Next Generation Medicine: The Invisible Wounds of War

[APPLAUSE] All right. Well no pressure to deliver
an entertaining talk. Thank you all so much for
coming out on a Tuesday night to listen to us. I hope this spawns
some conversation. And also, I really
appreciate the opportunity to come and talk in more
of a community setting about what we’ve been
doing on the research side. We are very honored when
our findings are published in high-end medical journals,
but that doesn’t always help us to get the
conversation out there to oftentimes the families
and the patients whom we work with in the communities, who
likely could be empowered by information and to
likely need it the most. So to kind of start off in
official disclosure side– I am right-handed,
so I think this is where this is going to end up. Yep, the left slide here. Or your right, I should say. But a variety of funding
sources for this. I am funded by the NIH and
the Department of Defense over a variety of years
to do these studies. And to kind of explain where
this all started for us, so there’s actually
been a lot of work. We’re not the only ones. I don’t stand up
here just by myself. I stand really on the shoulders
of some incredible giants in the field. But a lot of work in
combat brain injury has really taken
the role of looking at imaging and clinical
outcomes mostly with single time points of evaluation. These are
cross-sectional studies, where clinicians are asking
patients about exposures that happened months or years prior. And there’s still questions
about how brain imaging characteristics and
clinical outcomes might evolve or resolve over
time following these exposures and how they might impact
the service member’s long-term outcome. And our take on this has been
through a collaborative effort with Landstuhl Regional
Medical Center in Germany, which is the primary
triage point for all combat medically evacuated
casualties of war, and efforts at Kandahar
and Camp Leatherneck in Afghanistan,
directly in combat, and academic universities that
we work in the United States to really track
patients following the exposure from the initial
point in combat following these injuries, and then follow
them back and see where they’re at at a year and five years
and now 10-year outcome. So for those who
aren’t familiar, a little statistical
perspective just to kind of give you a
flavor of who and what and what we know
when we started, and to kind of say where
we’re at, what we don’t know, and what we need to know. There’s over 2 and 1/2
million service members who have deployed
to recent conflicts. And when we say
recent conflicts, we’re talking about
global war on terror– so Iraq and Afghanistan. And more than a third of those
completed multiple deployments, a lot of exposure to combat. There are over 22 million
service members and veterans from all previous service
in world conflicts still living to this day. So this makes up a large
portion of our US population. About a fifth of
those individuals from recent conflicts have
sustained at least one brain injury. And those from prior
conflicts, it’s actually a little less known. Part of this is because
the clinical definition of mild traumatic brain
injury and concussion has evolved so much
over the years, and the thoughts are that
previous reports just unfortunately are poorly
underestimated, if anything. You have all heard about
post-traumatic stress, but that’s actually one piece
of many types of mental health disorders that our service
members are returning with. About a third of them are being
diagnosed with various types of psychiatric conditions. And a sobering fact for many
of us when we think forward is just the estimated
cost of health care. It’s been estimated that it’ll
likely near a trillion dollars in recent years. And this may exceed
this estimate if these number of
complex cases continues to surpass these estimates
year after year after year. So this is really in the
bucket of public health concern on a broad scale. And for those of us
who work in this field, an extremely sobering fact–
and I am sad to say it is still true to this day– our current success rate of
translating preclinical models to human clinical trials for
traumatic brain injury is zero. We have failed over the years. And recently, a good colleague
of ours in neurosurgery at University of Minnesota
took a close look at this to better understand what
these were, what we were doing, what we thought we
were going to find, and why we didn’t find
it so that we actually do a better job going forward
to serve our TBI patients. And it turned out, of
the 30 clinical trials that have been done,
they all failed to find significant
treatment effects, even though they were supported
by extensive preclinical studies. So are we designing
our trials wrong? Are we using the wrong tools? Did we somehow misinterpret
the preclinical studies? And again, this
comes at a big cost. The estimated of
these trials alone is over a billion dollars. And private industry,
grant funding, taxpayers deserve better than that. And I think with the
advancement in technology that’s occurred over the
last five to 10 years, we absolutely are going
to be doing better. The challenge in particular
from mild traumatic brain injury and a subset of mild
TBI is, in fact, concussion. Concussions are a brain injury. I would challenge any
clinician or medical student who is learning about
this in the room to tell me with definitive
confidence which one of these people
has a brain injury. Which one of them has PTSD? Which one of them
has both or none? Now of course, a clinician would
be taking an extensive history and talking to this person. But the diagnosis requires
self-endorsement and self-report. And in particular with our
service member population, there’s often the likelihood to
minimize symptoms in the moment to maintain their support
of the service and the duty that they are providing. In the military, this
actually isn’t new. It’s gaining ground. We talk about it a lot
more now than we used to. But it’s kind of old
hat if you go back through the medical literature. As early as World War I, there
were actually written documents about British
expeditionary force members who were reporting
headache and dizziness and nausea and sensitivity
to noise and light without any signs of
external head wounds. And that, plus a
negative CT scan, nowadays would essentially get
