Laura Ngwenya, MD, PhD, Neurosurgeon at University of Cincinnati College of Medicine and UC Health, and Jed Hartings, PhD, Neuroscientist at University of Cincinnati College of Medicine talk about a new way to detect brain tsunamis
Interview conducted by Ivanhoe Broadcast News in 2024.
We haven’t known a lot about brain tsunamis and what happens in the brain of a traumatic injury patient until now. It seems amazing to me.
Ngwenya: Yes, it is. As a neurosurgeon and someone that specializes in traumatic brain injury, this has actually been revolutionary in terms of how we think about how we treat brain injury patients.
How has it changed? How long have you been working with traumatic brain injury in the ER?
Ngwenya: I’m actually a neurosurgeon, I work in the operating room as well as in the intensive care unit. I’ve been actually studying traumatic brain injury since my training, so I’m almost about 15 years or so. In my time here at UC in the last eight years, I really have had the opportunity to work with Dr. Hartings and really help him to recognize the importance of these brain tsunamis in our brain injury patients. So my role in terms of how we’re able to identify this is when I take a patient to the operating room that’s had a traumatic brain injury, we place an electrode strip on the surface of the brain and this allows us to detect seizure activity, but it also allows us to detect these abnormal brain tsunamis. In doing this over the past, about decade is how we’ve really been able to recognize how important these are to brain injury patients.
Is this the first time that you might have a chance of maybe preventing more brain injury for a TBI patient by knowing that his blood pressure is going up, his sugar levels are low?
Ngwenya: It really is. All of the neuro trauma community has been trying to find different treatments for traumatic brain injury, and we’ve been fairly unsuccessful. And finding that there are these brain tsunamis is actually something that we can target specifically for each individual patient. It does provide a new treatment opportunity that didn’t exist before, so it’s really exciting to be part of this trial because this is groundbreaking for us in the traumatic brain injury field.
Are you implanting these electrodes in a TBI patient’s brain during surgery?
Ngwenya: Initially, when we started doing them, it was just for research and over the years we found that we can actually detect seizures a lot better. So we are now placing these just routinely anytime we do a surgery for traumatic brain injury, and It allows us, if the patient is also enrolled into our study, to then look for these spreading depolarizations, but we found over the years that we can actually see seizures a lot better than the surface electrodes. The little sticky set are normally put on someone’s head. We can see seizures a lot better with them, so we actually do place them routinely in all of our patients now.
Can you explain what those are? What they look like?
Ngwenya: It’s a strip electrode. Essentially it’s a piece of plastic that’s about the length of your index finger, and it has six little metal circles on it, and those are the electrodes. And then there’s a tail that gets tunneled out underneath the skin, so just like if you had a drain after surgery. So it allows us to place it at the time of surgery and then after surgery when the patients in the ICU when are ready to remove it, we can just remove it at bedside, so the patient doesn’t need to go back to the operating room or anything.
What does this mean for patients with traumatic brain injuries that you can possibly detect these tsunamis? What does it mean for their quality of life in the future or their time in the hospital?
Ngwenya: A lot of that we’re still trying to figure out, but the prior studies that have been done and really spearheaded by Dr. Hartings have shown that patients that have these brain tsunamis, they tend to have worse outcomes. So when we look six months after their injury, and we look to see how they’re doing, patients that have these brain tsunamis are doing worse. So by being able to identify them, see them happening in real time, start to think about how do we treat them, the goal is that we’ll be able to make these patients have better outcomes in the future.
When you say worse, explain what worse is?
Ngwenya: So the way that we define a poor outcome or a good outcome is somewhat granular. We do it based on a scale that’s used for what we look at when we’re seeing the recovery for traumatic brain injury patients, so for instance, a poor outcome or doing worse would mean someone that doesn’t survive their hospital stay, or they survive their hospital stay, but they’re in a comatose state still, or they’re not able to interact with their environment versus a good recovery would be a patient that is able to follow commands, able to get back to their regular life, able to reintegrate into community.
How amazing is it for you to be in the forefront of this brain tsunami research?
Ngwenya: This is very exciting for me. Like I said a lot of this has been Dr. Hartings’ life work and I feel privileged just to be able to be part of it. The fact that I stumbled upon a job here at UC and have been able to work with him all of these years. I think that part of what we’re doing is so amazing because it’s not just here at UC, but around the country and around the world, people are starting to realize the importance of these, and it’s really exciting that we’re the team leading that effort to think about how can we actually identify these, treat these, and have better outcomes for traumatic brain injury patients.
What’s interesting is that this is something that’s been happening and, we’ve been studying stroke for such a long time, and the stats aren’t strokes, but we never really knew how widespread these SDs are.
Ngwenya: It’s definitely true. This is something that the phenomena itself has been known since about the 1940s, but it really wasn’t until recently, and all the work that’s been done with international spreading depolarization groups of which Dr. Harding’s founded. It’s really that work in the past, about decade or so that has really shown us the importance of these.
