Brad Means: First of all, Dr. John Vender, he’s the Vice Chair of MCG’s department of neurosurgery. Kind enough to take time out from his busy schedule to be here. Dr. Vendor, thanks to you.

– Thanks for asking us.

Brad Means: Absolutely, and Dr. Krishnan Dhandapani. Dr. Dhandapani is a neuroscientist at MCG as well. Thanks for your research and for your time too, Kris.

– Thank you.

Brad Means: My first question is about your research on TBI and how when we’re looking at ways to heal it, you turn to things that make a lot of folks think of Gatorade and M&Ms, especially the blue kind. Dr. Vender, I’ll start with you. Tell me how a chemical or an ingredient in those things, or at least a relative of those ingredients, has helped y’all recently in your research.

– Well I think there’s many chemical changes that occur in the brain with brain injury, and many processes that are set into motion that occur over the first hours and days after the brain injury that we’re trying to ameliorate with agents that we can give to the patient, you know. And basically, we’re finding some interesting drugs that do alter inflammation and brain swelling, edema, which are normal processes but can get out of control, and when they get out of control can actually add additional injury to the brain. Vary frustrating for a clinician, because we have that patient in the hospital in the intensive care unit, when these processes are occurring. And this is one of the exciting areas that Kris can expand upon that really gives us some hope to maybe blunt or break some of these cycles that are put into motion by the injury.

Brad Means: Alright, so you talked about all the chemical activity that’s going on after a brain injury. Kris, how in the world, you know, I referenced the dye that’s in those blue things, the brilliant blue G dye, what made you think, “Hey, this might be a good way to treat TBI”?

– So that’s a great question. It was a bit of serendipity I would say. So we were looking for compounds that would block a water channel in the brain called aquaporin 4. And there’s been studies showing that aquaporin 4 actually leads to edema, which is the swelling in the brain, or water in the brain, which is what Dr. Vender treats clinically. So When a patient comes in for example after a severe car accident, they may see swelling in the brain. And so it’s known that this water channel’s involved in that process, and so we were looking for potential molecules that may go and block that water channel and stop the expression of that channel. And one of ’em that we found, searching some old literature, we went back 40 years, where there was some sort of correlative data that suggested consuming this dye actually may decrease swelling in some indications. So we went and we tried it in a pre-clinical traumatic brain injury model, and we found that indeed it worked. It brought the swelling down, it was improving outcomes, and particularly was blocking one inflammatory factor called interleukin 1 beta. And interleukin 1 beta seems to be a biomarker. There’s been clinical studies, actually Dr. Vender’s done some of these, and elsewhere, that have shown that patients that have elevated levels of interleukin 1 beta have a worse outcome, worse prognosis, more swelling. So we’ve been able to block that with this blue dye. And the blue dye, it’s a cousin of FD&C blue dye #1, which you’ll find in your blue M&Ms, and any ice creams that have blue or purple colors. It’s in blue and purple Gatorades, at very low levels.

Brad Means: When you looked at that old literature, was that being used to treat swelling in the brain, or just other types of inflammation?

– No, it had never been looked at in the brain. And just sort of, people were just looking, what this dye would be doing. A lot of the research actually was in the early stages of getting FDA approval to put FD&C blue dye #1 into foods that we consume, to find out is it safe, is it safe through dietary consumption. So nobody had really applied it into the indications that we were looking for.

Brad Means: So whether it’s with these water channels or with interleukin 1, are you blocking our immune response?

– Not really, I mean this is more of a selective problem that we’re trying to address with the brain edema.

Brad Means: OK, thanks, and then what do those water channels and interleukin 1 do when everything’s normal with the body, what good are they?

– Well they’re part of the inflammatory response. What we’re finding with moderate and severe brain injury is that what are normally good responses of the brain and of the body and of the immune system are taken to such an extreme that they become harmful. So trying to blunt or adjust or modify or modulate those processes, not to completely shut them down per se, but to make them less impactful on the edema and therefore on what we call secondary brain injury, which is the injury that occurs after the original event.

Brad Means: Sounds like a bit of a balancing act.

