- Renee Meiller: Hello, everyone.
Here's a fact that might make your brain hurt.
When you receive a traumatic impact to your head,
your neurons start dying off in just six hours.
And over the next 45 minutes or so,
today's speaker will tell us why that's important.
I'm Renee Meiller.
I'm the communications director for the College of Engineering
and I'm a member of the Round Table Planning Committee.
On behalf of the committee,
I'd like to welcome you to today's talk.
A number of UW-Madison sponsors helped make this event possible.
They include the Office of the Chancellor,
the Office of the Secretary of the Academic Staff,
the Wisconsin Union,
and the Office of Learning and Talent Development,
so we thank them for their ongoing support.
Our speaker today is Christian Franck.
Christian is the Granger Institute for Engineering
Associate Professor in mechanical engineering,
and he joined UW-Madison in fall 2018
after several years on the faculty at Brown University.
Christian is kind of a pilot at heart.
He earned his undergraduate degree in aerospace engineering,
and while he was working toward his PhD
in mechanical engineering
at the California Institute of Technology,
he also earned his pilot's license.
Today, however, Christian studies the many ways
that mechanical forces can affect cell biomechanics,
and his work transcends disciplinary boundaries.
He seeks opportunities to work closely with neuroscientists
and other experts to bring his expertise in mechanics
to the study of the brain.
Currently, he is leading a multimillion-dollar,
transdisciplinary initiative aimed at understanding
how impacts affect the cells in our brain.
Christian, welcome.
[audience applauding]
- Thank you.
Thank you Renee, and thanks everybody for coming.
It's a real pleasure and honor to be here.
But big part of what I'm gonna tell you about today
is the story about how we think about, how we analyze,
and how we hope to be able to prevent any cells in the brain
from dying off by better understanding
the origin of concussions,
the origins of traumatic brain injury,
and how we can use that information
to think about better ways of protecting people
that are at risk of these kinds of injuries,
as well as new strategies of equipment
or personal protective gear that we might devise.
I wanna say a few things about the title
and then some things that happen in the tile slide.
I'll say a few things about sort of my coming to this.
I'm a little bit of a oddball in this.
As Renee mentioned,
I trained as an aeronautical aerospace engineer.
I went to graduate school very much thinking
I was gonna keep working on the next generation of passenger
or military aircraft.
Somehow in the process of graduate school, I lost my ways
and I got very interested in cell biology, human biology,
and human disease.
And turns out that every day,
from chewing to walking to fighting off colds
and infections, mechanical forces
play a significant role in the human body.
And this tale and this story about head injury
and concussions is yet another manifestation of that.
I think it's an obvious one; typically brain injuries,
neurodegenerative conditions and diseases in these cases
start with an insult to the head and it's mechanical in nature.
And what I found
when I sort of entered this field about 10 years ago
was that there was a lot of wonderful work being done
by the biological and neuroscience communities,
but one part of it, which was this interface
to the mechanical engineering communities
was sort of missing.
And that's the piece where I entered.
That's part of my background, and then as I was entering this,
I realized quickly that given the complexity of the brain,
given where we are today with our understanding of,
especially neurodegenerative diseases.
A lot of the headway that we're making now,
and a lot of the headway that's gonna be coming
in the next few years has really happened
because of two things:
one, because of recent advances in technology,
and the other thing of really people coming together
and communities blending.
This is certainly a problem that not a single person
can attack and solve on their own.
And so certainly I have benefited
from the many interactions I had with my colleagues,
the people in the community to work on this problem together.
So I'll talk a little bit about what we have going on now,
and kind of the footprint that we have established
and some of the vision,
and then hopefully I can guide you through it
and kind of explain some of our thinking.
So to reconcile with my title, it's Defining Neuromechanics:
Concussions and Traumatic Brain Injury.
This idea of neuromechanics is a subcategory of,
it's blending of neuroscience and mechanics of material,
which usually falls under the purview
of mechanical engineering right,
so this is the interpretation of mechanical forces
in the context of cell biology or the brain and neuroscience.
And again, to do this in an interdisciplinary setting
where we try to get as many experts as we can,
work together on this problem constructively.
We have built this center now, program
that lives under the acronym of PANTHER,
and I'll tell you what that stands for.
We're currently supported funding-wise
by the Department of Defense,
primarily the Office of Naval Research.
There's a lot of work that where the Department of Defense
worries about the war fighters and making sure they are
protected as good as we can, but at a basic scientific level,
this extends all realms of occupational risk to the brain.
Okay.
So this is who we are right now, again when I started this,
this was my vision was to come,
you know, have a program where people can work together freely,
a program that's fully transparent
and fully accountable, where anyone from the community
can have access to see what people are up to,
see what kind of business is being done
and see how it matters to relevant communities.
We started with just five of us.
I'm currently the acting director of this program.
We come from different backgrounds.
You can see different universities
are represented here.
We're about 12 in all, mostly spanning academia.
We have a couple of companies here.
So Ron is working for Team Wendy,
they are a helmet liner and manufacturing company.
We have Tony who runs the Helmet Division at Trek Bicycles
here in Wisconsin, and then we had some representation
from Milwaukee Tool Company, who are very much interested in
designing the next generation hard hat
for construction workers to keep them safe.
Funding is provided by through our program manager
at the Office of Naval Research,
and that's sort of the composition right now.
It's essentially like many gears in a very complex machinery
that all come together and work together.
I'll touch a little bit upon the different aspects
that some of the people do; it's gonna be a high level,
but I'm accessible for after the talk or afterwards
if you would like to learn more about each of us or contact us.
