Mapping the pharmacological modulation of brain oxygen metabolism: The effects of caffeine on absolute CMRO2measured using dual calibrated fMRI.
This study aims to map the acute effects of caffeine ingestion on grey matter oxygen metabolism and haemodynamics with a novel MRI method. Sixteen healthy caffeine consumers (8 males, age=24.7±5.1) were recruited to this randomised, double-blind, placebo-controlled study. Each participant was scanned on two days before and after the delivery of an oral caffeine (250mg) or placebo capsule. Our measurements were obtained with a newly proposed estimation approach applied to data from a dual calibration fMRI experiment that uses hypercapnia and hyperoxia to modulate brain blood flow and oxygenation. Estimates were based on a forward model that describes analytically the contributions of cerebral blood flow (CBF) and of the measured end-tidal partial pressures of CO2and O2to the acquired dual-echo GRE signal. The method allows the estimation of grey matter maps of: oxygen extraction fraction (OEF), CBF, CBF-related cerebrovascular reactivity (CVR) and cerebral metabolic rate of oxygen consumption (CMRO2). Other estimates from a multi inversion time ASL acquisition (mTI-ASL), salivary samples of the caffeine concentration and behavioural measurements are also reported. We observed significant differences between caffeine and placebo on average across grey matter, with OEF showing an increase of 15.6% (SEM±4.9%, p<0.05) with caffeine, while CBF and CMRO2showed differences of -30.4% (SEM±1.6%, p<0.01) and -18.6% (SEM±2.9%, p<0.01) respectively with caffeine administration. The reduction in oxygen metabolism found is somehow unexpected, but consistent with a hypothesis of decreased energetic demand, supported by previous electrophysiological studies reporting reductions in spectral power with EEG. Moreover the maps of the physiological parameters estimated illustrate the spatial distribution of changes across grey matter enabling us to localise the effects of caffeine with voxel-wise resolution. CBF changes were widespread as reported by previous findings, while changes in OEF were found to be more restricted, leading to unprecedented mapping of significant CMRO2reductions mainly in frontal gyrus, parietal and occipital lobes. In conclusion, we propose the estimation framework based on our novel forward model with a dual calibrated fMRI experiment as a viable MRI method to map the effects of drugs on brain oxygen metabolism and haemodynamics with voxel-wise resolution.
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK.
Alberto
A
Merola
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK.
Michael A
MA
Germuska
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK.
Esther Ah
EA
Warnert
Department of Anaesthetics and Intensive Care Medicine, Cardiff University School of Medicine, Cardiff, UK.
Lewys
L
Richmond
Department of Anaesthetics and Intensive Care Medicine, Cardiff University School of Medicine, Cardiff, UK.
Daniel
D
Helme
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK; Department of Anaesthetics and Intensive Care Medicine, Cardiff University School of Medicine, Cardiff, UK.
Sharmila
S
Khot
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK.
Kevin
K
Murphy
School of Experimental Psychology, University of Bristol, Bristol, UK.
Peter J
PJ
Rogers
Department of Anaesthetics and Intensive Care Medicine, Cardiff University School of Medicine, Cardiff, UK.
Judith E
JE
Hall
Cardiff University Brain Research Imaging Centre (CUBRIC), School of Psychology, Cardiff University, Cardiff, UK. Electronic address: wiserg@cardiff.ac.uk.
Richard G
RG
Wise
D000328:Adult; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004311:Double-Blind Method; D005260:Female; D059907:Functional Neuroimaging / Q000379:methods*; D066128:Gray Matter / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects*; D055815:Young Adult
D000697:Central Nervous System Stimulants; D002110:Caffeine
Caffeine; Calibrated fMRI; Cerebral metabolic rate of oxygen consumption; Gas manipulations; Randomised placebo-controlled drug study