– Yes, exactly, most things within our bodies work within ranges. Too low is bad, too high is bad. That’s true of practically every chemical system in our body. So the goal here is to try to rein in or control these processes that just become out of control. And it’s almost a downward spiral of additional swelling, additional inflammation causes additional brain compression, loss of blood flow to the brain, additional injury to the cells, and then additional swelling again. So we’re trying to stop or at least blunt that cycle that’s gone out of control, basically.

Brad Means: And how long do you have to try to stop it or blunt it before you can walk out of the room and let the patient be?

– Well, it’s an ongoing process that occurs anywhere from the time of injury up to at least three to five days post-injury, for what we call the acute, or the immediate, brain swelling. But the processes in some of our studies we’ve looked at, we’re seeing changes up to several weeks after the brain injury.

Brad Means: The swelling continues that long after?

– Swelling, yeah, usually peaks between three to five days. And changes go on well beyond that time point. I’m sorry.

Brad Means: No, go ahead.

– As a clinician, you know, my biggest concern is getting that traumatically brain injured patient through that three- to five-day window with minimal injury to the brain. And Dr. Dhandapani’s goal is to try to give me those tools to do that.

Brad Means: I wanna look into your toolbox a little bit deeper in just a moment Kris, but let me ask you this. If you’ll use one of the props that you were kind enough to bring, and sort of show the viewers what happens after a brain injury, when it comes to that swelling that you’ve referenced. I guess the skull at some point just isn’t big enough.

– Correct, let me if it’s OK clarify. When we’re talking about brain injury, we’re talking about a continuum of problems, from mild brain injury, which would be concussion, and you mentioned CTE, that’s a very important topic to cover also. Moderate brain injury, and then severe brain injury. And we’re discussing, when we’re talkin’ about uncontrollable swelling and critically ill patients, and high risk of dying or severe deficits, we’re referring to the severe brain injury. We have a Glasgow Coma Scale, which is a measurement of the severity of injury. And we give a score anywhere from three to fifteen based on eye opening, motor responses, and vocalizations.

Brad Means: But you’re still talkin’ about someone who got hit in the head, right?

– Right, yeah, brain injury is a dysfunction with or without brain damage due to an externally applied force.

Brad Means: So what happens inside our bodies?

– What happens is, I always like this model because it kind of helps people visualize where the brain sits relative to our skull, and you see the ear and the eye and the nose, kind of gives you an orientation.

Brad Means: I don’t know if the viewers can see, but is there always space in between the brain and the skull itself?

– There’s a small amount of space–

Brad Means: Wiggle room?

– Little wiggle room. Which can work for you or against you again. There’s a layer of what we call cerebrospinal fluid between the middle lining of the brain, the middle covering of the brain, and the brain surface, called cerebrospinal fluid. And that is protective to a small degree. But with severe forces applied to the head or to the body, the brain will shift and move within the skull. And I have a example here, when you look at the base of the skull, where the brain sits, you can actually hopefully see, there’s a lot of very rough corners and ridges that the brain can run up against. So not only does it impact upon the skull, but it can actually be injured against some of these surfaces. So when the brain starts to swell, the first job of the surgeon is to kind of try to control that swelling medically. We have a device that we can place in the brain through a drill hole at the bedside in the critical care unit called a ventricular drain. The brain has fluid spaces in the center just like the heart does. Our brain ventricles hold CSF, however. The cerebrospinal fluid. And we can drain that to help relieve pressure. And even a little bit of drainage can have a dramatic impact on the pressure in the brain. We also have the ability to monitor pressure in the brain through that catheter, that tube. We can also put a monitor just into the brain tissue itself and monitor pressure, and that helps guide therapy. In some cases, relatively uncommonly, surprisingly, there are surgical lesions like a big blood clot on the surface of the brain, or underneath the lining of the brain, or in the brain tissue itself, like a bruise in the brain tissue.

Brad Means: So Dr. Dhandapani, while Dr. Vender is trying frantically to rein these processes in and address this swelling, what are you doing, going back to this research, this federally funded research, that you all are doing over there, with your blue dye? Are you injecting the patient repeatedly while he tries to manage the things he outlined?

