Functional magnetic resonance imaging of the human spinal cord and brainstem with application to pain states

Lead Research Organisation: University of Bristol
Department Name: Experimental Psychology

Abstract

One in five people will experience chronic pain during their lives. Changes in the way the body processes pain signals are thought to underlie how, after injury, pain can become chronic.

When you hurt yourself, pain signals are carried from the damaged tissue to the brain. On their way to the brain, they pass up the spinal cord and through the brainstem. However, when trying to find out what goes wrong in chronic pain, current imaging methods only allow researchers to look within the brain and brainstem. We would like to develop new methods that would allow us to look within the spinal cord as well.

This is important for two reasons: (1) we know from animal experiments that the brainstem and spinal cord work together to increase or decrease the size of pain signals, and (2) abnormal changes in the function of the brainstem and spinal cord can make pain become chronic.

In this project we will see how pain signals are processed in the spinal cord and brainstem in humans, and by doing so, get a better understanding of how pain is controlled, and hopefully learn why some people develop chronic pain after injury.

Technical Summary

Background: Neuroimaging has revealed a network of brain regions thought to reflect how we perceive pain. However, nociceptive information relayed from peripheral nerves, is modulated at the spinal cord, brainstem and brain. Adjustment of signal transmission at each of these levels ultimately determines levels of brain activity observed. The spine‘s location makes it inaccessible to electrophysiological investigation, hence a non-invasive technique is needed. We propose to extend conventional blood oxygenation level dependent (BOLD) methods to the human spinal cord. Building on our recent research addressing physiological noise modelling in spinal images, we will expand this to the assessment of spinal cord function.

Aims/Objectives: (i) Verify existence of BOLD signal change in the spinal cord, using combination of: hypercapnic challenges and lateralised multi-modal stimulation; (ii) translate animal experiments demonstrating descending control of pain, to non-invasive studies in humans; (iii) investigate the effects of peripherally and centrally acting analgesic compounds in disrupting normal spinal - brainstem loops during painful stimulation; and (iv) determine brainstem and spinal predictors of secondary hyperalgesia, using the intradermal capsaicin model and novel connectivity analyses.

Methods/Design: In healthy subjects, using conventional BOLD sensitive imaging on a 3 tesla MR system: (i) examine the echo time (TE) dependence of signal changes in response to a hypercapnic challenge (CO2 breathing), and thereby determine the optimal TE for spinal FMRI. By delivering noxious (laser) and non-noxious (air-puff) stimuli to both sides of the body, we will record associated signal changes in the cord and brainstem. (ii) We will modulate pain-related activity within the spinal cord and brainstem, using either cognitively demanding tasks to distract subjects, or (iii) via centrally (remifentanil) or peripherally (lidocaine) acting analgesic compounds. Finall (iv) we will inject capsaicin intradermally, and examine whether spinal and brainstem responses during punctate hyperalgesia are correlated, and examine whether they predict the presence and intensity of provoked symptoms.

Scientific & Medical relevance: At the level of the spinal cord, maladaptive responses to tissue injury (central sensitisation) may underlie the pathogenesis of chronic pain. Animal studies have revealed that modulation of nociceptive signal transmission occurs at all levels of the neuroaxis, and there is a pressing need for these data to be translated to humans, as well as provide a completely novel means of assessing spinal cord function (e.g. for assessing recovery following spinal cord injury, or for investigating the consequence of spinal plaques in multiple sclerosis on motor/sensory function).

