An overview of the relevant aspects of the epidemiology, clinical presentation, basic disease mechanisms, diagnostic approaches and treatment options of the most common neurological diseases.
Module 3 Part 2: Brain Activity During Seizure
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Из курса от партнера University of California, San Francisco
Introduction to Clinical Neurology
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Epilepsy & Neurodegenerative Diseases
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Daniel Lowenstein, MDProfessor and Vice Chair, Department of Neurology
School of Medicine
S. Andrew Josephson, MDAssociate Professor
School of Medicine
Wade Smith, MDProfessor
School of Medicine
Okay here, here we go with module two.
So now that, here the question is, what is happening in the brain
during a seizure and what are some of the factors that affect network excitability?
So here's the set, here's the abnormal EEG that we captured in a patient with
epilepsy, and as, as we saw, filled with all kinds of rhythmic spiking activity.
And now we're going to literally, as I said before, dive in to what's
going on, with these spikes.
Well, with the discovery of, of, of this
type of abnormality, it was just a matter of
time, the development of techniques, that scientists were
a, a, actually able to do extra cellular recording.
Of neurons directly in the neocortex and in using animal models,
they were able to record from groups of cells, using an extracellular electrode.
A, and what you can see, the recording showed these wh,
what appeared to be kind of burse of high amplitude electrical activity.
With time again, further development of
techniques, intracellular recording became possible and here
you can see the electrode has actually popped right into an individual neuron.
And imagine if you will that this neuron is sitting
within a seizure focus, we're now able to then see
the actual electrical activity from an individual neuron within a seizure,
and again, what you can see is this high amplitude electrical activity.
That's, that occurs.
And just by stretching out the timescale, scientists were able to dissect the part.
What the components were of these bursts of activity from an individual neuron.
And this is shown here,
now the timescale, as you can see, is spread out.
This is about, that bar there represents 40 milliseconds.
And you can see a pattern of activity that really is characterized by
a series, or a train, of a burst of electrical activity.
Now, by using various tools, by being able to analyze the different receptors and,
and channels scientists have been able to really dissect apart
what gives rise to this abnormal activity that occurs in an individual neuron.
First of all, you can see that there's relative depolarization.
And that's due to glutamate being released
at the synapse, and activating the AMPA receptor.
With that, or following that, with that depolarization,
glutamate then actually acts on the
NMDA receptor, that causes even more depolarization.
And then there are voltage sensitive calcium channels that are opened.
And this gives rise then to a increase in
calcium in a cell that causes a wave of depolarization.
A long term wave of depolarization and if you can imagine, as the neuron
reaches threshold because of this depolarization.
It then sends off a train of individual action potentials.
And that's shown here.
With time, in addition actually it gets initiated and that's
through the GABA receptor, as well as voltage sensitive potassium channels.
So here you have it.
This is what the behavior is of an individual
neuron that's participating in a seizure within the human brain.
And this, this abnormality, or this
abnormal behavior that was described now many
decades ago, is referred to as a
paroxysmal depolariz, depolarization shift, or a PDS.
It's a depolarization of an individual neuron driven
in large part by calcium going into the cell
that has super imposed on it a chain of action potentials.
And with this I, I think now you have what you need
in order to visual what's going on in, in, in the brain of a person having a seizure.
If you can imagine a network of neurons.
That are creating a seizure, creating that spike on the EEG.
And now picture
what each one of those individual neurons is doing.
They are having these PDSs that, when you collect together as a population,
give rise to the abnormal electrical activity that we recorded on the EEG.
So this allows us to define what a seizure is.
A seizure is a paroxysmal or sudden derangement abnormality of
cerebral function that's due to uncontrolled,
excessive discharges from a group of neurons.
And what I have depicted here, in the cartoon, again, is
a population of neurons, each of which is having a PDS.
It's not as though they're occurring all at
exactly the same time, it's just that they have
to be time locked enough to occur within a
close enough time time period that as a group.
They give rise to the
excitation that can be detected by the EEG.
And that actually gives rise to the abnormal brain activity that
leads to the seizure and the, and the associated behavioral components.
And ultimately, it really comes down to being a mixture of hyperexcitability.
As well as hypersynchronization. Okay?
You got that?
Okay, so now let's, let's talk about the factors that affect network excitability.
It, well, up, up until now I've sort
of l, laid the groundwork for what's happening in
a network when a seizure occurs, but let's step
back just briefly and ask well, why is it?
