Epilepsy is the most common primary neurological disorder, with one new case of epilepsy diagnosed in children or adults in Europe every minute (~400,000 cases/ year; as reported in 2010 EU ‘Epilepsy Priorities in Europe’ document). Apart from a small group of patients for whom epilepsy surgery is an option, there is no current cure for epilepsy, and 30% of affected patients will not respond to the best currently available treatments and continue to have seizures despite medication. Immune factors are now recognised as a new specific aetiologic group in the latest International League Against Epilepsy classification of epilepsy and seizures, and increasingly implicated in the pathogenesis of drug-resistant epilepsy. In patients with new-onset refractory status epilepticus, almost half (48%) have an autoimmune aetiology. Moreover, neuronal antibodies, for example to the N-methyl-D-aspartate receptor (NMDAR-Abs), have been found in 10-30% of children and adults with less severe epilepsy, more commonly in focal, drug-resistant cases. Neuronal antibodies target ion channels and receptors (antigens), disrupting the dynamic function of neuronal circuitry through specific disruption of normal synaptic physiology. We are currently developing animal models and using target specific treatments to ameliorate the synaptic dysfunction. Developing such targeted treatments is challenging at least in part because even very specific changes of synaptic function may have multiple effects across different temporal and spatial scales. Furthermore, the nonlinear dynamics of cortical circuitry limit the ability to intuit and predict the likely effects of either the disruption in synaptic function, or indeed the actual effects of possible treatments.
One strategy to link the physiology of integrated cortical circuits and their underlying synaptic constraints is the use of computational models.
This PhD studentship will aim to investigate whether the combined data from in vivo and in silico models provide mechanistic insights into how antibody-mediated dysfunction at the synapse causes dynamic neurophysiological dysfunction leading to seizures, and identify specific synaptic treatment targets. This information will then be applied to patient data to see if these synaptic targets are relevant to autoimmune epilepsy or refractory epilepsy of other causes.
1. Analyse long term in vivo EEG data from disease models of neuronal antibody mediated epilepsy to explore spontaneous epileptic seizures, epileptiform activity and changes in background EEG activity.
2. Identify spectral changes of interictal EEG and the transition into seizure events. Use dynamic causal modelling to identify synaptic parameters that are associated with longer term changes, as well as the transition into seizures.
3. Use in silico simulations to identify synaptic changes associated with a decreased likelihood to undergo state transitions into epileptic seizures. Test whether candidate treatments tested in vivo produce effects that were predicted from such simulations.
The student will be based at the Aston Neuroscience Institute and enrolled at Aston University. Supervision will be provided by Dr Sukhvir Wright (paediatric neurologist and Wellcome Fellow), Dr Richard Rosch (epilepsy researcher based at Kings College London), Dr Boubker Zaaimi (Lecturer in Neuroscience, ANI), and Professor Gavin Woodhall (Professor of Neuropharmacology and Head of Neuroscience, ANI). ANI research is concentrated into three Themes (Cellular/Fundamental, Behavioural/Cognitive and Applied/ Clinical Neuroscience) with four cross-cutting key areas of research strength (Social Cognition/Autism, Reading/Dyslexia, Epilepsy, Eating/Nutrition). Translational research into epilepsy is a key focus of ANI, with groups focusing on drug-refractory syndromes, autoimmune, and absence epilepsies, closed-loop vagal-nerve stiumulation, stroke-induced seizures and synaptic plasticity in the epilepsies. ANI members also work closely with Birmingham Children’s Hospital and the Children’s Epilepsy Surgery Service, investigating the role of antiepileptic drugs in cognitive delay and cognitive sequelae of epileptic encephalitides. Researchers in ANI collaborate with industry (GW Pharma, Eli-Lilley and others) in development of novel anticonulsant medicines such as CBD (Epidiolex). ANI’s epilepsy research is funded by EU Horizon 2020, RCUK, The Wellcome Trust, The Academy of Medical Sciences, GW Pharma and Epilepsy Research UK.
The successful applicant should have been awarded, or expect to achieve, a Masters degree in a relevant subject with a 60% or higher weighted average, and/or a First or Upper Second Class Honours degree (or an equivalent qualification from an overseas institution) in neuroscience, computer science, mathematics or related subjects.
We are looking for an enthusiastic and motivated science graduate with a background and aptitude in quantitative analysis to undertake this translational research project. The majority of the work will involve computational analysis and development of models using Matlab-based programmes and tools, so interest and skills in this area are essential.
For formal enquiries about this project contact Dr Sukhvir Wright by email at [email protected]
Submitting an application
Details of how to submit your application, and the necessary supporting documents can be found here: https://www2.aston.ac.uk/lhs/research/postgraduate-research
Please note that a project proposal is not required, however your personal statement should address your ability & knowledge of the research area.
Please ensure to quote “LHS_Wright_Epilepsy” on your application form.
If you require further information about the application process please contact the Postgraduate Admissions team at [email protected]