Today, I'll focus about the work that we do here in my laboratory
at the University of Wisconsin-Madison,
and it will highlight a few snippets
from work that's done by Rika Wright Carlsen
at Robert Morris University.
She's helping us to try to understand what kind of motion
that the head undergoes is most injurious to the brain.
Okay, and this comes back
to understanding situational awareness,
this comes back to helping coaches and trainers
on the field trying to eliminate those kind of situations,
that kind of motion that then becomes most injurious
to the brain.
Similarly, we're trying to use that information as well
to see what kind of protective equipment,
what kind of engineering solutions could we send out
to protect people from that.
Okay.
So this slide is extremely busy,
it is not meant for you to actually read,
but I just wanna focus your attention on the center circle.
This was came from a very large-scale poster
that we presented,
and I just wanna highlight here the name.
So it's an acronym, but it's a sort of a very, you know,
convoluted acronym for PANTHER.
It stands for [laughs] exactly, it stands for
Physics-bAsed Neutralization of Threats to Human tissuE and oRgans,
and you know, you may get a kick out of this,
but when you work with organizations,
especially within the Department of Defense,
acronyms are very important, and usually you choose an acronym
that depicts an animal, okay.
So we went through several different ones.
We settled on PANTHER.
We have a logo, so the point is this is a center.
This is a research hub for people to come together
to address concussions and the origin of concussions,
especially the cellular origins
and ways we can mitigate it, ways we can learn about it,
and ways we can prevent it.
And this is sort of showing you in this inner circle.
So the first upper left hand quadrant is the cell-level,
tissue-level work that we do here
and that people do at Brown.
I'll talk about our portion here in a little bit,
but there's a larger space
where people do anatomically realistic simulation
of head motion, and I'll show a couple of snippets
of that, and then over here
is the realm of next generation material development
for head protection, okay,
and this space primarily right now
is centered around helmets, but in the future
it may have other products as well.
Okay.
This gives you another sort of a more linear progression
of the kind of work that we in the in the PANTHER program do.
This sort of middle line right here is powers of 10.
It gives you a size scale of the things that we encounter
in our research.
Far left here, this actually is, this little video that plays
is a degenerating neuron.
So that's a brain cell.
That's real data taken in the laboratory.
This is out of network of millions of neurons
centered around one, and I'll talk about this.
This is the sort of six to eight hour degeneration
breakdown cascade
that Renee was alluding to that can happen
if the insult to the head was severe enough.
Down here is sort of the next, so the next level up evolution
of kind of what we can do in the laboratory, this right here,
looks as a spherical cortical brain ball essentially,
and so what we can do these days with tissue engineering
and you know, engineering solutions,
we can start to construct tissues that approach you know,
some of the complexity of the native brain, okay?
So we're not quite there where we can make real brains
that have same degree of anatomical realism,
but we can get quite close.
The caveat with any of this is that at any given day,
any given experiment in the laboratory,
we're limited to how much data we can extract, okay.
So we're limited by the number of readouts.
so it's easy to increase the complexity, but it's very hard
to decipher the mechanistic and the causal relationships
between every single player with the network.
So what we do right now is we work mostly here.
We're trying to understand what is the root cause
of traumatic brain injury?
Specifically, we ask the question,
What is, what are the limits on force?
What are the limits on deformations,
we're gonna be phrasing it in terms of stress and strain.
What is the limit at which point the cell decides,
"I'm done.
"I'm just shutting down chemically,"
or "I'm being torn apart physically."
We then wanna use this information and we wanna be able
to put it into computer simulation algorithms
that we can use that could be cloud-based.
Now these days, a lot of talk about machine learning
and artificial intelligence.
All these are available, and we wanna connect this back
with life measurements that we could instrument players,
we could instrument helmets,
we could instrument vehicles, whatnot
to make sort of on the fly, real-life diagnostic assessment
of the state of health of the brain tissue.
And then the last two pictures here are the much larger scale.
Again, this is advanced material development.
The idea is to, once we understand what kind of motion,
what kind of forces are most injuriious to the brain tissue,
we wanna come up with engineering solution
that mitigate that.
So that's sort of in a nutshell
of what we think about within this program, okay.
So today, I'm gonna tell you a little bit.
We're gonna go inside the brain.
We're gonna look at the brain tissue,
and we're gonna talk about how we think about
and how we look at the initiation of these injuries.
Concussions are part of the umbrella
of traumatic brain injuries, so that will be included,
and I'll talk a little bit about this as well.
Okay.
So what I'm gonna have to do as we kick this off,
I'm gonna have to give you a little bit of vocabulary,
so you're gonna have to just hang with me here.
'Cause the problem is like when you blend fields together,
you get a lot of language that comes with it.
So I'll try to do my best to keep it digestible.
And then at the end when I'm done with my talk,
you can grade me
and you can tell me whether I did a good job or not.
But at a very high level,
there are sort of two distinctions.
There's something that we have referred to
as a primary injury and secondary injury
when it comes to traumatic brain injury.
I should say at an even higher level before that
there is a severity grading of traumatic brain injuries
that go from mild to moderate to severe,
and they're typically ranked on the Glasgow Coma Scale
that was developed many, many years ago.
So let's look in both neurosymptomatically,
how's a person responding after an accident,
and how is the sort of the state of health of the brain assessed
by something like magnetic residence imaging here, MRI
or CT scanning for example, in an ER.
Now in this case, when we talk about primary injury,
it's really immediate, physical damage
that is a result of that strike to the head,
a fall, an acceleration,
an explosion, whatever the cause was.
