Regional differences in the coupling of cerebral blood flow and oxygen metabolism changes in response to activation: implications for BOLD-fMRI

Abstract

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) signal changes is a sensitive tool for mapping brain activation, but quantitative interpretation of the BOLD response is problematic. The BOLD response is primarily driven by cerebral blood flow (CBF) changes, but is moderated by M, a scaling parameter reflecting baseline deoxyhemoglobin, and n, the ratio of fractional changes in CBF to cerebral metabolic rate of oxygen consumption (CMRO(2)). We compared M and n between cortical (visual cortex, VC) and subcortical (lentiform nuclei, LN) regions using a quantitative approach based on calibrating the BOLD response with a hypercapnia experiment. Although M was similar in both regions (~5.8%), differences in n (2.21+/-0.03 in VC and 1.58+/-0.03 in LN; Cohen d=1.71) produced substantially weaker (~3.7x) subcortical than cortical BOLD responses relative to CMRO(2) changes. Because of this strong sensitivity to n, BOLD response amplitudes cannot be interpreted as a quantitative reflection of underlying metabolic changes, particularly when comparing cortical and subcortical regions.

Fig. 1

Relationship between fractional blood oxygenation level dependent (BOLD) and fractional cerebral blood flow (CBF) increases in response to brain activation for different ratios (n) of the fractional changes in CBF and cerebral metabolic rate of oxygen (CMRO₂). Curves were calculated for different values of n using the BOLD signal equation (Eq. (1)) with M=0.06, α=0.4, and β=1.5. Filled circles indicate the BOLD and CBF responses for a fixed 20% increase in CMRO₂, illustrating that, for the same underlying change in metabolism, the magnitude of the BOLD response is strongly dependent on n. Relatively small differences in n from 1.5 to 2 or from 2 to 3 can lead to over 100% changes in the BOLD response for the same CMRO₂ change. The curve for n=∞ is the response for no change in CMRO₂.

Fig. 2

Experimental design for quantitative fMRI: mild hypercapnia calibration experiment and a functional activation experiment with simultaneous measurements of BOLD and CBF responses. (A) The two hypercapnia runs consisted of 2 min breathing room air, 3 min breathing a 5% CO₂ mixture, and then 2 min breathing room air. Following these experiments, a high-resolution anatomical scan was performed for structural correlation. (B) The three functional activation block design runs were approximately 7 min each in duration. ROIs for a single representative subject based on CBF activation (C) or the overlap of CBF and BOLD activation (D) are shown.

Fig. 3

BOLD and CBF changes in the visual cortex (VC) compared to lentiform nuclei (LN) of the basal ganglia for both hypercapnia and functional activation. The panels show average response curves and standard deviations (13 subjects) for the LN and VC ROIs based on CBF activated voxels. (A) CBF responses to hypercapnia, (B) BOLD responses to hypercapnia, (C) CBF responses to activation, and (D) BOLD responses to activation. The overall larger response in VC compared to LN may reflect differences in effective amplitude of the separate visual and motor stimuli driving the two regions, but the relative response amplitudes reflect differences in the coupling of CBF and CMRO₂ changes between the two regions. The solid black lines indicate stimulus presentation.

Fig. 4

Individual responses expressed as BOLD/CBF response ratios for hypercapnia and activation, illustrating the conversion of measured data into calculated model parameters. The essential information in calibrated BOLD data can be approximately captured by comparing the ratio of BOLD to CBF responses under hypercapnia and activation. Individual subject data for the two regions are plotted in panel A. The BOLD/CBF ratio measured under hypercapnia (y ordinate) reflects the local M value and is similar for both brain regions. However, the activation-induced BOLD/CBF ratio (x-axis) is sensitive to both local M and n values. A lower BOLD/CBF ratio associated with activation is observed in the LN, consistent with a smaller value of n in this region. Nonlinearities of the BOLD-CBF relation are shown by plotting lines of constant M and n for an assumed 50% change in CBF from the hypercapnia and activation experiments (B). The mean and standard deviations for VC and LN are also shown. The n = ∞ line reflects the assumption that there is no change in CMRO₂ with hypercapnia. Note that the M (horizontal lines) and n (angled vertical lines) contours are only approximate, because the full calculation of M and n requires all four measured quantities, and not just the two ratios. As seen in panel B significant differences in n but not M were seen for the two regions.

Fig. 5

Covariance of calculated and measured parameters. (A) Comparison of the calculated values of M and n for each subject, showing no significant correlation. (B) Comparison of n with baseline CBF, showing no significant correlation. (C) Comparison of M with baseline CBF, showing no significant correlation. (D) Changes in CBF as a function of CMRO₂.

Fig. 6

Correlation of different coupling ratios. (A) Data for individual subjects showing the CBF/CMRO₂ coupling ratio in the VC and LN (dashed line indicates equal values). The data show that n is higher in VC, but there is no correlation between the two regions. (B) For each region the response to activation, characterized by a CBF/CMRO₂ coupling ratio n, is compared to an analogous coupling ratio for hypercapnia, n_CO2, defined as the ratio of the fractional change in CBF to the fractional change in end-tidal CO₂ with hypercapnia (mean values with standard error bars). The two values n and n_CO2 can be thought of as characterizing the CBF responses to two quite different physiological stimuli: a change in neural activity and a change in arterial pCO₂. For both measures, higher values were observed within the VC compared to the LN, suggesting a greater vascular responsiveness in the VC.

Fig. 7

Sensitivity of the estimates of M and n to the assumed values of the model parameters. Using the average data in Table 1, values of M (left column) and n (right column) were calculated for different values of the model parameters. To test the effect of the assumption that CMRO₂ does not change with mild hypercapnia, a parameter k, defined as the CMRO₂ under hypercapnia normalized to normocapnic baseline, was varied and used in the calculation of M and n (A and B). The effect of varying α and β are shown in panels C–E, respectively. Although the absolute values vary, the basic finding of similar M values and different n values in the two brain regions remains. Standard parameter values are k=1.0, α=0.38, and β=1.5.