Caffeine alters the temporal dynamics of the visual BOLD response

doi:10.1016/j.neuroimage.2004.07.061

NeuroImage

Volume 23, Issue 4, December 2004, Pages 1402-1413

https://doi.org/10.1016/j.neuroimage.2004.07.061 Get rights and content

The blood oxygenation level-dependent (BOLD) responses to visual stimuli, using both a 1-s long single trial stimulus and a 20-s long block stimulus, were measured in a 4-T magnetic field both before and immediately after a 200-mg caffeine dose. In addition, resting levels of cerebral blood flow (CBF) were measured using arterial spin labeling. For the single trial stimulus, the caffeine dose significantly (p < 0.05) reduced the time to peak (TTP), the time after the peak at which the response returned to 50% of the peak amplitude (TA₅₀), and the amplitude of the poststimulus undershoot in all subjects (N = 5). Other parameters, such as the full-width half-maximum (FWHM) and the peak amplitude, also showed significant changes in the majority of subjects. For the block stimulus, the TTP, TA₅₀, and the time for the response to reach 50% of the peak amplitude (T₅₀) were significantly reduced. In some subjects, oscillations were observed in the poststimulus portion of the response with median peak periods of 9.1 and 9.5 s for the single trial and block responses, respectively. Resting CBF was reduced by an average of 24%. The reproducibility of the results was verified in one subject who was scanned on 3 different days. The dynamic changes are similar to those previously reported for baseline CBF reductions induced by hypocapnia and hyperoxia.

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 A_2A 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.

References (43)

G.K. Aguirre et al.
The variability of human, BOLD hemodynamic responses
NeuroImage
(1998)
B.M. Ances et al.
The effects of graded hypercapnia on the activation flow coupling response due to forepaw stimulation in alpha-chloralose anesthetized rats
Brain Res.
(2001)
M. Blaha et al.
Cerebral blood flow and dynamic cerebral autoregulation during ethanol intoxication and hypercapnia
J. Clin. Neurosci.
(2003)
O.G. Cameron et al.
Caffeine and human cerebral blood flow: a positron emission tomography study
Life Sci.
(1990)
R.W. Cox
AFNI-software for analysis and visualization of functional magnetic resonance neuroimages
Comput. Biomed. Res.
(1996)
D.A. Handwerker et al.
Variation of BOLD hemodynamic responses across subjects and brain regions and their effects on statistical analyses
NeuroImage
(2004)
K. Kashikura et al.
Hyperoxia modified activation-induced blood oxygenation level-dependent response of human visual cortex (V1): an event-related functional magnetic resonance imaging study
Neurosci. Lett.
(2001)
L.J. Kemna et al.
Effect of respiratory CO(2) changes on the temporal dynamics of the hemodynamic response in functional MR imaging
NeuroImage
(2001)
P.J. Laurienti et al.
Dietary caffeine consumption modulates fMRI measures
NeuroImage
(2002)
T. Matsuura et al.
Evoked local cerebral blood flow induced by somatosensory stimulation is proportional to the baseline flow
Neurosci. Res.
(2000)

T. Matsuura et al.

Hemodynamics of local cerebral blood flow induced by somatosensory stimulation under normoxia and hyperoxia in rats

Comp. Biochem. Physiol., A Mol. Integr. Physiol.

(2001)

J.E. Mayhew et al.

Cerebral vasomotion: a 0.1-Hz oscillation in reflected light imaging of neural activity

NeuroImage

(1996)

T.A. Mulderink et al.

On the use of caffeine as a contrast booster for BOLD fMRI studies

NeuroImage

(2002)

H. Obrig et al.

Spontaneous low frequency oscillations of cerebral hemodynamics and metabolism in human adults

NeuroImage

(2000)

W.A. Press et al.

Visual areas and spatial summation in human visual cortex

Vision Res.

(2001)

R. Aaslid et al.

Cerebral autoregulation dynamics in humans

Stroke

(1989)

R. Aaslid et al.

Assessment of cerebral autoregulation dynamics from simultaneous arterial and venous transcranial Doppler recordings in humans

Stroke

(1991)

R. Bakalova et al.

Frequency dependence of local cerebral blood flow induced by somatosensory hind paw stimulation in rat under normo- and hypercapnia

Jpn. J. Physiol.

(2001)

Y. Behzadi et al.

Modeling the effect of baseline arteriolar compliance on BOLD Dynamics

A.A. Birch et al.

Assessment of autoregulation by means of periodic changes in blood pressure

Stroke

(1995)

R.B. Buxton et al.

Dynamics of blood flow and oxygenation changes during brain activation: the balloon model

Magn. Reson. Med.