– So we’re pre-clinically looking at this, so it hasn’t reached the point of a clinical trial yet. But what we’re doing experimentally is, we’re trying to stop that process from ever happening. So very early on, for example after, let’s say you’re in a car accident, the ambulance will bring you to the emergency room. Our goal is to actually administer some of the compounds that we’re interested in, such as the brilliant blue G, very early on after the injury. For example, right when they reach the emergency room, that we hopefully will stop that swelling to happen two days, three days, four days, five days later. So we’re trying to intervene so it never needs to come to Dr. Vender operating on you.

Brad Means: How is it administered, through a shot?

– It’s through a shot–

Brad Means: Into the brain?

– No, it’s directly into the veins, so it’s an intravenous injection, like you’d receive for many other drugs that are out there, very simple. We’ve been able to give it experimentally up to several hours after the initial injury, so we could even wait four, five hours after the injury, and we can see our effect, that it brings down the swelling in the brain, brings down intracranial pressure.

Brad Means: What are y’all doin’ it on, mice?

– We’re using mice models, yes, experimentally.

Brad Means: And how’s it goin’ so far?

– Excellent, we’ve gotten really promising results. And really one of the big things our lab’s interested in is, why we targeted the brilliant blue G, we think the immune system has a big role in what’s happening in the brain after trauma. So classically over the last few decades, most neuroscientists treated TBI as a neuroscience problem. It’s a brain problem, the problem starts in the brain, it ends in the brain. And what we’re trying to look at at the Medical College of Georgia with our research is the possibility that the immune system actually has a role in this. And so what we’re actually blocking with the brilliant blue G is some of these early immune responses, these inflammatory responses. I think most people know you take aspirin, it’s a way to bring down inflammation and swelling. In some ways we’re trying to target that same pathway to bring down that initial swelling after an injury, because we think a lot of these immune cells that bring that inflammation, they’re actually bringing it into the brain from the outside. And so we’re trying to damp down a lot of that immune response early on after the injury.

Brad Means: And that’s the question I was trying to ask at the beginning, and I’m sure I asked it incorrectly. You are pushing back what the body’s trying to do.

– Correct.

Brad Means: And so I guess my question is, how long do you push back, and I think you’ve said until the swelling is manageable. And then, why doesn’t the body know to do it on its own? I mean it’s almost as if we’re fighting how we were made.

– Well I think one of the answers I’ve heard that made a lot of sense is that we’ve evolved and we’re exposed to things that we really were never exposed to before. I mean motor vehicles, and some of the sports and the level of impact and contact that we experience has really changed over the decades and over the centuries. So it’s possible that we’re just not catching up. But I think the biggest concern, and Kris mentioned, is timing. There’s a lot of medications, a lot of therapies, that work great, if they’re administered prior to the injury. So not only do we have to find agents that work effectively and safely on the processes we’re targeting without any effect on any other processes in the body, which may be critical to not disrupt. In other words, have a very specific therapy. But it has to be something that will have an effect delivered after injury.

Brad Means: I wanna take a break real quick, and then I’m gonna come back for a brief segment with you all, because I promised the viewers we’d talk about sports injuries and CTE. So we’ll do that just as soon as we come back.

Part 2

Brad Means: Doctors, thank you so much for being here. The time’s getting away from us. It’s fascinating information. We’ll be back. Dr. John Vender, Dr. Kris Dhandapani, both from the Medical College of Georgia at AU, here to talk about brain injuries. Thank you al for staying with us. We appreciate that, we appreciate your time. I wanted to ask you Kris, real quick, since we’re dealing with brilliant blue G dye, this relative of what makes M&Ms and Gatorade blue, is it cheaper since it’s not some big drug that Big Pharma developed? Will it save us money if you have to inject us with it?

– So yes, it’s very cheap, it’s much less costly than pharmaceuticals, which is a blessing and a curse actually when it comes to clinical trials, in that there’s not a big drug company behind it, so sponsoring these clinical trials, these large-scale clinical trials, can be very costly. And so, that’s one of the things, we’re trying to seek federal support from the National Institute of Health.

Brad Means: Yeah, we wanna keep that money flowing.

