Alberto Merola1, Esther AH Warnert1, Michael A Germuska1, Sharmila Khot1,2, Daniel Helme2, Lewys Richmond2, Kevin Murphy1, and Richard G Wise1
1CUBRIC, Cardiff University, Cardiff, United Kingdom, 2Department of Anesthesia and Intensive Care Medicine, Cardiff University, Cardiff, United Kingdom
Synopsis
The acute effects of caffeine on haemodynamics are not well
characterized across the brain with MRI. We aim at measuring these in a
double-blind, crossover, placebo-controlled study on sixteen healthy,
moderate caffeine consumers using mTI PASL acquisitions and a two-compartment
ASL model. Results show spatial variations in the CBF and TAT response across
grey matter at different levels of resolution (grey matter, ROI and voxel),
with the latter presenting mixed directions. Moreover we demonstrate that
great attention must be paid to physiological assumptions when modelling ASL
data to estimate CBF in studies on drugs that affect brain haemodynamics.Introduction
Caffeine is a popular psycho-active drug with effects on the central
nervous system and, in particular, on brain haemodynamics. As a non-selective
antagonist of the adenosine receptors it increases neuronal firing rates and reduces
cerebral blood flow (CBF) via vasoconstriction [1]. Effects on haemodynamics are
spatially not homogeneous, as they vary depending on the amount of receptors in
each specific area [2]. Previous MRI studies have shown effects on whole grey
matter baseline CBF or CBF responses to sensory stimuli in relevant ROIs ([3],
[4]), with just one study focusing on the spatial distribution of these effects
in resting state ([5]). In this study we examine the changes in CBF and tissue
arrival time (TAT) following caffeine consumption, in order to determine in
more detail the spatial distribution of these effects.
Methods
Sixteen healthy, moderate caffeine consumers (between
51 and 298 mg/day; 8 females, age = 24.7±5.1) were recruited for
a double-blind, crossover, placebo-controlled study. Each participant was
scanned on two separate days (30.1±18.8 days apart, same
time of the day). Each scan day (see Fig. 1) included a “pre” capsule multi
inversion time (mTI) pulsed arterial spin labelling (PASL) scan followed by the
consumption of a 250mg caffeine (or placebo) capsule and two post-capsule mTI
PASL session: one about 0.5 h later (“post1”) and another about 1h later
(“post2”). Mutiple TI times were used: 0.15, 0.3, 0.45, 0.6 s (short
mTI) and 1, 1.4, 1.8, 2.2 s (long mTI). A PICORE tagging scheme was used with a
QUIPSS II cutoff at 700ms for long mTIs. A dual-gradient echo (GRE) readout and
spiral k-space acquisition imaging was used (TE
1 = 2.7 ms, TE
2 = 29 ms, 64x64,
3x3x7mm
3, gap = 1 mm, 12 slices). Salivary caffeine concentration
samples were taken to monitor the stability of the post-capsule caffeine levels
and the compliance to the request of abstaining from caffeine prior to the
scans.
Data were pre-processed for motion and physiological
noise correction and then fitted with the Chappell two-compartment model [6], resulting
in CBF and TAT maps. Estimates of CSF equilibrium magnetization were used for CBF
quantification and a low resolution minimal contrast image was used for
sensitivity correction. Whole grey matter values of CBF and TAT were calculated
for each subject. In order to examine differences between placebo and caffeine
conditions voxel-wise t-tests were calculated between the pre and post
2
conditions. Finally changes between pre and post
2 conditions were calculated
for both parameters in seven ROIs.
Results
Salivary
caffeine concentration values underwent an average increase of about 2 mg/l 30
min after caffeine consumption and a further 2 mg/l increase at 80 min, while
they were not significantly different from baseline in the placebo condition
(Fig. 2).
Whole
grey matter values of CBF averaged across the subjects significantly decreased
by 30.2% (±8%) at post1 and 34.6% (±8.4%) at post
2 with
caffeine, compared to non-significant variations of 5.2% (±17.3) and -2.5% (±11.3)
respectively with placebo (Fig. 3, top). A significant difference is also found for
TAT with an increase of 4.9% (±4%) and 5.1% (±4.9%) compared to 0.9% (±3%) and 0.3%
(±3.5) with placebo (Fig. 3, bottom). Neither salivary concentration, nor
average daily caffeine intake correlate with CBF or TAT grey matter values
(data not shown).
T-test
maps show a widespread significant decrease in CBF (Fig. 4, top). TAT presents
more localized and mixed effects: areas of significant increase are found in
medial and inferior brain regions, while areas of significant decrease where
smaller and are localized in superior regions (Fig. 4, bottom).
The ROI analysis
supplies a more complete picture of the distribution of the changes in
haemodynamics across the brain (Fig. 5, top), highlighting a seemingly uniform significant
response of CBF to caffeine, compared to a more varied variation in TAT (Fig.
5, bottom).
Conclusions
This study reports a comprehensive picture of the acute effects of caffeine
on brain haemodynamics, at both bulk, regional and voxel-wise levels. Grey
matter changes in CBF confirm previous literature reports ([3],[4],[5]), while more
extended regional differences are found compared to previous studies ([5]),
possibly explained by the more complex ASL model employed here ([6]). TAT
results highlight the heterogeneity of the response, whose physiological nature
should be investigated further. The regional and voxel-wise variability
reported also suggests that great attention must be paid to physiological
assumptions when modelling ASL data to estimate CBF in studies on drugs that affect
brain haemodynamics.
Acknowledgements
We thank the UK Engineering and Physical Sciences Research Council and Cardiff University President's Scholarships for supporting this work.References
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