Understanding hippocampal internal architecture in human temporal lobe epilepsy -- from MRI to epigenetics

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Project Summary/Abstract This project centers around the hippocampus, a part of the brain where seizures frequently occur in the most common form of epilepsy in adults, temporal lobe epilepsy. Through a career development grant I have had over the last five years through the National Institute of Biomedical Imaging and Bioengineering I have developed a technique called HR-MICRA that produces exceptionally high-resolution MRI images. This is meaningful for the study of epilepsy because the hippocampus is not only the most epileptogenic structure in the brain but it also has an extremely complicated internal architecture that is difficult to visualize with conventional MRI techniques. Our preliminary data shows that the HR-MICRA technique is far superior to conventional MRI techniques in regard to visualizing the internal structure of the hippocampus clearly and consistently. Our preliminary data also shows that subtle abnormalities of the internal structure of the hippocampus occur more frequently than previously thought even when the hippocampus overall looks relatively normal. In this project we will compare the HR-MICRA technique on a regular 3T MRI scanner to an equivalent technique using a powerful 7T research scanner at Auburn University, which there are only a few of in the nation. If we show that 3T HR-MICRA is equivalent to 7T imaging, it will provide a tool to epilepsy specialist and neuroscientists that can be relatively easily implement on most clinical scanners. In the second part of this project we will use these high-resolution imaging techniques to study the internal structure of the hippocamps in two groups of epilepsy patients -- those whose seizures are well-controlled and those whose seizures are poorly controlled. We hypothesize that the high-resolution technique will show a subtle but definite degree of blurring of the layers in the internal structure of the hippocampus that is more prominent in patients with poorly controlled seizures. We then hypothesize that this blurring is due to activation of certain types of cells in the brain called astrocytes. We will test this by scanning a series of patients with poorly controlled seizures who then subsequently go on to have surgery to remove the hippocampus that is causing their seizures. We will then examine their resected hippocampi under the microscope and assess whether there is an increased degree of astrogliosis (more activated astrocytes) in certain layers, which would make certain layers harder to see on the MRI scan. In the last phase of the project we will determine whether epigenetic modification of the astrocytes' DNA is playing a role. Epigenetic modification refers to a natural process whereby certain genes are turned on or off. If we do find that epigenetic mechanisms are at play in temporal lobe epilepsy it may provide new therapeutic targets and advance our understanding of how the brain works in disease and in health.