(1998)

Cited by (103)

Hemodynamic timing in resting-state and breathing-task BOLD fMRI
2023, NeuroImage
The blood flow response to a vasoactive stimulus demonstrates regional heterogeneity across both the healthy brain and in cerebrovascular pathology. The timing of a regional hemodynamic response is emerging as an important biomarker of cerebrovascular dysfunction, as well as a confound within fMRI analyses. Previous research demonstrated that hemodynamic timing is more robustly characterized when a larger systemic vascular response is evoked by a breathing challenge, compared to when only spontaneous fluctuations in vascular physiology are present (i.e., in resting-state data). However, it is not clear whether hemodynamic delays in these two conditions are physiologically interchangeable, and how methodological signal-to-noise factors may limit their agreement. To address this, we generated whole-brain maps of hemodynamic delays in nine healthy adults. We assessed the agreement of voxel-wise gray matter (GM) hemodynamic delays between two conditions: resting-state and breath-holding. We found that delay values demonstrated poor agreement when considering all GM voxels, but increasingly greater agreement when limiting analyses to voxels showing strong correlation with the GM mean time-series. Voxels showing the strongest agreement with the GM mean time-series were primarily located near large venous vessels, however these voxels explain some, but not all, of the observed agreement in timing. Increasing the degree of spatial smoothing of the fMRI data enhanced the correlation between individual voxel time-series and the GM mean time-series. These results suggest that signal-to-noise factors may be limiting the accuracy of voxel-wise timing estimates and hence their agreement between the two data segments. In conclusion, caution must be taken when using voxel-wise delay estimates from resting-state and breathing-task data interchangeably, and additional work is needed to evaluate their relative sensitivity and specificity to aspects of vascular physiology and pathology.
Imaging faster neural dynamics with fast fMRI: A need for updated models of the hemodynamic response
2021, Progress in Neurobiology
Fast fMRI enables the detection of neural dynamics over timescales of hundreds of milliseconds, suggesting it may provide a new avenue for studying subsecond neural processes in the human brain. The magnitudes of these fast fMRI dynamics are far greater than predicted by canonical models of the hemodynamic response. Several studies have established nonlinear properties of the hemodynamic response that have significant implications for fast fMRI. We first review nonlinear properties of the hemodynamic response function that may underlie fast fMRI signals. We then illustrate the breakdown of canonical hemodynamic response models in the context of fast neural dynamics. We will then argue that the canonical hemodynamic response function is not likely to reflect the BOLD response to neuronal activity driven by sparse or naturalistic stimuli or perhaps to spontaneous neuronal fluctuations in the resting state. These properties suggest that fast fMRI is capable of tracking surprisingly fast neuronal dynamics, and we discuss the neuroscientific questions that could be addressed using this approach.
Memory enhancement with stimulants: Differential neural effects of methylphenidate, modafinil, and caffeine. A pilot study
2021, Brain and Cognition
Human memory is susceptible to manipulation in many respects. While consolidation is well known to be prone to disruption, there is also growing evidence for the enhancement of memory function. Beside cognitive strategies and mnemonic training, the use of stimulants may improve memory processing in healthy adults. In this single-dose, double-blind, within-subject, randomized, placebo-controlled pilot study, 20 mg methylphenidate (N = 13) or 200 mg modafinil (N = 12) or 200 mg caffeine (N = 14) were administrated to in total 39 healthy participants while performing a declarative memory task. Each participant received only one substance and functional magnetic resonance imaging (fMRI) was used to assess drug-dependent memory effects of the substance for encoding and recognition compared to task-related activation under placebo. While methylphenidate showed some behavioral effect regarding memory recall performance, on the neural level, methylphenidate-dependent deactivations were found in fronto-parietal and temporal regions during recognition of previously learned words. No BOLD alterations were seen during encoding. Caffeine led to deactivations in the precentral gyrus during encoding whereas modafinil did not show any BOLD signal alterations at all. These results should be interpreted with caution since this a pilot study with several limitations, most importantly the small number of participants per group. However, our main finding of task-related deactivations may point to a drug-dependent increase of efficiency in physiological response to memory processing.
Noxious pressure stimulation demonstrates robust, reliable estimates of brain activity and self-reported pain
2020, NeuroImage