you a diagnosis of mild TBI or concussion. And as early as the
1900s and by 1915, we had paper after
paper coming out about this concept
of shellshock. And some of the classic
symptom characteristics of this included fatigue,
anxiety, depressive mood. And today, in a
constellation of symptoms, this has now been
recharacterized and called PTSD. So with all of this
history you would think that we’d be at a
position to say who has TBI, who has PTSD quite definitively. But it’s a little more
complex than that. And I like to think of
it like a Venn diagram. You can have TBI without PTSD. You can have PTSD without TBI. You can have both. You can have none. But the challenge
really comes when you start looking at the
actual symptom profiles that are currently
utilized in describing what is a mild traumatic brain
injury, what does characterize PTSD. And the fact that,
unfortunately, this can be confounded
by medications, and this doesn’t often account
for potentially confounding other mental health conditions,
many individuals who have PTSD may also meet clinical criteria
for depressive disorders, anxiety adjustment disorder,
mood disorder, and others. So these are complex. In general, this concept is
what has surrounded this idea of the invisible wounds of war. And I like this quote that says,
“Just because someone doesn’t have scars that
you can see doesn’t mean they’re not battling.” And with mild TBI, that’s
one of the hardest things because people come back
looking very similar to when they deployed, but they could
be acting very differently. And it can be hard for
them and for their families to understand. But we sought out to try to
embrace the new advancements in technology to say, are
these are really invisible, or have we just been
using insensitive tools to visualize them? And from an imaging
perspective, there’s this catch phrase
in brain injury about this clinical
conundrum that there’s a type of pathology in the brain
called traumatic axonal injury. And think of the
axons in your brain like the wiring in your house,
and that the wiring can get cut and the axons can
get disconnected. And a lot of work has
shown that axonal injury, diffuse axonal injury,
is a contributor to cognitive
dysfunction and now even mood disorders, mental health,
behavioral health changes that can happen following TBI. But from an imaging
side, it can be hard to really drill down into
does this patient have injured axons. And some of the
scenarios that arise are an individual with
mild traumatic brain injury who presents in
the emergency department. The physician is
concerned about TBI, so they go and have a CT scan. And the neuroradiologist
takes a look at it, and the CT scan is
completely normal. Is that patient lying? Or did we just miss
it on the CT scan? Or is there something
else that’s going on? Are they impaired for
some other reason? Or are they telling
us that they’re impaired because there’s
some medical legal concern? And a lot of times it
can be very ambiguous. On the severe TBI
side of the fence, there’s also
challenges there when you have a patient in
poor clinical status, because they can
be groggy and foggy and seem like they’re kind of
in and out of consciousness for a variety of
different reasons. And the question
comes up, is that because of things
like axonal injury, or is it because of
their sedative drugs? Or maybe they’re intoxicated. Or they might have
significant injuries outside of the brain called
extracranial injuries that are complicating the situation. Unfortunately, within imaging,
our imaging modalities that we use for brain injury have
really been optimized for the visualization of
hemorrhage and ischemia– so blood, blood products, and
then also alterations in blood flow and alterations in the
amount of oxygen content– and aren’t directly assessing
this thing that we think is so crucial for
this population. So a quick crash course
in neuroradiology when it comes to head injury. If you come into the
emergency department in any major hospital
of the United States and you’re suspect
for a head injury, you’re likely going
to get a CT scan. And in the context of
traumatic brain injury, a CT scan really
recognizes blood products. That’s what we’re looking for. And we’re talking
about mild TBI. It’ll sometimes pick up these
things called contusions. In more severe injuries,
things are much more apparent. But we’re talking specifically
in these challenging mild TBI situations. Now that recognizes
blood, but that’s through the sharing
of blood vessels. That’s not actually
looking at axons. So a CT scanner uses radiation. An MRI scanner uses magnets. And if you go for an MRI scan–
anybody who’s been for an MRI scan will know– very similar to a
CT, you go in a tube, this machine make some noise. The difference is
that the machine’s going to make different
kinds of noise because with magnets,
we can kind of exploit the magnets in
different ways to get different kinds of pictures. And there’s a compilation of
pictures that you can take. And when we look at the
brain trauma protocol at every major emergency
department in the United States, some of the photos,
the pictures that we’re taking, are examples like this. So there’s a T2-weighted
image shown here. And in the context
of brain injury, what we’re really
using that for is to look at edema,
which is like swelling, fluid accumulation–
again, associated with, but not directly assessing
this axonal injury. There’s also these
things like a T2* image– nowadays, most commonly an SWY– that also recognizes
blood, blood products, and does so just with
greater sensitivity than CT. And then things like
diffusion-weighted imaging, where it will recognize the
global movement of water, but again, not
directly assessing this pathology that we think is
so important to brain injury. And diffusion-weighted imaging
is used a lot even with stroke and really has made a lot
of headways with stroke. But stroke is not
always similar in pathology to these traumatic
brain injury situations. It’s a type of brain
injury, but different. When we compare CT and
MRI, just purely talking about the diagnostic
tools that are most commonly
available in hospitals, we see some interesting things. And this is very
elegant work that’s been done by our colleagues. We participated in
a multi-center study called TRACK-TBI. This is Dr. Mukherjee and Dr.
