Translator: Elena McDonnell Reviewer: Peter van de Ven
I would argue that a lot of us spend most of our time learning.
From the very early days of our lives, we start by learning to walk, talk,
and with years of painstaking effort,
we even become amazing artists,
athletes who outperform any possible imagination,
and scientists and engineers with creative minds,
which makes the world that we live in
as interesting as we have seen.
However, when a brain disorder strikes,
we take an absolutely devastating setback
which most of us never recover from.
It's not a matter of effort,
where no matter what you do,
most of us can never get back to all the painstaking-effort achievements
that we achieve throughout the life.
World-class athletes can no longer walk,
and the most beautiful minds find themselves unable to conduct
the most basic daily routines of life.
Why is that?
Why is it that still, to this day, we remain in this really dark age
where we cannot do anything about these neurological diseases?
One possible explanation for this
is that we have been completely ignoring
one very important fact about the brain,
which is that it is a circuit.
In many of our efforts to attack neurological disease
we have ignored this fact, putting us, possibly, in this situation.
With the amazing developments in science over the past decades,
where for example, with the Human Genome Project,
we now know a lot about all of genes in our body,
and with subsequent developments in molecular and cellular biology,
that also is now equipping us with a lot of knowledge
on how all of the cells in our body work.
However, in the context of the brain,
one of the most important things to know
is the status of your neural circuit.
Your main goal in maintaining brain health
is to keep the neural circuit function in this normal range.
There are many reasons why we might get kicked out of this normal range,
where it might be genetic predisposition or your lifestyle or injury, infection,
and even just aging by itself.
And some of the efforts to return back to the normal range can include
removing the cause that took you out to the brain disorder realm to start with,
but actually, removing the cause may not necessarily bring you back
to your normal circuit status.
It's also important to remember that you might have to do something else
in order to take you back to the normal range.
But importantly, in order to achieve this task
of getting your neural circuit function back to the normal stage,
you need to know what that is.
Without having the knowledge of your circuit function and your goal,
it is very difficult to achieve that task.
And so in short, if we can find what is wrong with the brain circuit,
we can fix the brain, possibly, like we readily fix electronic circuits.
However, if you currently go to the clinic,
you will find something very far from such systematic approach.
There is very little that they can do to measure your brain circuit status,
largely due to technological limitations.
The only place where you might find a brain circuit function measurement
is in an epilepsy clinic where they use EEGs,
which are electrodes that you place on the skull
to measure the electrical activity of the brain.
And while you do these measurements in the state-of-the-art clinic,
what the doctors would do is look at the lines like these,
that show the electrical activity,
and the doctor would just sit there for hours
trying to detect abnormal events,
and also, possibly, trying to imagine
what that might mean in the context of your circuit dysfunction.
Obviously, this is a very difficult task,
and there is very limited information that comes out of this.
Interestingly, despite the fact
that our ability to understand the circuit status of the brain is so limited,
one of the newest and most promising therapies for brain disease
includes neurostimulation therapy.
Neurostimulation therapy
is where you place electrodes directly into the brain and pulse currents
in the hope that you can normalize the circuit function.
It's a direct electrical intervention that truly recognizes the fact
that the brain is in fact an electronic circuit.
One of the most amazing accomplishments of using neurostimulation therapy
includes the fact that one could arouse patients
that were in a minimally conscious state for over six years,
by using electrical stimulation.
The patient could wake up from a minimally conscious state
just by pulsing the electrical current,
which is an amazing accomplishment.
However, when you do something without knowing exactly what you are doing,
there are many problems.
It's been difficult to replicate that outcome,
and in other scenarios,
you also find that the same kind of therapy you apply to the disease
sometimes makes the patient better
and sometimes even makes the patient worse.
Why is that?
Imagine trying to fix your electronic circuit.
All of you, who don't necessarily know how the circuit is working,
are trying to zap it into life, back again.
If you are lucky, it might work.
And if you try hard enough many times, you might get lucky,
but obviously, this will be a very difficult task.
The reason why, so far, we have been doing this in a trial and error fashion
has been largely due to, again, technical limitations.
In my laboratory,
we recently tried to solve this problem by combining new technology
that allows us to individually control different neuronal circuit elements
while also doing high spatial resolution imaging
to see what the consequences of different manipulations are.
And in this example, we stimulated the central thalamus,
the area that was stimulated for arousing the patients from the comatose state,
and in one case, when we stimulated them at low frequency, 10 Hz,
you could see that the subject actually loses consciousness,
while if you just simply change the frequency of stimulation
to high frequency, 100 Hz,
the same subject now gained consciousness.
