**Transcript of Cyberseminar**

**Mild TBI Diagnosis and Management Strategies**

**Hyperbaric Oxygen for SMs with PCS after mTBI**

**Presenter: David X. Cifu, MD**

*This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact Dr. Cifu at David.Cifu@va.gov.*

Dr. Ralph DePalma:It is a pleasure to have the chair of Physical Medicine and Rehab at VCU and the National Director of PM&R for the VA speaking to us today about very important work on HBOT, a good scientific trial. David?

Dr. David X. Cifu:Thank you, Ralph. I appreciate that and I am going to do my best to start from the basics of hyperbaric very briefly and then just take you through some of the research that we have just completed. This is because we get a lot of questions about its role for the population of veterans and service members who have sustained a mild, traumatic brain injury and are having persistent symptoms from that and so we are going to just highlight some of those areas.

Before I dive into my talk, however, there is a slide to get some information on you all so we can engage you in the talk, but also so we can learn who you are. So I guess I am supposed to stop for a second and let you somehow interact with this.

Moderator:Yeah. So for our attendees, we do have a poll question up. So we are trying to figure out what is your primary role within the VA. So your answer options are student, trainee or fellow; clinician; researcher; manager or policy-maker; or other. And while we are waiting for those answers to stream in, David, what name are you under so I can promote you to a presenter?

Dr. David X. Cifu:I am under the name Micaela Cornis. It is sort of a pet name of mine; it is from my partners’ offices. Micaela, M-I-C-A-E-L-A, Cornis, C-O-R-N-I-S.

Moderator:Okay, great. We will get that going in just a second. So it looks like the votes –oh, sorry to interrupt. It looks like the votes have stopped coming in. So we have about 2 percent student, trainee or fellow; 63 percent clinicians; about 12 percent researchers; 10 percent manager or policy-maker; and 14 percent describe themselves as other. So I just want to let all of our attendees know if you do have a question or comment for myself or for David, simply type it into the Q&A box in the upper right-hand corner. And let us see. Sorry. Thanks for your patience. I am just going to promote David real quick. Okay, David, so you should see the arrow in the lower left-hand corner and you can advance that way.

Dr. David X. Cifu:I do not see any arrows. It is okay. I have been advancing by moving the – I do not see the arrow. What should I do – let me think. 

Moderator:Just [overlapping voice].

Dr. David X. Cifu:I – I got it. I am back. Okay. 

Moderator:Great.

Dr. David X. Cifu:Okay, good. All right. Then the slide just change?

Moderator:Yeah, it did. Yes, it did.

Dr. David X. Cifu:Okay. And so I was promoted from an “other” to a “somebody.” That is special. Thank you.

Moderator:[Laughter] 

Dr. David X. Cifu:Okay. Moving on. Hyperbaric oxygen treatment is the use of pressurized oxygen typically above 1.3 atmospheres – or atmospheric at the pressure at ground level to try to enhance disease processes in humans. It is more commonly used for the bends or an excess of nitrogen in the blood during scuba diving or deep diving. It is used in carbon monoxide poisoning; and more recently, it has been used in the healing of skin ulcers as well as the skin in general from burns, from pressure ulcers, probably through Michael Jackson, et cetera.

It has been also been used for a number of non-FDA approved, off-label indications related to the neurologic system for more than 20 years that ranged from spinal cord injury to cerebral palsy to traumatic brain injury. And because of the absolute incidence of traumatic brain injury in the OAF, OEF and now OAD populations and some of the persistence of symptoms in about 8 to 10 percent of individuals who are returning from theatre, there is still interest in looking at alternative approaches to treatment and hyperbaric oxygen has been one of them. 

Of note, this is a treatment that has been used by NFL players for probably a long time. I just finished reading the book *Legal Denial* and there is a little section in there on how a number of NFL players are going to a number of these clinics. And on page 308 of that book, they actually reference the first study we completed. They quote it wrongly, but still they reference how it was shown not to work. So it was kind of nice to sort of be in the book but be in it wrong.

Anyway, so we are going to talk about the background of hyperbaric oxygen. It has been looked at to some degree, specifically in the use in traumatic brain injury, in the animal world, in animal research—back to the human world in animal research—and it has been predominantly used in acute traumatic brain injury for animals. Not so much chronic, and again chronic in humans being labeled more than three months out.

