INFLAMED: INFLAmmatory pathways in Multi-modal imaging of Epileptogenesis and Depression

Epilepsy is one of the most common serious neurological conditions, affecting around 1 in 100 people, about 600.000 people in the UK alone. People with epilepsy often also suffer from depression. Both conditions have a huge impact on a patient's life, and some people with epilepsy feel more affected by their symptoms of depression than their seizures. Studies have shown that suffering from depression in the past increases the risk to develop epilepsy after stroke or other brain trauma, and makes it more likely to continue suffering from seizures, even after trialing several seizure medications, and after epilepsy surgery. Studies in animals and humans have shown that inflammation in the brain can lead to both, the development of epilepsy and depression.
In this study, we plan to use recently-developed brain imaging techniques to identify and measure inflammatory changes in the brain. This will help us shed light on how inflammation in the brain may lead to both epilepsy and depression.
We will then explore:
1. Whether inflammatory changes may explain why some people with epilepsy also suffer from depression; and
2. Whether the amount of brain inflammation leads to more severe epilepsy by changing the structure and function of the brain.
To answer these questions, we will study people with temporal lobe epilepsy, which is the most common type of epilepsy, as well as people who do not have epilepsy as a control group. First, we will compare people with epilepsy and controls to characterize the amount of inflammation in the brain in those with epilepsy. We will then compare people with epilepsy with and without depression, to see how different the amount of inflammation is in those with depression. In people with epilepsy, we will also gather information on how frequent their seizures are, and in case they have depression, how severe their symptoms of depression are.
We will use a new brain imaging technique, which measures changes in the blood vessels (so called "leaky vessels"), a phenomenon commonly seen in brain inflammation. We will also use imaging techniques that measure changes in brain structure and function. We will then investigate how inflammation in the brain may lead to changes of brain structure and function.

So far, we can only treat epilepsy symptoms by controlling seizures, which means that people with epilepsy have to take anti-seizure medication over many years, often throughout their whole lives. Unfortunately, only in a small group of patients can we identify and treat an underlying cause of the condition with epilepsy surgery. With this project, we hope to measure how inflammation leads to epilepsy and depression by using advanced imaging techniques. As a next step, we aim to use these markers in future studies to study the benefit of new medications, which treat the brain inflammation as an underlying cause of epilepsy and depression. Overall, this research could eventually lead to preventing epilepsy, instead of only controlling its symptoms with anti-seizure medications.

Epilepsy (point prevalence: 1%) is a major public health issue. Depression (median prevalence: 30%) is a major epilepsy comorbidity, and its negative effects on quality of life are greater than those of seizure frequency. Depression is a risk factor to develop epilepsy, particularly refractory epilepsy. Compelling evidence, both from animal and human data, identifies neuro-inflammation as a common pathological mechanism of epilepsy and depression. In rodent models of depression, pro-inflammatory pathways are activated, and animal models of inflammation cause depressive-like symptoms. Several models of acute seizures and chronic epilepsy are associated with activation of microglia, inflammatory cytokines and blood brain barrier (BBB) dysfunction. Measures of BBB permeability may therefore serve as markers of a localized inflammatory response.
We propose a pilot study to investigate patients with temporal lobe epilepsy (TLE) with and without depression and healthy controls. All will undergo Dynamic Contrast Enhanced (DCE) MRI, a novel technique quantifying BBB dysfunction as a marker of inflammatory response. In addition, all participants will undergo 3-Tesla 3D T1-weighted, T2-FLAIR and resting-state BOLD fMRI. We will obtain information on seizure frequency and depressive symptoms in patients.
We will investigate:
1. Whether there is an effect of depression on inflammatory changes in patients with TLE, by firstly comparing patients to controls, and subsequently patients with depression to those without. We hypothesize that patients will exhibit inflammation changes compared to controls, and that the latter will be more marked in patients with depression.
2. (a) How inflammatory changes relate to clinically accepted measures of disease severity, (b) how they relate to established imaging markers of disease severity, i.e. patterns of whole-brain cortical atrophy, and (c) how they are associated with abnormalities of resting-state fMRI-based functional networks.

Our proposal addresses a key area of high strategic importance for the MRC: to prevent disability and promote wellbeing, based on better understanding of causes, risk levels and new approaches to early preventive interventions. The proposed research will benefit patients with epilepsy and depression, clinicians treating those patients, as well as the wider public, by overall decreasing the disability burden associated with epilepsy and depression and promoting re-integration of patients as more active and productive members of society.
In the long-term, the research may benefit the pharmaceutical industry by providing new treatment targets for anti-epileptic agents.

Our research will lead to the development of clinically-useful tests helping the early identification of patients at-risk of developing refractory epilepsy, and patient stratification for specific therapy (anti-inflammatory treatments), once available. Validated biomarkers, obtained with Dynamic Contrast Enhanced (DCE) MRI, a novel technique quantifying blood brain barrier dysfunction as a marker of inflammatory response, will also be useful for monitoring treatment response. Inflammatory imaging markers identified through this research can also be integrated into the presurgical work-up of epilepsy surgery candidates to better define the epileptogenic focus and regions belonging to the epileptogenic network, and may serve as a predictor of successful surgery. Ultimately, we therefore aim to establish the assessment of inflammation levels as a routine component of the presurgical assessment in epilepsy.

Patients at risk, with evidence of neuro-inflammation, could be monitored closely for mood changes with additional depression screening tools. Clinicians would have a lower threshold to offer social help and begin available anti-depressant agents.
Currently, the development of anti-inflammatory therapy is a growing field, and includes compounds such as anakinra or losartan. Developing such agents is an area of interest after recent reports of beneficial effects on seizure control. At-risk epilepsy patients identified via DCE-MRI imaging could be potential candidates for anti-inflammatory drug trials, or may benefit from other anti-inflammatory therapies once available. We have chosen DCE-MRI as this will ensure direct translation into clinical practice, given the fairly straightforward methodology and wide application in clinical centres. In previous MRC and Wellcome funded research, we have shown the translational value of imaging research with the implementation of functional imaging techniques for prediction of postsurgical cognitive deficits. The stage is now set to extend these methodologies to the benefit of larger patient populations, beyond those few undergoing surgery. This will have a much wider impact, and could be of benefit to all patients suffering from seizures and mood disturbances. Ultimately, findings from this pilot study will be exploited for validating imaging of inflammation and serum biomarkers for epilepsy and mood changes in larger trials, which will establish helpful benchmarks for patients with depression, or at risk of developing refractory epilepsy. If this application were to be successful, we would apply for funding for larger clinical trials already during the pilot study phase, with the overall aim of commencing those within the next five years.
The costs for DCE-MRI would be off-set by the impact which anti-inflammatory agents might have on preventing mood disturbances and refractory epilepsy. Economic development and scientific competitiveness will benefit from the potential for commercialisation of imaging methodologies. Overall, benefit for the wider public in general will result from decreasing the disability burden of epilepsy and depression, and facilitating reintegration of patients into the working world.