And it's a physical discussion, okay?
The secondary injury is the one that's much more subtle,
and it's a change in the chemistry of the cell, okay?
So this is something where yes,
there was a sudden mechanical change
in the environment of the cell.
The cell is being pulled or twisted or sheared,
but not quite enough to break it apart fully,
not quite enough to rupture capillaries or vessels,
but enough to change the biochemistry in the cell.
And when you do that,
you activate a whole bunch of chemical reactions in the cell
and then eventually, the cell comes to a decision point,
and the decision point is simple.
"Can I still repair myself, or am I past that point
"and I need to shut down?"
And when the cell decides to shut down,
we're following this classical cascade
of what we call apoptosis, in some cases also in necrosis,
it depends on exactly what chemical species are involved.
And that process, typically on a cell level,
takes about anywhere from 6 to 24 hours, okay?
But that's a single cell.
We have billions of them in our brain.
A single cell is gone, cells live within networks,
networks would give us function, cognitive function,
motor control, speech control, right?
So we may be losing a single cell there,
some rewiring of that network, restructuring,
maybe we'll never know.
If you lose enough cells within a network,
that network becomes compromised,
and then most certainly we will see a deficit.
Could be a cognitive defecit, could be a speech deficit,
could be loss of motor control.
We want to be very wary and aware of if there are changes
in the biochemistry internally.
So this is something where we have to track
both immediate damage given by the primary injury
as well as this developing secondary injury.
And there is some beautiful work that's actually being done
up at Boston University by a UW alum by the name of Ann McKee,
and she has really done some pioneering contributions
in this field.
There is an image right here, and what you're seeing is
these are cross-sectional slices of brain tissue,
there is sort of three rows.
The first one is a person
with no documented concussions or falls,
and you can see it looks clear,
and down here, are these sort of staining patterns.
That's something that would you expect from normal tissue.
The second two, the second and the third column
shows brown staining, and the brown staining here
is indicative of accumulation of a protein called tau.
Tau clinically is tied to a disease
or something called tauopathy,
which is involved in several neurodegenerative diseases,
including dementia, including Alzheimer's,
including Parkinson's.
Some of the links are still being worked out
exactly to what extent,
but that is significant levels of degeneration that happened
in these brains, and you can see here that the line is,
so this was an NFL linebacker who had eight,
and I will say eight reported concussions.
That's another really big thing, and I'll tell you
in a little bit too the problem with concussion
as a metric for injury.
We have another problem with that.
I'll just say it right now.
Diagnosis of concussion is neurosymptomatic, okay?
What that means is it relies on a doctor on the field
to run a number of tests to make an assessment
whether or not a concussion has happened.
That does not mean that physical brain trauma did not happen.
And in fact, a study published by Ann McKee's group
a few years ago showed that almost 99,
or a very high percentage of NFL players,
all had significant brain trauma,
which ended up manifesting itself postmortem
into what was known as chronic traumatic encephalopathy,
known short as CTE.
The problem with that is that it's something
that at current, we don't have the tools to diagnose
on the field, on the spot, on the fly.
So part of our effort here in Wisconsin
with the PANTHER program is to have this kind of diagnosis.
Is to say that like we don't wanna rely on
just the manifestation of a concussion
to tell us that a real physical injury
has happened to the brain.
The implication in the military realm is even more complex,
given the kind of workload that warfighters have to sustain
and the decision making process they have to do.
Again, there is significant brain trauma,
there was significant signs of CTE,
but only eight reported concussions, okay.
So there's definitely a problem with this.
It's a problem with the reporting in itself.
And so big part of what we wanna do with the research here
is we wanna move away from classification of injury
that's based on the symptoms.
We wanna go down and classify based on real structural changes
that happen at the tissue and the cellular level.
Okay, it's hard, it's a hard task,
a challenging task, but I think we're making good strides
to get there, okay.
So this just gives you an orientation,
so we're gonna be tracking this vocabulary,
primary and secondary injury, as we go along.
I wanted to introduce the protagonist of my story today.
The first one is gonna be, so the key player
that we spend most time thinking about,
and that is the neuron.
Again, the neuron and the neural networks in our brain
are one of the main units
that give us our cognitive abilities.
What you see here is actually,
this is a rendering of a real-life image
taken with a microscope in the laboratory.
It's color-coded for what I will show you later
is the level of compressive loading strain
during an impact, and you can see white colors
mean high values and darker colors mean lower values.
And when we looked at this, we wanted to understand
what does a cell see, what does a cell experience
during an impact, during a blow to the head?
So I'll come back to this, but this is one of our key players.
The other thing is the notion of what we call stress,
strain, and strain rate.
So a very simple, in very simple terms,
if you take a rope and you pull it, to pull a rope takes force
that you have to exert, like a tug of war.
If you divide that force that you're applying
by the cross-sectional area of that rope,
you get something that's called stress,
and it's a quantity
that any mechanical engineer works with daily
because that's how we design buildings
and how we design structures, cars.
Turns out biology and evolution is also heavily driven
by these terms of stress and strain,
and strain is nothing else but the resulting change in shape
that the force of the area causes, right,
so if I take a rubber band and I pull it,
the amount of force that I did in my hands
to pull a rubber band, give an extension,
and the level of extension
normalized by its original length is strength.
So it's a percent of shape change essentially.
And then you can imagine like in the complexity of the brain,
these things get a little bit more complicated,
and we try to make sure that we track that carefully.
But that's, so we wanna quantify the level of stress and strain
that's being loaded or that the neuron is subjected to,
and then we wanna track the biological response
of that neuron in response to that.
