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

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

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Technical Summary

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.

Publications

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Bulte D (2007) Measurement of cerebral blood volume in humans using hyperoxic MRI contrast. in Journal of magnetic resonance imaging : JMRI

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Bulte DP (2007) Cerebral perfusion response to hyperoxia. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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Dunckley P (2007) Attentional modulation of visceral and somatic pain. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Edden RA (2010) Edited MRS is sensitive to changes in lactate concentration during inspiratory hypoxia. in Journal of magnetic resonance imaging : JMRI

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Harvey AK (2008) Brainstem functional magnetic resonance imaging: disentangling signal from physiological noise. in Journal of magnetic resonance imaging : JMRI

 
Description EPSRC, Improving EEG reading of brain states for clinical applications using a data-driven joint model of FMRI and EEG
Amount £132,000 (GBP)
Funding ID EP/I01487X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 05/2011 
End 05/2012
 
Description ESA project grant
Amount £10,000 (GBP)
Organisation European Society of Anaesthesiologists (ESA) 
Sector Charity/Non Profit
Country European Union (EU)
Start  
 
Description International collaboration award, Cardiff University
Amount £3,000 (GBP)
Organisation Cardiff University 
Sector Academic/University
Country United Kingdom
Start 06/2009 
End 07/2009
 
Description Marie Curie FP7 Fellowship
Amount £200,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 09/2010 
End 09/2012
 
Description NIAA Project Grant
Amount £50,000 (GBP)
Organisation National Institute of Academic Anaesthesia 
Sector Learned Society
Country United Kingdom
Start  
 
Description Pfizer project grant: Pharmacological modulation of free-running EEG
Amount £61,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 11/2010 
End 11/2011
 
Description Pfizer, Project grant. FMRI for drug development
Amount £257,000 (GBP)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 08/2008 
End 08/2010
 
Description Wellcome Trust Value in People via Cardiff University
Amount £35,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 09/2011
 
Title Single trial eeg analysis 
Description Software for single trial analysis of EEG (especially useful in simultaneously collected FMRI). 
Type Of Material Data analysis technique 
Year Produced 2006 
Provided To Others? Yes  
Impact Use of software in other publications 
 
Description Brainstem control of blood pressure 
Organisation University of Bristol
Department School of Physiology, Pharmacology and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Neuroimaging (brainstem) expertise: functional MRI and cerebral perfusion
Collaborator Contribution Intellectual contribution in studying brainstem control of blood pressure
Impact Successful pilot grant application as collaborator (SARTRE, MRC). A further successful application was made in 2010 to BHF. This collaboration is multidisciplinary involving physicists and physiologists.
Start Year 2008
 
Description Caffeine effects on brain function 
Organisation University of Bristol
Department School of Experimental Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of neuroimaging expertise (EEG-FMRI) to study anxiety effects of caffeine. Neurovascular coupling alterations induced by caffeine.
Collaborator Contribution Intellectual contribution in evaluating neurocognitive effects of caffeine in low caffeine consumers.
Impact 2 preliminary grant applications made to the BBSRC (unsuccessful). One abstract accepted in 2011 and another in submission. Neuroimage article published.
Start Year 2008
 
Description Cardiff Anaesthetic and Intensive Care Medicine 
Organisation Cardiff University
Department Department of Anaesthetics, Intensive Care and Pain Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Neuroimaging (EEG-FMRI, MEG) expertise for studying anaesthetic action.
Collaborator Contribution Intellectual contribution in anaesthetic research. Provision of practical anaesthetic research (drug delivery and patient care).
Impact Successful grant applications. International conference presentations. Manuscripts in submission. This is multidisciplinary involving physicists and anaesthetists.
Start Year 2008
 
Description Cerebral blood flow 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Application of cerebral blood flow measurement to human drug studies
Collaborator Contribution Supply of software to measure cerebral blood flow using MRI
Impact Manuscripts in preparation. Successful grant application.
Start Year 2008
 
Description Neurophysiology of pain 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Advanced EEG data analysis strategies. Access to EEG-FMRI facilities and MEG imaging facilities.
Collaborator Contribution Intellectual exchange and practical advice/experimentation in EEG and pain-related neurophysiology. Analysis of EEG signals.
Impact Grant applications in preparation. International presentations (Royal Society Workshop, Berlin). 2 publications
Start Year 2006
 
Description Optimising pharmacological FMRI for drug development 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution Employment of a new post-doc to develop FMRI methods that are of interest to Pfizer in drug development and testing in humans.
Collaborator Contribution This new project supports a post-doctoral researcher in my team, expanding our capacity to develop FMRI as a tool in drug discovery.
Impact This new project supports a post-doctoral researcher in my team, expanding our capacity to develop FMRI as a tool in drug discovery. Further grant applications (recently leading to a successful one to the Wellcome Trust). Manuscripts for publication are in preparation
Start Year 2008
 
Description Quantitative FMRI 
Organisation University of California, San Diego (UCSD)
Department Center for Functional MRI
Country United States 
Sector Academic/University 
PI Contribution Expertise on physiological challenges performed in the MRI scanner.
Collaborator Contribution Software for controlling MRI scanner to make quantitative measurements of cerebral blood flow and oxygen consumption.
Impact Manuscripts in preparation. Successful fellowship applications from Wellcome Trust.
Start Year 2006
 
Description Respiratory FMRI 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual collaboration and supervision of research fellow (Dr Kyle Pattinson). Development of FMRI for assessing cerebral physiology.
Collaborator Contribution Intellectual collaboration and practical advice in neurophysiology and anaesthetic research.
Impact Collaboration in successful subsequent MRC fellowship application. 7 publications. Grants applies for in 2011. This collaboration is multidisciplinary involving physicists and anaesthetists.
Start Year 2006
 
Description University of Rome, La Sapienza 
Organisation Sapienza University of Rome
Country Italy 
Sector Academic/University 
PI Contribution Visits to Rome to present current research. Joint drafting of fellowship applications to EU and Wellcome Trust.
Collaborator Contribution Two joint applications for funding of a travelling fellow in Cardiff to research EEG-FMRI. Successful FP7 Marie Curie fellowship funded.
Impact Joint grant (fellowships) results pending. Award of a visiting fellowship to Prof Wise in Rome during 2011. Marie Curie Fellowship awarded.
Start Year 2008
 
Description Educational films 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Schools
Results and Impact We have also made a film, posted on the internet, to encourage A level students to read Engineering at University. A second film was made about "brain biology" for A level students commissioned by Edexcel exam board.

Films used as part of A level Biology curriculum
Year(s) Of Engagement Activity 2008,2009
 
Description Invited presentations to the drug development industry 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact Presentations to industry conferences on the use of imaging in drug discovery in London and across Europe. The audience mainly comprised R&D from the pharmaceutical industry.

Enhanced industry collaborations (e.g. Pfizer project)
Year(s) Of Engagement Activity 2007,2008,2010,2011
 
Description School visits to Cardiff Laboratory 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact We conduct frequent tours of the Cardiff University Brain Research Imaging Centre for local Schools.

Public engagement
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012