Consequently, the motor thalamus is released and fires action potentials that
then trigger the output of the motor cortex.
So this is what happens with respect to the motor programs that we actually
intend to activate. Well what I want you to appreciate is
that There is a, a large surround of possible movements that could interfere
or antagonize the desired motor program. So, while we have a specific program in
mind to activate. Bait.
We also want to enforce the suppression of all other possible motor programs that
pertain to the same musculoskeletal units.
And this is where this concept of surround inhibition I think might be
useful. So we can think of this surrounding
repertoire of movement that we want to suppress.
As being under the influence of the indirect pathway.
And that surround comes in play schematically by this[UNKNOWN] .
So we imagine that there is a kind of movement surround being represented in
the thalamus that we want to suppress. With this activation of the indirect
pathway. So, if anything, to facilitate the
specific expression of movement, we want to make sure that nonsynergistic
movements or antagonistic movements. Are held in check.
So, the activity in the indirect pathway then, serves to reinforce this inhibition
of this surround of potential movement. And that's where the subthalamic nucleus
comes in. So, when we activate the indirect
pathway, we are driving the subthalamic nucleus to increase the inhibitory output
of this internal segment of the globus pallidus.
So this center surround model I think is, is a useful way of considering, how is it
that we can execute a very particular movement Like a visually guided reach.
So as I'm expressing this, sort of, reaching and pinching motion, I'm
supressing all other kinds of activities that potentilaly could be done with the
same muscular skeletal units, and so the focused activation of a very particular
motor program Requires a shift in balance in favor of the direct pathway for this
particular motion, and the suppression of all the other unwanted movement programs
that potentially could interfere with the goal of the behavior.
Now, I want to apply some of these concepts to some of the disorders of
movement that you'll see clinically. And as I've suggested in our opening,
there's really a continuum of movement disorders.
On one end of the continuum we have disorders that produce too little
movement, and on the other end of the continuum are disorders that allow too
much movement. So I want to begin first on the
hypokinetic side of that continuum. And used a rather familiar example
unfortunately. And that's Parkinson disease or
Parkinsonism which refers more to the symptoms associated with idiopathic
Parkinson disease. So those symptoms involve a reduction in
movement. Or perhaps, even a cessation of movement.
We call this akinesia or bradykinesia. It involves a highly rigid posture, that
rigidity is not exactly the same thing as the spasticity that's seen with damage to
upper motor neurons. Rather, it reflects a suppression of
movement. That is reinforced by the over activation
of the indirect pathway. Somewhat paradoxically, there is a
resting tremor that's seen in Parkinson's Disease, particularly in the hands.
Sometimes this is called a pill rolling tremor, as if The hands of the patient
are trying to roll a pill in the fingertips.
But sometimes, the tremor can be a little bit more approximate.
And can be expressed at rest. So it seems somewhat paradoxical that we
might have a slowness of movement or an absence of movement together with a
positive sign like a tremor. But it reflects the activity that is
disordered in different parts of the basal ganglia.
Well, the bradykinesia doesn't only affect the appendicular movements that we
do with our limbs. But it also affects our facial
expressions. So, people who are afflicted with
Parkinson's disease. They tend to have a reduction in facial
expressions. So with the problems attending
bradykinesia it's not surprising that there would be disorders of gait.
And there's a very characteristic gait pattern that's seen in people with
parkinsonism. It is a shuffling of the feet with very
small steps. And very little elevation of the foot
above the walking surface. So, one of the characteristic signs of
Parkinsonism is difficulty initiating and terminating movements.
So it's very, very difficult to get a motor program started and then once that
program is started It's difficult to terminate it precisely.
So we can think of this as a real challenge in shifting from one mode of
program to another. From go to stop and to go again.
Eventually there are changes that afflict not just the motor system But other parts
of the brain as well, so quite tragically, advanced Parkinson's disease
often leads to the development of cognitive decline and dementia.
Now in idiopathic Parkinson's disease, we typically see these symptoms setting on
after the fifth decade of life. So, the underlying neuropathology that
makes it appropriate to consider this disorder here, in this discussion of the
basal ganglia, is that in Parkinson's Disease, there is a loss of these
dopamine neurons that are so important for regulating the balance between direct
and indirect pathways. So in order for a patient to present
clinically they need to lose some 75- 80% of the dopamenurgic neurons.
