Basal Ganglia, Nigrostriatal Pathway and Parkinson’s

“Hope arouses, as nothing else can arouse, a passion for the possible.” William Sloane Coffin

“Walk on, walk on with hope in your heart, and you’ll never walk alone, you’ll never walk alone.” Oscar Hammerstein II

Introduction: I have been trying to learn more about brain physiology and the inner workings as it relates to Parkinson’s. To do this, the region of the brain known as the basal ganglia has been a learning point for me. One of the big issues motor-wise with Parkinson’s is that we have slow movement, well, the functioning of the basal ganglia explains it. Or should I say, the absence of dopamine in the basal ganglia provides us with the answer.

Remember, if you have Parkinson’s, we have all learned that our symptoms are caused by the loss/reduction of dopamine from the pars compacta region of the substantia nigra in our mid-brain. Okay, then what happens? Before venturing into the description of how the basal ganglia works, let me start by comparing the human body to an automobile. See if this analogy makes any sense to you.

“In a time of destruction, create something.” Maxine Hbowong Kingston

The Automobile in Comparison to the Human Body: The car I am getting ready to describe is an older model, like me, and the car of today operates slightly differently. However, the general principles are much the same.

•In my mind, a car is somewhat like the human body, and here are some similarities.
•The car engine is like the human heart.
•The gas tank holding the fuel in a car is like the bone marrow making blood.
•And the electrical components controlling the engine are like the basal ganglia of the brain.

•Some simple comparisons:
-Your engine stops running, for whatever the mechanical reason, and your car stops. Likewise, your heart stops functioning, you are not going very far.
-You run out of gas, your engine stops no matter how much power you have. 
Likewise, run out of blood from your bone marrow, you stop too.
-Faulty pistons in your engine won’t run as well; bad knees the same thing in a human.
-Timing bad in the electrical system of a car, spark plugs misfire, and the engines may not run smoothly or not run at all. Likewise, faulty wiring from a failing basal ganglia leaves one with an awkward step, prone to falling, and miscommunication between brain and body.

•I called on my expert automobile person, my brother-in-law Ed, and he gave me a detailed explanation of how a car used to operate and how it operates today (to read his wonderful description, **please read below at the end of the blog post). Why? He provides a detailed description of how the car engine functions (yesterday and today) and it is very interesting reading; however, I want you to focus on the below image.

Check out the image below and ask yourself the question, does this make sense to you? I think that the electrical system of a car, as it relates to controlling motion (motor function), is similar to the basal ganglia in the brain controlling motor function. Do you see my analogy? If an electrical system in a car misfires, the car still moves but it may shuffle and not drive smoothly; thus, it may not function in the way it was designed. In Parkinson’s, a dysfunctional basal ganglia affects movement because of the reduced amount of dopamine being supplied to that part of the brain. From here I can now present and try to explain, the more scientific explanation, of motor function of the basal ganglia.

“In a time of destruction, create something.” Maxine Hbowong Kingston

Dopamine: Parkinson’s is described as a process that leads to the death of dopaminergic neurons in the substantia nigra pars compacta. This loss of dopamine in the basal ganglia results in the motor dysfunction that characterizes Parkinson’s. The culprit of Parkinson’s is the result of alpha-synuclein accumulation and aggregation within dopaminergic neurons; these aggregates are named Lewy bodies (Diagram below shows a neuronal cell on the left, and red-deposits simulate the accumulation of Lewy Bodies on the right). There are clearly different genetic risk factors combined with environmental influences that promote the development of Parkinson’s. However, the reason why dopaminergic neuronal cells are the target of this pathological insult(s) has not been fully delineated.

The therapeutic goal for a person-with-Parkinson’s is to try to maintain what is left of these dopaminergic neurons by attempting to achieve neuroprotection of this critical part of the brain. Here is what is important regarding physiological function of the motor function of the basal ganglia.

“A leader is a dealer in hope.” Napoleon Bonaparte

Basal Ganglia: Basal ganglia circuits affect movements of the contralateral body. Contralateral is occurring on or in conjunction with the opposite side of the body. As shown in the drawing below, the basal ganglia is situated at the base of the forebrain brain and consists of four subcortical nuclei: striatum (caudate nucleus, putamen, and nucleus accumbens); globus pallidus (internal and external segments); subthalamic nucleus; and substantia nigra (pars compacta and pars reticulata; they are considered components of the midbrain). The basal ganglia nuclei help regulate movement, which increases and decreases motor activity, respectively.

“Never talk defeat. Use words like hope, belief, faith, victory.” Norman Vincent

Movement Powered Through the Direct and Indirect Pathways:  You want to grab a coffee cup off the kitchen counter, now what? Your basal ganglia takes over to manage movement, and it’s a complex series of excitatory and inhibitory steps. It starts when you decide, ok, time for coffee. The frontal lobes send an excitatory signal through glutamate to the striatum (see the below image). The striatum then sends additional inhibitory signals to the globus pallidus internus and the pars reticulata of the substantia nigra neurons. As a result, the globus pallidus internus and substantia nigra pars reticulata have lost their ability to inhibit the thalamus. The thalamus is now ‘uncoupled’ (or ‘uninhibited’) and is able to contact the cerbral cortex and says, we’re good to go, let’s move; and this signals the motor neurons down the spinal cord resulting in the desired movement.