Yuh, our colleagues at UCSF, where we took initially just shy
of 700 brain-injured patients from different hospitals
and then repeated this in a 3,000
brain injury patient cohort from 17 Level I trauma
centers throughout the United States. And when we compared the CT scan
that was taken in the emergency department to the MRI scan that
was collected within a few days afterwards, we saw an
interesting trend– which was known in radiology,
but not appreciated as much, especially when
you’re drilling down into these specific populations
in our case brain injury– which is that across the board,
that the MRI consistently identified much more
lesion pathology consistent with brain injury
than the CT scan did. And the most striking finding–
and this has now been repeated in this larger 3,000
patient cohort– was that for mild TBI patients
who had a normal head CT– somebody said,
gosh, I’m concerned you have a head injury,
let’s go get a CT scan, the CT scan is normal– a third of those
individuals had lesions identified on MRI that
were consistent with brain injury just missed by CT. And so we know that the
technology that is currently in play, specifically when
we’re talking about mild brain injury, is likely insensitive
to all of the potential brain changes that are associated with
these head injury exposures. And there’s even
situations where the MRI scan, the conventional
imaging, can be normal, and we’re still
asking the question, how do we know, how can we
say with definitive confidence this person had a head injury? And that’s where some of the
newer technology comes in. There is an approach called
diffusion tensor imaging, and this is something
that we sought out to utilize and test out with
our combat concussion patients. It builds off of that
diffusion-weighted imaging I was telling you about
that used often with stroke. And it essentially
takes the concept of water moving
throughout the brain and does a little bit
more than just care about the bulk movement, it
cares about the direction of the movement as well. And so the example
we often give is that if you took a
drop of dye and you drop that dye in a
cup of water, you’d see it kind of move
all over the place. It diffuses randomly. And the mathematicians
will tell you that can be modeled as what’s
called Brownian motion, the random walk. But if you took that
same drop of dye and dropped it onto
a stalk of celery– and I bring up celery because
historically this is actually what they tested this technique
in– the celery, your brain, it’s about the same– but that on celery, you’ll
see– and actually we do this nowadays with kindergartners
on science day, and they’re just amazed– but you drop of dye
on celery, and you’ll see that it’s going to move
more prevalently along the stalk of celery than kind
of radiating out and perpendicular to it because
it’s path to least resistance, right? It goes down the tube,
and it takes a while to get out through the walls. The wiring in our brain,
the axons in our brain, essentially work the same way. And this is just a
graphical depiction of what white matter with
what’s called a myelin sheath– think of it like insulation– has in our brain. And if we take a picture of
that and we use this technique, we would see that the
water would diffuse more prominently in one
direction versus call it perpendicularly. And this has a term. It’s called anisotropy. Everybody loves exciting terms. And so there’s this
effect basically, this directional
dependence of something to move in one direction
more than the other. And why would we care about
this for brain injury? Well if we went in and
had a pure simplified model, where all we did
was just sever the axon– we cut the celery stalk– well then the
water is likely not going to diffuse as much down
the axon because it’s been cut. It’s been severed. It’s crushed. And so the directional
dependence of that water will now move less
prevalently along the axon versus perpendicular to it. And so you can
imagine that there’s a reduction in that kind
of asymmetry effect. This looks much more
ellipsoidal than this. And then in the
converse, if all we did is go in and just strip
off the insulation– path of least resistance– now
there’s not a barrier for water to diffuse out. And in fact, individuals who
are studying disease states, like multiple sclerosis, are
actually using this technique to try to better inform
relapsing remitting MS, for example. Or those with white
matter lesions following extended viral
[INAUDIBLE] with HIV, they’re using this as
well to better understand how the brain unfortunately
is being affected, that you’ll see that
the diffusion will then go out more so. It still is cruising along
that tube that we talked about, but overall, that
directional dependence– this nice tight ellipsoid– goes down and is reduced. And if in the very simplified
version both of those things happen, we end up
with something where we take kind of the
American football, and it looks more like
the world’s football. We get a vast reduction
in anisotropy. And again, why does this matter? Because fundamentally, we think
that there is a sensitivity. For the math
aficionados in the room, I’ve put the equations here. I’m not going to
walk through them because way too complex
for a Tuesday night. Bless your hearts for even
coming out for this talk. Goodness gracious, the
last thing we want to do is go into complex math. But that said, when we
compare the anisotropy with DTI versus the
diffusion-weighted image that I was telling
you about with stroke, fundamentally, this
is the take home, which is in a mixed
injury scenario or within the complexes that
would happen following brain injury, there’s a
lot of things that are probably changing
in the brain, and we know this is the case. So you can imagine
that in one hand, we would see a vast
reduction on this DTI signal that we’re talking about. Now this math I think
we can all handle. It’s three things added
together divided by 3. I think I can do this
on a Tuesday night. And the bottom line is that
depending on what went up and what went down, we
could completely miss it. And that fundamentally this is
why neuro imaging techniques, like DTI, maybe,
just maybe, will help us better inform things
like traumatic brain injury. And so we sought
to try that out. And it turned out that
we had the opportunity to do this with the US military. And so the objective
really of what’s now been called the evolved
study, when you set out in science and medicine
and you go to write grants, and you create clinical trials
and clinical research studies, they always ask, well,
what’s the title? What’s the acronym? And none of us are trained
in flashy acronym design, but we worked hard to
try to find something that would make sense. Behind the scenes, EVOLVE