Publications

10 25 50

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Brooks JC (2013) Physiological noise in brainstem FMRI. in Frontiers in human neuroscience

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Brooks JC (2012) Assessing spinal cord function in multiple sclerosis with functional neuroimaging: insights and limitations. in Multiple sclerosis (Houndmills, Basingstoke, England)

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Brooks JC (2012) Stimulus site and modality dependence of functional activity within the human spinal cord. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Brooks JC (2017) Resolving the Brainstem Contributions to Attentional Analgesia. in The Journal of neuroscience : the official journal of the Society for Neuroscience

 
Description Above and Beyond
Amount £17,331 (GBP)
Organisation University Hospitals Bristol NHS Foundation Trust 
Department Above and Beyond Grants
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 12/2014
 
Description Collaborative Project, Large-scale integrating project
Amount £862,107 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2014 
End 12/2018
 
Description Data Visualisation Challenge - Exploring complex datasets using data visualisation in VR/360
Amount £8,000 (GBP)
Funding ID The Secrets of Better Brain Health 
Organisation University of Bristol 
Department Jean Golding Institute
Sector Academic/University
Country United Kingdom
Start 02/2018 
End 07/2018
 
Description Experimental Medicine Challenge Grant
Amount £2,718,000 (GBP)
Funding ID MR/N026969/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2017 
End 12/2021
 
Description IASP Collaborative Research Grant
Amount £6,031 (GBP)
Organisation International Association for the Study of Pain (IASP) 
Sector Learned Society
Country United States
Start  
End 03/2015
 
Description UoB-MRC Centenary Award
Amount £46,497 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Title Array coil for MRI of the brainstem and cervical spinal cord 
Description In conjunction with Stark Contrast (Erlangen, Germany) we have designed and had constructed a 22-channel brainstem and spinal cord coil for use in a 3T MRI scanner (Siemens TIM Trio). The coil provides a 2-fold increase in signal to noise (compared to standard equipment) over an extended field of view, and allows us to acquire higher resolution images of these areas than is normally possible. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact By using this new coil we are now able to routinely image the grey matter of the spinal cord, which will increase the ability of neurologists to detect spinal lesions that affect patients with diseases such as multiple sclerosis, amyotrophic lateral sclerosis and spinal cord injury. 
 
Title Inner field of view diffusion imaging of the human spinal cord 
Description In collaboration with Dr Jurgen Finsterbusch, who provided the pulse sequence, we have developed optimised techniques for assessing the structural connectivity of the human spinal cord. Previously this has proven to be extrememly difficult and un-reliable. We believe that in conjunction with the purpose build spine/brainstem array coil, we can begin to investigate further the structure of the human spinal cord in vivo. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2010 
Provided To Others? Yes  
Impact As part of this ongoing collaboration I have been invited to speak at the end of November 2010 at the Lectures in Neuroscience series at University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 
 
Title Physiological noise model 
Description The physiological noise model is a computational technique for removing/correcting for the presence of signals of a cardiac or respiratory origin from fMRI data. The technique has been incorporated into the FMRIB Software Library (FSL) which is released world wide. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2009 
Provided To Others? Yes  
Impact The technique will be used to correct data acquired as part of the Human Connectome Project. The PNM has been applied in several projects in which I have collaborated, leading to high impact journal publications. 
URL https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/PNM
 
Description Characterisation of the BOLD response in the spinal cord using hypercapnia 
Organisation University of Montreal
Country Canada 
Sector Academic/University 
PI Contribution Analysis of data acquired in Montreal as part of the hypercapnia project.
Collaborator Contribution We have demonstrated that conventional blood flow sensitive imaging techniques, utilising blood oxygenation level dependent (BOLD) contrast, reveal blood flow changes in the human spinal cord that are of a similar magnitude to those observed in the brain. This is of crucial importance for the development of robust markers of spinal activity, and is validation of previous BOLD based studies in the cord.
Impact (1) Journal article published in NeuroImage. (2) Collaborator from Montreal travelled to Oxford and gave a presentation as part of a spinal cord imaging symposium I organised. (3) Currently working on new methods for analysing data from this experiment.
Start Year 2008
 
Description Development of analysis techniques and array coils for high-field imaging of the structure and function of the human spinal cord 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Development of new techniques for motion correction; provision of design details for 22 channel brainstem/spinal cord coil.
Collaborator Contribution Collaboration on motion correction and analysis of functional images recorded from the spinal cord. Assistance in the development of a new brain, brainstem and spinal cord coil. Longer term this collaboration will hopefully provide a "fast-track" to obtaining suitable coils for imaging the spinal cord at 7T, as the MGH team are currently working on such designs.
Impact MGH have provided coil characterisation software that is being used to test the performance of the 22 channel coil purchased with grant funding from the MRC. We are still waiting for Oxford's legal team to sign the license so that we can use the software from MGH. Have several experiments planned, but currently waiting for this approval.
Start Year 2009
 
