This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to develop new methods for evaluating neocortical epilepsy. By nature of its poorly defined focus, neocortical epilepsy is perhaps the most difficult of human epilepsies to diagnose and treat surgically. This project focuses on the development and evaluation of methods to obtain ultra-high resolution spectroscopic images of N-acetyl aspartate (neuronal marker), glutamate and GABA in human brain. These methods will be assessed in patients with neocortical epilepsy to determine their specificity and sensitivity. During this past year, we have made significant progress in the following areas: 1) we have implemented the N-acetyl aspartate (NAA) 1H spectroscopic imaging sequence on the AECOM system and have begun acquiring data from both controls and patients with neocortical epilepsy using the 1H volume coil for transmission and reception (640ul voxels). NAA is synthesized only in neurons and provides a non-invasive measure of neuronal injury. We have developed and implemented a novel glutamate spectroscopic imaging sequence and have acquired control data from normal subjects at 1cc resolution in a variety of locations including cortical gray and white matter, the thalamus, striatum and hippocampus. Glutamate is the primary excitatory neurotransmitter in the mammalian brain and increases in extracellular levels are associated with seizure activity. Finally to improve the achievable spatial resolution we have constructed a actively detunable homogeneous TEM resonator with a 4 coil phased array for reception which allows has enabled spectroscopic imaging of the human brain at 125ul resolution (5mmx5mmx5mm). This project is a component of larger a multi-investigator grant (Biomedical Research Partnership) directed by James S Duncan (Yale University) involving investigators from Yale University, the Albert Einstein College of Medicine, the University of Minnesota and Brain Lab Inc. The goal of the overall project is to develop and evaluate new methods for identifying, visualizing and characterizing epileptogenic regions in patients with neocortical epilepsy. The goals of this specific project are to: 1) develop methods to acquire in vivo spectroscopic data of NAA, glutamate, glutamine and GABA at very high spatial resolution and 2) to utilize these methods to evaluate changes in bioenergetics and neurotransmitter metabolism in these patients. Studies will be performed at AECOM, recruiting patients from the Yale Epilepsy service. Unlike temporal lobe epilepsy, where the seizure focus is easily identified in most cases by a combination of anatomic, functional and metabolic imaging, the localization of the epileptogenic region in neocortical epilepsy can often be difficult, and frequently requires extensive invasive EEG monitoring. Due to the difficulty in localizing the epileptogenic region in neocortical epilepsy, our understanding of the metabolic changes occurring in this pathology and their relationship to the electrical abnormalities present is limited. Therefore, the goals of this project are to: 1) improve our ability to localize the epileptogenic region in neocortical epilepsy utilizing high resolution metabolic imaging of a marker of neuronal damage and loss; and 2) evaluate the extent to which alterations in the primary excitatory and inhibitory neurotransmitters of human brain are altered in the regions of neuronal damage. These goals will be achieved by developing and applying novel MR methods to evaluate: 1) the degree to which regional reductions in N-acetyl aspartate, a marker of neuronal damage and loss correlate with the presence of epileptogenic tissue; 2) the degree to which elevations in glutamate, the primary excitatory neurotransmitter in mammalian brain, occur within the region of altered NAA levels; and 3) the extent to which GABA, gamma amino butyric acid, the primary inhibitory neurotransmitter in mammalian brain is reduced in the regions of altered NAA. As such, the successful completion of this project may not only enhance our ability to localize the epileptogenic region in neocortical epilepsy, but through a better understanding of the metabolic alterations occurring in neurotransmitter metabolism, may help guide the development of new, novel therapies.
Aim #1 : Develop improved MRSI methods. To provide a more comprehensive evaluation of the energetic, metabolic, and functional status of the tissue we will develop improved methods for the measurement of NAA, glutamate and GABA. Specifically we will: 1) Develop ultra high-resolution multi-slice spectroscopic imaging of NAA (N-acetyl aspartate) using phased array coils and automated statistical analyses to identify abnormal regions. 2) Develop improved sequences and analysis methods for mapping glutamate. 3) Develop novel spectral editing and encoding methods to measure GABA.
Aim #2 : To evaluate the relationship between metabolic alterations, EEG abnormalities, and neuronal loss and damage in neocortical epilepsy. A clearer understanding of the biochemical and energetic alterations in neocortical epilepsy may enhance the detection of epileptogenic regions. In turn, improved localization and understanding of these regions may dramatically enhance neurosurgical planning or suggest alternate therapies. Therefore in this aim we will: 1) Evaluate the relationship between neuronal damage and loss (NAA) and electroencephalographic (EEG) abnormalities. Due to the close relationship between NAA level and neuronal loss and damage,1 decreased NAA has proven to be a highly sensitive indicator of the epileptogenic region in medial temporal lobe epilepsy and in malformations of cortical development. Therefore we will test the hypothesis that: decreased NAA levels correlate significantly with regions of EEG excitability. 2) Evaluate the relationship of altered excitatory glutamate levels and neuronal damage/loss. Previous studies in animal models have suggested that glutamate is elevated in the epileptogenic region. Furthermore, due to the close relationship between mitochondrial function and neurotransmitter cycling, we expect that abnormalities in NAA and glutamate will correlate. We therefore hypothesize that: regions of abnormal glutamate levels will closely correlate with regions of decreased NAA. 3) Evaluate the relationship of altered inhibitory GABA levels to neuronal loss/ damage (NAA). Previous studies of epilepsy patients have shown a close relationship between occipital lobe GABA level to overall seizure control, suggesting an important role for GABA in the control of seizure propagation. Thus, in neocortical epilepsy we hypothesize that there is an insufficiency of G
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