stands for EValuation Of mild TBI Long-term outcome
in active-duty US military and VEterans. Say that five times fast. So we just call it
the EVOLVE study. But our objective really
with this was to, first and foremost, test
out this new imaging, but also do so in a way
that would be clinically meaningful for the
patient population that we’re attempting to
serve, which is to say, we are going to look at
imaging and clinical outcomes in mild concussive
brain injury that sustained during deployment. And we think that by leveraging
in particular early clinical and imaging measures
that we can do a better job of predicting trajectories. I’m sorry to say, no two
brain injuries are alike. That means that no two
patients are alike. So anything that
we’re trying to group and say, we can do
this as a uniform thing for every patient, is going
to just inherently be limited. So by leveraging
stuff early on, we can embrace this
heterogeneity, and we can do so in a way that would
be flexible to each patient’s trajectory. This was the goal. And so the study design. There’s a lot of
words on this page, and the main take-homes
are the following, which is to say
that this is still a prospective observational
longitudinal research study. So this is not intervention. We’re not giving any drug. But we are trying out
these new diagnostic tools in similar capacity and trying
to understand the relationship with clinical outcome
and with the diagnoses that these individuals
were given over time. I want to be very clear that
all the patients that we’ll be talking about met the
Department of Defense definition for mild
uncomplicated traumatic brain injury, which by definition
is considered a concussion. These should be the mildest
of the mild of everything that potentially people
are sustaining in combat. So why am I as a civilian
standing up here telling you about military combat trauma? Well as luck would have
it, we wrote these grants to start these
collaborations, and the Chief of Trauma Surgery at Landstuhl
Regional Medical Center said, great, come on in. We’re too busy. We can’t help you. But if you want to come and do
this, you can come on board. You can work with us. And away we went. So for five years,
from 2008 to 2013, I, for a period of a month,
two months at a time, lived and worked at
Landstuhl Regional Medical Center in Germany seeing
medically evacuated casualties of war. I was in trauma surgery there. Here, I’m in
neurological surgery. And then I’d go back
to the United States to try to catch these folks
six to 12 months later. And then I’d go back again,
and rinse and repeat over time. And you’ll see that
there’s a few flavors of patient groups
up on this slide, and there’s a few
points of starting. So the first point of
starting is Landstuhl. Now these are
medevac casualties. And the reason we
went to Landstuhl, it was the closest MRI scanner
to the combat theater at time when we started. We’ve decided to focus on
blast traumatic brain injury because at the time, blast TBI
was getting a lot of press. And everybody was very concerned
about whether or not blast TBI as a mechanism might be
different than other forms of traumatic brain injury. Would we need to have a blast
TBI clinic, specific treatments for blast TBI distinct from
other forms of head injury? And decisions were starting to
be made without actually good evidence base support for them. We said, we should look at this. Importantly, there’s also
controls in this group as well. And these are individuals
where they did not have a head injury,
and a subgroup of them actually had blast exposure. And so with a blast control,
it gave us an opportunity to study sub-concussive events. So people who came
into Landstuhl and were screened for head
injury, determined to not have a head injury
by the neurology clinic, but had blast exposure. And this is similar to
sub-concussive exposures that you hear about in
different forms of athletics. In the case of combat,
this was a version and a very common mechanism. And then we actually
had individuals who had a head injury
that were not from blast, and they didn’t have a
history of being blown up, so that we could compare head to
head this question of mechanism And importantly, we got a lot
of flak about the fact, well, these are medically
evacuated individuals. That’s a biased sample. That’s not representative
of the deployed force who gets injured. So many of them still
stay in theater. Well as luck would have it,
in 2012, Lieutenant Commander Octavian Adam, who was
deploying to the combat theater at the time, reached
out to us and said, hey, they’re deploying MRI
scanners to Afghanistan. There’s going to
be three of them. I was in Germany at
the time, and he said, can we work together? And I said, yep, terrific,
let’s make this work. And so we were then
provided the opportunity to actually evaluate and
scan individuals in combat. And we did this at Camp
Leatherneck and Kandahar Airfield over a period of about
18 months starting in 2012. And that allowed us
a couple of things. One, the opportunity
to look at individuals who were not medically
evacuated with blast exposure. Again, these more mild injuries. And two, to have the
comparison– medevac versus non-medevac. OK, let’s compare
them head to head, and let’s see what
they look like. And then we had the opportunity
to follow them out to a year, and then follow them out
to– we just finished our five-year follow-up. And you will note that on
here, there are actually individuals at this time
point under each arm that are showing as deceased. And every single one of
those is from suicide, minus one that was an accident. No one was over the age of 45. And so we are working
very hard to do a better job of that as well
and better understand that. But the basic flow
was essentially you come through Kandahar,
for example, or Landstuhl, you’re going to get imaged,
and then you’re followed out. Between the one-year
and five-year follow-up, I made the very
confusing transition from Washington
University in St. Louis to the University of
Washington in Seattle. I still screw that up to
this day, so my apologies to my colleagues and
esteemed colleagues here. Wash U, U Wash,
someday I’ll get it. That said, at the
later time points, we were able to scan them. And also at this point,
evaluate with a battery of neurological, psychological,
as well as a cognitive test battery that I’ll show
you on this slide. And I have to say
on an aside, I’m so proud of our patient
coordination team. Since the beginning,
we’re just getting folks as they’re coming in. Multiple flights a
day into Landstuhl, all the casualties
screening through. We’re rounding the
folks in Afghanistan [INAUDIBLE] however we got. That meant that when people