And the last thing that we have here is time, okay.
We wanna understand time, and time comes back to,
really the biology, it comes back to the chemistry,
the change in the internal chemistry of the cells,
chemical reactions, where we find if we have some time
before degeneration occurs in the brain.
Whether that's four hours, six hours, eight hours.
First of all, we wanna know about it.
Second of all, if the time is long enough,
it gives us a window of therapeutic intervention.
And what we show in the laboratory
where we have all the access in the world
because we get to play with the tissue directly,
we have shown that, for example,
one good intervention is cooling.
So if we cool these cells, we can actually like shut down
a lot of those neurodegenerative cascades.
How you implement cooling on a person and a human being,
that's a discussion and a question for another day,
but at least like we wanna understand the role of time
in the injury response of these cells.
Okay.
Now, the objectives here for us and again,
this is just bringing back what I've said.
It's, we wanna understand
what are the critical injury thresholds
in terms of the quantities of stress and strain.
In the laboratory, we like to work with strain
simply because it's a change in length, a change the dimension.
It's easier to measure internally.
In the olden times when you step on a scale,
what would happen is our weight compressed
or extended a spring.
And seeing that visually
is much easier than knowing what the spring constant is
and backing this out and calculating force and stress.
So we typically work with strength.
Models can help us to get the stress,
and then we wanna also understand strain of rate.
So that's the loading rate.
That's slower versus fast, right?
Is a slow fall or a slow blow to the head
versus a really fast strike to the head,
is one worse than the other?
And I'll talk about why that's important and again,
it gives us a sense of the physical scenarios
that are most injurious.
So we wanna look at that, and then ultimately
we wanna take all of this information
that we learn about the biology of the injury
in the laboratory and we wanna bring it back to the real world,
we wanna bring it integrated into a model
that can make predictions, right,
that can make predictions about when an injury might occur
and it can help us to design better materials
that would prevent it in the first place, okay?
So again, a lot of words here.
I'll keep it short.
The goal is to develop these critical injury metrics
that tell us when an injury occurs, okay.
So again, a little bit more vocabulary.
This is a schematic,
and I'll kinda walk you through it.
Some of this, the details here
are not as important as you know, the bigger pictures,
but here is a schematic of a sort of a cartoon person's
being subjected either to an impact to the front head
or a blast over pressure.
Again, this in the civilian world
is usually very rare to find,
but certainly a lot of veterans were exposed to this
during the wars in Iraq and Afghanistan,
and there was a lot of question what happened to the brain
in these cases.
When we think about the initial insult,
so if I were to fall off the stage and hit my head
on the floor, if you could slow everything down times
and had high-speed cameras to do slow motion, what you would see
is there would actually be a mechanical wave
entering my brain.
And if we think about this wave,
we can think about it in two parts.
We can think about one part.
So this is two potentials, so you can think of about one part
of mechanical wave energy that goes in,
it tends to distort the tissue.
It tends to really stretch the cells, deform it,
twist it, turn it.
There's another part that is the pressure,
and the pressure would just tend to compact everything,
and what we've seen in the recent literature is that
the pressure itself is not really that you know, injurious
until it reflects intercranially and it switches sides.
So instead of being compressive, it becomes what we call tensile.
And why is tensile bad?
Well, if you try,
if you take a liquid and lower the pressure,
you can form bubbles.
And the problem with bubbles and the brain
is that typically these bubbles, when they grow,
they displace the tissue around them.
So again, they mechanically deform the tissue
and that's not good, but it can get even worse
because when these bubbles expand and when they collapse,
they tend to counter a lot of their kinetic energy
into a single spot.
And that spot could be a spot,
it could be a jet, but this high energy content
can literally tear through tissue.
If you ever go to, if you go to the Web
and type in cavitation erosion,
the first picture that you see
are hard steel propellers of ships,
and you can see metal being torn out
by this exact process, a bubble forming and collapsing.
And so we wanna do a good job
and we wanna track these things.
The big difference for us as far as the brain is concerned,
this pressure-driven cavitation injury is very localized, okay,
to specific regions in the brain
that experience these tensile pressures.
This deformation-driven is much more widespread.
So part of the work that we do here
is we're trying to understand the pathology
of these measurements and see you know,
can we reconstruct an individual's?
Whether you know, one was more exposed to these pressures
or one was more deformation-driven.
It's complicated and we don't have a full answer yet,
but we do have good approaches in the laboratory
to isolate this,
and I just wanted to kinda put this out there.
Ultimately, as I stated in my objective, we want a plot that
looks something like this, right?
So there's green area, there's this red area,
there's this curve, this curve in between.
This curve in between tells you when injury occurs
and when injury doesn't occur at the cell level.
We wanna take the cell level to the tissue level
and then the tissue level to the whole brain level.
This curve right here, which right now the way it's plotted,
it's plotted strained magnitude right,
so how much you're changing shape,
how much you're stretching, deforming something
as a function of how fast you're doing it.
So if I show you this plot the way it's written right now,
it says that, and we find this in the laboratory
and we find this actually in the community too.
It's very interesting observation.
That is to say like when someone gets hit in the head,
you don't necessarily have to remove all
of that kinetic energy.
You don't necessarily have to shield the brain
from all that energy, as long as you can let some of the energy
enter the brain slow enough, the cells can respond.
And the simplest analogy I have to that
is if you're thinking about stepping up to bat
at a Major League game, right?
If you have a pitcher and the pitcher throws you
a curveball at 50, 60 miles an hour
and the ball is coming right at you,
you may have enough reflexes to step out of the way.
