV) changes is critical. Currently, this relationship is widely assumed to be characterized by Grubbs power‐law, derived from primate data, where the power coefficient (α) was found to be 0.38. The validity of this general formulation has been examined previously, and an α of 0.38 has been frequently cited when calculating the cerebral oxygen metabolism change (ΔCMRo2) using calibrated BOLD. However, the direct use of this relationship has been the subject of some debate, since it is well established that the BOLD signal is primarily modulated by changes in ‘venous’ CBV (ΔCBVv, comprising deoxygenated blood in the capillary, venular, and to a lesser extent, in the arteriolar compartments) instead of total CBV, and yet ΔCBVv measurements in humans have been extremely scarce. In this work, we demonstrate reproducible ΔCBVv measurements at 3 T using venous refocusing for the volume estimation (VERVE) technique, and report on steady‐state ΔCBVv and ΔCBF measurements in human subjects undergoing graded visual and sensorimotor stimulation. We found that: (1) a BOLD‐specific flow‐volume power‐law relationship is described by α = 0.23 ± 0.05, significantly lower than Grubbs constant of 0.38 for total CBV; (2) this power‐law constant was not found to vary significantly between the visual and sensorimotor areas; and (3) the use of Grubbs value of 0.38 in gradient‐echo BOLD modeling results in an underestimation of ΔCMRo2. Copyright

MRI measurement of the BOLD-specific flow-volume relationship during hypercapnia and hypocapnia in humans.

It is widely assumed in fMRI that the relationship between cerebral blood flow (CBF) and volume (CBV) changes observed during end-tidal CO(2) (PETCO(2)) perturbations is equivalent to that elicited by neuronal activation. This assumption has been validated in PET studies insofar as relating total flow to total CBV changes, but remains unconfirmed for venous CBV changes, which pertains to the primary vascular compartment modulating the BOLD signal. In this study, we measured CBF and venous CBV changes in healthy subjects in response to graded hypercapnia and hypocapnia, induced using computerized end-tidal CO(2) targeting, with a DeltaPETCO(2) range of between -6 and +9 mm Hg. Hypercapnia was found to elicit robust increases in CBF and venous CBV, while hypocapnia produced decreases in both. We used steady-state flow and volume changes to estimate the power-law relationship for cortical and subcortical brain regions, and did not observe significant difference between the two. The combined fit resulted in a power coefficient of 0.18+/-0.02, substantially lower than Grubbs coefficient of 0.38, but comparable to previous observations during neuronal activation. These results confirm that the BOLD-specific flow-volume relationship during CO(2) challenges is similar to that characterizing neuronal activation.

Human whole blood T2 relaxometry at 3 Tesla

A precise understanding of human blood spin–spin relaxation is of major importance for numerous applications, particularly functional magnetic resonance imaging (fMRI), which is increasingly performed at 3 Tesla. It is well known that T2 measured from partially deoxygenated blood depends on the Carr–Purcell Meiboom–Gill (CPMG) refocusing interval (τ180) and on blood oxygenation (Y), yet debate remains over the quantification of this phenomenon, primarily with respect to the accuracy of its characterization by the diffusion and fast two‐site exchange models. In this study, a detailed characterization of the deoxygenation‐induced T2 reduction in human whole blood, as well as a comprehensive assessment of the role of τ180, were performed at 3 T. The diffusion model was found to better fit the observed T2 behavior as compared with the exchange model. The estimated diffusion‐model parameters suggest the T2 decay enhancement at 3 T is due to a linear increase in the magnitude of deoxygenation‐induced field inhomogeneities with field strength. These findings also confirm the potential of τ180 manipulation in measuring changes in venous blood volume. Magn Reson Med 61:249–254, 2009.

HIPPOCAMPAL DEGENERATION IS ASSOCIATED WITH TEMPORAL AND LIMBIC GRAY MATTER/WHITE MATTER TISSUE CONTRAST IN ALZHEIMER’S DISEASE

Recent studies have demonstrated alterations in cortical gray to white matter tissue contrast with nondemented aging and in individuals with Alzheimers disease (AD). However, little information exists about the clinical relevance of such changes. It is possible that changes in MRI tissue contrast occur via independent mechanisms from those traditionally used in the assessment of AD associated degeneration such as hippocampal degeneration measured by more traditional volumetric magnetic resonance imaging (MRI). We created cortical surface models of 95 cognitively healthy individuals and 98 individuals with AD to characterize changes in regional gray and white matter T1-weighted signal intensities in dementia and to evaluate how such measures related to classically described hippocampal and cortical atrophy. We found a reduction in gray matter to white matter tissue contrast throughout portions of medial and lateral temporal cortical regions as well as in anatomically associated regions including the posterior cingulate, precuneus, and medial frontal cortex. Decreases in tissue contrast were associated with hippocampal volume, however, the regional patterns of these associations differed for demented and nondemented individuals. In nondemented controls, lower hippocampal volume was associated with decreased gray/white matter tissue contrast globally across the cortical mantle. In contrast, in individuals with AD, selective associations were found between hippocampal volume and tissue contrast in temporal and limbic tissue. These results demonstrate that there are strong regional changes in neural tissue properties in AD which follow a spatial pattern including regions known to be affected from pathology studies. Such changes are associated with traditional imaging metrics of degeneration and may provide a unique biomarker of the tissue loss that occurs as a result of AD.