Functional neuroimaging techniques have provided great insight in the field of pain. Utilising these techniques, we have characterised pain-induced responses in the brain and improved our understanding of key pain-related phenomena. Despite the utility of these methods, there remains a need to assess the test retest reliability of pain modulated blood-oxygen-level-dependant (BOLD) MR signal across repeated sessions. This is especially the case for more novel yet increasingly implemented stimulation modalities, such as noxious pressure, and it is acutely important for multi-session studies considering treatment efficacy. In the present investigation, BOLD signal responses were estimated for noxious-pressure stimulation in a group of healthy participants, across two separate sessions. Test retest reliability of functional magnetic resonance imaging (fMRI) data and self-reported visual analogue scale measures were determined by the intra-class correlation coefficient. High levels of reliability were observed in several key brain regions known to underpin the pain experience, including in the thalamus, insula, somatosensory cortices, and inferior frontal regions, alongside “excellent” reliability of self-reported pain measures. These data demonstrate that BOLD-fMRI derived signals are a valuable tool for quantifying noxious responses pertaining to pressure stimulation. We further recommend the implementation of pressure as a stimulation modality in experimental applications.
The potential for gas-free measurements of absolute oxygen metabolism during both baseline and activation states in the human brain
2020, NeuroImage
Quantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO₂) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO₂ in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R₂*; VSEAN to estimate baseline O₂ extraction fraction (OEF) from a measurement of venous blood R₂, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO₂; and FLAIR-GESSE to measure tissue R₂′ to estimate the scaling parameter needed for calculating the change in CMRO₂ in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample of 17 subjects (8 female, mean age = 25.3 years, range 21–31 years). The primary findings were that OEF values measured with the VSEAN method were in good agreement with previous PET findings, while estimates of the dynamic change in CMRO₂ in response to a visual stimulus were in good agreement between the traditional hypercapnia calibration and calibration based on R₂′. These results support the potential of gas-free methods for quantitative physiological measurements.
Cerebral blood volume changes during the BOLD post-stimulus undershoot measured with a combined normoxia/hyperoxia method
2019, NeuroImage
Cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) signal measurements make it possible to estimate steady-state changes in the cerebral metabolic rate of oxygen (CMRO₂) with a calibrated BOLD method. However, extending this approach to measure the dynamics of CMRO₂ requires an additional assumption: that deoxygenated cerebral blood volume (CBV_dHb) follows CBF in a predictable way. A test-case for this assumption is the BOLD post-stimulus undershoot, for which one proposed explanation is a strong uncoupling of flow and blood volume with an elevated level of CBV_dHb during the post-stimulus period compared to baseline due to slow blood volume recovery (Balloon Model). A challenge in testing this model is that CBV_dHb differs from total blood volume, which can be measured with other techniques. In this study, the basic hypothesis of elevated CBV_dHb during the undershoot was tested, based on the idea that the BOLD signal change when a subject switches from breathing a normoxic gas to breathing a hyperoxic gas is proportional to the absolute CBV_dHb. In 19 subjects (8F), dual-echo BOLD responses were measured in primary visual cortex during a flickering radial checkerboard stimulus in normoxia, and the identical experiment was repeated in hyperoxia (50% O₂/balance N₂). The BOLD signal differences between normoxia and hyperoxia for the pre-stimulus baseline, stimulus, and post-stimulus periods were compared using an equivalent BOLD signal calculated from measured R₂* changes to eliminate signal drifts. Relative to the pre-stimulus baseline, the average BOLD signal change from normoxia to hyperoxia was negative during the undershoot period (p = 0.0251), consistent with a reduction of CBV_dHb and contrary to the prediction of the Balloon Model. Based on these results, the BOLD post-stimulus undershoot does not represent a case of strong uncoupling of CBV_dHb and CBF, supporting the extension of current calibrated BOLD methods to estimate the dynamics of CMRO₂.

View all citing articles on Scopus

View full text

Caffeine alters the temporal dynamics of the visual BOLD response

Introduction

Section snippets

Experimental protocol

Results

Changes in BOLD dynamics

Conclusions

Acknowledgments

NeuroImage

Brain Res.

J. Clin. Neurosci.

Life Sci.

Comput. Biomed. Res.

NeuroImage

Neurosci. Lett.

NeuroImage

NeuroImage

Neurosci. Res.

Comp. Biochem. Physiol., A Mol. Integr. Physiol.

NeuroImage

NeuroImage

NeuroImage

Vision Res.

Cerebral autoregulation dynamics in humans

Stroke

Assessment of cerebral autoregulation dynamics from simultaneous arterial and venous transcranial Doppler recordings in humans

Stroke

Frequency dependence of local cerebral blood flow induced by somatosensory hind paw stimulation in rat under normo- and hypercapnia

Jpn. J. Physiol.

Modeling the effect of baseline arteriolar compliance on BOLD Dynamics

Assessment of autoregulation by means of periodic changes in blood pressure

Stroke

Dynamics of blood flow and oxygenation changes during brain activation: the balloon model

Magn. Reson. Med.