Brain architecture and connectivity at epilepsy diagnosis: markers of cognitive dysfunction and pharmacoresistance

Epilepsy is one of the most common serious brain disorders; every day in the UK, 87 people are diagnosed with epilepsy, affecting over 600,000 people. The condition can be characterised by devastating seizures, which severely affects a person's quality of life. Epilepsy frequently affects a person's cognitive and mental health, and the disorder contributes to elevated propensity for depression, suicide and sudden and unexpected death compared to the general population. Despite this, research in epilepsy has been grossly underfunded compared to other medical conditions of similar economic, social and personal impact. The vast majority of existing work in human studies has been performed in chronic epilepsy. However, newly diagnosed epilepsy (NDE) is only rarely studied despite that this represents a key point in time to understand the underlying biology of epilepsy and identify potential treatments. It is important to understand the reasons why people with epilepsy experience cognitive problems and seizures after treatment using safe imaging technologies from the earliest time point of the disorder. If we can understand these reasons in the early stages of epilepsy, we may be able to predict which patients will continue to experience seizures despite standard drug therapy. If identified early, patients who will not respond to drug therapy could potentially have alternative or adjunctive treatments, saving time, cost, and the experience of undesirable side effects of certain anti-epileptic drugs (AEDs).

MRI and EEG are routinely used to assess people with epilepsy; however the application of these brain imaging techniques in context of standard care cannot determine why some patients have cognitive problems and why others don't, and why some patients do not respond to AED therapy while others do. A new direction of brain imaging is therefore required; and preferably one that can be incorporated into standard clinical evaluation of patients.

In patients with longstanding epilepsy the study of brain connectivity and networks (how different regions of the brain work together by virtue of their connectivity) using MRI and EEG has recently provided valuable insights into how the brain is structurally and physiologically altered in epilepsy and has provided a novel way of predicting postoperative treatment outcome in severe epilepsy. We propose that these approaches will provide new explanations for the causes of cognitive problems and future treatment outcome from the beginning of a patient's life with epilepsy.

The proposed study will be the first to prospectively investigate brain structural and physiological architecture and connectivity in adults with NDE with overarching goals to (i) understand the neural basis of cognitive impairment and (ii) identify why and in whom seizures persist despite AED therapy. We will recruit adults with a new diagnosis of focal epilepsy and perform cognitive assessment and sophisticated analysis of MRI and EEG data. Patients will be followed up longitudinally to determine their response to AED therapy. MRI/EEG data will be used to identify the neural correlates of cognitive impairment and to predict treatment outcome. This work will be performed in an environment with demonstrated excellence in the care of people with epilepsy, recruitment of adults with NDE into clinical trials, and expertise in MRI and EEG analysis.

It is anticipated that this work will have significant scientific and clinical impact, with a fundamental aim to improve human health. The scientific impact will be felt most strongly through a new understanding of how the brain contributes to the spontaneous onset of seizures in the early stages of epilepsy and the mechanisms underlying cognitive problems. The clinical impact will be felt through the development of brain imaging markers of epilepsy treatment outcome.

Research objectives will be delivered in the medium term (~5 years).

The aim of this proposal is to characterise brain architectural and physiological alterations using advanced MRI and EEG techniques in patients with a new diagnosis of epilepsy, and, in particular, determine whether measures of brain connectivity and networks provide insight into cognitive dysfunction and permit the prediction of future pharmacoresistance. There has been no prospective study of brain connectivity and networks in patients with epilepsy through the early course of the disorder. Newly diagnosed epilepsy (NDE) is rarely studied despite that this is a key time to understand the underlying biology of epilepsy and identify potential interventions.

We will acquire MRI and resting-state EEG data in patients with a new diagnosis of epilepsy, and use state-of-the-art analysis methods to reconstruct structural and functional networks in patients and healthy controls. Targeted networks will involve thalamocortical structural and functional networks based on our preliminary data. Whole-brain networks will be investigated using connectome approaches, which we have shown to have predictive value for postoperative seizure outcome in patients with pharmacoresistant epilepsy. Patients will be followed up longitudinally to determine treatment outcome. All participants will be cognitively assessed. Based on our preliminary data, large-scale resting-state functional MRI and EEG networks will be used to determine the neural basis of cognitive dysfunction in patients.

The proposed study will be the first detailed prospective study of human focal epilepsy from the point of diagnosis using brain connectivity imaging methods. We anticipate that this work will provide crucial new insights into the disorder by revealing brain network alterations that explain and predict cognitive dysfunction and future pharmacoresistance in people with a new diagnosis of epilepsy.

In accordance with MRC guidance, this section emphasises impact for non-academic beneficiaries.

Our work has the potential to impact on people with epilepsy. This research will provide the opportunity for a detailed understanding of the early stages of epilepsy, including the causes of cognitive dysfunction, and prediction of pharmacological treatment response. The development of imaging predictive markers could enable a rapid and definitive choice of treatment. Given that chronic seizures may contribute to worsening cognitive status and quality of life, the fastest route to seizure freedom is paramount; prognostic markers of outcome offer people with newly diagnosed epilepsy a prediction of the fastest route to seizure control. Therefore, this work has the potential to bring pharmacologically intractable seizures under control at an earlier time point. This will be achieved through exposure of the proposed work to clinicians managing epilepsy and the incorporation of the methods used in this research in hospital settings, as described below. It is expected that this benefit will be felt in the medium term (~5 years).

The work generated in this proposal will arm clinicians with a mechanistic understanding of the aetiology of cognitive problems patients experience on a daily basis, which may inform patient counselling. The identification of a reliable early biomarker of future treatment outcome will greatly enrich a clinician's ability to manage patient treatment; this is particularly true with respect to the identification of an imaging prognostic marker of pharmacoresistance, as MRI and EEG are routinely performed for all patients with a diagnosis of focal epilepsy. Patients who are identified as unlikely to respond to drugs could be fast-tracked to under-utilised but effective invasive treatment procedures (or alternative / adjunct non-invasive treatments that would not ordinarily be considered early in the disease course e.g. inflammatory treatments, ketogenic diet etc). Furthermore, we will work closely with clinical neuroradiologists to optimise MRI acquisition protocols and develop supplementary quantitative imaging reports for clinical appraisal of patients beyond what is the current standard, with particular consideration of brain architecture and connectivity. For a new approach to be taken up in the clinic we will require clinical trials of our findings and engagement with healthcare managers and policy-makers, which will be enabled through translational research following completion of the project. It is expected that this benefit will be felt in the medium to long term (5-10 years).

If our imaging measures of brain architecture and connectivity are intimately related to cognitive dysfunction, and more specifically, cognitive performance, these imaging measures could be used as a surrogate marker of cognitive ability in intervention studies. This would represent an interesting application in clinical trials that attempt to improve cognitive ability / recovery after, for example, a pharmacological or surgical intervention in neurological, neurodegenerative or psychiatric disorders.

Antiepileptic drug (AED) prescription constitutes the main health care costs associated with treating epilepsy, which totals 15.5 billion Euro in the EU per annum. The identification of future pharmacoresistance at the point of epilepsy diagnosis will potentially reduce the many combinations of AEDs trialed to control seizures through the early years of epilepsy; alternative (e.g. surgical, stimulation, anti-inflammatory, diet) therapies may be explored sooner. Reducing health care costs associated with treating pharmacoresistant epilepsy with multiple AEDs by virtue of earlier and successful alternative therapies would likely impact in the long term (~10 years).

In the short to medium term we intend an impact on public understanding of science, through public meetings we will hold throughout the duration of the project.