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

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.