How is it that a network goes from being normal to being abnormal in
the setting of seizure activity and to put it in an over simp, and immediately
over simplified way we generally think that it is a change in
the balance, the normal balance between inhibition and excitation in the brain.
One that of course then would favor more excitation,
that kind of hyper excitability, that's the basis of seizures.
Now, what are some of the factors that could affect network excitability?
Let's consider again, in pretty simple basic way, the network
that we're talking about, I'll just start with individual neurons.
So here is, you know, our prototypic neuron
that pyramidal cell that we were looking at before.
Just think for a moment, what are the factors
that govern the normal excitability of an individual neuron?
Well, could be things like the the density of, of ion channels.
Where the receptors are located?
What the second messenger
system properties are within the cell?
How much turnover there is of a variety of molecules.
Including those ion channels and receptors.
The concentration of ions inside, relative to outside the cell.
Determined, in part by ion pumps and so forth.
Any of these things could alter the relative
excitability of the neuron and therefore our potential
causes of a change in excitability that
could increase excitation of that individual neuron.
So that would be the characteristics of the neuron cell.
Then of course a neuron doesn't live or exist in isolation It's part of a large
neural network, and here I've drawn in one
interneuron, of course there are a gazillion of them.
And the input from the interneurons can actually affect the excitability of the
circuit, both the intrinsic properties of the
neuron, the interneuron, as well as the
nature of the synapse that it's making on its target.
And just as, again, one example, imagine if the input from this interneuron was
altered so that it was more distal in the dendrites of this pyramidal cell.
You can, you can picture how that would
alter the relative excitability of now this simple network.
And, finally, there are lots of other cells in the brain.
Most notably astrocytes for example.
And astrocytes, have a tremendous amount of, of, of control over
the excitability of, of networks, both in terms of their own electrical properties,
as well as their control over the, the, formation and uptake of neurotransmitters,
control over the extracellular MLU, and, and, and many other aspects.
So, this simple exercise is meant to just allow you to think what are the different
ways that network properties can be altered, again,
to create an increase in excitation relative to inhibition.
Having considered the factors that can, can lead to alterations in network
excitability I'm ready to cover the
definition of the other two important terms.
So, so the first one is epilepsy. When we use the term epilepsy, we mean
that we determine that the patient has a tendency towards recurrent seizures.
Now importantly, what this means is that if a person has an
individual seizure, a single seizure it
doesn't mean that they necessarily have epilepsy.
Its only if they have recurrent seizures or the
circumstances are such that we conclude that there's a very,
very high likelihood of having recurrence that we use the term epilepsy.
And I think it's really important to be clear
about the difference between the term seizure and epilepsy.
Because epilepsy, in particular, is still associated with a great amount of stigma.
Something that we really need to try and remove worldwide.
But it's a term that should really be
designated only for the person who has the more
chronic condition of a tendency for having recurrent seizures.
And then the third term is
epileptogenesis, and that's the sequence of
events that takes a normal network, and turns it into the hyperexcitable network.
And in the previous slide we covered
some of the different characteristics that could
be altered, say from a genetic point of view or from trauma and so forth.
That could, that could cause epileptogenesis.
Now that leads of course to what the different causes are, of epilepsy.
And I've listed them, in a very, very short list here.
We're going to return to this when we talk about
the, evaluation of a patient, with seizures and epilepsy.
But just as, just to give you a sense on brain injury.
Someone who has had trauma or stroke, you could imagine how
that could change the intrinsic properties of individual cells or alter
the way they're connected together leading to hyper excitability.
Same thing with tumor, the effects of a tumor either the, the, the molecules that
it produces in a neighboring region or the scaring that's created in in the brain.
Or other factors can lead to hyper excitability.
Genetics, a very important cause of seizures and epilepsy.
Imagine if the the, the gene
coding an individual ion channel leads to a significant change in its
function so that, for example, much more sodium is flowing into the cell.
Giving rise to more depolarization of an excitatory neuron.
This would be a cause of epilepsy.
Developmental abnormalities in the way the brain has developed in
utero can lead to an altered network and hyper excitability.
Infection and the inflammatory factors
that are associated with that can lead to hyper excitability.
And finally, a whole variety of
both endogenous and exogenous metabolic changes which
again would effect the properties of the brain giving rise to hyper excitability.
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