It's a remarkable difference in an opposite-polar spectrum.
And what you can see by directly observing what the brain is doing,
you'll see that this is indeed due to the fact
that the brain network responds in a completely different way.
In the case of a 10 Hz stimulation,
you can see that large areas of the brain are inhibited,
denoted by the blue colors,
and in the opposite case, where it's stimulated at high frequency,
large areas of the brain are recruited, as you can see with the red-color video.
And because of the fact
that high-frequency stimulation recruited really large areas of the brain,
this functioned as a boot-up circuit,
bringing you back into an aroused state,
while in the other case,
your sensory areas were inhibited where you were losing consciousness.
And as you can see, by directly observing
what circuit intervention does and what the underlying mechanism is,
you can now understand
how the circuit can be intervened to obtain the desired outcome.
And further, taking this technology
and adding computational modelling approaches,
what we've been able to do is understand what the circuit's algorithm is
underlying different units of behavior.
In this case, we are manipulating a very important circuit,
a very important cell type implicated in Parkinson's disease.
And by selectively modulating this cell type,
you can see that there is increased movement in the rodent here,
with clockwise rotation.
And that particular behavior, we can pinpoint to an algorithm you see
where different parts of the brain engage functionally,
where they talk to each other to generate these movements,
where now, we can start to build building blocks
of how different behavioral units are controlled by the brain.
We talk a lot about the complexity of the brain.
The brain consists of a hundred billion neurons;
it's such an impossible task;
we still need to learn more and more about it
to do anything about the problems we face.
We may need to be able to construct
all the different kinds of activities of the brain,
counting every neuron and being able to record from them
and learning about their activity -
those are all very helpful information
that will help us get closer to getting a complete understanding of the brain.
However, now, by having these different building blocks
of how different behavioral units relate to an algorithm,
we can start to make sense of the circuitry
without even having a complete map.
When we build skyscrapers,
we don't necessarily solve all the differential equations
for every single element in the building.
We do that by understanding specific organizational principles.
Now we have this level of understanding where we can start to build on it.
And to take this principle into the clinic,
we have started to build platforms
where we can now take circuit information from individual patients.
In this case, you can see familiar lines that you saw in earlier EEG diagrams.
Now, we can take these EEG,
make automatic detection of various events,
and then, from these significant events that you are interested in,
you can build maps of how the circuit functions,
you can directly visualize the dynamic changes
throughout the brain network
and also construct diagrams of how they are interacting with each other.
And we can now do this in live patients for every individual.
And by being able to understand the individual patient's brain network,
we can start to customize and address them
in a way that we might fix electronic circuits.
And so, now, by having this level of understanding,
we can start to imagine a future where we can take data from the clinic,
provide individual-level diagnosis of what might be going wrong
in each one of your brains,
and based on this circuit knowledge,
we can also optimize therapy from whatever is currently available.
Even though we don't have a cure for any of the neurological diseases,
there are many different therapeutic options that are currently available
that we also have trouble applying to patients
because of the fact that they are mostly done in a trial-and-error fashion.
But now, with the information on the neural circuit,
you can start to give accurate predictions on how the patients will respond
and optimize it for the individual patients.
Some of these therapies are very invasive. They're surgical options.
And currently, patients are told that you have run out of non-invasive options,
and so it's up to you to try whatever is available.
That's a very brutal choice for patients.
Now, by being able to provide systematic information on your circuit,
whether a certain therapy is indeed restoring your dysfunctional circuit,
you can make accurate predictions.
Furthermore,
by building individual brain profiles of each and every one of the patients,
we can, for the first time, have a clear understanding
on how different parts of the circuit are malfunctioning
in the case of a neurological disease.
And once you have this,
we can think of a completely different approach to developing therapy
for brain disease.
Now only cellular, molecular mechanisms are targeted,
and when you design things like neurostimulation therapy,
they are being tried on a trial-and-error basis.
We don't have to do that anymore.
By having an approach that's systematic,
that corresponds to something like fixing electronic circuit,
taking a new stance,
we can completely change the landscape.
Watching friends and family who suffer through neurological disease
is one of the most heartbreaking and devastating experiences one can have.
The fact that you cannot do anything
is something that makes us all despair.
However, we are now starting to see light.
We have now learned how to make building blocks of solutions,
and we have a clear direction.
Once we have some of these building blocks in place,
we can imagine building skyscrapers.
And so, we will work hard to achieve this goal
and to be able to take us to a new era
of directly fixing neurological disease soon.
Thank you very much.
(Applause)