came back to the United States, they could come
back to anywhere. And since the
one-year follow-up, we actually maintain patients
in the study in all 50 states to US territories,
and it bounces between 9 and 11 countries. And so I have incredible pride
for my patient coordination team, who stays in contact
with folks, works with them. And then for each
of these follow-ups, they’re physically
flying in to see us, oftentimes traveling with a
caretaker because they cannot travel alone at this point. So this stuff that never
makes it to publications, but I just really
want to acknowledge their incredible support
and talent that they’ve provided over the years. So these are the
neuropsych assessments. For anybody who’s in
psych or neuroscience, yep, they’re pretty
common assessments that are done in rehab clinics
for traumatic brain injury. So for those of you who
are still awake or not checking your cellphone,
this is the entire slide of conventional imaging
findings we found in this group. I hope you’re going,
wait, what am I missing? There were none. And that’s precisely
what we thought we would see because these
were concussion folks. But the point is that all
of the CT, all of the MRI scans, all the conventional
imaging to show any indication of brain injury was normal. There were no
abnormalities identified by boarded neuroradiologists
who examined the scans and provided a radiological
report for interpretation. That said, when we
looked with DTI, we actually found something. And we found evidence
with these newer imaging methods that was consistent
with traumatic brain injury. And these are group
findings, and we all do this. We publish– and you can see
that I’ve published this, too– group findings
with these methods. But at the end of
the day, a clinician is not going be looking
at a group of patients. They’re going to be
looking at one patient and having to make a decision
about that single patient sitting in front of them. And so it was very
important and very rewarding to us to be able
to say, you know what, these imaging
findings are also being able to distinguish these
patients on a single subject level. That even with these
heterogeneous brain injuries– no two brain
injuries are alike– this technique, not only did
we see the normal group stuff, but we saw stuff that
actually helped even for a single patient
sitting in front of us. And importantly, when we
look at the early scans versus the one-year scans,
approximately one-year scans later, we’re seeing an
evolution, not resolution of these abnormalities. Because the argument
can be made, well, you have an abnormality. It was just because of
something pre-existing. It was an injury years ago. Well then it should have
been stable, and it wasn’t. And this really
supported the fact that this is likely from
a more recent exposure. Now I stand up here to
tell you all about imaging, but I have to say I really don’t
care about imaging unless it actually helps inform
the patient that’s sitting in front of me. And for that, I’d
like to tell you a little bit about
the information that we identified with
all of the measures of clinical outcomes and what
did these folks look like. And does the imaging even
relate to clinical outcomes? So for that, we’ll
start with the one-year. At one-year follow-up,
we were quite surprised. This is global disability data. Again, remember, these across
four independent cohorts are mild concussive
traumatic brain injury. And those percentages
are the number of patients across
every cohort that met the clinical criteria from
moderate to severe disability. It should also be noted that
the control groups themselves are not immune. But importantly, the blast group
and this non-blast TBI group, there was no difference. The also striking thing
for us was the fact that the medically
evacuated cohort didn’t actually
statistically differ from the non-medically
evacuated cohort. This was really
surprising to us. How can the non-medically
evacuated cohort be doing, quote, “so poorly”? They’ve never been
followed over time. It just wasn’t something
that had been looked at. But here we are able to
provide for the first time some direct comparisons. Importantly, I also provide
the percentage of individuals from a large scale
multi-center brain injury study looking at mild TBI
and TBI with poly-trauma. You see it’s about a
third of the group. And these percentages
are much, much higher. Where is that coming from? A lot of it seemed to be
driven by mental health. These are scales that are used. These are structured
clinical interviews that were administered blinded
to the clinical status. So we have a team that comes in
blinded to the clinical status of the patient. And you see that
across the board, the red are the
concussive blast folks. This pink fuschia– I don’t
even know what to call it– is the non-blast TBI folks. And across the board, these
guys are sitting in much, much higher than the
gray and black groups, which are the control groups. And so repeated across four
independent cohorts over this five-year period– because there’s
influxes in the war, there had been change in health
care policy during this time– we’re not seeing a
dramatic improvement. We’re seeing actually a
significant mental health load on two primary measures. And again, no
distinction by the type of exposure blast or non-blast. Concussion in combat
just wasn’t so great. And importantly again, that
there is this almost step effect with the blast controls,
the sub-concussive group, versus the non-blast
controls, again, repeated across the two cohorts
of which they were collected. And so this also
played out when we looked at what’s called
neurobehavioral impairment. It’s a multi-domain clinical
structured interview for a lot of
different things that include irritability,
disinhibition, many of kind of the symptom
clusters that make up what we know about mild
traumatic brain injury. And also, headache
frequency intensity was a big part of that as well. And so this is a pretty
significant load. And yeah, we got
a lot of pushback. Oh, you must have
done something wrong. Clearly, there’s
something skewed about this particular
population. And also that many of us
when we went through school and were trained, there was
always this discussion about, well, with traumatic brain
injury, six to 12 months out is basically the
vast majority recovery, and then people are kind
of stable over time. So at least that when you’re
counseling family members, you would say, well,
you’re about a year out. This is about the
recovery you’ll have. This is where you can
start kind of figuring out where to go next. And so we asked the
simple question of just, well, are these impairments–
maybe they would just resolve. Maybe there’s just something
