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The Role of Network Connectivity in Post-Surgical Seizure Recurrence in Temporal Lobe Epilepsy – 1R01NS110130

Epileptic seizure burden decreases health related quality of life, and is associated with increased morbidity and mortality. Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. For about 60-70% of these patients, anti-epileptic medication is a successful treatment. In a subset of TLE patients gold standard clinical assessments identify the hippocampus as the seizure focus (mesial TLE or mTLE), and surgical resection of this region is a potential treatment for those that are drug refractory. However, even in these seemingly homogeneous patients with a well-defined seizure focus, seizure freedom rates from surgery range from approximately 58% to 80% of patients. Our recent work suggests that while the seizure focus may be the same across this group of patients, the network of seizure propagation may be variable. Using Magnetic Resonance Imaging (MRI) a presurgical functional and structural model network was characterized in those patients that were seizure free one year post surgery. Subsequent patients with networks that differed from this model had unsuccessful outcomes with no improvement or worsening of seizures within the first year after surgery. In patients with improvement from surgery whose presurgical propagation network was consistent with the model, variations in a few specific connections were associated with length of time until seizure recurrence (up to 3 years). This suggests a similar network is responsible for late seizure recurrence in these patients. Furthermore, by identifying this unique cohort of mTLE patients with similar network properties in whom late seizures may recur, we hypothesize that it is possible to quantify networks longitudinally as recurrence develops after surgery. Therefore, the overall goal of this project is to quantify presurgical and post-surgical MRI network connectivity and their relationship to seizure recurrence after mesial temporal lobe surgery. In Aim 1 the previously defined presurgical MRI functional and structural connectivity model of mTLE will be further developed and validated as a biomarker of long term seizure outcome. While the biomarker will include only presurgical connectivity measures, the development will be informed by the knowledge of how networks evolve after surgery as determined in Aims 2 and 3. In Aim 2 longitudinal post-surgical MRIs will be used to quantify functional and structural network evolution for three years after surgery and localize networks responsible for post-surgical seizures. Finally, Positron Emission Tomography (PET) will be used to localize the seizure focus via hypometabolism after seizure recurrence to compare with and to inform the networks identified in Aim 2. This work will ultimately result in the quantification of network evolution in seizure recurrence, and biomarkers of long term seizure outcome in mTLE.



MRI Structural and Functional Connectivity Changes in Temporal Lobe Epilepsy – R01NS075270 (ending Feb 2019)

It is known that temporal lobe epilepsy (TLE) causes seizures with widespread effects across the brain that result in complex events including loss of consciousness and motor phenomena. Additionally, repeated seizures can also produce cognitive deficits, primarily of memory and language related functions, suggesting an interaction between seizure propagation networks and those associated with these cognitive functions. These extensive connections and their potential interaction may play an important role in determining whether a drug-resistant TLE patient becomes seizure free and is without cognitive decline after surgical resection of the seizure focus. Therefore, the challenge is to quantify neuronal reorganization in TLE and utilize this information to accurately predict post-surgical seizure and cognitive outcome in order to identify the most appropriate surgical candidates. The overall goal of this project is to investigate and quantify the relationship between functional and structural network integrity in seizure propagation and language networks in TLE non-invasively using Magnetic Resonance Imaging (MRI); and to relate these network alterations to disease and cognitive characteristics before and after surgery. Both functional connectivity and structural connectivity will be measured in seizure propagation and language and memory networks of TLE patients prior to surgical treatment. The structural connectivity will be quantified with diffusion tensor MRI methods, while functional MRI will be used to determine the functional connectivity parameters. These measures will be compared to healthy controls, and the relationships between functional and structural connectivity in the networks will be determined. The structural and functional connectivity of the networks will then be related to the disease characteristics and language and memory function of the patients prior to surgery. Finally, a novel statistical method, robust Biological Parametric Mapping (rBPM), will be used to develop multivariate, multimodal linear models of presurgical MRI connectivity, disease characteristics and neuropsychological test scores to predict post-surgical seizure and cognitive outcome.

The ultimate impact of this research is to provide the link between the structure, function and behavior of the two most relevant and widespread brain networks in TLE. This information would provide a significant advancement in identifying and quantifying neural reorganization and its consequences associated with this condition; and may improve clinical treatment of this disease by providing a more accurate method to predict post-surgical seizure and cognitive outcome in these patients. Furthermore, the proposed approach may be expanded and applied to other forms of focal epilepsy in both adults and children to increase the utilization of surgical treatment for these patients.