What are brain tsunamis?
Hartings: Brain tsunamis is a colloquial term for what’s known as spreading depolarizations. Spreading depolarizations, are a severe dysfunction of nervous system tissue that was first discovered actually in the 1940s. We discovered them in the human brain for the first time only in 2002. What they are is severe short circuits of the electrical potential that’s stored in brain cells. This happens as a mass process that affects a whole volume of tissue and not just individual cells and once that short-circuiting process gets started, it propagates as a non-linear wave throughout the brain tissue. So it’s a tsunami in the sense that it’s a propagating wave and the weather analogy is apt because the magnitude of these waves. The magnitude of the dysfunction in the brain tissue is 10-20 times anything we’ve ever observed before in the human brain. Actually, it’s the largest dysfunction of brain tissue that can occur in the living brain.
What happens to a person when they experience that?
Hartings: Here we can think about a different disease migraine with aura. In particular, patients that experience migraine with aura have this aura phase in which they experience some neurologic deficits such as a blackout in their visual field that will propagate across their visual field, or they’ll have tingling sensations moving up their arm almost a feeling of paralysis, they’ll creep across the face. So these are spreading phenomena, and they occur before the migraine headaches sets in and it’s known that the sensory manifestations of a brain tsunami occurring in the cerebral cortex. That gives us an idea in an awake patient how they’re experienced by an individual. So in brain trauma when we monitor these events, they’re happening in massive numbers. Dozens up to 100 of these events but the patients are comatose. We can’t actually see the manifestations of what’s happening to the patient neurologically, because of the coma.
This is something that happens to people with migraine. Someone is just an explanation it’s not a precursor of migraine.
Hartings: No, it is a precursor migraine. It is something that happens in a subset of migraines. I think about one-third experience these sensory symptoms that are manifestations of spreading depolarization occurring spontaneously.
Do more people than we know experience these events?
Hartings: Yeah, a massive number. I did the calculations a few years ago. I don’t recall exactly what percentage of the population experiences spreading depolarizations in a lifetime, but it’s a huge number because migraine with RA is a rather prevalent disease.
Is this something that lasts for a second, minutes, hours?
Hartings: It’s something that’s so unique in neuroscience, because everything that happens electrically in the nervous system happens very fast. Meters per second would be the conduction velocity of an action potential, sending a signal from one nerve cell to the other. These spreading depolarizations, on the other hand, are extremely slow. They move through brain tissue at only three millimeters per minute. So it can take 15-20 minutes for one of these waves to propagate across just a small- across one lobe of the brain and we can see that again in the migraine patients where these sensory deficits will last about 20 minutes.
Does it have lasting damaging effects to the brain?
Hartings: In some cases, yes, and in some cases, no. The difference is based on whether or not the metabolic structures and the blood flow to the brain tissue is intact. So if I’m sitting here, I’m otherwise healthy, and I start to have a migraine with a spreading depolarization my brain tissue and has the resiliency to recover from this insult. It’s a very different situation when we talk about acute brain injury, such as a stroke or a brain trauma with contusions, where the vasculature is disrupted, the blood flow to that tissue is decreased. The spreading depolarizations can be fatal to the tissue. That’s what’s been shown through three decades of research in animals. It’s a proven concept that in fact it’s the spreading depolarization that’s the causal mechanism for that acute lesion, that necrotic lesion called an infarct in a stroke. It’s the mechanism that causes that to develop.
After researching this, do you believe that the brain tsunamis or SDs could be the root of a lot of problems that are larger problem?
Hartings: Absolutely. It feels like a fundamentally transformative discovery that we’re finding out is a likely culprit in more and more diseases than we ever thought imaginable. It’s like the hidden iceberg below the surface that we never knew was there and we’re starting to realize that, and when we began this research in 2002, it really felt like a significant breakthrough and all the research that we’ve done since then has borne that out to be true. It it could have been possible to be a spurious finding or something that’s relatively uncommon but what we’re finding, we’ve monitored say 500 patients or so with severe acute brain trauma, and these waves occur in over 60% of the patients. They don’t just occurs as an occasional event. They are the predominant pathology of the brain as the brain lesions evolve.
When you’re talking about brain trauma, you’re talking about accidents and stroke. Are you also talking about things like Parkinson’s, epilepsy, Alzheimer’s?
Hartings: We predominantly study spreading depolarizations in acute brain injury so that would encompass stroke, various forms of stroke, such as ruptured aneurysms or occlusive strokes from blood clots, and then we also look at brain trauma, which you’re right, can come from gunshot wounds or motor vehicle accidents, or falls from a ladder, or that type of injury. We haven’t yet found a way to study these events in neurodegenerative diseases.
How do you normally treat it if they are degenerative?
Hartings: Well, that’s what the current trial is about. It’s actually the first trial globally, to try to monitor the spreading depolarizations and then treat them and see if we can impact the course of the organic evolution of the brain injury, but also impact the patient’s outcome.