What we see acutely, particularly in moderate to severe injuries that are in animal research, was we do see reduction in cerebral edema. We see improvement in some of the cerebral markers of information, what we would call biomarkers, which are easier to obtain in animals than in humans. We see improvement in cerebral perfusion. And we actually see functional improvements. We see improvements in spatial learning tasks in different testing paradigms, particularly water mazes; but again predominantly this has been moderate to severe. There have been a couple of, maybe two papers, that have looked at in the rodent population more chronic injuries several weeks out in animals, and it has been shown to enhance some of these same spatial learning tasks, the memory tasks, in rodents with moderate to severe TBI.

So again like most things in TBI, in the animal world everything seems to work and we see that working nicely with hyperbaric oxygen.

This is not just a very high-level review, but as I have indicated, these are predominantly acute injury and it has been slowly and moderate to severe traumatic brain injury. It is very hard to successfully execute a mild traumatic brain injury in animal research. It is quite challenging. And in the past there has not been great translation of findings in animal TBI to human TBI research or clinical efficacy. So we take these positive results with a grain of salt.

Looking at the human research, there has been nothing but reviews and research in this area for the last 10-15 years, mostly just kind of rehashing. Researchers have done them as well as [inaud.] interviews in some of the more for-profit companies have put together reviews in these areas. There are 23 publications from ’72 to 2001. At the time these slides were put together, there were two more reviews and two more trials. We have published a trial since then, so make it as three trials have been published.

But of the 23 publications, 19 of them earliest case reports a case series that did not allow for analysis in a meta-type way. Four of the studies did meet criteria where we could study them in a more overview. They again looked at acute TBI that was moderate to severe, so it may not be relevant regardless. The bottom line of these reviews was that really was no evidence to support the use of hyperbaric oxygen even in the acute and moderate to severe TBI.

Here is a summary of what the trial did say, that if you get hyperbaric oxygen early enough, you actually have a lower rate of dying after a moderate to severe TBI with the numbers to treat being seven. But there was no change in the level of initial neurologic condition you were in. So if you were in a coma, you stayed there, et cetera. 

What they did find, what may have been a bias is that while the people had compromised pulmonary status, so people that had elevated intracranial pressures, were assisted by using hyperbaric oxygen. We know that hyperventilation, we know that oxygen helps pulmonary status as well as ICP, so that may have been one of the reasons why they were surviving and it probably was not a direct brain effect as far as we know other than the pressure on the brain.

The caveats of these were not very good studies. There was never a sham used, so in terms of the assessment of cognitive functioning, if we had seen a positive outcome, it might have been related to a bias. There was not good randomization and so on. So essentially we do not know much about acute TBI, moderate or severe, and we know nothing from chronic TBI based on these studies.

So because of this background lack, available research lack, to support or refute the use of HBOT in the population with concussion or mild TBI and those with persistent episodes, there has been much pressure from the private sector and some from the DoD sector, to test whether we see any opportunity for intervention with hyperbaric oxygen in this cohort. About 10 percent of folks returning from OAF, OEF are coming into the VA system have persistent symptoms related to a TBI. But their symptoms may also be related to other factors, so we call it polytrauma, but TBI is one of those factors in that 10 percent.

And so there are four studies that the military in partnership with the VA has sponsored. I have been fortunate to be involved with either the planning or the implementation of all four of those studies.

There was a pilot study that came out in fall of 2012, an internal mirror [00:10:01] trauma which was done through Advancia in San Antonio. It looked at the use of a sham of hyperbaric delivery, at 1.3 atmospheres or pretty close to sea level with room air compared to a hyperbaric trail looking at 2.4 atmospheres or just about double sea level using 100 percent oxygen. That study showed no effect in terms of no improvement in cognition, no improvement in balance, no improvement in a number of symptoms. I can report that one was published in November of 2012. 

We are going to highlight and go through the more recent study that we just completed in the last several months. But I am going to go through the other study, which was completed, which was an outcome measure validation looking to see if brain injury, predominantly mild, but ranging from mild to moderate as well as including some hypoxia. The brain injury symptoms could be measured using the Rivermead Post Concussion Questionnaire if it could be measured using neuropsychological batteries, et cetera, and if those individuals with brain injury could tolerate being in a chamber. That study was published about six months ago and it demonstrated that yes, we could accurately measure these outcome measures – we could use these outcome measures to measure some of the symptoms and some of the cognitive performance that we were seeing after TBI and that folks could tolerate being in a chamber. That was needed because looking to get an FDA indication for hyperbaric oxygen if it works and you need to do those types of trials.