– And that’s, yes, we’ve been trying to target them to fund our research to get it to the point where we can implement it with some of Dr. Vender’s patients.

Brad Means: Alright, you wanna talk about something that I just cannot get my head wrapped around, no pun intended. Talk about the hemicraniectomy procedure. It’s pretty drastic.

– Yes, this is an example of a skull which has this side contained, and then this is actually the removal of the skull bone. What we do is we try to, as a last ditch effort, if we can’t control the swelling, what we’ll do is we’ll actually remove the side of the skull, and you can see how that gives access for the brain to swell away. Brain swelling actually causes the brain components to shift or move out of their normal positions. They typically come up against the bone of the skull, which is one solid box of bone, basically. Won’t stretch, won’t bend. And therefore the pressure’s exerted towards the middle, which is where our brain stem is. Our brain stem is similar to a fuse box. It keeps us alive. And if the swelling gets to the point where the brain stem gets compressed, we lose the patient. So the hemicraniectomy allows the brain to swell away from the middle, out towards the outside. And we’ve seen improvements in survival from the teens up into the 80, 90% range with hemicraniectomy.

Brad Means: When the swelling goes back down, you put their skull back together?

– Yes, interestingly enough, the brain does need the skull. And with the skull missing, we notice a lot of changes in blood flow, or what we call perfusion, to the brain. And it’s obvious that after a certain amount of time when the swelling’s subsided, it’s best to put the bone back, and that’s–

Brad Means: Do they wear a helmet in the meantime?

– Many patients, yes, wear a helmet to protect that side of the brain.

Brad Means: Speaking of helmets, I wanted to hit CTE, concussions, real quickly before I lose y’all. Any progress being made on that front when it comes to helping our athletes be healthier?

– I think there’s tremendous progress. I think mainly with just recognition of the significance of the problem. I mean for decades, mild brain injury, which is the most common form, 90% of brain injuries are gonna be what we call a concussion. A concussion is a transient, or time-limited, alteration in brain function from force, often without an identifiable structural problem. In other words, you do a CAT scan at the hospital, you don’t see anything. And for years people thought, “Oh, everybody gets better, it’s no big deal.” But what we’re learning and what we’re acting upon is the knowledge that there is chemical change or possibly structural change in the brain with concussion. And that, until the brain is completely healed, a second mild brain injury, or concussion, can have dramatic impact upon the brain.

Brad Means: Can you diagnose CTE in a living person?

– There’s clinical things that you can do to be suspicious, yes.

Brad Means: To be suspicious, has there been a football helmet invented yet, or will there be, that’s concussion-proof?

– I’m not sure, I think they’re trying, they’re trying to improve the helmets. And I think to get into more sports-related, I think a lot of it is technique, and I think techniques change as the helmets have actually gotten better. I think football players feel a little more secure, and maybe they’re leading with their head for tackling. Which is leading to maybe some of this increased incidence that we’re seeing now.

Brad Means: Would you let either one of your children, would you let your children play football?

– Well I have daughters, and they’re welcome to if they want. They all do martial arts, which is a high-risk activity.

Brad Means: How ’bout you, football?

– I would say no.

Brad Means: No, no football, for you if they want to yes.

– One of the things I think we’re seeing a lot more of now is there’s actually on-the-field assessments. There’s several apps out there that can pretest athletes, and then if there is a suspected concussion, then they can be tested to see their response, and they can be tested multiple times until they return to their baseline.

Brad Means: And so what advice would you have for parents who are out there, follow these new rules that say don’t lead with the head, have fun playing the sport you love but please be careful? What more can we do, if we do give them the green light to play?

– Well as parents you need to be informed about concussion, and you need to be informed about the protocols that they have now for concussions, and return to school, return to work, return to play restrictions, which are becoming very well-documented. There’s several organizations and several good websites that I can provide to you if you’d like, that you know, provide a lot of good education for parents and teachers and coaches. But I think the understanding that repetitive mild brain injury, or repetitive concussion, is a real major threat to health, is important.

Brad Means: If I knock my head on something when I’m just going about my daily routine, or if I fall, and hit my head, how can I tell if I have a brain injury?