about that first year that’s just kind of a delay effect. Or are they sustained over time? And so with the
five-year follow-up, one of the beauties–
although there’s some painful logistical moments
of trying to follow somebody literally around the world, and
500 of them, for that matter. So there’s very humbling
experiences behind the scenes here. But to truly do that was really
eye-opening, which was we were able to compare that
same person over time. And we were seeing,
again, these reductions in this new imaging method,
again, at the group level. No significant volume
changes, so this is important because it wasn’t just
that these people’s brains, the patient’s
brains, were atrophying, meaning dying away. This was the
microstructural stuff, which meant that the
conventional imaging still looked normal. And importantly,
with imaging, we asked the question at five
years, did they get better? Did they get worse? How were their brains looking? We were quite surprised to
see when we went in and looked at the anatomical
abnormalities using DTI that 74% of these
patients had reductions in this anisotropy measure now
indicative of chronic brain injury. That not only is it not
stable in a large proportion of these folks,
things are changing. Things are evolving. Not just their
outward appearance, but in their brains, too. And so when we did ask that
question that I started with– does the imaging actually
help inform the patient– the answer was a resounding yes. And that is to say that we did
this intentionally because DTI is something that cannot
be done everywhere, and it can be difficult to
actually get stable measures unless you are following
somebody very carefully and you get into all the
technical weeds. So we said, can we
be informed by this? And can we come
up with something that’s useful, no matter
where folks are at, that any provider could utilize? And the answer was, if all
we had was the early data, we could predict with
about 80% accuracy what their brain
basically was going to look like five years later,
if we just knew their TBI diagnosis, their age and injury,
their depression load, and then two measures of cognitive
performance reaction time and what’s called
verbal fluency. And this is important to us
because although we started with this kind of
fancy schmancy imaging, the reality of what
we do is the hope is that there
would be an ability to impact care everywhere. I came from a very
poor farming community in northern California, and
I think about my neighbors and how can this help them now. I don’t want to help
them 30 years from now. I wanted to help them now. And this information can
be used by any clinician even without the imaging. But it also really
drove home the point that, yes, this imaging is
helping us inform what’s happening to these folks. At five years, as
we said at one-year, the global disability
wasn’t so hot. And we thought, gosh, we were
getting all these critiques. Oh, it’s wrong, or,
oh, these people are still going to recover. Great. Let’s look at them at five
years hoping that everybody is going to be better. Not only were they
not better, 72% of the blast
patients experienced a substantial decline. They got worse. And so this mantra about six or
12 months and stable, six or 12 months and stable is really
challenged in this population. And it turns out that there
are large scale efforts in moderate to
severe brain injury that have reported
the same thing. A large group called
TBI Model Systems are saying the same thing. But no one has ever
looked in mild TBI, and no one certainly had ever
looked in military service members. And so again, we
were quite surprised. This is a very busy
slide, but there’s a couple take-homes
to be aware of, which is to say that the
PTSD symptoms, the depression symptoms, the anxiety, and
in particular, the poor sleep seem to be a chronic impairment
for a lot of individuals with these combat
concussion exposures. Even when we compare them to
all the grays or everybody that deployed right
along with them, they just didn’t
have the head injury. Interestingly from Vietnam
head injury study, people look a lot at alcohol, so
this is the alcohol data. There actually is not a
difference in the group as far as alcohol
misuse or abuse, at least at this 0.5 years out. And indeed, in fact, the entire
total load, the dot line here, indicates where you would
actually be concerned. There’s only a handful
of folks, very few, that cross over that line. And so we’re seeing that there’s
this significant elevation of these mental health symptoms. And interestingly, when we
asked the very simple question, because we got these
critiques all the time– well, it’s because the service
members are doing bad because they’re just
not asking for help– OK, well let’s
ask that question. And in almost 350 of these
patients, at five years, we asked that question. We went through the
structured interview about, did you seek mental
health services? What was it? Did you complete treatment? Et cetera, et cetera, et cetera. What did you do? What medications were you on? And we found that
80% of the patients endorsed seeking
mental health symptoms, and this was the
group that had to have completed the treatment. But when we asked about
sustained resolution, only in 19% said
it actually helped. That means that we’re
failing a lot of patients with traditional psychiatric
treatment strategies. And where is that
coming from, and why? Well that’s where
we think the brain injury might be contributing. It’s not the whole story. And the imaging
that we’re now doing is able to inform
now, when we get down to the networks in our
brains that are involved in emotional regulation and
mood control, that maybe, just maybe, that might be
part of the factor here. So again, we see a lot of
nerve behavioral symptom load and sustained headache
frequency and intensity. What you’ll probably be
asking yourselves is, wait, didn’t you say you did all
this cognitive testing? Where’s the cognitive data? Turns out, when we
compared them head to head at every single time point
across every single cohort, there was no difference
in cognitive performance across the groups in
comparison to the controls. People are talking about,
I have memory deficits, I have intentional deficits. But when you actually test
them on standardized neuropsych testing, there is no
difference in the groups. And what we’re left with are
the nerve behavioral issues, the somatic issues, the
mental health issues. And that seems to be influencing
disability and also the sleep. And so then we ask
the question– again, building upon this concept of
not only do we want to be able to help those who can make it
to Level I trauma centers and do fancy schmancy imaging,
but for the rural clinics, for the combat austere