The trial that is currently underway, which I will not be presenting results, obviously we do not know those results yet, is a large trial of about 100 service members that led through Fort Carson in Colorado. That is about halfway done. I am involved as a consultant in that. I do not know the code yet so we cannot break the code either. In that trial, we have a control group who is getting no treatment, they are just being monitored. We have a group that has a mild TBI and is symptomatic and is receiving a sham, and I am going to describe the sham in a second. And then we have a group that had a mild TBI and is symptomatic and is getting 1.5 atmospheres of hyperbaric oxygen. We will hopefully know the results of that trial in six to 12 months.

And finally, before I get to the trial that we just completed, there is a non-DOD-funded, open-label trial, so not blinded, not randomized, no sham, that is being done through LSU under the guidance of Dr. Paul Harch. That trial, the first 16 subjects were published and there was a report that hyperbaric oxygen had a positive effect and had positive or had improvements on SPEC scanning as well, had a positive effect on symptoms as well as cognition. But as I noted and as was noted in a number of letters to the editor, it was not randomized, there was no sham control and it was open label, so we do not know what to make of that information other than it is interesting.

So referring to the trial that we have completed, it is the Richmond-Pensacola Naval military base. It is a three-arm; single-center, meaning all the people are treated in one site; double-blinded; dose-ranging study with sham control. And so 60 Marines were randomized to one of three conditions. They either got Sham Air that was pressurized. They got hyperbaric oxygen that simulated at 1.5 atmospheres. Or they had 100 percent oxygen that was simulated at two atmospheres. 

The reason those numbers were chosen were first of all they had not been studied yet in this population, but more importantly 1.5 atmospheres to 2.0 atmospheres hyperbaric oxygen is the typical treatment dose that is being used in the project and with academic sector of four individuals with neurologic compromise. And so that is the standard clinical dosing. Note that that dosing has been shown to be safe, meaning there have not been seizures or changes in cognitive or neurologic status at those doses, and those are the doses that have been recommended by the for-profit chains in terms of the appropriate dosing. So we chose those.

We also chose the number of guys that have typically been recommended as being used in the private and/or academic sector, and not 40 guys or 40 exposures given once daily five times a week. The exposures are an hour long or sixty minutes long. 

This was completed over an eight- to ten-week course. The reason some folks needed longer than others was sometimes the folks had head colds or had some congestion; they did not go in the chamber, so they missed a dose or two, which is pretty standard of practice. But we were able to factor all of the treatments in that period of time.

As I mentioned, we had 60 active-duty Marines predominantly recruited from Fort Lejeune in North Carolina, where they had their traumatic brain injuries an average of 8.5 months. They were 23 years old and they were in the E1-E6 range in terms of their status in the military.

Next slide. The primary outcome measure was symptom questionnaires specifically looking concussive symptoms, the Rivermead Postconcussive Questionnaire, which is similar to the NSI or Neurobehavioral Symptom Inventory that is used in the VA system to well validate it. It is a 16 Likert scale looking at the common symptoms of the traumatic brain injury: headache, dizziness, cognitive deficit, irritability, et cetera.

We had a number of secondary outcome measures. One of them looked at symptoms related to PTSD. We used the PCL PTSD checklist, which is 17 Likert items consistent with PTSD, and both of these are self-report measures, as you are very well aware, and lower scores show improvement.

We had tertiary measures that was a balance measure, a computerized posturography. We used a neurophysiologic measure. We used computerized eye tracking and we used a battery of neuropsychological tests, which we will list shortly.

As I mentioned, the Marines were recruited at Camp Lejeune using exclusion criteria. We only chose mild TBI guys, so if they had moderate or severe, we were not going to include them. They could not have had a prior exposure to hyperbaric oxygen and they did not have a contraindication to hyperbaric oxygen such as an air-trapping pulmonary condition, a ruptured membrane that had not healed and things of that sort.

