Glutamate Imaging Identifies Previously Undetected Seizure Sites

NIH-funded research offers hope for patients with few treatment options

People with epilepsy experience uncontrolled seizures that can impair quality of life and cause stigma that leads to social isolation. The neurological condition can limit some activities most people take for granted, such as sustaining work or operating a vehicle. Researchers at the University of Pennsylvania and funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) have developed a non-invasive brain imaging technique for a class of patients whose epilepsy symptoms do not respond to drug treatment and who would otherwise be poor candidates for seizure-relieving surgeries.

Epilepsy affects approximately 65 million people worldwide. Seizure-controlling medications are ineffective in approximately one third of these patients. Alternatively, doctors can perform surgery to remove the source of the seizures, which often is a lesion, or scarring, within the brain. Conventional imaging procedures, such as magnetic resonance imaging (MRI) and positron emission tomography (PET) help surgeons identify and remove brain lesions. Approximately one third of those with drug-resistant epilepsy, however, do not have lesions that conventional brain imaging can detect. Now, researchers report a new specialized imaging technique that can trace the location of seizures that are not detected with conventional MRI or PET.

The imaging technique, known as glutamate chemical exchange saturation transfer (GluCEST), was developed in the laboratory of senior author Ravinder Reddy, Ph.D., a professor of radiology and director of the University of Pennsylvania’s Center for Magnetic Resonance and Optical Imaging. The work is reported in the October issue of Science Translational Medicine.

“This non-invasive MRI technique images distinct patterns and changes in glutamate levels in brain structures that could be indicative of neurological disorders” explains Richard Conroy, Ph.D., director of the NIBIB Division of Applied Science and Technology. “The research team is pursuing the tracking of glutamate because it is a key amino acid involved in transmitting signals between neurons, making it a potential marker for identifying the region of the brain where abnormal firing of neurons could cause epileptic seizures.”

Normally, glutamate acts as an excitatory signal that relays messages through the brain and then quickly dissipates. In previous studies, researchers showed that glutamate does not dissipate in animals and humans with epilepsy, resulting in a build-up of glutamate that causes overstimulation and the onset of seizures.

The specialized MRI technique relies on unique chemical properties of glutamate that permit water molecules surrounding the chemical to be visualized at a very high resolution. The increased signal from the surrounding water molecules indicates increased levels of glutamate.

The researchers studied how GluCEST imaging detects glutamate in the hippocampus. The hippocampus is a bilateral area of the brain involved in spatial navigation and the conversion of short-term thoughts into long-term memories. Seizures often originate in the temporal lobes of the brain, which include the right and left halves of the hippocampus.

In four patients with drug-resistant epilepsy, GluCEST imaging enabled the researchers to detect consistently higher levels of glutamate in the side of the hippocampus where the epileptic seizures originated. The researchers confirmed the results with electroencephalography, which identifies the side of the brain emitting irregular waves as a seizure is occurring. In 11 healthy individuals tested for comparison, the GluCEST signal for glutamate was the equivalent, or normal, in either side of the hippocampus.

MRI shows glutamate levels in the hippocampus.
GluCEST MRI reveals increased glutamate levels in the hippocampus (orange) on the side of the brain where epileptic seizures were detected by electroencephalography. Credit: AAAS/Davis et al./Sci Trans Med. Oct, 2015.

“The demonstration that GluCEST can localize hot spots of increased glutamate is a promising step towards improved treatment,” says Kathryn Davis, M.D., an assistant professor of neurology at the Perelman School of Medicine at the University of Pennsylvania and lead author of the study. “Finding the epileptic foci in a specific brain region gives clinicians critical information to guide targeted therapies that have the potential to control seizures in patients that currently do not have treatment options.”

The researchers are optimistic that the GluCEST imaging technique offers patients the possibility for expanded epilepsy treatments, which could include surgery or laser ablation therapy. Neurostimulation—electrical stimulation similar to therapy for patients with Parkinson’s disease—may also be able to reduce abnormal excitation that produces erratic movements and seizures.

About this neurology research

Funding: The research was supported by the National Institutes of Health through a grant (EB015893) from NIBIB and a grant from the National Institute of Neurological Disorders and Stroke. Additional funding was provided by a McCabe Pilot Award and a University of Pennsylvania Center for Biomedical Image Computing and Analytics Seed Award.

Source: Thomas Johnson – NIH/NIBIB
Image Credit: The image is credited to AAAS/Davis et al./Sci Trans Med. Oct, 2015
Original Research: Abstract for “Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy” by Kathryn Adamiak Davis, Ravi Prakash Reddy Nanga, Sandhitsu Das, Stephanie H. Chen, Peter N. Hadar, John R. Pollard, Timothy H. Lucas, Russell T. Shinohara5, Brian Litt1, Hari Hariharan2, Mark A. Elliott2, John A. Detre and Ravinder Reddy in Science Translational Medicine. Published online October 14 2015 doi:10.1126/scitranslmed.aaa7095

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