MRC DiMeN Doctoral Training Partnership: Mechanism-based prediction of chronic post-stroke pain using advanced neuroimaging techniques

Background:

Central post-stroke pain (CPSP), a severe neuropathic pain syndrome, affects 5-10% of stroke patients. Some CPSP patients improve with neuromodulation techniques such as transcranial magnetic stimulation (TMS) but outcomes are variable with resulting multi-morbidity, frailty and poor life quality. CPSP is poorly understood. Strokes affecting ‘pain’ relays appear critical but these pathways target several brain regions that connect within a wider complex brain network. CPSP develops weeks following a stroke indicating that maladaptive network-level neuronal processes underlie symptoms. 

We recently identified a major cortical target for pain inputs from the spinothalamic tract - nociresponsive 3A. Pre-clinical research predicts that strokes that spare nociresponsive 3A but that affect brain areas that normally inhibit the region will disinhibit nociresponsive 3A, leading to unstable feedforward circuits (e.g., to anterior cingulate cortex) that amplify pain suffering.

This PhD will address the network level development of CPSP using cutting-edge neuroimaging methods and analyses combined with detailed clinical assessment. It will increase understanding of circuit wide brain mechanisms and delineate biomarkers of CPSP that are clinically informative with the potential to define more targeted, mechanism-based treatments to ameliorate and prevent pain.

Aims

This PhD project aims to understand the brain circuits involved in the development of CPSP. Using advanced lesion mapping; and functional and network-based quantitative neuroimaging methods this studentship will determine:

·        Dysfunctional brain circuits that cause CPSP

·        Biomarkers predicting the treatment response

·        Biomarkers predicting the transition to CPSP

Methods:

Existing work is correlative, hindered by small (N<10) cohort sizes, and approaches lacking sophisticated network based image analysis. We will acquire high quality MRI data in patients with and without established CPSP from a large database at local NHS Trust. Sophisticated brain-wide and region of interest (e.g., nociresponsive 3A) morphometric and functionnectomic analyses will be performed and related to clinical and pain phenotype. The relationship between neuroimaging and therapeutic response to neuromodulation will be assessed. Machine learning approaches will address causality by determining whether imaging biomarkers of established CPSP predict pain development in patients presenting with acute stroke.

Student experience

Framing CPSP in the light of state-of-the-art methods that unravel the relationship between brain circuits and functions (funtionnectomics); and a fundamental basic neuroscience discovery - the recent identification of nociresponsive 3A; this studentship will be at the interface of cutting-edge science and medicine. We are entering an era of precision medicine. This studentship will identify pathophysiologically determined brain networks potentially amenable to targeted treatments using innovative neurotechnologies.

You will join a vibrant, multidisciplinary group in collaboration with basic neuroscientists and pain medicine specialists. You will gain training in a multitude of techniques, ranging from MRI acquisition, state-of-the-art lesion mapping and connectomic/funtionnectomic analysis, machine learning techniques, neuronavigated brain modulation using TMS as well as detailed patient clinical and pain phenotyping methods. This will ensure a well-rounded training environment with a multitude of transferable skills forming the groundworks of a successful independent scientist.

https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/research/groups/brain-imaging/

https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/andrew-marshall/publications/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

Further information on the programme and how to apply can be found on our website:

http://www.dimen.org.uk/how-to-apply/application-overview