Here is the table of folks that were screened for eligibility, those that were included and then the randomization. The reason it says 61 and not 60 is one of the individuals – we did not have all of the followup data, so we did not do a full analysis on that person. When we did look with intention to treat analysis, it did not change our outcome measures, but we have published on 60. And so here are the individuals who were seen. 

Here is the randomization and I think I have a table on whether the randomization was successful or not. If the randomization was successful, they had similar demographics. They had similar  Rivermead, similar secondary measures, et cetera. And here are the demographics listed and as it notes here, no between group differences, so the randomization was successful. 

And here is the type of blast they had. We used the most recent blast, the blast of record, which is kind of the standard in research. Eighty-five percent of blasts were from improvised explosive devices and you can see the rest. And, as I mentioned, they were 8.5 months from their most recent blasts and they were all symptomatic, which was one of the admission criteria.

Without cutting to the chase, we will dive in a little bit, not too great a depth, just to give you a feel. Looking at the primary outcomes after looking at their symptoms on their Rivermead, were these folks continuing to have concussion-related symptoms? The answer is yes. There were no differences across the groups.

So there was no demonstrable effect of the hyperbaric oxygen in looking at the primary outcome measure.

When we looked at any group, so someone who was just in the 2.0 atmosphere group or someone who was just in the 1.5 or just in the sham, we see improvements within all of the groups. So just being in the chamber, just being away from their regular duty for two months: when they were on the base in Pensacola they did have duty and did have duty hours and had a supervisor and all that. They were still in the military, but it was a different type of duty. 

So just being away from Camp Lejeune duties, just being in this research study, just perhaps having a different frame of mind, or perhaps just being in Florida, helped all groups. Interestingly, the most improvement was in the 2.0. So that would beg the question, would a larger sample have seen something? We do not know that. We do not believe that is the case, but we are doing a larger study to look at it. 

But using these data, we see no improvement in the TBI symptoms.

When we look at the subanalysis, because there are 16 different scores in the RPQ, we did not see anything specific in the sham group. We did not see anything across either group that got hyperbaric oxygen. They did not demonstrate any improvement either in single items or in the entire analysis of RPQ.

We also looked at in the 13-point RPQ, which is in the literature, and did not see that either. 

But interestingly, within each group, there was some improvement. So just being in a chamber or being in this research study or being in Pensacola or being off their regular duty seems to improve. And here are some of the areas that we saw improvement. It was not in one area. It was light sensitivity in the 1.5 group. It was noise sensitivity and frustration or impatience in the 2.0. Interesting, but does not give us anything more than that.

When we looked at the PCL or the post-concussive symptoms, the secondary outcome measure, again we do not see anything across groups. So we do not see that the hyperbaric oxygen is specifically helping folks. But, as one might expect, when one is in a potentially more relaxed environment, we do see improvement in the PCL within each of the groups. So people did get better, but they got better at equal rates across groups.

Looking again at these secondary measures, there were no differences between any of these groups. Within groups we saw differences in all of the compressions of RPQ and the PCL, but not between groups.

We have to backtrack and try to look at whether there were interactions between different symptoms and whether they were changes that were being affected such as did pain affect these individuals? Did how they did on certain tests affect other tests? And I am going to present that briefly, but I do not want to confuse you. There were no primary effects. 

Here are some very interesting tables. You can download it and the 12 percent of you who are researchers can look at it. I am going to summarize what we found in a second. Here is a lovely graph that you can see that shows that people did have some mild improvement and the 1.5 group seemed to actually demonstrate some worsening actually in the RPQ, but it was not statistically significant. 

But I am going to cut to the chase in terms of what the results were. I am a verbal kind of guy, so I summarize verbally. For those of you that want to look at the specific tables which I just flashed through, please feel free to do that. 

How folks did on the Rivermead was influenced by some secondary factors. It was not influenced by the hyperbaric oxygen group they were in, but it was influenced just over time. Over time, people did improve overall. It was higher initially in those that had more significant mild TBI, those that had a longer period of post-traumatic amnesia, those that had a great number of blasts. That might be logical, but that is what we found. It makes sense as well.

It was higher in those that reported pain. Again, that would make sense. If you had more pain, they may have more symptoms that they feel are directly related to their traumatic brain injury. But that pain was body pain, it was not headache. So I mean non-brain injury-type pain, torso pain or extremity pain.