environments that many of our casualties
were coming in from– what could be done? What could be utilized? What was there at the time that
could inform these trajectories just for the clinical
decision-making with these patients? Because medevac getting
somebody out of combat doesn’t come without risk. It’s a big decision to do that. And it turned out that
with 92% confidence, we could tell where
someone was going to be for global disability five
years later from a few pieces of information early on. And that was, again,
TBI diagnosis, neurobehavioral symptoms,
and just three measures of cognitive performance. And that is something
that can be used now. Even though we’re
rooted in the imaging, we’re rooted in
the fact that we’re able to say with greater
certainty there are changes that are indicative
of head injuries, the fact that there is
something we can do about it now we think is really important. And we’ve been working
with DoD policymakers to actually change
policy around this. And they’ve even altered the
care of concussion in combat from work that we’ve done
and from other individuals that we submitted data for a
congressional hearing, which is a unique
opportunity for myself. Many folks get into research
and they go, oh yeah, this will be impacting patients
in the next generation, 30 to 40 years from now. And our goal in this was to
kind of flip that on their head and say, no, we should care
about the patients now. We should care
about the survivors that are out there now. What could we be doing better? So I’m going to quickly
summarize for you kind of what we’ve talked about. This has been a huge data dump. There’s a lot of
information here. A decade’s plus of
work in 25 minutes. Of course everybody gets it. And then I’ll spend
about 10 to 15 minutes on a couple of closing thoughts
on some of the new work we’ve been doing. So what I’ve showed you– and
I hope I’ve convinced you– is that neuroimaging
potentially can help. And in our case, it consistently
identified abnormalities that are suggestive of brain
injury both in combat following medevac at one-year and
at five-year outcome. And we’ve just started the
ten-year wave very recently. And that combat
concussion appears to worsen global outcome,
again, over time, and that there’s something
about these exposures that is exacerbating symptoms
of mental health. And we’ve observed
this repeatedly across all four
independent cohorts that were examined over the years. And so these are kind of
important points of comparison. As I told you, one
of the questions that was kind of the burning
question which we started, which was there
must be differences between non-medically evacuated
patients and medically evacuated patients. And while absolutely there is,
in regards to clinical outcome profile at a year and five years
down the line, there wasn’t. That also held true for blast
and non-blast concussion at the one-year follow-up. And we’re starting to look at
that five-year follow-up data. And while on one
hand that can seem really disappointing and
saddening, on the other, that’s actually really
powerful because that means that we don’t
have to come up with blast specific treatments. We don’t have to figure out
blast specific or blast-plus versus non-blast. That if we do have treatments
for traumatic brain injury at large for our
combat service members and they do sustain
a concussion, that it can be applied
across the board. And that surprisingly,
there was a difference in these blast exposed controls
versus the non-blast exposed controls, the
sub-concussive group. This is important because
right now clinically, those patients are
lumped together. And this has a big
bearing on when they separate from the service,
their disability ratings. It has a direct impact
on them and their lives. And this just resounding
finding that the vast majority of these patients did seek
assistance for mental health, it is not for lack of trying. They are using the programs. It’s just that they’re not
getting sustained resolution, and that we need to do a
better job of focusing in on patient-specific strategies. This is not a one size fits all. It’s complex. And unfortunately, that
there was an evolution, not resolution, when we carefully
followed the very same patient over time from the point
of combat to one year and then to five-year. And I would submit to you
that these findings really do suggest a greater impact of
these seemingly mild concussion exposures than
previously appreciated. And this has a very
important implication when we start thinking about
the millions of service members out there as the
population ages. So a few closing thoughts in
the next five to 10 minutes. I tried to hit all
of the disclaimers. This is not the opinion
of my funders, not the UW’s School of Medicine,
not the opinion of my husband, our dog, our family. Just my personal opinion. So if you’re going to
throw the rotten tomatoes, I deserve them, not
these amazing folks. In my line of work,
this is what I hear. Although people complain
about, I cannot remember, I hear remembering is easy. It’s forgetting
that’s the hard part. They want to hold
on, but also, they’re worried about forgetting. And that unfortunately for many
service members coming back, the battle actually isn’t over. The war has just begun. There’s fights that
have just begun, that as they and their
families and their friends and their children attempt to
adjust to kind of a new normal, as people call it, and adjust to
the clinical outcomes following brain injury. And unfortunately,
it’s not even, OK, I have this figured out. Unfortunately, what
we’re seeing is, you might have it figured
out, but then there’s things that are
happening and people are getting worse and getting
better and getting worse and getting better. And in our line of
the work for many, the real battle is unfortunately
lost for far too many. This was published
a few years ago. This actually was just
re-reported this year and reconfirmed. Almost every hour, 65
minutes– it’s actually just shy of 65 minutes, to be
precise– a service member, a veteran, commits suicide. And the afternoon picnic with
one’s spouse, giving mom or dad a hug takes on a whole
cold new meaning. And we should be able to do
better for this population. Serve those who serve us is
kind of where we come in. And this has led us to work. This was started
a few years ago, when we started losing
individuals to suicide. Teamed up with my
neuropathy colleagues to try to understand this
at a more fundamental level. We’re talking about
these imaging changes, but what does the actual
brain tissue look like? If we’re going to
hit a drug target, we need to understand
what’s really there and understand the pathology
