This multidisciplinary, translational study will result in the collaborative effort between researchers at the University of Texas Health Science Center at San Antonio (UTHSCSA), Research Imaging Institute (UTHSCSA), and Department of Neuropathology at the University of Erlangen, Germany. Improvements in structural and functional MRI in humans have provided a new understanding of idiopathic generalized epilepsy (IGE). One of the most common and difficult to treat IGE syndromes, juvenile myoclonic epilepsy (JME) is associated with multiregional morphometric cortical abnormalities and these regions demonstrated altered connectivity. Because of the limited access to brain pathology in humans with JME and limitations regarding functional imaging in this syndrome (risk for motor seizures, brevity of discharges), an animal model is required. The baboon provides an excellent, natural epilepsy model for JME. One goal of our study is to demonstrate regional morphometric changes in epileptic baboons and then to correlate these findings with histopathology. We intend to do this by reprocessing previously acquired structural MRI data and analyze gray and white matter volumes by voxel-based morphometry. Histological samples will be acquired from morphometrically-altered regions of harvested brains belonging to epileptic and control baboons. The Texas Biomedical Research Institute has extensive experience in collecting brain pathology and sharing specimens with national and international collaborators. These specimens will be analyzed for evidence of cortical developmental abnormalities or seizure-induced injury by Dr. Blumcke, a neuropathologist, who is an expert in human epilepsy and cortical dysplasia, but who also has experience in nonhuman primate brain anatomy. The second goal is to evaluate functional connectivity on resting-state functional MRI, with the goal of understanding how the structural abnormalities are interconnected or associated with brain regions participating in the epileptic network. We will evaluate both global and inter-regional functional connectivity to this end. In order to better understand the role of functional connectivity in the generation of seizures or interictal epileptic discharges, we will compare the effects of antiepileptic drug (AED) therapy on functional connectivity between epileptic and control baboons. Finally, our study will not only improve our understanding of the mechanism underlying JME in humans, but will provide potential targets for neurostimulation or ablative therapies and, possibly, a new neuroimaging platform for evaluating the effects of AED therapy in IGE.
Using the baboon as a natural model for idiopathic generalized epilepsy in humans, we will try to link structural changes on brain MRI findings to brain pathology, and evaluate how the interactions of the structurally abnormal brain regions may give rise to seizures. In our first aim, we propose to confirm that the regional MRI changes are related to developmental brain abnormalities, while in the second aim, we will evaluate the connectivity of structurally altered brain regions using functional MRI. Finally, using this functional MRI platform, we will also evaluate whether by altering brain connections, antiepileptic medications can subdue seizure activity.