And also the number and the amount of symptoms on the Rivermead was higher in those that had evidence of post-traumatic stress disorder. Again, that makes sense. That harks back to some of the research of Hoag and others that perhaps there is the post-traumatic stress disorder is brain-apt or maybe even causing some of the symptoms we are attributing to traumatic brain injury.

But what interactions between secondary measures? I want to reinforce hyperbaric oxygen could not interact at all with the RPQ. Here are some further specifics in terms of things that interacted. We did see that over time individuals improved on their neuropsychological testing. So we measure folks initially and then at eight to ten weeks out, so just after finishing the hyperbaric oxygen and then three months after that, so another 12 weeks after that. So over time, people did improve on the neuropsychological testing, which could be due to testing effect. It certainly could be due to the fact that they had a nice “R&R” in Pensacola.

Folks that had either loss of consciousness or not after traumatic brain injury or had a worse traumatic brain injury as evidenced by longer post-traumatic amnesia, we did see worsening on their computerized posturography, their balance, if they had a worse initial brain injury or a more severe brain injury initially. Again, we expect that, but that was not influenced by hyperbaric oxygen. They did not improve more if they started off at a lower level.

And lastly, on this slide, folks that had more blasts did worse on their Trails B, one of the neuropsychological measures. That would be something we would expect. People that have a more significant injury—that has not always been supported in the literature. Either you have a mild injury or you do not have one. The gradations of the mild range are not necessarily expressed as easily on the neuropsychological batteries.

So in conclusion, this study duplicated doses that we see in the clinical world, in the for-profit and the not-for-profit world and that has been recommended by some of the advocates of hyperbaric oxygen in traumatic brain injury, as well as use in the NFL. If that matters to anybody. So we tried to replicate what was used and what our non-VA, non-DoD counterparts recommended.

We did not see any main-effect or primary outcome effect for hyperbaric oxygen at any of the doses when compared to the sham. We did see some association, as one would expect, between having PTSD and having symptoms after traumatic brain injury, as well as having symptoms of traumatic brain injury and having pain of the body and the extremities. We also saw association in folks that had more significant, mild traumatic brain injury as measured by post-traumatic amnesia or the presence of loss of consciousness at the time of injury. 

And I think that is the last slide. Yes. So I am going to stop and try to take a look at if there are any questions. Otherwise, I am going to turn it over to Molly for any questions on the phone. Molly, back to you.

Moderator:Great. Thank you so much. Actually, we do have several questions that have come in. For those of you that joined us after the top of the hour, to submit a question or a comment, just use the Q&A box at the top right of your screens. So the first question that came in: Somebody is interested in getting a copy of the study. Is that possible?

Dr. David X. Cifu:Yeah. It will be in print probably in the next – it is in the Journal of head Trauma Rehab probably within the next month, but it is available ahead of print. I am going to hate myself for doing this, but if they send me an email, I am sure I have a PDF of it somewhere that we have downloaded that I can send out. I wish I had not said that, but feel free to look me up under david.cifu@va.gov. I am an outlaw.

Moderator:Thank you.

Dr. David X. Cifu:[crosstalk]

Moderator:If you would like to, you are welcome to send me a pdf and [overlapping voice].

Dr. David X. Cifu:All right, I will do that. Yes, let me do that. Forget what I just said, people. I am going to send it to Molly and we will just post it on some important website.

Moderator:Yeah. I will put it up with the archive of this video.

Dr. David X. Cifu:Bless you.

Moderator:No problem. Somebody else asked: So the results of your study basically shows that mTBI veterans need rest as a focal [PH] acutely?

Dr. David X. Cifu:Well, I would not say rest and I don’t know where that’s coming from. The thing is, a situation where they can be physically active, hopefully somewhat cognitively active, but have a lower degree of what we believe is perceived stress. These men—they were all men—were physically active even though they were working on the base in typically physically active jobs. They were outdoors. They were lifting things, moving things; as well as cognitive. They were doing some things on the computer as part of their activity. They were sleeping in regular cycles. They were sleeping six to eight hours a night. They were encouraged to be physically active in the gym or whatever they were doing. So they were not rested. But they were probably in a less stressful condition than being at their base at Lejeune where they were perhaps pensive looking to back into combat or they were in a routine maybe they did not like as much. And that is our perception. That is why we are trying to explain the result as well. That is why we said physical rest, cognitive rest is not what we are encouraging. It is getting your life under control, perhaps, or maybe doing some stress reduction activities even while resting well, blossoming physically and cognitively active.