– It’s difficult I think, because we don’t have clear-cut diagnostics. Like Dr. Vender said, many times with a mild you can put them on a CAT scan and you don’t see anything. And that’s been one of the big challenges, both in research and in clinical care of these patients is, you know, growing up it was always just, “Eh, dust yourself off, you’re fine again.” And I think that’s what Dr. Vender’s referring to, is that don’t rush it back out there after you’ve had a first one. You may feel better, you may have a headache the first day, you go sleep it off, or you know, when we played sports as a kid, just dust yourself off and get back in there. And I think what we’re learning now is you need to rest. Your brain needs time to recover. And that means resting, don’t go back in and play your sport. You may have to sit out, and you may feel better a day or two later, but that doesn’t mean you’re ready to go back in and compete. And cut down things like screen time, where you’re stimulating your brain. You don’t wanna just sit there on an iPad and watch TV all day. You really need cognitive rest, mental rest, and physical rest. And I think that’s really the key that we’ve learned in research over the last few years, is it just takes time. It can’t be rushed, and you know, I know as a fan of many sports teams we wanna see our favorite athletes back out there after a concussion. Maybe it’s not time yet, and we need to rely on these concussion protocols which have been developed and they’re evolving.

Brad Means: Are any two brain injuries the same?

– No, I mean every human being is different, every body responds differently to injury. The mechanisms are, although similar, never identical. There are some warning signs. If you bump, and we all bump our head, we all slip in the shower, we all stand up quickly and hit the cabinet door.

Brad Means: You don’t wanna race to the doctor.

– No, but you know, any loss of consciousness needs to be evaluated. Anybody who’s disoriented, confused. Patients say, “Oh, I felt woozy or unsteady.” Any ringing in the ears, headache that doesn’t go away, worsens with exertion. You know, if you’re witnessing another person, warning signs, if the pupils aren’t symmetrical, if there’s a loss of consciousness, and they wake up, even though they look perfect, there’s still a very high risk they’ll deteriorate again. So any weakness or asymmetry in body function is a red flag, so there are times when you have reason to be concerned and call for help. If you’re not sure, call for help.

Brad Means: You know I thought we were gonna have to wrap up the show very quickly. My producer was kind enough to give us just a few extra seconds, but going back to the martial arts that your daughters take part in, I had not heard that that was a high-impact sport for the head. Do they get hit or kicked in the head a lot?

– When they do sparring there’s a risk, and when they do some of their kicks and some of their jumps, they can slip and fall.

Brad Means: So is this like mixed martial arts?

– Oh no, it’s taekwondo.

Brad Means: This is taekwondo. But they might get kicked or hit in the head.

– Or fall, when they’re doing one of their techniques, yes. It’s all padded, but again, it’s still an impact.

Brad Means: What do you tell them, be careful, don’t get hit or kicked in the head? Or you know, I mean really, I’m not tryin’ to be silly, but what do you say to ’em? Because there is a reluctance, I’m tellin’ ya, among parents out there today, to let your child leave the house, much less play an impact sport. So what’s your advice to your girls?

– And I’m one of those parents. I’m very worried about their safety every day, all day long. But at some point, you have to do those things that give you pleasure, and you have to enjoy your life. And you know, as Kris said, use the safety equipment, use the protection, be careful. If you do injure yourself, get checked, and wait until you’re ready to go back 100%.

– And actually just to interject, I think it’s not just impact sports that you can get concussions. Actually some of the fastest-rising places where concussions are found are girls’ soccer, cheerleading, things you don’t traditionally think of as contact sports. They actually have an incident rate that’s rising even faster than football. Obviously many more football players, hockey players, are showing up with concussions, but cheerleading, girls’ soccer, they’re not immune to the same problems.

Brad Means: Listen, I’m never gonna let my kids leave the house now. But no, you do have to let them live their lives, just be aware of what’s out there. Dr. John Vender, Dr. Krishnan Dhandapani, thank you for the work that you do, it’s fascinating. Thanks for breakin’ it down.

– Thank you.

– It’s our pleasure, absolutely.

Brad Means: Well you’re welcome any time. We hope y’all come back.