Stratifying Chronic Pain Patients By Pathological Mechanism- A Multimodal Investigation Using Functional MRI, Psychometric And Clinical Assessment

Lead Research Organisation: King's College London
Department Name: Neuroimaging

Abstract

Approximately one person in five suffers with pain every day. Despite our best efforts we often struggle even to partly alleviate their pain. One reason is that current diagnoses are based upon symptoms, but the same symptoms can occur for different reasons. If we could diagnose pain based upon 'mechanisms', the biological processes underlying symptoms, then patients might get more precise treatment earlier.

Several mechanisms can be faulty in chronic pain. They can be 'peripheral'- when sensors in the body that detect danger persistently send messages via the spinal cord to the brain. Sometimes 'crossed-wires' occur in the spine, where messages representing touch become scrambled, resulting in an incorrect or amplified pain signal- 'central sensitisation'. These processes might be due to disease (e.g. osteoarthritis (OA)) or because of nerve damage-'neuropathy'. Brain imaging has told us that changes in the way parts of the brain communicate with one another -'connectivity'- predicts transition to chronic pain, but we don't know whether connectivity differences cause pain or are a 'knock-on' effect of dysfunction elsewhere; perhaps peripherally or in the cord. Finally, pain control systems in the base of the brain (brainstem)- the 'descending modulatory system'- can fail, producing symptoms similar to central sensitisation. One or all these mechanisms might be involved in patients with chronic pain. As the symptoms can look the same we don't currently know which.

This project aims to predict the mechanisms underlying individual patients with chronic pain of the face or upper limb. We will use computerised pattern recognition (PR) techniques to determine which combination of clinical assessments (examinations, interviews, questionnaires); specialised nervous system tests and brain/spine imaging techniques best detect the underlying pathophysiological mechanisms. Historically it has been difficult to get clear 'functional' images of the brainstem and spine during rest and stimulation but we now have new methods to help solve these problems.

First, we will use electrical stimulation in the arms of healthy, pain-free people to see how the periphery transmits a normal ongoing pain signal. By changing the characteristics of the stimulation we can also temporarily create central sensitisation in the spine. In the face, we can examine pain due to peripheral and central sensitisation after wisdom tooth surgery. We can use an anaesthetic injection to 'block' the peripheral signal to look at central sensitisation only in these patients. Rarely, but sometimes wisdom tooth surgery produces nerve damage, leading to chronic facial pain. We will also study these patients too, again using anaesthetic injections to look at the peripheral and central signals separately. We will also study patients with chronic arm pain due to OA. Historically OA was considered a 'peripheral' disease, but some patients may also have 'central' changes, which we will determine in the brain and spine. Finally, we will use a technique called 'Conditioned Pain Modulation' (CPM) to assess, in all patients and healthy people, how well their 'descending modulatory' pain control systems are working.

We will capitalise on all of these clinical data (imaging, examination, questionnaires) and use PR to develop distinct 'fingerprints' that classify peripheral and central pain mechanisms. We will apply the classifier in each chronic face and arm patient to make predictions about their individual underlying pathophysiology. Similarly, a second classifier will be trained to recognise 'normal' versus 'abnormal' descending modulatory pain control in each chronic pain patient. Success in this project will help us get the best treatment, more quickly to suit the needs of each patient in persistent pain. The new knowledge that we generate about how the brain and spine represent these mechanisms will also stimulate the development of much-needed new treatments.

Technical Summary

Chronic pain remains an area of considerable unmet need. Up to 20% of the population suffer psychological distress and poor health status. Classification remains disease-based, despite evidence that multiple pathophysiological processes underpin diseases, and that patients with similar symptoms can have different aetiologies. As most current pharmacotherapies target only one mechanism, it is not perhaps surprising that many offer only moderate pain relief. Mechanism-based patient stratification should facilitate timely, appropriate and cost-effective treatments.

We will use multimodal techniques to stratify patients according to their underlying pain mechanisms, examining patients with intractable painful osteoarthritis, orofacial pain and pain-free controls. Evoked-response and resting-state functional and perfusion magnetic resonance imaging will be employed to investigate brain, brainstem and spinal cord structures underpinning mechanisms of ongoing peripheral drive, central sensitisation, descending pain modulation (DPM) and functional connectivity. We will decouple peripheral from central phenomena using anaesthetic blocks. Gold-standard subjective report, psychometric and sensory testing data will also be acquired. We will use multimodal machine learning across all data to predict the mechanisms underlying patients' persistent pain, namely: (i) does persistent pain originate peripherally, centrally or as a combined state? (ii) is the DPM system functioning? We will determine which data types contribute most to patient stratification, deriving simple, identifiable fingerprints of each pathophysiological state for clinical use.

