Seizures and the Brain: The Role of Perturbed Dynamic Networks

Accurate diagnosis, prognosis and management of epilepsy is a significant unmet medical need. Epilepsy is a serious brain condition whereby susceptible individuals have recurrent seizures. It affects almost 1% of the UK population at some point in their lives. Every year 125,000 people attend first seizure clinics across the UK. Of these, 40,000 eventually receive a confirmed diagnosis of epilepsy, typically following an average delay of a year (Joint Epilepsy Council, September 2011). Whilst two-thirds of these confirmed cases can ultimately be controlled by anti-epilepsy drugs (AED), approximately 50% remain uncontrolled a year after commencing treatment, with no clear indicators of choice of AED or dose. Treatment response is currently a case of "watchful waiting" to see whether further seizures occur and adjusting choice of medication and dose accordingly. For those who do not respond they continue to have seizures, apparently at random, which leads to a significant reduction in quality and quantity of life. Every year over 1,000 people die in the UK as a direct consequence of epilepsy.

I propose an exciting programme of research in which mathematical models and computer algorithms will be developed to improve our understanding of how seizures occur. These models will describe how different regions of the brain interact with each other and how internal and external stimuli can influence these interactions. The interplay between neural activity within brain regions and the connections between regions critically determines whether seizures can occur and how frequently they are likely to happen. Having developed this fundamental understanding, computer algorithms can be developed to inform key parameters of these models directly from clinical recordings collected from people with epilepsy. This makes the models personalised and therefore suitable to address key questions for people with (suspected) epilepsy:

- is the diagnosis accurate?
- are the drugs being prescribed effective?
- will exposure to stress make seizures more likely?
- can I know when my seizures are most likely to happen?
- will surgery stop my seizures happening?

I will work with a software engineer and people with epilepsy to translate this understanding into a prototype tools to address these questions. For example, developing a tool that can aid a multi-disciplinary clinical team in determining where in the brain seizures originate from and using this information to better plan for surgery. Alternatively, a smart-phone based app that receives electrical brain recordings from a wireless headset to provide a forecast of seizure risk. Co-designing and developing these prototypes with people with lived experience and clinicians will maximise the likelihood of their leading to impact of the fundamental research.

There are many groups who will benefit from the research I plan in this Fellowship. These include clinicians and allied healthcare professionals; people with epilepsy and their families and friends; MedTech companies; health sector managers and health insurers; as well as policy makers and research funders.

To ensure these broad classes of stakeholders benefit from my research, I plan a range of activities including:

- a lived experience group consisting of people with epilepsy, their carers and family members. This group will help to shape the research through advice and guidance to researchers. Additionally they will play a key role in designing prototypes in the context of seizure forecasting and trialling them in the community.

- a visitor programme that will enable neurologists and other relevant healthcare professionals to interact with members of my team for periods of up to six months. This will enable them to introduce key concepts, as well as to benefit from developing understanding of state of the art in relation to perturbed dynamic networks, seizure generation and epilepsy.

- "hot topics" workshops will enable researchers (both academic and industry), as well as clinicians and regulators to focus on emerging research challenges throughout the lifetime of the Fellowship. Building close collaborations between these key stakeholders will accelerate research and realise impact on people with epilepsy more quickly.

- involvement in policy making will maximise the likelihood of findings from my research to impact on clinical decision making. For example, I am a member of the International League Against Epilepsy (ILAE)'s Task Force on the Network Basis of Disease. This new task force was established in late 2017 with a focus on developing quantitative descriptors for the network basis of seizures and epilepsy. My membership increases the likelihood of dynamic network markers of seizures ultimately being adopted in ILAE guidelines.

- through my continued involvement in research funder strategy and decision making knowledge and expertise generated through this Fellowship will impact on the broader research community. In this regard I currently serve on the Healthcare Technologies Strategic Advisory Team for EPSRC; a role I have been asked to extend for an additional year to the end of 2020. I am currently a member of the MRC's Senior Non-Clinical and Career Development Panel and am also a member of the Scientific Advisory Committee of Epilepsy Research UK. I will look to regularly invite funders to engage with our team during the course of the Fellowship.

- the proposed research offers the opportunity to advance both diagnosis, prognosis and management of epilepsy. Successful delivery of this research will lead to increased efficacy and efficient of treatment. This will lead to savings in the cost of treatment, positively impacting on health sectors managers and health insurers.

Within my broader research Centre we have a number of additional mechanisms for facilitating impact including the "research incubator". This brings together researchers from quantitative disciplines and those from healthcare backgrounds, supported by expertise from researchers within the Centre, to accelerate emerging research opportunities with a focus on delivering impact through involvement of relevant industry partners.