Moderator:Thank you for that reply. The next question: Recognizing that you did not stratify for position of the subject as to within an enclosed space versus in an open environment during your stratification, still is there any trend that might be related whether the subject was in a truck or tank versus on foot?

Dr. David X. Cifu:I imagine the question is, at the time of the injury. You do not mean obviously in the chamber because they were set differently in the chamber. You mean at the time of injury? I would not believe that the brain would know where it was when it was injured. And I am not a huge believer that the blast wave, a permanent wave that is causing these injuries—the people that we interviewed, the 128, their injuries were related to a tertiary effect of a blast wave. Meaning a rapid movement of the head back and forth or perhaps a fall related to the blast wave where their head may have hit the ground or a surface. So it is not some kind of a mysterious over-pressure or under-pressure change in the brain. These folks had normal imaging. It was a tertiary, so I do not think that where they were at the time of injury would have an effect. The end certainly was not big enough to do that. And these folks were not that close to a blast unless they were in a vehicle, but they did not have other bodily injuries. So it is a good question. I do not think that would have an effect. There is no reason to suspect that the brain inside the hard skull is getting affected by anything other than the rapid movement or acceleration/deceleration injury. So good question, but I do not think that would have an effect.

Moderator:Thank you. The next question: Did you account or correct for time since injury in primary and secondary outcome analyses where you saw improvements in time for all groups?

Dr. David X. Cifu:An excellent question. The answer is yes. And we certainly identified that the further they were out from injury, the less likely they were going to have the symptoms. The symptoms were actually less the farther out they were from injury. There were some dramatic events that got included. When we did the analysis, the only factor that time played other than the initial symptoms were less further out than they were was that over the time course of the study, there was improvement in these different factors. So just being in the study, whatever that means affected them at the time post-injury was associated with a lower number of, and not statistically significant, but lower number of symptoms on the RPQ.

Moderator:Thank you for that reply. The next person writes: I appreciate that all the groups improved to a nearly equivalent degree in the aggregated score. But can you give a percentage of individuals within each group that improved?

Dr. David X. Cifu:I wish I could, but in my head I cannot. It is in the paper. It is very close. I think probably 80 percent of folks in all groups, give or take, improved on the primary measure of the RPQ as well as on the secondary of the PCL. So the majority of the people did have a change. There may have been one in each group that had a decline and one of four or whatever that stayed about the same. So there was improvement in most and it was typically in the area I outlined: visual, sensitivity to light, sensitivity to noise and some irritability. But good question. But it is in the full paper. And there are two more papers that are in process related to this looking at some of the secondary factors as well. So there is more information to come, so hopefully will answer all of those further questions. Thank you, Molly.

Moderator:Great. Yep. Is there any evidence regarding use of HBO2 after anoxic brain injury?

Dr. David X. Cifu:Yeah. So I don’t know that everything works in hyperbaric oxygen. But in terms of looking at control, the second study that I highlighted and it goes by the acronym of HYOBIBBI or something like that. It looked at verifying the utility and the feasibility of using an HBOT as well as some of the common measures. It had a number of individuals who have hypoxic injuries. It was done in Salt Lake City and there has been a power study out of the Salt Lake City group as well. In this study they did not demonstrate efficacy in hypoxic injury. In the early study, which was not controlled, which was not related to the military, they did demonstrate improvement in hypoxic injuries. But it was not controlled and they tend to be more moderate to severely injured. So in this population we obviously did not study that, but in the HYOBIBBI trial they did study it and they did not an effect. That was not the primary goal, so it was not powered to study it. They tried to get that money on hypoxic injuries. But Dr. Weaver out in Salt Lake City has been kind of the foremost leader in research in the area of hypoxia and his work has been invaluable. But for mild hypoxia, we do not see improvement. For moderate to severe in uncontrolled studies, he has found improvement.

Moderator:Thank you. Somebody else writes: What side effect was this study powered to detect?