So sot here is a bit of redundancy built into this dopamenurgic system thankfully
but nevertheless with loss of these dopamine neurons beyond that critical
threshold one can see the development of the signs and symptoms that I just
described for you. So, let's look at the circuitry of the
basal ganglia and consider the consiquences of losing this input from
the Substantia nigra pars compacta. What we would find is the inability to
facilitate the activity of the direct pathway.
And then inability to supress the activity of the indirect pathway.
These two factors synergize in a rather unforturnate way that results in an
increase in the tonic output Of inhibition from the internal segment of
the global pallidus to the motor thalamus.
So, the problem in Parkinsonism is bradykinesia.
A slowness of movement, an absence of movement.
That's because the motor thalamus is tonically suppressed, and it's very
difficult to overcome that suppression. As a consequence, there is decreased
excitation of the motor cortex. And tremendous difficulty initiating
movement. So now, let's back up into the basal
ganglia, and see why that would be. So if there's too much tonic inhibition.
That suggests that the activity in the eternal segment of the globus pallidus
is, is too high. And, again, the reason why it's too high
is that we have a severe reduction in our ability to inhibit the inhibition.
So we have a failure of disinhibition. matters are made worse by the absence of
dopamine on our d2 receptors. Which means that we cannot suppress the
activity of this indirect pathway. So we have a lot of inhibition coming out
of the indirect pathway which will shut down the external segment of the globus
pallidus and that means that it's likely that we will have disinhibition.
Of the subthalamic nucleus. So the subthalamic nucleus is the main
culprit here because it's driving the increased tonic outflow from the internal
segment of the globus pallidus. Well, really the principal culprit is the
loss of these dopaminergic neurons. But we can see the importance now of the
subthalamic nucleus in modulating the output of the basal ganglia, because if
we cannot reduce the tone of the subthalamic nucleus we will see a marked
elevation in the inhibitory output of the internal segment onto the thalamus.
The end result of all of this is bradykinesia.
Perhaps even akinesia. Well thankfully collaborations between
basic scientists be they neuroscientists or biomedical engineers and the clinical
communities have led to the development of new interventions.
One that I would invite you to read more about is deep brain stimulation.
Now, the idea with deep brain stimulation is to stimulate strategic locations in
the circuitry of the brain that will produce a desired clinical outcome.
Now, one might imagine that stimulation means an increase in excitatory activity.
For the neurons at the tip of the electrode, but that isn't necessarily the
case. What we see with deep brain stimulation
is a change in the firing patterns of circuits.
So in this illustration we see patterns of activity recorded in the basal ganglia
prior to turning on the deep brain stimulator.
During stimulation, there is obviously an increase in activity, but really
fundamentally a change in the pattern. And this change in the pattern of
activity in the circuitry of the basal ganglia seems to be what allows for the
normalization of motor function. So, there's a lot of[INAUDIBLE] .
There's a lot of ongoing study of deep brain stimulation, really trying to
understand what we're doing, are we driving expiatory output, are we
inhibitory input, are we just adding noise to the system, or are we
depolarizing the tissue at the tips of the microelectrods to the point where the
insodium channels are inactive and the signaling is lost.
Well, I think we're probably doing all of the above.
And the point is that it need not matter. that we target one particular type of
physiological effect. What really matters for the patient is
whether there's freedom of movement. And the goal of deep brain stimulation.
Is to normalize patterns of activity in the basal ganglia to facilitate the
expression of movement. And, thankfully many people around the
world have been helped with this technology and I want to encourage you,
if you have access to YouTube or other social media outlets.
to go and look at some of the stories of these people who have volunteered their
stories and videos of their lives to share with the world.
And many of them are just really wonderful personal stories of triumph.
Unfortunatly, this approach doesn't work for eveyone.
And so we need to be cautious. We need to recognize that this is an
invasive prodcedure. it has risks involved.
And not everyone can be helped. So, as sort of my colleagues in neurology
here at Duke like to say, that deep brain simulation is not going to cure
Parkinsonism. But what it will do is it will increase
your level of function if you are afflicted with the disease, and together
with pharmacelogical approaches, behavioral approaches, excercise deep
brain stimulation might actually be an important adjunct to a more
multidisiplinary approach to intervention.