How do you say that name in trial?
Hartings: Indict.
What does an indict trial involve?
Hartings: Let me explain first how we actually monitor these spreading depolarizations in patients. When there’s a very severe injury, the patients will often need neurological surgery to remove a severe blood clot that’s on the brain. So they go to the operating room, a portion of the skull gets removed, the clots removed, and that allows us access to the brain itself, where we can place a strip of electrodes to measure the electrical activity directly from the brain surface. Then when the patient is recovering in the intensive care unit for several days or up to a week or two, we can record that electrical activity. When we record that, we can see when spreading depolarizations occur, and then we can treat the patient accordingly. So the trial involves- and this is an entirely new technique, it involves new software, new hardware to make these recordings because they are also different than anything else we do in clinical neurophysiology. The trial involves being able to diagnose these in real time, and then organize a medical team to react, to treat them according to new algorithms for neuro-intensive care. So, in a major sense, it’s a feasibility trial because no one’s tried to implement a treatment algorithm based on this novel decision-making process that hinges on the monitoring of spreading depolarizations.
What is the treatment?
Hartings: The treatments multifold, the strongest inhibitor of spreading depolarization is a drug, Ketamine, which blocks electrical signaling between cells and decreases the short-circuiting mechanisms that give rise to spreading depolarizations, so that’s a one line of defense. The other treatments are simple adjustments of the physiologic variables that we typically target in the neuro-intensive care unit, such as body temperature, such as blood pressure, intracranial pressure. These are all variables that we’ve been measuring for decades, but in many cases, it hasn’t been well established what exactly is an optimal level to maintain these various physiologic, systemic vital signs or brain vital signs. And so since we can now monitor directly the brain tissue and the dysfunction occurring in the brain tissue, we believe that that provides the signal to indicate whether or not how we’re managing the patient physiologically is adequate or not. So we now have a direct readout of the downstream for the endpoint as to the brain’s health. We can use that as a guide to making decisions about whether we should raise the blood pressure a little bit or leave it where it is as one example.
Because of the blood pressure, blood sugar, body temperature, those are levels that’s the precursor, there’s going to be an SD happening, right?
Hartings: They seem to have some impact, yes. They’re not quite that strictly that definitively causal, but they seem to influence the probability that spreading depolarizations do occur absolutely.
You’ve implanted four already, right?
Hartings: Well, we’ve been doing this observationally, just studying these events for a couple decades, but in this particular trial where we’re treating the patients based on this information, yes, we’ve now enrolled 12 patients in the trial.
Have you been able to reach out to patients who have been able to stop from happening?
Hartings: Yes. Absolutely. The trial has gone very well so far. There’s a very significant difference between the patients who are treated and those who are not treated. So we randomize one to one into a control arm where we just observe and then a treatment arm where we’re treating the patients and there’s definitely seems to be in effect to suppress the depolarizations and possibly even improve the outcomes but it’s very early. It’s almost absurd to talk about that with 10 patients enrolled, five in each arm. Yet I don’t know. I’m hopeful. I think when you find significant things in science, you don’t need sample sizes of 1,000 or 2,000 or 5,000 to prove it. So we’ll see.
Is it reminding you that it makes clear that it is widespread and ground floor and learned about it and treating them?
Hartings: Absolutely. It’s that idea, that possibility, that took coal to me back as I was telling you before when I was in the military doing research and trying to decide between a military career versus a medical research career. I got involved in this research on the ground floor and decided this has such potential widespread importance to human health and disease. It’s almost like a gift that was given to me as an insight into how important it could be, and I just had to pursue that. So it’s incredibly thrilling now, after 15 years of documenting, learning to diagnose these events, and documenting how patients that have them tend to have worse outcomes. Getting to the point of being able to intervene and make a difference for patients. It’s absolutely thrilling. We’re monitoring one patient right now, and my colleague and I, who actually read the data, we’re up at 11:00 PM, 2:00 AM, 4:00 AM. Texting back and forth about what patterns we’re seeing and whether we need to adjust the care so, but we’re doing it because we really feel like we’re making an impact.
Anything we’re missing?
Hartings: Well, just one other point about the trial. One reason why I believe that this is such a breakthrough is that the traumatic brain injury field has been searching for the mechanism of the injury evolution. For such a long time, we’ve always referred to the bad things that happen after the initial trauma, very generically as so-called secondary injury. Using this very vague term and not really understanding what the mechanism is, I think we have the mechanism for the first time. Here’s been dozens and dozens of trials in the past and traumatic brain injury that have not yielded positive results and there’s always this sense of what are we doing wrong? And I think the answer is we’ve never been able to actually monitor and target the mechanism that’s happening in the brain. So we’re doing that now for the first time, and I think it’s going to make a difference or at least yield some very intriguing insights.
END OF INTERVIEW
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