Success in this project should impact on clinical practice. Diagnostic uncertainty is associated with poor outcomes, distress and suffering. Delivery of new mechanistic insights should catalyse treatment development; better identification of aetiologies should expedite implementation of treatments tailored to individual patients.

Planned Impact

Who will benefit from this research and how?

Successful completion of this project will have identified a new way of stratifying patients according to the mechanisms underlying their persistent pain. We envisage that a wide-range of patients awaiting investigation of their pain or struggling to achieve effective pain relief will be the most likely beneficiaries. The impact of pain on individuals overall is immense. Miserable and debilitating in itself, it damages quality of life and long-term mental and physical well-being; over half of these patients will develop symptoms of depression. Pain costs jobs. 19% of people with chronic pain will eventually lose their job due an inability to work. The estimated cost to the UK economy for back pain alone is £12.3 billion per year. The last pan-European survey, completed almost ten years ago, suggested that one in every five people was suffering with chronic pain. Every indication suggests that this number is gradually increasing. We know that uncertain diagnoses of pain strongly predict a poor treatment outcome and that the longer pain persists, the more intractable to treatment it becomes. A mechanism-based approach should help sufferers get on the right treatment pathway as quickly as possible. This approach is very much aligned to research in psychiatry where 'RDoC (Research Domain Criteria) has been proposed as a new way of classifying mental health disorders based on behavioural dimensions and neurobiological measures, thus using the power of modern research to better categorise and treat patients.

We also envisage academic, commercial and healthcare communities may benefit from this work. At its simplest, healthcare cost efficiencies can be made by starting with the correct treatment. For example, in the treatment of low back pain, practically all patients are still considered to have pain of a peripheral origin, despite the fact that increasingly it is recognised as many as a third of those patients are likely to have a significant central nervous system component involved in their pain. Academics, clinicians and industries dedicated to the development of new treatments may also stand to gain. We will generate vital new insights into how the human central nervous system represents pain that will be informative to these groups of individuals. The optimised strategies for imaging brain and brainstem in particular will further our neurobiological understanding. Pattern classification methodologies are well-suited to drug development. Classifiers learn by example; here we used them to stratify patients but a real opportunity exists in late phase I/early phase II studies to use these technologies to refine inclusion criteria. Further, the pharmaceutical industry has already demonstrated their interest, not only to understand putative new analgesics and how they might work but also to provide an early indication of when drug development should be discontinued, or 'no-go' decision-making.

Publications

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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 Award from QMUL Wingate Institute for Neurogastroenterology
Amount £30,000 (GBP)
Organisation Queen Mary University of London 
Sector Academic/University
Country United Kingdom
Start 03/2018 
 
Description Defining descending inhibitory pathway functionality in health and disease
Amount £496,929 (GBP)
Funding ID MR/W004739/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2022 
End 12/2024
 
Description Refinement: The impact of peri-operative analgesia on neuropharmacological outcomes in rodent models of chronic pain
Amount £90,000 (GBP)
Funding ID NC/T002115/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2020 
End 09/2023
 
Description What is the role of baroreceptors in descending pain modulation?
Amount £32,161 (GBP)
Organisation Grunenthal Ltd. 
Sector Private
Country Germany
Start 11/2019 
End 11/2021
 
