Caffeine alters the temporal dynamics of the visual BOLD response
Introduction
The blood oxygenation level-dependent (BOLD) signal measured in functional magnetic resonance imaging (fMRI) experiments is a complex function of cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism (Buxton et al., 1998). The shape of the BOLD hemodynamic response (HDR) exhibits significant variability between subjects and somewhat less variability in repeated scans of a single subject (Aguirre et al., 1998, D'Esposito et al., 2003, Handwerker et al., 2004). This variability in the BOLD temporal dynamics has a direct impact on the interpretation of fMRI experiments, especially for event-related experiments in which the shape of the HDR is often of interest (Rosen et al., 1998). An understanding of the factors that contribute to the variability of the HDR is therefore important when comparing responses between populations or experimental conditions.
Recent studies have suggested that the temporal dynamics of the BOLD response are strongly dependent on the baseline CBF state. Kemna and Posse (2001) modified CBF levels by adjusting the arterial partial pressure of carbon dioxide (Paco2) with either controlled hyperventilation (hypocapnia) or CO2 breathing (hypercapnia). Using a 1.5-T system, they found that the temporal width and time to peak (TTP) of the BOLD response to a short visual stimulus increased with the baseline level of Paco2. In a later study at 7 T, Cohen et al. (2002) observed a similar dependence on Paco2 and noted that the peak amplitude of the visual BOLD signal decreased with hypercapnia and increased with hypocapnia. In addition, the poststimulus undershoot in the response resolved more quickly with hypocapnia and appeared to be abolished with hypercapnia.
The carbon dioxide studies suggest that similar dynamic effects should be observed with other vasoactive agents that modify the baseline CBF state. One such agent is caffeine, which is the most widely consumed neural stimulant in the world with most of the intake coming from dietary sources such as coffee and tea (Fredholm et al., 1999). In addition to its neurostimulant effects, caffeine acts to reduce CBF, primarily by inhibition of the adenosine A2A receptors (Cameron et al., 1990, Ngai et al., 2001). Several studies have examined the effect of caffeine on the amplitude of the BOLD response. In a study using a 1.5-T system, Mulderink et al. (2002) found that a 200-mg caffeine dose increased the amplitude of the BOLD response to a brief 2-s stimulus by 37% and 26% in the visual and motor cortices, respectively, and suggested that caffeine could be used as a contrast booster for BOLD studies. Laurienti et al., 2002, Laurienti et al., 2003, however, found that the BOLD response to a 30-s-long visual stimulus was not increased uniformly in all subjects and also observed a dependence on chronic caffeine usage. The discrepancies in the studies may have been due to the difference in stimulus duration and intrinsic variation in the subject populations. Aside from the amplitude changes, neither study examined changes in the temporal dynamics of the BOLD response, which may have also affected the analysis. For example, a change in the shape of the hemodynamic response, such as a decrease in the temporal width, would affect the correlation with a canonical reference function.
In this study, we examined the effect of a 200-mg caffeine dose on the temporal dynamics of the BOLD response to visual stimuli of both short (1 s) and long (20 s) duration. In addition, we used arterial spin labeling (ASL) to noninvasively measure the effect of caffeine on baseline CBF.
Section snippets
Experimental protocol
Six healthy adult male volunteers (ages 23 to 40 years) participated in the study after giving informed consent. Each subject was asked to refrain from ingesting any food or drink containing caffeine for at least 12 h before the imaging session. The estimated daily caffeine usage of the subjects based on self-reports of coffee, tea, and caffeinated soda consumption is shown in Table 1. The assumed caffeine contents for an 8-oz cup of coffee, an 8-oz cup of tea, and a 12-oz can of soda were 100
Results
The group average predose and postdose BOLD responses are shown in Fig. 1. A qualitative assessment of the responses indicates that caffeine speeds up both the single trial and block responses and also appears to decrease the poststimulus undershoot amplitude of the single trial responses. A quantitative assessment of the single trial and block responses is provided in the scatter plots and paired t test results shown in Fig. 2, Fig. 3. When data from subject 1's second and third experimental
Changes in BOLD dynamics
Caffeine alters the temporal dynamics of the BOLD response, leading to significant decreases in TA50 and the time to peak for both single trial and block responses and a significant decrease in the amplitude of the poststimulus response for the single trial responses and T50 for the block responses. In addition, other parameters were found to show significant decreases in many of the subjects. The shapes of the block responses exhibit a qualitative difference that is reflected in the
Conclusions
Caffeine usage significantly changes the dynamics of the BOLD response and may be partly responsible for the subject-to-subject and day-to-day variability in the shape of the hemodynamic response. The effects of caffeine should therefore be considered in the interpretation of fMRI experiments, especially event-related experiments in which estimates of the hemodynamic response are of interest. It appears that the caffeine-induced changes are due primarily to the decrease in baseline CBF.
Acknowledgments
This work was supported by a Biomedical Engineering Research Grant from the Whitaker Foundation and by NIH Grant NS36722.
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