Bolder than BOLD: Changes in Neurophysiologic Underpinnings of fMRI Signal With Age and Task Demand

Many theories of mechanisms involved in brain aging are based on age differences in bloodoxygen-level-dependent (BOLD) signal as measured with functional magnetic resonance imaging (fMRI). The contour of the hemodynamic response function (HRF), the signature of the evolution of BOLD signal through time, reflects a combination of influences from neural, glial, and vascular systems. Each of these systems forms one tier of a three-tier model used here to describe the process of neural-vascular coupling (NVC). Based on a preponderance of evidence from physiologic research of the aging brain, the often-invoked assumption that NVC does not change in healthy aging is unlikely to be based in fact and could explain disparate and conflicting results in neurocognitive aging literature. The BOLD signal, comprising multiple physiologic factors including cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2), serves as an index of the health of the NVC system, the process that links these two quantities. Disentangling the physiologic factors underlying age-related changes in BOLD would allow formulation of more precise models of neurocognitive aging. Separate measurement and derivation of these quantities is possible through use of a calibrated fMRI paradigm that employs dual-echo pseudo-continuous arterial spin labeling and a hypercapnia manipulation. While these quantities have been measured individually in previous studies, the way in which they change with task frequency, and age-group differences therein, remains unresearched. Sixty participants (thirty-three younger and twenty-seven older participants) completed a hypercapnic breathing challenge as well as a visual stimulation paradigm that presented flickering radial checkerboards at three frequencies (2 Hz, 4 Hz, and 8 Hz). The deoxyhemoglobin dilution model was used to estimate the theoretical BOLD signal ceiling for each participant to calculate CMRO2. Results indicate that, for small regions of interest (ROIs; approximately 5,000 μL in volume) there was a significant linear effect of Flicker-Frequency of the checkerboard in both BOLD and CBF, as well as a significant negative quadratic effect of Flicker-Frequency in CMRO2 (increases from 2 Hz to 4 Hz, but decreases from 4 Hz to 8 Hz). There were also significant main effects of AgeGroup, with younger adults showing higher BOLD signal than older adults, but older adults showing higher CMRO2 than younger adults, in the presence of group-equivalent CBF. This replicated a prior study using a similar experimental paradigm and similarly sized ROI. AgeGroup × Flicker-Frequency interaction effects were not observed in any of these measures. However, a significant Age-Group × Flicker-Frequency interaction was observed in the NVC ratio, with younger adults showing activity-dependent NVC and older adults showing activityindependent NVC. Further, when larger ROIs are examined, the main effect of Age-Group disappears in CMRO2, but a main effect of Age-Group emerges in CBF (greater in younger adults than in older adults). These results are interpreted as an empirical demonstration that the assumption of age-equivalent NVC is not valid, and that variability in the nature of the metabolic demands of different conditions of a task further complicate straightforward interpretation of BOLD signal as a faithful proxy of underlying neural activity.