Title Probabilistic brainstem masks 
Description From Brooks JC, Davies WE, Pickering AE. Resolving the Brainstem Contributions to Attentional Analgesia. J Neurosci. 2017;37(9):2279-2291. doi:10.1523/JNEUROSCI.2193-16.2016 Data acquisition. Imaging was performed with a 3T Skyra MR system (Siemens Medical Solutions) and 32-channel receive-only head coil. Subjects were instructed to remain as still as possible during scanning, and head motion minimized by placing memory foam padding beside their head. Following acquisition of 3-plane localizer images, T1- and T2-weighted structural scans were acquired for the purpose of spatial normalization and brainstem atlas development, respectively. A sagittal T1-weighted volume scan was acquired with MPRAGE pulse sequence with the following parameters: TE/TI/TR = 2.25/800/1900 ms, flip angle = 9°, averages = 2, GRAPPA acceleration factor = 2, resolution 0.94 × 0.94 × 0.9 mm, and a sagittal T2-weighted volume scan with SPACE (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution) pulse sequence with the following parameters: TE/TI/TR = 388/1800/5000 ms, variable flip angle, GRAPPA acceleration factor = 2, resolution 0.45 × 0.45 × 0.9 mm. The T2-weighted sagittal volume scan was prescribed with its y-axis (i.e., superior-inferior) parallel to the floor of the fourth ventricle. Data analysis To aid identification of brainstem nuclei, a gray matter probability map was constructed using the DARTEL (Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra) spatial normalization technique available in SPM8 (Ashburner, 2007) running in MATLAB R2015a software (The MathWorks). Briefly, T2-weighted volumetric data were segmented using the VBM8 toolbox (http://dbm.neuro.uni-jena.de/vbm8) into gray, white, CSF, and other tissue types, and the segmented gray matter maps registered to one another using the DARTEL algorithm. The final result is a probabilistic template specific to the study group, which was then transformed into the space of the MNI atlas. With the threshold for the probabilistic map set at p = 0.7 (i.e., at least 70% gray matter), masks were defined for the PAG, RVM, and LC taking advantage of the inherent high contrast between the gray and white matter structures of the brainstem (see Fig. 2). These were validated with reference to anatomical sections on a human brainstem atlas (Naidich et al., 2009). 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact Masks were used for J Neuroscience (2017) paper, and have been applied to all papers originating from this lab since then. 
URL https://osf.io/xqvb6/
 
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 EUDAIMON/IMPACT collaborations with Dr Juan Luciano, Universitat Autònoma de Barcelona 
Organisation Autonomous University of Barcelona (UAB)
Department Institute for Biotechnology and Biomedicine
Country Spain 
Sector Academic/University 
PI Contribution Ms Medina-Hernandez and Dr Howard have fostered a strong collaboration with Dr Luciano's research group in Catalunya, Spain. Historically, Dr Howard had provided external advice to Dr Luciano on the development of a Neuroimaging asessment battery to examine chronic pain patients receiving non-pharmacological therapies. We developed a formal collaboration in late 2018 to assist in the analysis of these data, provided by Ms Medina-Hernandez. This was apposite during the pandemic, as collection of similar clinical data in London envisaged for this award was on hold due to research efforts being focussed upon COVID-related projects only. As a result of this collaboration, Ms Medina-Hernandez has published one account of fMRI readouts of the effects of non-pharmacological mindfulness treatment in fibromyalgia, with a further report under review. Further analysis of similar interventions in Low Back Pain are ongoing. Importantly, these data will continue to be available to us and will contribute to the development of multivariate signatures of clinical pain states, envisaged as a core part of this MRC award. COVID-19 has had a particularly detrimental effect on the collection of research data from potentially vulnerable patients with chronic pain. This collaboration has provided a useful alternate route to acquiring these data to help us meet our goals.
Collaborator Contribution Dr Luciano's group have provided us with multimodal (fMRI, clinical, psychophysical) data from real world chronic pain patients suffering with Fibromyalgia and Low Back Pain.
Impact A publication resulting from this collaboration has recently been published here: http://dx.doi.org/10.1007/s12671-021-01806-2
Start Year 2018
 
Description Randomised cross-over study of the effect of Transcutaneous Vagal Nerve Stimulation (tVNS) on brain activation at rest and during oesophageal pain in healthy humans. 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution The MRC EMCG research team are offering input on paradigm design, MRI acquisition and analysis on a study that will examine the effects of vagal nerve stimulation on visceral pain.
Collaborator Contribution Professor Williams is offering support on electrocutaneous stimulation, Dr Howard on paradigm design and analysis, and Professor Barker on optimisation of MRI sequence parameters and MRI safety
Impact The project is still in its gestational stages.
Start Year 2017
 
