Hello and welcome to this video on Parkinson’s Disease pathophysiology by Soton Brain Hub.
In our Parkinson’s Disease anatomy video we looked at 3D representations of the anatomy
relevant to Parkinson’s Disease. In this video we will look at the functioning of these
structures, and see what happens to them in Parkinson’s Disease, explain some of the
symptoms along the way.
We will examine two important motor pathways in the brain, the Direct and Indirect pathways
and look at how these function in the healthy brain and then look at what happens during
Parkinson’s Disease. So in our last video we looked at the brain
from an anterior view like this, but to understand what Parkinson’s Disease does to the brain
we need a new model – not anatomically correct, but better for explaining pathophysiology.
So here we have representations of the Cortex, the Striatum, the Substantia Nigra, this structure
as a whole is the Globus Pallidus but for the Direct Pathway we are only concerned with
the medial Globus Pallidus, then we have the venteroanaterior and venterolateral nucleus
of the Thalamus, and the Motor Cortex. It is important to note that in our model this
is all on the left hand side of the brain- and remember that the left side of the brain controls
the motor function of the right side of the body.
We will be talking a lot about the actions of these structures on one-another. So it
is key to understand that these actions can either be excitatory, which increase the activity
of the structure being acted upon, or inhibitory, reducing its ability to function. In our video
green arrows will always be excitatory (think green for go!) and red arrows will always be inhibitory
(think red for stop!). Each arrow will be labelled with the neurotransmitter it represents.
So let’s start with the Direct Pathway. The Striatum projects inhibitory GABA neurons
to the medial Globus Pallidus reducing its ability to act. The action of the medial Globus
Pallidus is to inhibit the VA/VL nucleus of the Thalamus from doing its job. What is the
job of the VA/VL nucleus of the Thalamus? To send excitatory glutaminergic neurons to
the Motor Cortex to stimulate it. The Motor Cortex then sends projections via the Corticospinal
Tract to the muscles. So from this we can see that if we increase
the activity of the Striatum, it will inhibit the medial Globus Pallidus to a greater degree.
This will reduce the inhibiting effect of the Globus Pallidus on the VA/VL nucleus of
the Thalamus allowing the Thalamus to more strongly stimulate or excite the Motor Cortex,
ultimately allowing the Motor Cortex to stimulate the muscles more by creating more motor activity.
Now let’s see what happens if we reduce the activity of the Striatum in the Direct
Pathway. The reduced activity of the Striatum means that it doesn’t inhibit or supress
the medial Globus Pallidus as much allowing it to get on with its job of inhibiting the
VA/VL nucleus more. This inhibition of the VA/VL nucleus causes less excitation of the
Motor Cortex and ultimately reduced motor output to the muscles of the body.
So now let’s look at the effect of the Cortex and the Substantia Nigra on the Direct Pathway.
The Cortex sends excitatory glutaminergic neurons to stimulate the Striatum. The Substantia
Nigra also stimulates the Striatum in the Direct Pathway, but does so using Dopaminergic
neurons through the action of the neurotransmitter Dopamine at D1 receptors.
The effect of both is to increase the actions of the Striatum, allowing it to enhance its
inhibitory effect on the medial Globus Pallidus, thereby reducing the inhibitory effect of
the medial Globus Pallidus on the VA/VL nucleus of the Thalamus. This allows the VA/VL nucleus
to increase its excitation of the Motor Cortex, and leads to a greater motor output to the
muscles. But what happens in Parkinson’s Disease?
In Parkinson’s Disease there is a degeneration of these dopaminergic neurons which excite
the Striatum, so the Substantia Nigra is unable to stimulate the Striatum to the extent that
it used to. This causes the Striatum to reduce its inhibition of the medial Globus, allowing
the medial Globus Pallidus to more strongly inhibit the VA/VL nucleus of the Thalamus.
This reduces the excitatory output from the VA/VL nucleus to the cortex and so reduces
the motor output from the Motor Cortex to the muscles of the body. This causes hypokinetic
symptoms, such as Bradykinesia (or slowness of movement), one of the main features of
Parkinson’s Disease. We are now going to focus on the Indirect
Pathway, and aside from all the other structures we have already seen, we now have the Subthalamic
Nucleus added in. So this time, the Striatum projects inhibitory neurons to the lateral
Globus Pallidus. The lateral Globus Pallidus inhibits the action of the Subthalamic Nucleus,
which is to excite or enhance the activity of the medial Globus Pallidus. The medial
Globus Pallidus inhibits the VA/VL nucleus of the Thalamus which stimulates the Motor
Cortex. And the Motor Cortex provides motor output to the muscles of the body.
So if we increase the activity of the Striatum, the Striatum is able to inhibit the lateral
Globus Pallidus to a greater extent. This reduces its activity and so it inhibits the
Subthalamic Nucleus less, allowing the Subthalamic Nucleus to stimulate the medial Globus Pallidus
more. This increases the activity of the medial Globus Pallidus, making it inhibit the VA/VL
nucleus to a greater extent, reducing the amount the VA/VL nucleus excites the Motor
Cortex, and ultimately leading to reduced motor output.
The opposite occurs if we decrease the activity of the Striatum in the Indirect Pathway. This
is done by the action of dopamine from the Substantia Nigra acting at D2 receptors. The
Striatum doesn’t inhibit the lateral Globus Pallidus to the same extent, allowing it to
increases its inhibition of the Subthalamic Nucleus. This reduces the extent to which
the Subthalamic Nucleus can excite or stimulate the medial Globus Pallidus, reducing its inhibition
of the VA/VL nucleus. This allows the VA/VL nucleus to stimulate the cortex to a greater
extent and results in increased motor output to the muscles.
In Parkinson’s Disease however, there is degeneration of the dopaminergic neurons of
the Substantia Nigra, so there is reduced inhibition of the Striatum, allowing it to
increase its inhibition of the lateral Globus Pallidus. This causes the lateral Globus Pallidus
to reduce its inhibition of the Subthalamic Nucleus, leading to the Subthalamic Nucleus
stimulating the medial Globus Pallidus to a greater extent. This stimulation of the
medial Globus Pallidus allows it to inhibit the VA/VL nucleus more strongly, reducing
its activation of the Motor Cortex, leading ultimately to less motor output from the Cortex
to the muscles. This creates the hypokinetic symptoms we spoke of earlier such as slower
movements or Bradykinesia.
So there you have it, thank you very much for watching!
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