Mapping the end-tidal CO2 response function in the resting-state BOLD fMRI signal: spatial specificity, test-retest reliability and effect of fMRI sampling rate.

The blood oxygenation level dependent (BOLD) signal measures brain function indirectly through physiological processes and hence is susceptible to global physiological changes. Specifically, fluctuations in end-tidal CO2 (PETCO2), in addition to cardiac rate variation (CRV), and respiratory volume per time (RVT) variations, have been known to confound the resting-state fMRI (rs-fMRI) signal. Previous studies addressed the resting-state fMRI response function to CRV and RVT, but no attempt has been made to directly estimate the voxel-wise response function to PETCO2. Moreover, the potential interactions among PETCO2, CRV, and RVT necessitate their simultaneous inclusion in a multi-regression model to estimate the PETCO2 response. In this study, we use such a model to estimate the voxel-wise PETCO2 response functions directly from rs-fMRI data of nine healthy subjects. We also characterized the effect of sampling rate (TR=2seconds vs. 323ms) on the temporal and spatial variability of the PETCO2 response function in addition to that of CRV and RVT. In addition, we assess the test-retest reproducibility of the response functions to PETCO2, CRV and RVT. We found that despite overlaps across their spatial patterns, PETCO2 explains a unique portion of the rs-fMRI signal variance compared to RVT and CRV. We also found the shapes of the estimated responses are very similar between long- and short-TR data, although responses estimated from short-TR data have higher reproducibility.

The Relationship between Cortical Blood Flow and Sub-Cortical White-Matter Health across the Adult Age Span

Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain.

Comparing cerebrovascular reactivity measured using BOLD and cerebral blood flow MRI: The effect of basal vascular tension on vasodilatory and vasoconstrictive reactivity

Cerebrovascular reactivity (CVR) is an important metric of cerebrovascular health. While the BOLD fMRI method in conjunction with carbon-dioxide (CO2) based vascular manipulation has been the most commonly used, the BOLD signal is not a direct measure of vascular changes, and the use of arterial-spin labeling (ASL) cerebral blood flow (CBF) imaging is increasingly advocated. Nonetheless, given the differing dependencies of BOLD and CBF on vascular baseline conditions and the diverse CO2 manipulation types currently used in the literature, knowledge of potential biases introduced by each technique is critical for the interpretation of CVR measurements. In this work, we use simultaneous BOLD-CBF acquisitions during both vasodilatory (hypercapnic) and vasoconstrictive (hypocapnic) stimuli to measure CVR. We further imposed different levels of baseline vascular tension by inducing hypercapnic and hypocapnic baselines, separately from normocapnia by 4mmHg. We saw significant and diverse dependencies on vascular stimulus and baseline condition in both BOLD and CBF CVR measurements: (i) BOLD-based CVR is more sensitive to basal vascular tension than CBF-based CVR; (ii) the use of a combination of vasodilatory and vasoconstrictive stimuli maximizes the sensitivity of CBF-based CVR to vascular tension changes; (iii) the BOLD and CBF vascular response delays are both significantly lengthened at predilated baseline. As vascular tension can often be altered by potential pathology, our findings are important considerations when interpreting CVR measurements in health and disease.

Metabolic and vascular origins of the BOLD effect: Implications for imaging pathology and resting-state brain function.

The blood oxygenation level‐dependent (BOLD) phenomenon has profoundly revolutionized neuroscience, with applications ranging from normal brain development and aging, to brain disorders and diseases. While the BOLD effect represents an invaluable tool to map brain function, it does not measure neural activity directly; rather, it reflects changes in blood oxygenation resulting from the relative balance between cerebral oxygen metabolism (through neural activity) and oxygen supply (through cerebral blood flow and volume). As such, there are cases in which BOLD signals might be dissociated from neural activity, leading to misleading results. The emphasis of this review is to develop a critical perspective for interpreting BOLD results, through a comprehensive consideration of BOLDs metabolic and vascular underpinnings. We demonstrate that such an understanding is especially important under disease or resting conditions. We also describe state‐of‐the‐art acquisition and analytical techniques to reveal physiological information on the mechanisms underlying measured BOLD signals. With these goals in mind, this review is structured to provide a fundamental understanding of: 1) the physiological and physical sources of the BOLD contrast; 2) the extraction of information regarding oxidative metabolism and cerebrovascular reactivity from the BOLD signal, critical to investigating neuropathology; and 3) the fundamental importance of metabolic and vascular mechanisms for interpreting resting‐state BOLD measurements. J. Magn. Reson. Imaging 2015;42:231–246.