Description Dr Nanna Brix Finnerup: Danish Pain Research Centre, Aarhus, Denmark. 
Organisation Aarhus University Hospital
Department Danish Pain Research Center
Country Denmark 
Sector Academic/University 
PI Contribution We have provided technical expertise in the area of data acquisition and analysis for a study involving patients with phantom limb pain. To date we have scanned 7 patients and 12 controls to study the spinal cord with fMRI. We have a second scanning session booked for this May (2017), where I will travel to Aarhus, Denmark to acquire the remaining data for the study. We recently presented the initial results from this study at the International Association for the Study of Pain in Yokahama, Japan.
Collaborator Contribution Dr Finnerup has identified an interesting area for investigation in patients with phantom limb pain, namely the potential for spinal cord plasticity to produce these patients' pain symptoms. Dr Finnerup has recruited patients and confirmed their diagnosis with quantitative sensory testing, prior to scanning at CFIN. Working alongside Dr Finnerup, Dr Francesca Fardo has programmed stimulation paradigms, and arranged logistics and testing for these patients and controls, and will continue to be involved with the project during her Fellowship in Aarhus.
Impact Poster presentation at the International Association for the Study of Pain, Yokohama, Japan (September 2016).
Start Year 2010
 
Description Imaging the central nervous system in multiple sclerosis 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided technical expertise in the development of imaging protocols for the spinal cord, as well as the means for correcting imaging data for the presence of physiological noise. The purpose built spinal coil, purchased with funding from the MRC has been used to improve the image quality from the cervical cord, and will hopefully aid in the detection of spinal cord lesions.
Collaborator Contribution We are establishing new protocols for imaging the spinal cord in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). The collaborators have provided clinical expertise and patients, which we have examined with the purpose built spinal coil purchased with funding from the MRC. We are in the process of submitting a grant to the MS Society, which will (if successful) provide funding for an additional postdoctoral researcher, equipment costs, scan fees and a proportion of Clinical Research Scientist's salary.
Impact Through working with the clinical team, it became obvious that there is an unmet need with regard to detecting and assessing the functional significance of spinal cord lesions. Following on from this, I was invited to speak at the MAGNIMS (MAGNetic Imaging in Multiple Sclerosis) meeting in Basel in 2010, and am currently preparing a manuscript based on the presentation.
Start Year 2009
 
Description Investigating altered function and connectivity in the spinal cord and brainstem of patients with neuropathic pain 
Organisation Aarhus University Hospital
Department Danish Pain Research Center
Country Denmark 
Sector Academic/University 
PI Contribution Obtained funding from the International Association for the Study of Pain, wrote application and presented data during visit to Aarhus. Optimised image acquisition and data analysis protocols, visited Aarhus on several occasions to develop stimulus delivery apparatus. Acquired data from patients with phantom limb pain and healthy age matched controls. Processed data and prepared results for conference poster.
Collaborator Contribution Dr Nanna Brix Finnerup (Neurologist in the Danish Pain Research Center) recruited patient and healthy controls. Dr Finnerup confirmed the diagnosis of phantom limb pain by performing quantitative sensory testing. Dr Francesca Fardo (Post doc in the DPRC) has helped design the experimental paradigm and programmed electrical stimulation paradigm, which has been used successfully during scanning.
Impact Poster presentation at the International Association for the Study of Pain (IASP), Yokohama, Japan (September, 2016).
Start Year 2011
 
Description Investigating safety of MRI in patients with deep brain stimulators 
Organisation North Bristol NHS Trust
Country United Kingdom 
Sector Public 
PI Contribution Developing methods for assessing local warming effects on implanted deep brain stimulators using thermometry during MRI
Collaborator Contribution Technological development - new DBS probes
Impact None as yet.
Start Year 2014
 