But when the fastball comes at 95,
at least if I stand at the plate,
there's no chance. [audience laughing]
I'm just gonna get hit.
So the loading rate comes into play
and when the cells have time to respond
to the change in that mechanical environment,
to that sudden stretch, they can react,
they can react internally,
and we can actually like,
they can actually take a good amount of strain,
and stress strain gives you energy,
so they can actually absorb a good amount of energy
without being injured or being destroyed.
But if that happens relatively quickly down here, and then,
you can see that that barrier is lowered significantly, okay?
So a lot of the work that we're doing now with the community
is trying to really hone in on what that shape of the curve is,
where is a crossover occurring,
and then you see, there's two color, two color demarcations.
So there's this darker red region
and there's this lighter red region,
and the difference between the two
is one is purely the you know,
the primary physical damage to the cells, right?
That's rupture, that's physical stretching.
And this other inner region,
that's the change in the biochemistry, okay?
That's that slow progress degeneration,
and we want to be able to track both,
we want to know what both are.
And then from an engineering prospective,
what we like to do is we like to develop techniques
and protective equipment that takes you know,
a scenario where an individual would be out here
and shifts them to the left, into the no injury zone, okay?
So that's the basic premise, I gonna show you the data
that we have today later on to build this curve,
but there's a lot more work needed to really get there.
Okay, so what I'm gonna show you now is a little bit of,
sort of a length scale evolution,
a little bit of a historical evolution here.
This video was from a collaborator of mine
at Brown University, who at the time
had a larger study with them that was sponsored
by the National Institute of Health,
with several colleges that set out on a very simple mission.
It was to say, let us take accelerometer-based sensors,
instrument our students with it in their helmets,
and track some of the collisions that they suffered
during practice and during the play.
In this video, what you see
is there's a Virginia Tech running back right here,
and then there's a stop, hard stop here
is a head-to-head collision, and there's an accelerometer,
acceleration time profile that's being recorded,
and at the time, the simple-- again this was in 2003,
so this was some time ago.
At the time, the thinking was if there was a correlate
between these numbers here and a concussion,
then we could start to make some predictions.
The problem was it didn't work.
And part of it, the problem didn't work
is because this measurement was too simple.
The brain is much more complex and again, as I said earlier,
like if I were to fall off,
there's this wave that enters the brain.
There's the pressure part that moves rather quickly,
and then there's sort of the tissue rate that moves slowly,
and you can already see these hot spots, right?
And these hot spots depend on the anatomy of the brain.
The hot spots depend on all the curvatures,
and they depend on the different constituents within the brain
and their mechanical properties.
So there's the geometry, the anatomy of the structure,
and then there's actually the mechanical properties,
whether something is soft or stiff in the brain.
And all those things matter in order for us to get a prediction
on whether we have an injury or not.
So just having a sensor out on the skull to say,
"I see a linear acceleration of 20, 50, 60 G,"
is not enough to tell us whether an injury has occurred, okay?
So in large part, what the community has been doing
since then, since 2003 and up to now is working on refinements,
trying to really better capture the biology
of the input of the brain and connect that with measurements
that we can do on the field.
So again, if we go through this sort of cascade and we go down,
again, there's a network level that I said gives us you know,
a cognitive ability,
but then there's these individual cells,
and particularly, like here we focus on the neurons.
The thing to keep in mind too is like,
to really understand the injury response of a neuron,
you have to understand the neuron's environment.
You have to understand how these cells connect
and how they talk to their neighbors.
And so for me, this was you know,
it was funny, like I got my PhD in 2008
and then I became a postdoc,
which is really when I got involved in this,
and I thought I was done studying and learning
and I just went right back being a student, okay?
'Cause I ran into this problem and I said,
"Look, like the way we think about the brain
"is not necessarily how the cells think about the brain."
Because the cells doesn't know there's all of us,
it doesn't know they're individuals.
The cells knows its neighbors.
It knows signaling, it knows action potentials.
It knows certain structures, and so for us to really be able
to understand how a cell responds,
we have to sort of go in there and understand the cell.
Okay, the next few slides gonna orient you on how we think about
and how we classify injury and neurodegeneration
that's due to a traumatic brain injury at the cellular level,
and what again, what I'm doing here, I'm dropping you down
in powers of 10 from the centimeter head scale
all the way down to the sort of atomic,
well, not atomic but cellular micro scale.
So we're going from centimeters
all the way down to microns.
There's a lot of pump date and color here.
So this is a coronal cross section of the brain
as a sort of inside focus around the corpus callosum,
you can see these sort of black spots.
Again, these are microbleeds,
these are signs of axonal or cellular degeneration
that happened post a traumatic insult to the brain.
And again, you can see the sort of in a more,
sort of larger scale tissue slides.
People will highlight
different broken structural components of the cell,
depending on what disease they're interested in, okay?
And so earlier I showed you work from Ann McKee
that's looking at this protein called tau
in the context of tauopathies.
Here, people look at amyloid precursor protein,
which is involved as sort of one of the hallmark proteins
in Alzheimer's disease.
What's interesting is like all these proteins initially belong
to the structure of the neuron, and they're in the right order.
When the cell gets impacted and when the cell breaks apart,
these proteins get released.
They get cleaved, and they accumulate in these patterns
that we understand to be hallmark features
of neurodegenerative diseases.
So part of it is the puzzle, trying to figure out
how did we get there,
and what does an impact have to do with all of this?
Okay, so to do this, we go down in scale.
