Parkinson's Disease: How is the brain affected?

Introduction

In this article  we will look at the functioning of  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. 

Pathophysiology:

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 .

Medial Globus Pallidus:

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. 

Action of the structures:

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. 

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. 

Direct Pathway

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. 

Job of the VA/VL Nucleus of the Thalamus:

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. 

If we Reduce the 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. 

Effect of the Cortex and the Substantia Nigra on the Direct Pathway:

So now let’s look at the effect of the Cortex and the Substantia Nigra on the Direct Pathway. The Cortex sends  the excitatory glutaminergic neurons to mainly  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.

What Happens in Parkinson's Disease:

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. 

Indirect Pathway

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. 

If we Increase the Activity:

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.

If we Decrease the Activity:

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.

Conclusion:

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.