Dr. David X. Cifu:I love that question. That has got to be a researcher! We looked at – the research and there is very little but using the RPQ, but the research indicated that a clinically significant improvement of the RPQ could be found with a seven-point improvement. And so we powered it to a seven-point improvement, which was an 80 percent treatment effect, is what I believe we would have expected to see. It was clinically going to be significant if there was an RPQ improvement of seven points. The n of 60 that we used for the three groups, 80 percent effect would have seen an effect. So the goal of the study was to just make sure we could recruit patients, which was not easy; make sure they could tolerate this; make sure we could successfully do followup; and we met those goals. But also we did power it by a treatment effect of 80 percent or improvement of seven points, which we did not cross that threshold. And the study is by – the one we based it off is by E-Y-R-E-S, Eyres, is in the paper. That is the one study that put the clinical and statistical significance of the RPQ. Love that question.

Moderator:Thank you for that reply. So are we to assume that veterans with mTBIs from three to ten years ago are being impacted cognitively by the stress of their current life as opposed to experiencing symptoms of their mTBI?

Dr. David X. Cifu:I wouldn’t assume that, I think that that is absolutely true. People who had a mild traumatic brain injury who have not had full neurophysiological recovery within their brain who undergo a stress. If someone had a concussion and continue to have deficits, whether they be based on the psychological testing, functional testing, however they are tested, when they are in a stressful period, they are going to demonstrate symptoms of that stress. They are going to get cognitively worse. And this is well known. That is true of anybody who has had a brain injury. When you are under stress, you can have some cognitive decline. Those that have some persistent functional deficits such as an executive functioning, further have functioning day-to-day find in a non-stressed or where a standardized standard of life when a new stressor comes on like if a loved one, monetary decline, monetary challenge, problems in the environment are causing stress, medical needs, they are going to have a worsening. No question about that, and that has been well documented and that is well known. And we may also see folks that are having persistent kinds of deficits or are seeing deficits day-to-day when they get stressed physically, emotionally or both, they are also going to have a decline. They are going to do worse. Some people can adapt well and use other techniques. Some people cannot. So yes, stress is a very real and significant factor in those that have had traumatic brain injury as well as in those who have not.

Moderator:Thank you. The next question we have: What is the size of the study in progress now?

Dr. David X. Cifu:Excellent question. The last that I was aware, it was initially going to be 300, but the money was not there and the recruiting possibility was not there, so they identified the size to an N of 100 in three groups. They are not equal groups. It may be that it is a group of 60, a group of—see if I can do this math quickly—and two groups of 30—see, that is not going to work—and 20/20 may have been the way they eventually ended up. I believe it is an N of 100. I think there are going to be 60 folks in the active arm, 20 in the sham arm and 20 in the control arm. That is my latest understanding.

Moderator:Thank you for that reply. Is there a significant reason why no women were included in this trial?

Dr. David X. Cifu:Women came in, in the trial in Carson, they are being included. We recruited everybody, anybody who was in the brain injury clinics at Lejeune and about 99 percent of the people in the brain injury clinic at Lejeune are women. We also recruited from Quantico and maybe got four people. We recruited anybody and everybody. The numbers of individuals who are getting brain injuries from combat in Iraq and Afghanistan tend to be men, tend to be folks that are in the infantry as well as Marines so that is who we get, but we actively try to recruit women and we are doing so for the study in Carson as well. So it’s a great question, obviously we are sensitive to that, but no, it was – we recruited – we tried to over-recruit for women by reaching out and could not get any.

Moderator:Thank you for that reply. That does look like the last question that has come in. I do again want to apologize to people for our loss of the audio. Please do hit the archive video when you get a chance and you will be able to hear the rest of the answers. With that, David, do you have any concluding comments you would like to give.

Dr. David X. Cifu:No, but thank you for the opportunity and certainly welcome folks to reach out to me not to get a copy of the study because we will get that to Molly, but if you have any questions or any followup information, we will be happy to dialog with you. And lastly, we just want to just thank Ralph for continuing to include our research efforts in these HSR&D updates. So thanks, Ralph. I appreciate that. All right, thank you and have a great day.

Moderator:Thank you very much.

Dr. DePalma:Thanks, David.

Moderator:Thank you, Ralph, and thank you, David, and thank you to all of our attendees for joining us, and I will be happy to send out the reminder email tomorrow with the link to the archives. So thanks again for joining us. And when I end this meeting in just a second, you will have a survey pop up on your screen, so please do take just moments to fill out those questions. Thanks so much.

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