underneath the hood. And so we have tried hard to
learn from these tragedies. And the family members,
even some service members themselves, agree
in life that they’d like to donate their brain
at the time of death. And we will accept those brains. It’s one of the ultimate gifts,
an incredible generous gift that people give, to research
to the next generation. We have family
members say, please, if you can find anything to
help anybody, it’s worth it. And this is one of the cases. We’ve now unfortunately
had over 100 cases that have come to autopsy that we’ve
examined in this way, where we’ve, in fact, actually linked
the imaging that we’ve had. Antemortem just means in life. So we linked the imaging
and the clinical outcomes that we have on these patients
to postmortem imaging, meaning after the
brain is procured. We do a high resolution
imaging approach, and then we actually
utilize that to do what’s called image-guided
tissue sectioning for neuropathological research. Unfortunately, as it turns
out, the neuropathologists, when they’re looking
at the tissue slabs, can’t see everything that we can
see on imaging and vice versa. They can see things
that we cannot. But by working together,
we are able to get a more comprehensive
appreciation of the underlying injury
that has occurred. And because brain injuries,
heterogeneous disease– meaning it can be
anywhere in the brain– this helps us into very
quickly strategically focus where we should look. And it’s not just even
postmortem imaging. It’s by linking
back to the scans that we had of somebody
in life that we’re able to find interesting
indications of pathology that help explain what
happened to somebody. This was a case
of a young man who committed suicide in mid-20s
after repeated head injury exposures. And it actually
was on the MRI scan that was collected three
years prior to death where we see this dark blob that
is indicative of blood product. And only by alignment to
the postmortem imaging and then to the tissue slabs, I
was able to tell my neuropathy colleagues, we go in,
got everything laid out, you want to look here. I know this looks normal, and
there’s nothing about this that you would think
otherwise, but you should look here because years
ago, this person had an injury. And we do this throughout
the entire brain. And it turns out, for example,
in this case– and this has now rung true a variety of times
over and over by doing so– and they go and
microscopically and look, they see evidence of
brain injury pathology. And in this particular
young man’s case, evidence of
[INAUDIBLE] pathology. And it was because of
this that he actually was given the
diagnosis of low stage chronic traumatic
encephalopathy. It would’ve been missed by
traditional neuropathy methods because they have
to decide upfront, we’re going to look at
this region, this region, and this region. It’s not flexible
to brain injury. And they know this, but
they have no good way to go in and try to better
strategically section. And so by teaming up, we’ve
been able to really shed light on also the what we
call pathophysiological underpinnings of
these exposures. So where does this leave us? Well, I would say this is an
opportunity for us to act now. And one of the things that’s
unique about the military and in prior conflicts is that
the way that the health care delivery system is set
up, it’s more essentially kind of like a universal
health care delivery system, where everybody
that’s active duty has a certain kind of
health care system database that basically that you
can go back and look at. And then veterans,
they don’t have to, but the vast majority of them
will apply for VA benefits. And so there’s VA health
care information as well. And it turns out that again
learning from lessons learned, learning from prior
conflicts exposures, when we go back even in
World War I, World War II, and Vietnam– the last
time it was checked– it turns out that
the peak disability payout, the compensation, the
cost, the health care cost doesn’t peak until
decades down the line. And if we assume global war
on terror ended in 2014, and we’ll potentially
near a trillion dollars in coming years, the true cost
to these current conflicts on not just our servicemen and
women, but on our children, on our children’s
children, I humbly believe is yet to
be appreciated. Do keep in mind– on one
hand, it’s extraordinary. The service members have
decades of life to live out, and we hope those are
amazing, good quality years. But oftentimes,
they are challenged with brain injury
and mental illness, among other disabilities. Keep in mind that’s not
just the whole story. And while mortality
rates have decreased, meaning the number
of deaths, meaning we can keep the heart beating
under very austere conditions. I was actually in
Landstuhl when one of the quadruple traumatic
amputations came through, and he survived. And he’s thriving actually
still to this day. But morbidity rates, the things
that happen after the events, have just exponentially grown. And so our focus,
we believe, really should be on quality of life. This is not about survivability. We got survivability
under control, minus a very small
percent of the population. And importantly, quality of
life as this population ages. This is dating me a
little bit, but years ago, there was a sign over the LA
County Public Health Department that said, it read, “Prevention
is caring, curing is costly.” And I would submit to you,
early intervention is caring, curing is costly. By helping that service member,
you’re not just helping them, you’re helping their family. You’re helping their kids. And this brings down the
personal cost, the family cost, and importantly for any of you
in the room, the public health and societal costs. With that, I’d like to say
thank you so much for your time. I don’t stand up here by myself. I have an amazing
team of individuals literally around
the world that I’ve had the opportunity to work
with through these studies. Everybody with letters
in front of their name are active duty folks, and
even individuals out here who are government
contractors, meaning we could not pay them
at all for this. They literally did this
because they believed in it and thought it was
going to be helpful. In Landstuhl, I
always tell folks, when you come through the ED
in Landstuhl, there is a sign, the motto of Landstuhl is
actually “selfless service.” And I felt that
day in and day out, and I feel like that’s
where we are now, which is we have a
duty and an opportunity and a responsibility to serve
those who have served us. And this is our way
of contributing back. So I will stop
there, and I think we have time for some questions. OK. Thank you so much for your time. [APPLAUSE]

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