Description Neural correlates of social learning abnormality in social anxiety 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution I helped the applicant prepare the application, and will be involved in the final design and execution of the project.
Collaborator Contribution Dr Kate Button applied for and obtained this funding which was made available via a UoB-MRC Centenary Award
Impact None yet
Start Year 2013
 
Description Neuroimaging in painful diabetic neuropathy 
Organisation University Hospitals Bristol NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution I devised the protocol, wrote the grant application and ultimately will conduct the research
Collaborator Contribution Professor David Wynick is the clinical lead on the project
Impact Ethics being applied for
Start Year 2012
 
Description Radiofrequency (RF) coil building for CNS imaging 
Organisation Massachusetts General Hospital
Department Martinos Center for Biomedical Imaging Massachusetts
Country United States 
Sector Academic/University 
PI Contribution We are currently designing the next generation of human cervical spinal and brain coil for imaging the entire CNS during a single examination. I have provided expertise via the design choices made when we commissioned our 22 channel spinal cord/brainstem coil. I have established connections with the RF researchers in Bristol University (Dr Paul Warr), who will be travelling to the Martinos Centre to acquire the skills necessary to fabricate a new generation of spine/brain coil. These techniques are currently lacking in the UK, so we see this as a skills transfer and acquisition of new IP.
Collaborator Contribution Dr Larry Wald is the Physics Director at the Martinos Center and is providing expertise and equipment for construction of a 64 channel head and neck coil for use in humans.
Impact As part of this collaboration we are planning to transfer pulse sequences to Bristol via C2P agreements between Bristol University and MGH and Siemens.
Start Year 2012
 
Description Resting state spinal imaging with Hamburg 
Organisation University Medical Center Hamburg-Eppendorf
Country Germany 
Sector Hospitals 
PI Contribution I and Dr Kong provided technical expertise in the analysis of resting state data acquired from the spinal cord. We used physiological noise clean up and group independent component analysis (ICA) to show that resting networks can be observed in these data.
Collaborator Contribution Dr Falk Eippert and Dr Jurgen Finsterbusch optimised the pulse sequences and acquired data from a large group of subjects in Hamburg
Impact Paper ready for submission
Start Year 2011
 
Description Spinal cord imaging and conditioning 
Organisation University of Oxford
Department Oxford Centre for Functional MRI of the Brain (FMRIB)
Country United Kingdom 
Sector Academic/University 
PI Contribution I have been directly involved in the experimental design, data acquisition and analysis phases of this study.
Collaborator Contribution Dr Falk Eippert has been using the 22 channel spinal and brainstem coil purchases through funding from my MRC Fellowship to study the effect of classical conditioning and the extinction phase using painful electrical stimulation.
Impact Paper in preparation
Start Year 2011
 
Description The Neurobiology of Decision-Making in Eating - Innovative Tools 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution I was approached by the lead PI (Prof Jeff Brunstrom) to enquire whether we could add an imaging component to this study. I helped devise the protocol that was included in this multi-centre FP7 project grant. I will provide imaging support for this project.
Collaborator Contribution Professor Jeff Brunstrom is the PI on this proposal, and will lead the research.
Impact No formal announcement of the award has been made yet. Scheduled for early 2014.
Start Year 2012
 
Description The effects of opioids and sleep disturbance on pain 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution This project forms a research theme of part of a larger grant application funded by the Elizabeth Blackwell Institute (Wellcome Trust funding). I co-authored the grant with Dr Claire Durant and Ms Lee Harrison.
Collaborator Contribution Dr Cathy Stannard (North Bristol NHS Trust) and Dr Johanna Herrod (North Bristol NHS Trust) helped identify and recruit patients for inclusion in this study. Dr Charlotte Powell and Dr Tony Pickering (University of Bristol Hospitals Trust) helped identify and recruit patients for inclusion in this study.
Impact none yet
Start Year 2013
 
