DiMeN Doctoral Training Partnership: Identifying non-invasive imaging markers of neuroinflammation in treatment pharmacoresistant epilepsy

Epilepsy is the most common serious neurological disorder (prevalence about 1%). The mechanisms underlying the development of epilepsy are still poorly understood, but there is accumulating evidence that inflammation plays an important role, and may be an important stratifier for treatment strategies. However, evidence of the importance of inflammation comes from brain biopsy studies, and studies using positron emission tomography (PET), which is a scarce technology. Neither of these approaches could be implemented in the NHS to investigate and stratify patients. There is an urgent need to identify and validate biomarkers of inflammation using readily available technologies including magnetic resonance imaging (MRI) and serum biomarkers.

This ambitious PhD project will attempt to detect signatures of brain inflammation in people with epilepsy using MRI markers of neuroinflammation and simultaneous correlation with blood serum markers of peripheral inflammation.

Free-water imaging is a new MRI technique that is sensitive to water
molecules diffusing in extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation that can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in brain tissue. Free-water imaging has not previously been applied to epilepsy, but has been used to identify markers of neuroinflammation in Schizophrenia (Pasternak et al., J Neurosci., 32(48): 17365-72). The successful applicant will apply this technique to separate markers of neuroinflammation from axonal degeneration in three groups: patients with uncontrolled (medically intractable) seizures, patients with well-controlled (medically responsive) seizures, and healthy controls. Non-invasive imaging data will be correlated with peripheral serum markers of inflammation taken from each subject. In particular, molecular isoforms of high mobility group box-1 (HMGB1), which is a protein critically involved in the initiation of the inflammatory cascade in epilepsy, will be the blood marker investigated.

If it is identified that neuroinflammation is prevalent in only patients with uncontrolled seizures, this may suggest that MRI markers of neuroinflammation could be used as a non-invasive biomarker to predict treatment response in epilepsy. The ultimate goal of this programme of work is to be able to reliably prospectively stratify people with a new diagnosis of epilepsy as to their likely chance of future seizure control.

This PhD project will take place within the Epilepsy Research Group (ERG) at the University of Liverpool in collaboration with the Walton Centre NHS Foundation Trust, which provides leading care, facilities and therapies for people with epilepsy. The ERG, lead by Professor Tony Marson, is a nationwide leading research group that addresses significant clinical issues related to the causes and treatment of human epilepsy. Neuroimaging research within the ERG is lead by Dr. Simon Keller, and is principally directed towards the use of MRI to predict treatment outcome in people with epilepsy. This project will be supervised by Dr. Keller and Professor Marson, and supported by additional mentors at the University of Liverpool.

Funding notes:
DiMeN (Discovery Medicine North) DTP studentships are funded for 3.5 years and include the following annual package of financial support over the duration of the studentship:
•A tax-free maintenance grant set at the UK Research Council’s national postgraduate rate
•Full payment of tuition fees at the Home/EU rate
•A research training support grant (RTSG) to support your research studies (managed through the host institution)
•Opportunity to apply to our Flexible Fund to enable you to attend training workshops and visit research groups to advance your skills training.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship or just fee support depending on the excellence of their qualifications and their employment/residency status (http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/). Overseas students are not eligible to apply.

Entry requirements:
You should be someone with an outstanding academic track record and can demonstrate your potential for the research project of your choice.
You must hold (or be expected to hold by October 2016) a First or a good 2:1 UK undergraduate degree, a suitable qualification at Masters level or an equivalent degree from a recognised EU institution, in the biosciences or a related area. The multidisciplinary training experience and interdisciplinary nature of some of our projects means that we welcome applications from students with physical science and/or mathematical backgrounds who are interested in using their skills to address the challenges of 21st century bioscience research.

How to apply:
Please carefully read the instructions on how to apply at our website and use the link on the page to apply: http://www.dimen.org.uk/how-to-apply/application-overview