The acute effects of caffeine on brain oxygen metabolism: a dual calibrated FMRI study
Alberto Merola1, Michael A Germuska1, Esther AH Warnert1, 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

Caffeine acute effects on oxygen metabolism 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 a dual calibrated fMRI approach and a novel forward estimation model. Results show spatial variations in OEF0, CBF, CVR, venous CBV and CMRO2 across grey matter at different levels of resolution (grey matter, ROI and voxel), in agreement with most of the literature findings. Therefore we propose this approach as the first viable method to assess the effects of drugs on brain metabolism with a voxel-wise resolution.

Introduction

Caffeine is one of the most common and widely consumed psycho-active substances. It is a non-selective antagonist of the adenosine receptors causing stimulation of brain activity, via increased neuronal firing rates, and reduction of cerebral blood flow (CBF), via vasoconstriction [1]. Caffeine’s effects can be heterogeneous across the brain, depending, for example, on regional receptor expression [2]. Previous MRI studies have shown effects of this drug on brain metabolism, mostly looking at grey matter changes in CBF [3] and cerebral metabolic rate of oxygen consumption (CMRO2), with CMRO2 having been shown to both increase [4] and decrease [5]. Recently, methods [6] exploiting fMRI acquisitions during hypercapnic and hyperoxic respiratory tasks have been developed to estimate absolute CMRO2 (an approach known as dual calibrated fMRI or dcFMRI) potentially allowing brain oxygen metabolism to be mapped in drug studies.

Purpose

We want to show how a dcFMRI approach can be used to assess the acute effects of caffeine on oxygen extraction fraction (OEF0), CBF, cerebrovascular reactivity (CVR), venous cerebral blood volume (CBV) and CMRO2 across grey matter.

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), with each day including two dcFMRI experiments: one before (“pre” condition) and one about 45 min after (“post” condition) delivery of an oral caffeine capsule (250 mg). The dcFMRI experiment consisted of an 18 min dual-gradient echo acquisition (TE1 = 2.7 ms, TE2 = 29 ms, 64x64, 3x3x7mm3, gap = 1 mm, 12 slices) while performing a respiratory task including three periods of hypercapnia (5% CO2 balanced air) interleaved with two periods of hyperoxia (50% O2 balanced air). A spiral k-space acquisition was used along with a PICORE tagging scheme and a QUIPSS II cut-off at 700ms. These data were analysed using a novel forward model ([7]), to estimate maps of OEF0, CBF, CVR, CBV and CMRO2. Results from one subject were excluded because of the poor quality of end tidal traces, leaving N=15 subjects for the following statistical analysis. Along with grey matter statistics, voxelwise t-tests were performed on the estimated maps to test the difference of the changes from pre to post session with placebo and caffeine. Averaged values of each parameter were also calculated in seven ROIs (caudate nucleus, frontal lobe, insula, occipital lobe, parietal lobe, putamen and thalamus) to further explore spatial distribution of the effects.

Results

Plateau levels of hyperoxia and hypercapnia caused an average increase of approximately 210 mmHg and 11 mmHg in end-tidal O2 and CO2 pressure respectively, compared to baseline (Fig. 1). Grey matter values of CBF, CBV and CMRO2 averaged across the subjects significantly decreased by 30.4% (±6.1%), 31% (±13.8%) and 18.6% (±11.1%) with caffeine, compared to a non-significant variation of 1.3% (±7.3%), -2% (±23.5%) and 0.7% (±21.3%) respectively with placebo (Fig. 2, B-D-E). A significant difference is also found for OEF0 with an increase of 15.6% (±18.9%), compared to 1.9% (±19.7%), while for CVR the increase of 17.4% (±27.7%) with caffeine is not significantly different from the increase of 7.9% (±23.1%) with placebo (Fig. 2, A-C). T-test maps show a widespread significant reduction compared to the pre-dose scan with caffeine compared to placebo for CBF and CBV, while more localized decrease for CMRO2 and increase for OEF0 and CVR (Fig. 3). The ROI analysis supplies a more complete picture of the distribution of the changes in metabolism (Fig. 4), highlighting the different contribution of CBF and OEF0 to oxygen consumption across the brain.

Conclusions

Results show significant differences in response to caffeine compared to placebo, with directions of the effects consistent with what is expected from previous findings as regards CBF and OEF0 ([1],[4],[5]) and with part of the MRI literature as regards CMRO2 [4]. Statistics on the estimated maps show the spatial distributions of the response to caffeine both at a ROI and voxelwise resolution, allowing us to localize areas of significant effects. We therefore propose the dcFMRI approach using our novel forward model ([7]), as the first viable MRI method to assess the effects of drugs on brain metabolism with a voxel-wise resolution.

Acknowledgements

We thank the UK Engineering and Physical Sciences Research Council and Cardiff University President's Scholarships for supporting this work.

References

[1] Fredholm et al., Pharma. rev., 83-133 (1999); [2] Laurienti et al., AJNRm 1607–1611 (2003); [3] Chen et al., Neuroimage, 647-52 (2009); [4] Griffeth et al., Neuroimage, 809-816 (2011); [5] Xu. et al, Neuroimage, 39,-47, (2015); [6] Wise et al., Neuroimage, 135-147 (2013); [7] Germuska et al., ISMRM meeting 2015, abstract 2131;

Figures

End-tidal O2 and CO2 pressure during an 18 min respiratory task averaged across subjects.

Mean grey matter values of the five estimated parameters for N=15 subjects. In red the calculated means with bars representing the standard deviations. Significance of t-tests between pre and post condition denoted with asterisks (*p<.05, **p<.01).

t-tests performed between changes from pre to post condition in caffeine and placebo. Maps show t values for which p<0.01 either in negative or positive direction (t>3.33 and t<-3.33 respectively, 14 dof), and thresholded for cluster size with significance level α=0.05.

Mean changes from pre to post condition in caffeine and placebo in different ROIs. Significance of t-tests between caffeine and placebo is denoted with asterisks (*<.05, **<.01, FDR corrected). ROIs considered: 1 - caudate nucleus; 2 - frontal lobe; 3 - insula; 4 - occipital lobe; 5 - parietal lobe; 6 - putamen; 7 - thalamus.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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