Title Physiological noise model, part of FMRIB's Software Library (FSL) 
Description An interface and algorithm co-developed my Dr Mark Jenkinson and Dr Jonathan Brooks for the creation of nuisance regressors that attempt to explain physiological noise in fMRI data. Released as part of FSL 5.0 September 2012. 
Type Of Technology Software 
Year Produced 2012 
Open Source License? Yes  
Impact Has been used by several groups world-wide for analysis of brainstem and spinal cord fMRI data. Formed part of the FSL course (Bristol 2012), which was attended by over 100 national and international visiting scholars. Is part of the syllabus on a planned meeting: http://www.spmworkshop-hannover.de/index.php/brainstem-fmri 
URL https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/PNM
 
Description Bristol Festival of Neuroscience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presented to around 200 members of the public, which included a large proportion from local secondary schools. Discussion following the presentation ranged from "how can we control pain?" to "is it all mind over matter?"

During the same meeting we presented posters detailing the research output and projects we are involved in at CRiCBristol. I got chatting to a representative from a Bristol Patient Support Group, and I am planning to give a talk there.
Year(s) Of Engagement Activity 2013
URL http://www.bristol.ac.uk/neuroscience/events/diary/2013/101365.html
 
Description National Science Learning Centre Training Course 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Presentation to secondary school age students identified as "gifted and talented". 15 minute presentation on the role of the central nervous system in pain sensation, followed by 10 minute question and answer session.

The session was recorded on video, and looking back it was remarkable how much the students were able to glean from such a short talk, and how much they understood, which was evident from their tricky questions!
Year(s) Of Engagement Activity 2007
 
Description Newspaper Article Is Pain All In The Mind? The Times (July 26th, 2008) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was approached by Kate Wighton (The Times, Body & Soul) about an article she was researching about the role of the brain in pain sensation. I gave a telephone interview, then assisted Ms Wighton with final article.

None
Year(s) Of Engagement Activity 2008
 
Description Pain workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Clinicians attending the meeting have approached me to discuss various opportunities for future collaboration, some of which have an industrial sponsor.

Planning to study patients undergoing chronic pain treatment with deep brain stimulation
Year(s) Of Engagement Activity 2014
 
Description Presentation to Multiple Sclerosis Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Contacted local Multiple Sclerosis Society member to enquire about possibility of giving presentation to local patient support groups. Was invited to speak at meeting in Banbury. The talk "The role of the spinal cord in MS" was well received, and was presented in conjunction with a clinical colleague (Dr Lucy Matthews). The mostly lay members of the audience were particularly interested in new techniques for studying MS, and asked insightful questions. It was clear that not many patients appreciated that a large part of the burden of MS is due to damage to the spinal cord (e.g. bladder problems, sexual dysfunction). I outlined my research background and current plans to translate my research in healthy controls to patient groups.

Feedback from the meeting was very positive.
Year(s) Of Engagement Activity 2010
 
Description Radio Broadcast on BBC Radio Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Was invited to be part of a discussion with Bill Heine on Radio Oxford, discussing the role of the brain in the sensation of pain. Haven't received any meaningful feedback as a consequence of this work.

My neighbour mentioned that she heard it!
Year(s) Of Engagement Activity 2010
 
Description Radio Interview (BBC Radio Oxford 2012) 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Following my previous work with BBC Oxford discussing the role of psychological factors in pain perception, I was contacted to speak on their early morning radio program about how pain could be experienced in the absence of obvious tissue injury.

I was subsequently contacted by the BBC and asked to appear on their local TV broadcast (South Today, November 15th).
Year(s) Of Engagement Activity 2012
 
Description Schools visit to Bristol Neuroscience Festival 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact School children attended the Bristol Neuroscience Festival to see work carried out in the University. I coordinated a stand for our imaging unit, arranging for hands-on demonstrations of 3D printed brains which were taken from subjects scanned on the MRI.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/neuroscience/bnf/
 
Description TV Interview (BBC South Today 2012) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was invited to appear on BBC's South Today television programme to speak about how pain can alter the central nervous system, and how pain can persist beyond the normal tissue healing period.

None.
Year(s) Of Engagement Activity 2012