Pharmacological neuroimaging: assessing FMRI as a biomarker of changes in neuronal activity using combined EEG and FMRI

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There is a coupling between neuronal activity measured electrophysiologically and the haemodynamic response to which functional magnetic resonance imaging (FMRI) is sensitive. It is the neuronal effects of pharmacological agents that interest us when investigating drugs that affect perception or behaviour. FMRI is becoming the preferred functional imaging method of choice for non-invasive human studies and is considered by the pharmaceutical industry as a key methodology for assessing drug action early in development. However, we know little about how a change in the FMRI response relates to non-neuronal drug effects rather than specific drug-induced changes in neuronal activity. We must therefore characterise, more fully, the coupling relationship between neuronal activity and the FMRI response, and pharmacological influences on this neurovascular coupling.
Electroencephalography (EEG) enables us to assess neuronal activity. The only way to powerfully investigate the neurovascular coupling in humans is to collect simultaneous EEG and FMRI data. Simultaneous acquisition has several key advantages: it ensures for both techniques, an identical mental state; it permits individual, rather than averaged, stimulus-response characteristics to be compared, utilising the variability in inter-trial responses; and it allows the resting state to be investigated through spontaneous fluctuations in electrical and haemodynamic activity.
We will study mu-opioid induced analgesia using noxious laser and non-noxious sensory stimulation. Opioids are clinically important drugs which are likely to have regional effects on neurovascular coupling.
To characterise the coupling relationship, we would identify electrophysiological predictors of the blood oxygen level dependent FMRI response to stimulation. We would measure the change in this coupling relationship induced by a mu-opioid analgesic and potential causes of that change. Opioids can induce global physiological changes that may modify the coupling e.g. hypercapnia with increased cerebral blood flow (CBF), and a reduction in blood oxygenation. We would examine the influence of such changes on stimulus-evoked EEG and FMRI responses. Many drugs are vasoactive. We would, therefore, characterise opioid-induced changes in cerebral blood volume (CBV) and vascular reactivity. Such measures could be factored into the interpretation of future FMRI studies. Finally, drugs may modulate the baseline or resting level of neuronal activity. FMRI and EEG can reveal resting networks of brain activity. We would test the hypothesis that an opioid modulates ongoing activity in brain regions involved in pain perception.
Having demonstrated our methodology using an opioid, the techniques could be applied to a wide range of centrally acting, clinically important drugs, such as anaesthetics.