In the laboratory, we work with microscopes,
so we tend to operate on a size scale
that's usually millimeter and all the way down
to about what light can allow us to see,
so that pushes us down to about submicrons,
so about a hundred nanometers in scale,
and when we look at injury at that scale
or we typically look for these sort of round blebs
that could form along an axon,
then the naive axon just looks very beautifully curved
and has none of these little blebs on it.
Once you see these blebs, these are essentially
like broken internal structures of the cell
and they're indicative of an injury.
Once the cell gets to this point, there's no,
there's no more return.
This cell will die.
And so this is the sort of hallmark feature
that we look for in the laboratory
that's indicative of a traumatic brain injury.
Okay, a little bit more about the cell
because it gets more complicated,
and you shouldn't be surprised as it's the brain
and the brain is very complicated.
This is a schematic again of a neuron.
You have to imagine this cell lives with millions of neighbors
and they connect, each cell has this long axon
and it has an axon terminal,
and that terminal will connect to these little spikes up here,
these dendrites for other cells,
and they form a large-scale network.
There's this different components,
there's these dendrites,
there's the cell nucleus that holds the DNA, and so you have
electrical connectivity of signal propagation
all the way through the axon into the terminals
to the dendrites, and then it continues.
Thanks to technology and really advanced imaging
and thanks to the neuroscience community at large,
we have a good understanding of actually the proteins
that make up most of these structures.
And that's kind of shown here schematically,
so we can zoom in on one of these structures
and it's actually just not a solid structure,
but it has many, many proteins
that have a very complex hierarchy that come into play.
The reason I'm telling you all of this
without going more in detail on that is to say
that when we apply a mechanical load of force on this,
we have to be aware of this.
We have to understand how these proteins get loaded
how to talk to one another.
It's the same thing when you build a house
and you all of a sudden see a hurricane sweep over it.
Whether your house falls or not
depends on how the house is built
and depends on what materials you used to build the house.
And the same is true for these cells.
And right now, what we do in large part,
we're trying to understand
if different types of deformation compression,
which is you take something and compress it,
shear, which is something that you would you know,
take and you sort of shear it along,
or tension and straight-up pulling,
whether any of these tend to be more injurious
to the naive structure of the cell or not.
And again, the reason why this is all important
is because there's alignment in the brain,
there is structure, and if we can understand this,
maybe we can make a prediction
that certain parts of the brain are more vulnerable
or more susceptible to injury,
or that certain parts for a given scenario
are more susceptible than not.
So there's a lot of things that we have to track, okay.
What I'm gonna do is I'm gonna take you in the laboratory.
This is gonna be so, to give you just an overview,
what I'm showing you here
is these are sort of the gel-like constructs
that we make, we use a mechanical scaffold.
That's extracted collagen.
We build these neural networks here in green.
You can see these networks that form in three dimension.
We have three-dimensional imaging modalities in the lab
that we can image them and we can track individual cells.
We can look biologically of all the different cell types
that are in these networks from neurons to astrocytes
to stem cells, progenitors,
again, a lot of details that we go through.
And then what we do is here.
So we mimic an impact that we can devise from the literature.
Again, this is typically for blunt, head-to-head collisions
on the order of milliseconds,
and if I play this again, which you can--
So over here is a real impact.
So in green are the neurons.
This is a small window, imaging window of a much larger sample.
You can see there's a compression,
compressive impact top-down.
In blue, I actually track a particles
that we can track in three dimensions
to map out the entire loading scenario around the cell.
We can take this information in high resolution,
we can reconstruct it,
we can look and see how the cell is connected to neighbors,
how it's connected to the tissue,
and essentially what we're going for
is we're trying to understand
how the mechanical forces are being transferred
from the environment onto the cell, okay?
And so there's, and then what we do is
there's a lot of imaging involved
that we have to go through.
It's interesting, like I showed this to you in one slide,
this took about six years to build, it took a lot of people
and it surprisingly took a lot of detailed information
from different communities.
So like I said, our background is in mechanics,
we did backgrounds in neuroscience,
but a lot of this imaging
actually came from computer science, computer vision,
like there's a lot of things that we had to do,
to implement to get to this point,
but ultimately what you end up with is,
and I'm gonna skip some of these details,
is a fully reconstructed depiction of every single cell
in this like thousands of millions
of network-sized artificial gel that we grow
where we can now do an analysis and we can understand
how these cells are being mechanically loaded, okay?
And remember, we do this all on the microscope live,
so we can do the scanning.
This is a quantification of the injury metrics that we do.
Again, I'm not gonna go through all the details.
Just suffice to say that if you can use
all of what you've learned in mechanical engineering
to predict failure in buildings and cars and planes
and you can apply it to this problem
to understand when these cells show damage and injury,
and then we can make correlations and predictions.
Again, I told you this is the sign of a traumatic brain injury
at the cellular level, and we can ask questions now.
When you see this, what was the critical strain?
What was the critical stretch at that point, right?
So we can make these correlations.
The interesting result that we found
is that shear seem to be very critical for these cells.
And it seems to be a critical threshold
to generate this kind of varicosities,
blebs that we find.
It was a bottom number of 14%, again,
there's a lot of questions that we're addressing
and refining, but what was interesting
was not all cells showed this sort of feature.
So we said, like "Okay, this cannot be the full story."
And so after a lot more other experiments,
what we found is like it turns out
that for these impact-like rates
that we generate in the laboratory, there seems to be
a critical sheer strain magnitude, about 10%.
Above, once you hit that mark,
then cells start to display this classical injury
of traumatic brain injury that you would see
that was documented postmortem in humans
as well as in animals.
