Mapping Connectivity in Brains with Epilepsy

White matter paths connecting grey matter in the brain, as mapped by a diffusion tensor imaging MRI. Photo courtesy of Wikimedia Commons.
White matter paths connecting grey matter in the brain, as mapped by a diffusion tensor imaging MRI. Photo courtesy of Wikimedia Commons.

by Poncie Rutsch
BU News Service

For years, neuroscientists have defined epilepsy as a case when too many nerve cells in the brain fire at once, provoking a seizure. Researchers could differentiate a few types of epilepsy, based on which parts of the brain were over-firing. Now, researchers have determined that it isn’t just a matter of function – the brains of people with epilepsy  structurally differ from those of people without the disorder.

According to lead researcher Steven Stufflebeam, a neuroradiologist at Massachusetts General Hospital, the differences between the two brains suggest new ways to diagnose and treat epilepsy moving forward.

Stufflebeam and medical student Matt DeSalvo focused on temporal lobe epilepsy, the most common type of epilepsy among adults. Temporal lobes are part of the cerebral cortex, and aid in visual memories, processing the senses, language, and emotion. During a temporal lobe epileptic seizure, neurons in the brain randomly begin firing too frequently, sending those parts of the cortex go into overdrive.

The researchers compared the brains of people with epilepsy and people without to understand the white matter, the tissues that form connections between grey matter, or the brain cells. They used a type of MRI brain imaging called diffusion tensor imaging. Unlike a typical MRI, which shows some brain tissues or inflammation, this type of imaging induced a magnetic field to show the movement of water molecules through the brain, illuminating the paths molecules use to travel the brain.

The researchers induced sixty different magnetic fields to highlight sixty possible directions in the brain, and then compiled the images in one all-inclusive brain scan.

The researchers found that brains with temporal lobe epilepsy have very different structures from those without epilepsy. Patients with epilepsy have less long-range connectivity, and more short-range connectivity that patients without the disorder. The white matter that the researchers mapped connected parts of the brain located closer together, rather than farther apart.  These short range connections in epileptic brains appeared within the brain structures responsible for wakeful rest such as daydreaming or introspective thought.

The study helps neurology researchers move toward the idea that epilepsy could be an issue in the the brain’s network, not necessarily the result of brain damage. Researchers used to blame temporal lobe epilepsy on injuries to the temporal lobes. But more and more studies like DeSalvo’s are showing that that’s not the case. “Injury can still play a role,” says DeSalvo, “but more and more it’s thought of as a network disease.”

Stufflebeam and his colleagues published their findings this week in Radiology. The study is part of the National Institute of Health’s Human Connectome Project, which seeks to map brain connections.Stufflebeam and his colleagues published their findings this week in Radiology. The study is part of the National Institute of Health’s Human Connectome Project, which seeks to map brain connections.

The findings offer insight into which people might benefit from surgery. “With temporal cases,” said Stufflebeam, “about 90% of those patients will benefit from surgery.” The surgery excises the part of the brain from which the seizures seem to start. “But there’s still 10% that fail,” said Stufflebeam. “They still have seizures and aren’t completely cured.”

Both researchers think this may be due to connectivity within the brain. Surgeons can estimate how much brain to remove to decrease epileptic seizures, but it’s an educated guess. In the future, doctors and patients could use the images from this research to determine whether surgery will be effective.

“We may be able to predict outcomes based on the connectivity we see,” said DeSalvo.

New Laser-based Tool for Brain Tumor Detection

By Kate Wheeling
BU News Service

Brain tumor surgery is a balancing act. Cut out too much and your patient leaves with neurologic damage; too little and the tumor grows back. Surgeons use MRIs to locate tumors, but in the operating room they’re left with visual and tactile cues – discoloration here, a firm spot there – to guide them around tumors. These methods are surprisingly imprecise for a field in which precision is critical.

Stimulated Raman scattering microscopy brain tumor image
Image courtesy of Minbiao Ji/Harvard University
Image of human glioblastoma tumor (blue) in mouse brain made by stimulated Raman scattering microscopy.

Now researchers at Harvard University and the University of Michigan are applying Stimulated Raman Scattering Microscopy, a technique recently developed in Dr. Sunney Xie’s Harvard laboratory, to differentiate between tumors and healthy tissue on a microscopic scale.

A study to evaluate the technique, published in September in Science Translational Medicine, focused on a tumor type called glioblastomas that grow winding tendrils throughout the brain. Glioblastomas are a particularly aggressive form of brain tumor – patients rarely survive more than a year after diagnosis. Tumor cores are easy to spot because they are crowded with dying cells, but the edges can be tricky. Tumor edges are a mixture of tumor cells and healthy tissue, making it impossible to tell where the tumor ends and normal tissue begins.

That is why these tumors recur “almost universally,” says Dr. Daniel Orringer, a neurosurgeon at the University of Michigan and co-author on the study. According to Orringer, surgeons routinely leave behind tumor cells that could have been safely removed. They just can’t see them under standard operating conditions.

To test whether Stimulated Raman Scattering Microscopy could help surgeons visualize tumor margins, researchers implanted human glioblastoma cancer cells into mice and waited for them to grow into tumors. Then they placed a laser scanning microscope over a hole in the skull of live mice and focused laser beams over a single focal spot of tissue at a time. The lasers caused different tissue types (e.g. healthy, lipid-rich brain tissue or protein-rich tumor tissue) to vibrate at different intensities. A computer program turned the vibrational signals from each point into a color-coded picture of the brain in real time, where tumor cells appeared blue and normal brain as green.

Using these computer generated images, researchers could distinguish tumors in tissue that appeared normal with standard techniques. Then when the group used the microscopy technique on human brain tissue samples, they found that the same cues used to distinguish tumor and normal tissue in mice held up in human tissue.

The group hopes to use Stimulated Raman Scattering Microscopy to maximize tumor removal and optimize surgical outcomes in humans, but right now the apparatus is too cumbersome for human applications. “What I would like to be able to do and what my colleagues tell me is possible to do is to develop a toothbrush-sized probe that we can place into someone’s head during surgery,” Orringer explained.

A prototype of this probe already exists, but several obstacles keep it from operating rooms. The concept needs to be validated using more human tissue samples and animal studies of the probe itself will need to be carried out. Aside from probe development, the group needs to build new lasers to achieve the same image quality in surgery that they had in the lab. They’re teaming up with two start-ups, Invenio Imaging and AdvancedMEMS, to address these engineering problems.

The cost may end up impeding biomedical applications even more than the technological obstacles, but experts say it’s worth it. Jerome Mertz, Professor of Biomedical Engineering at Boston University explains, “It’s a very expensive technique, but it’s really the only way to do what they’re doing.”