Title A novel implementation of spinal fMRI using high-order and 3D slice wise shimming to optimise temporal signal-to-noise ratio and reduce geometric distortions. 
Description Spinal cord fMRI is an imaging modality which correlates changes of the regional blood flow and the blood-oxygen-level dependent (BOLD) signal with the local neuronal activity. Progress in spinal fMRI has been remarkable over the last few years, however there are inherent challenges in this imaging technique. Focusing on the cervical spinal cord, its morphological characteristics such as the small cross-sectional dimensions and its proximity to various tissue types (bone, CSF, intervertebral discs, lungs) combined with the periodic movement of the heart and lungs during the cardiac and respiratory cycle, induce severe susceptibility artifacts (distortions and signal dropout), low signal-to-noise ratio (SNR) and increased physiological noise. To improve B0 magnetic field homogeneity, reduce distortions and regional signal loss and increase SNR values, we implemented custom high order and slice-specific linear shimming techniques. All development has been performed on a General Electric Discovery MR750 3T scanner, using a head, neck and spine coil and a neurovascular array. Our technique includes two separate steps for high order and x-, y-, z-shimming optimisation. In contrast with similar methods implemented by other groups, we use a spectral-spatial excitation for the EPI calibration and fMRI scans. The high order and static linear shims are optimised using a custom Matlab Runtime interface running on the scanner. To improve B0 homogeneity, a field map is acquired, and high order shims (HOS) are optimised over elliptical ROIs manually defined on axial images of the lower brain and spinal cord. For the ROIs through the cord, some of the surrounding tissue is included, as a compromise between including too few voxels in the cord (which would bias the high order shim fit to the brain) and including too much tissue in the neck. Additionally, to increase SNR values along the cervical spinal cord and reduce regional signal loss from dephasing by susceptibility-induced gradients, we optimise slice-specific x-, y- and z-shims using another custom Matlab Runtime interface running on the scanner. Images are generated 1) representing the case with no x-, y- z-shimming applied and 2) the maximum intensity projection through all the x-, y- and z-shim steps, representing the best possible signal recovery for each voxel. The maximum intensity projection image is displayed sequentially for each slice and elliptical ROIs defined for the brain and cord. In contrast with the high order shimming procedure, ROIs in the spine are defined to only include the cord, excluding the CSF when it is clearly visible. Following drawing of the ROIs, the x-, y- and z-gradient steps that maximise the total signal within each ROI are determined, and their details are saved on the scanner for use in subsequent fMRI scans. High order shimming significantly improves image quality and reduced distortions, especially at the lowest part of the c-spine, while x-, y- and z-shimming leads to reduced signal loss and increased tSNR along the entire cervical spinal cord. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2021 
Impact On a development cohort of 10 individuals, significant increases in temporal signal-to-noise ratio are gained via the optimised technique, as indicated below. P-values relate to comparison of tSNR at each vertebral level, assessed by a paired t-test. TSNR measurements Before and After slice-specific shimming application  No Shimming  HOS and x-,y- & z- shimming  Mean  SD  Mean  SD  p-value  Level C3  16.11  5.60  34.24  13.26  0.004511  Level C4  18.99  6.17  38.47  11.36  0.001467  Level C5  11.99  4.07  31.67  10.74  7.99E-05  Level C6  8.23  3.13  35.37  10.88  9.89E-06  Level C7  3.24  1.00  29.35  .89  5.96E-06  
 
Description 7th Quadrennial International Conference on Orofacial Pain and Temporomandibular Disorders (ICOT) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact International meeting of orofacial pain and headache experts discussing latest scientific developments in the field.
Year(s) Of Engagement Activity 2018
 
Description Artzt Symposium, Montabaur, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact European Symposium on Body-Brain Interactions and their relationship to pain. Approximately 150 delegates from across Europe, a mix of pain researchers and healthcare providers for two days of discussion.
Year(s) Of Engagement Activity 2019
 
Description Bristol Neuroscience Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact This was our bi-annual Bristol Neuroscience Festival appearance, where we delivered a pain/distraction stand that was well received by the school children and general public that took part or viewed the participants!
Year(s) Of Engagement Activity 2018
URL http://www.bristol.ac.uk/neuroscience/bnf/2018-event/
 
Description Contribution to an advert for 'Time for Can' Parkinson UK fundraiser 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Parkinson's UK team came to the hospital where my research project is taking place and they interviewed me and my research team members while also taking pictures and videoing application of our project tests to patient Clare Bale. This all fed into media material for the 'Time for Can' campaign
Year(s) Of Engagement Activity 2021
 
Description Interview for national news 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by free-lance journalist who wanted to hear about the Parkinson's UK funded project that I am carrying out. His piece was featured in the Daily Mirror newspaper on November 16th 2021.
Year(s) Of Engagement Activity 2021
 
Description Philanthropy team (fundraising mailing) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact I was asked to participate in the Parkinson's UK 'Philanthropy team' to provide content for a fundraising mailing drive for supporters giving >£1000.
Year(s) Of Engagement Activity 2022
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact In collaboration with Prof Tony Pickering we took our pain/attention stall out into a pub as part of the Pint of Science series of talks. I had some fascinating and enlightening discussions with some nurses who attended the talk, and were interested to learn more about the secret life of pain.
Year(s) Of Engagement Activity 2018
URL https://pintofscience.co.uk/event/gin-and-beer-it
 
Description Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Pint of Science talk on the problem of pain
Year(s) Of Engagement Activity 2021