The interesting thing is like,
this level of strain was actually like,
was the average strain across the entire set of cells.
So what this says in a nutshell
is that cells are very good at regulating their own chemistry,
but they're also very good at regulating their own physics.
And it is like you know, when you exceed this
sort of threshold, when a cell says you know,
"This is too much force.
"I can't take this anymore."
That's when it needs to shut down, okay?
We looked at the time window here.
There's a time of cell death
as a function of the mechanical loading.
We did some analysis here.
The big part is here that like we started to see
that there is a critical onset of strain
when the cells become injured.
We track the pathology over time points to 0 to 10 hours.
We can see, we can follow the degeneration of individual cells
within these networks live.
We can look,
we actually discovered a new pathology of injury,
which is at much slower loading rates.
So these are like really fast hits,
these are small hits, and I will say
we can reconstruct head-to-head collisions
from the playing field very accurately.
It's still a jump to understand
once the wave enters the brain,
what is the exact loading rate that the cells see, okay?
So that's something that we're still working on,
but for us it was we wanted to pick
the whole of you know, pathology atlas
of what the injury may look like,
so we found some interesting things there.
We can look at high-rate loading.
Again, this is now much, much faster,
and this comes back to the piece
I mentioned about cavitation and little bubbles in the brain.
This is a bubble right here that expands and collapses,
and the color coding is the level of strain that this bubble
is exerting the surrounding material.
Suffice to say this requires a whole 'nother set of experiments
and apparatus.
This event is typically over in about a hundred microseconds.
So a hundred billionth of a second.
It happens extremely fast and it's highly localized.
So my students right now
are looking at what the pathology looks like to this.
Here is sort of one final example
and then I'm just gonna wrap up.
So here, what you see in green, star-like,
this is a neural network projected all the way down
into a two-dimensional slice.
And right here is where a bubble formed.
It expanded and collapsed, and it was very violent
because all the cells are gone in the center.
And what was interesting is we can then go in
and use high resolution imaging,
and we can then look at individual breakdown
of these cells.
And with you know, working with other collaborators
that are very good at making models and theories,
we can actually map out what the strain is
as a function of this field.
We can map out what the strain is
that each individual cell sees.
In this case because you have a bubble here,
the strains for the bubble are very high.
The strains far away from the bubble are very low.
And you can see in the far field cells are healthy,
and very close cells are completely destroyed,
and this right here by the way,
this is all primary injury, okay?
So this is all physical, direct injury
because the bubble was pulling the material
as it was off splitting around.
And so what we're looking now
is like are is there any other activations
that happens you know, 4, 6, 8, 12, 24 hours afterwards?
In other models, tissue-level models,
you can look at inflammatory response,
so there's other things we can look at.
And just to give you a sense, again,
We're looking for pathologies right,
because when you do a postmortem analysis, one thing
that we already saw with the pictures I showed you earlier,
the fact that we discovered a new pathology
that was not centered around finding these
little ring-like spots was to say that if you look,
if you do a postmortem analysis on a human being
and you have to look for something,
for some features, right?
If you say "I wanna look for these rounded features,"
you may miss actually a significant amount of damage
that that individual sustained.
And so part of this what we're trying to do is
develop more complete pathology maps that we can map that out
and then map that back, okay.
And again, this is sort of like you can travel around.
Beautiful thing is that at this point in time,
we have a lot of imaging power at our disposal to do this.
These are not easy experiments.
And if my students were here, they'd probably laugh at me
because I'm making this sound so simple
when their everyday life is actually very difficult
in the laboratory, so. [laughing]
But I will acknowledge them later
because they really carry all the heavy load.
We can make predictions of how the strain, this blue curve,
how this strain drops off again
to identify critical injury thresholds.
What was interesting here is the threshold here
was also around 10 percent, so it was very similar.
So here I'm bringing back this curve
as my sort of final slide.
I can tell you kind of where we are with our injury prediction
based on the data we go on
that we take from the laboratory.
The green, this ciruclar point is our data points right,
so we can we can see here at very slow rating,
loading the cells to remain healthy and non-injured.
Once you move into this realm of falls,
motor vehicle accidents,
collisions on the football field.
You enter the injury realm, your strain level drops,
and then there is data points
from the literature that we could find,
whatever we could find that people reported well.
So this was another side note of what my students found too,
that often times we all, and by we I mean we as scientists
can do a better job in reporting what we actually do
when we write papers.
So often times it was hard
to do an apples to apples comparisons,
but there was some pivotal studies that we found
and we could put on this curve.
So you can see that's the curve.
That's the data points.
You can say like, "Well, you don't have nearly enough
"data points to make this curve,"
and you are absolutely correct.
So we have a lot more work ahead of us
to really figure out what the shape is,
but the hope is that we'll get there.
I think we'll get there.
I think we do have a good approach.
I'm gonna call us very much a work in progress.
We'll see what this brings,
but the good thing is we're very--
This lends itself into a form that it can be integrated
relatively quickly into a computer model
and make some predictions.
I wanted to talk about Rika's work a little bit.
I'm not really gonna have time to do this,
but maybe I'll share with you one slide.
So she's been looking at doing simulations
of rotations on the head.
We know rotations are very injurious.
She's been making connections to use some of this information.
She's been looking at rotations
around different planes of the head,
coronal, axial, seeing what's most injurious,
and I'd kind of just like give you a sense here
These plots where you sees it off the top levels here.
This is tissue-level strain,
which we know can be injurious,
so that's what we wanna look for
as a function of angular acceleration
and angular velocity.
