UC neurosurgeon awarded $5 million in grants

Specifically, Ngwenya and her team of researchers will be looking at the role the hippocampus plays during these spreading depolarizations and how it affects the patient’s recovery. 

The NIH grant will be used to define the remote effects of cortical spreading depolarizations on the hippocampus after traumatic brain injury. The five-year grant hopes to expand on information collected during a previous study conducted by Ngwenya, associate professor and Director of Neurotrauma in UC's Department of Neurosurgery and a translational researcher.

In that previous study, funded by a K08 grant, Ngwenya studied animal models that had both traumatic brain injury and induced spreading depolarizations to see what type of effect it had on brain tissue. Ngwenya and colleagues discovered changes to an area of the brain that wasn’t being stimulated: the hippocampus. 

In these types of studies, a subdural electrode strip is placed on the cortex to record spreading depolarizations.

“This R01 grant is looking more specifically at what’s happening, as I like to call it, beyond the strip," Ngwenya said.

There are three major aims of the study. First, Ngwenya and her team will be looking at how different patterns of spreading depolarizations after traumatic brain injury may be affecting the brain and the areas beyond the strip.

“The reason we're looking at different patterns is because clinically we've seen that these spreading depolarizations can either be sporadic, clustered or they can be what we call isoelectric, which is when they cause essentially the baseline electricity to flatline," Ngwenya said.

Those patterns will be replicated in the animal models to see if they have a different effect on what happens to the brain tissue beyond the strip. 

Secondly, the study will examine the process of adult neurogenesis on patients who have both traumatic brain injury and spreading depolarizations. Adult neurogenesis is the creation of new neurons in the hippocampus of the adult brain.

This function is important from creating new memories and it helps the brain with recovery after injury.

“There’s still a lot we don’t know about this process,” Ngwenya said. “But, I have some preliminary data suggesting you make more of these neurons after traumatic brain injury, and even more if you have spreading depolarizations. This is important because there is the thought that maybe making new neurons, in the context of injury, is actually bad because they’re not able to incorporate properly into the brain, causing even more problems.”  

The third and final aim of the study is looking at what happens in the hippocampus when the spreading depolarization does not spread to that part of the brain. Researchers will be using a technology called DREADD, which stands for designer receptors exclusively activated by designer drugs.

“Using that approach we're going to turn off certain neurons in certain parts of the brain and see if that changes how much they began to seize when there's a combination of traumatic brain injury plus spreading depolarizations,” Ngwenya said.  

The grant provides nearly $4 million dollars to answer these questions, which could eventually improve the quality of patient’s lives who suffer from the effects of traumatic brain injury and resulting spreading depolarizations.

“Together, the goal is to essentially see what's happening beyond the strip because clinically we know that these patients are having spreading depolarizations, we know they're having bad outcomes, but we don't know that much about how the spreading depolarizations are causing the bad outcomes," Ngwenya said.

The DOD grant will be used to investigate spreading depolarizations as a predictive biomarker of post-traumatic epilepsy.

In Ngwenya’s previous study, she concluded that the combination of traumatic brain injury plus spreading depolarizations is causing changes in the hippocampus, but she and her team haven’t discovered why or how. The next study with the DOD hopes to answer that.

“One of the things that we have found in our preliminary work with animal models, we were seeing a variety of changes in the hippocampus,” said Ngwenya. “One of them has to do with those new neurons that I talked about in the NIH study. In the epilepsy world, when you have new neurons that are generated in the hippocampus and they do not integrate properly, that can actually be a seizure focus.” 

This grant also has three aims. First, researchers hope to determine if animals who have experienced traumatic brain injury plus spreading depolarizations are more likely to develop epilepsy than the animals who experienced traumatic brain injury, but not spreading depolarizations.

“We’re going to wait three to six months to see if those animals develop epilepsy. We’ll be monitoring them on video EEG for seizures,” she said.  

If they determine that the animals who experienced spreading depolarizations are more likely to develop epilepsy, then aims two and three will try to determine what the pathology is that may be contributing to this development. 

In earlier research, Ngwenya discovered that models with both TBI and SDs have neurons that are dying in the hilus, a part of the hippocampus. The neurons that tend to be in the hilus are interneurons meaning that they are inhibitory bonds, or they turn things off.

“When you have neurons that normally turn things off, and then they’re no longer there, that means the rest of the neurons are more active and that could cause a seizure,” said Ngwenya. “In aim two, we’re looking at how many of these neurons that normally shut things down are dying because of this combination of TBI plus SD which may then predispose to seizures down the line.” 

The third goal will look at the new neurons that are being created after the combination of traumatic brain injury plus spreading depolarizations.

“We have evidence that the new neurons that are created are abnormal,” Ngwenya said. “We’re actually going to block the creation of the new neurons to determine if that decreases the bad tissue and potentially the seizure potential down the line.” 

The DOD grant will provide more than $815,000 over the next three years to fund this research.