So there is this question of like you know,
is it more injurious
if something happens really, really,
accelerates really, really quickly,
or if the velocity is larger,
so we're still trying to understand that.
One thing that I can tell you is that rotations to the head
that happen quickly and that are sustained are really bad, okay?
So part of it is, and again, this comes back to
how we think about it,
any situation where the head rotates, and we've seen
this now evidence from playing field from various sports,
so take football, take boxing.
And then we did, we looked at a study
with some collaborators at Stanford, who followed a cohort
of mixed martial arts fighters, and they looked at them
as well, and again, it comes all back to rotation.
Rotation, rotation, rotation.
There's critical rates at which
rotations really become injurious,
there's rates at which it's not.
I don't have final answers for you yet,
but this information is coming.
So if you're interested, ping us,
let us know, connect with us.
We're hoping to get some of these results
out into the literature within the next six months to a year.
So I'll leave it there.
So you can kinda see color coding here
is that you can see the red is,
so that is predicted injury
based on the tissue-derived injury model
that I just presented to you, okay?
So we have to do a lot of fact-checking refinements
and this is coming, but the foundation is there, okay?
The foundation is there to start to make this predictions,
and a lot of this what Rika is doing now with her work
is trying to just like get an intuition of like
what kind of motion is most injurious to the brain.
The great thing is with simulations and computers,
you can do that, you can explore that space.
So I'll leave it at that.
I'm gonna leave the summaries here.
I talked about them.
This is our program, please visit us.
We do have a news outlet page.
We're trying to get information pushed out.
We always welcome any input, any feedback
from anyone in the community, and I really, really--
This is the most important slide here for me
is to acknowledge all the great students,
everybody that's been involved,
all my former students, my current students,
and then my program manager at the Office of Naval Research,
who is a strong proponent for basic science
and basic research to really, to move this ahead.
And with that, I'd like to thank you.
- Woman: Hi, thank you, that was really interesting.
My question is not related to impact injury,
but to the injury caused by stroke.
And I was wondering if that lighter red curve,
if that's an area where the biochemistry of cell damage
and death could be applied to a stroke model?
Can you learn something from that to help people with stroke?
- That's a really good question.
It's possible.
I will say that the premise of that curve
is based on a mechanical origin, right?
So it's a deformation-based origin.
So in the short model, it just depends on how the stroke
is being induced at the level of the cells.
So you know, whether that's hypoxic or,
it just depends on the exact condition of that.
So maybe.
Which is-- [all laughing]
- Man: Is it known if the deployment of an airbag
in an accident has enough force,
the time and force is large enough to mimic a blast injury?
- Christian: It, as far-- - Man: So that you might be,
your life might be saved,
but you might have an unknown brain injury?
- Christian: Right, to my knowledge, it's not known.
And I think it's a very pertinent question,
and you know, you sort of touched on
a very interesting point right, like in the beginning,
a lot of safeguards that we have now
were put in place to you know, stop people from dying.
But then the second thing is like now that people live,
do they live with healthy brains or do we actually induce damage
by having too crude of a protection mechanism?
With what I think what you have is a good question.
So we're hoping that like once we have a better sense
of what kind of motion induces that,
we can come and look at that.
- Man: Excellent presentation, and my question
is related to soccer. - Christian: Okay.
- They do the heading, which is becoming so popular.
Has anybody tried to study it
and what-- well, people should be studying it
because they could start playing when they're very young
and they start heading
when they're about 10 or 11 years old,
and I think yeah, what do you know about it?
So thank you.
- So there are several groups that have looked at this.
The studies, it's had to draw conclusions
from some of these studies, in part
because we still don't know what really causes the injury.
So once we know what causes the injury
and what level of acceleration and strain causes the injury,
we'll be able to make better interpretation
of some of those studies.
I will say that like within the world of soccer,
the fact that the ball itself is fairly deformable,
it helps the cause.
So usually like as far as the studies that I've read,
where we find the highest concussion risk in soccer
is actually player to player collision
and player to goal post collisions.
Okay, so in those cases you have rigid skull against rigid skull
or rigid skull against you know, an aluminum post.
The heading question is a good question,
and I think, I am hoping that at some,
I'm hoping that within the next few years
we'll be able to really get to that question.
In terms of like,
how much attention is the community paying to it,
it sort of comes and goes.
There's a couple of studies that pop up
and then it sort of goes away.
It's marginally small compared to the studies
that focus on heavy-duty contact sports like football
or like boxing.
- Woman: My question is whether your model for the neuron
in the laboratory is assumed to be applicable equally
to adults and to children and to men and to women.
- That is a great question.
And the truthful answer is we don't know yet, right?
We have to keep in mind that the laboratory model
is still a very big simplification
of the real brain.
And I think that's a level of refinement,
that's a level of community engagement
that we will have to see.
I think part of the effort is that we come
and work on these problems together.
One of the things that we have sort of taken here is to say
that every cell is precious, right?
And so maybe initially, the thought is
that we over-engineer the protective solutions
and then we can refine.
In children, certainly the regenerative potential
is much higher.
So there's that aspect to it too.
People look at the state of myelination in the brain,
which also comes into play.
I have not touched upon this in this talk.
The point being is this is something
that we will look at,
and we will look at it more closely.
So it's on our to-do list, on our very long to-do list.
[all laughing]
- Man: We're out of time for today,
but I wanna thank everybody for coming out
on a very cold day. - Yes.
- And thanks to Christian for a wonderful presentation.
- Thank you.
[audience applauding]