The nigrostriatal pathway describes the link provided by dopamine between the corpus striatum and the substantia nigra. Dopamine comes from the pars compacta region of the substantia nigra. Dopamine binds to dopamine-type-1 receptors on the neurons of the striatum, which stimulates these cells. Thus, dopamine causes an increase in movement because it activates the striatum, and this is called the Direct Pathway. Remember, from the above discussion, and this inhibits the internal segment of the globus pallidus.

By contrast, the striatal neurons that support the Indirect Pathway project to the external segment of the globus pallidus. From there, they contact the subthalamic nucleus, which then project to the internal segment of the globus pallidus. In the nigrostriatal pathway, the striatum with D2-type-dopamine receptors receives inhibitory dopaminergic innervation from the pars compacta of the substantia nigra. Ultimately, the Indirect Pathway turns down the thalamus motor, and then follows the motor cortex; thus, motor activity is diminished.

Another Analogy- Think of a Train Station: Try to visualize you are trying to go from Point A to Point B, let’s say from Amsterdam Centraal Station, the Netherlands to Paris Gare du Nord, France. You find the right train, get in and go. But controlling the train moving, and controlling the complexity of the traffic arriving and departing, is a central hub and control office sending and receiving signals. In your brain, think of the basal ganglia receiving and sending signals to coordinate movement. The pictures below illustrate the train tracks, now imagine your brain controlling movement.

Recap of Events- The Loss of Dopamine Changes the Basal Ganglia to Reduce Motion:
•The effect of the dopaminergic nigrostriatal projection is to increase motor activity since dopamine excites the Direct Pathway and inhibits the Indirect Pathway.
•Thus, Lewy bodies in the substantia nigra reduce dopamine, altering both the Direct and Indirect Pathways to reduce motor activity.
•Unaffected by the loss of dopamine is the neuronal circuitry in the striatum of cholinergic neurons; cholinergic neurons inhibit the Direct Pathway and excite the Indirect Pathway. 
•The net result in the loss of dopamine is an overall turning down of the motor system due to the reduced activity of the Direct Pathway (turning on) combined with the increased activity of the Indirect Pathway (turning down).
•In summary, the function of motion through the basal ganglia and other regions of the brain is complex. I admire and congratulate all of the neuroscience experts who have spent their careers trying to understand how motion happens; and based on their work, I have tried my best to simplify its description here.

**Personal Communication From my Brother-in-Law Ed (an expert in automobiles; italics and bold added below for emphasis done by Frank):
“Your diagram is of an ignition system used in vehicles for many years but is no longer used. I very much like your comparison of the human body and a piston driven engine.  Never thought of it that way but it makes sense to me.

The vehicles today have no distributor  and normally have a coil for each spark plug.  That coil is located, generally, just over or very near the spark plug it fires.  In the diagram, the distributor has a set of points a condenser, and a rotor, all inside the distributor cap.  The distributor had a shaft going into the engine block and a gear at the end which was driven by another gear on the cam shaft.  When the distributor was properly set in place and adjusted the rotor would turn as the points opened and closed sending an electrical impulse to the coil, which greatly increased the voltage and then through the rotor to the spark plug wire for a cylinder as the piston moves into the proper position and the camshaft had opened the intake valve to allow a mix of air and fuel into that cylinder.

That fuel/air ratio was determined by a properly set carburetor (another part no longer used). The cam shaft was the part that controlled all of this action to get the cylinder to fire and drive the crankshaft. Then another cylinder would fire as the one before it and continue driving the crank shaft which powered the vehicle.

Now to modern vehicles.  The carburetor has been replaced by fuel injectors.  Some vehicle have an injector system mounted where the carburetor was and others have an injector for each cylinder.  The cam no longer drives a distributor ( some vehicles have 2 cams).  The sequence of firing today is determined by a computer and, multiple electronic components and the “timing” to fire each cylinder is driven by an electronic pickup which reads a signal as the flywheel turns.  All of the tuning is done by the computer and can change instantly depending on what the driver is asking the engine to do. i.e. go faster, slow down, pull harder etc.

Since the new vehicle is so complex I would stick to the old diagram you have as it was simple to adjust and repair, and more importantly, to understand.”

“I am not an optimist, because I am not sure that everything ends well. Nor am I a pessimist, because I am not sure that everything ends badly. I just carry hope in my heart. Hope is the feeling that life and work have a meaning. You either have it or you don’t, regardless of the state of the world that surrounds you. Life without hope is an empty, boring, and useless life. I cannot imagine that I could strive for something if I did not carry hope in me. I am thankful to God for this gift. It is as big as life itself.” Vaclav Havel

References used in writing this blog post:
Albin, R. L., Young, A. B., & Penney, J. B. (1989). The functional anatomy of basal ganglia disorders. Trends in neurosciences, 12(10), 366-375.

Bergman, H., & Deuschl, G. (2002). Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back. Movement disorders: official journal of the Movement Disorder Society, 17(S3), S28-S40.

Lanciego, J. L., Luquin, N., & Obeso, J. A. (2012). Functional neuroanatomy of the basal ganglia. Cold Spring Harbor perspectives in medicine, a009621.

Obeso, J. A., Rodriguez-Oroz, M. C., Rodriguez, M., Lanciego, J. L., Artieda, J., Gonzalo, N., & Olanow, C. W. (2000). Pathophysiology of the basal ganglia in Parkinson’s disease. Trends in neurosciences, 23, S8-S19.

Rommelfanger, K. S., & Wichmann, T. (2010). Extrastriatal dopaminergic circuits of the basal ganglia. Frontiers in neuroanatomy, 4, 139.

Smith, Y., & Kieval, J. Z. (2000). Anatomy of the dopamine system in the basal ganglia. Trends in neurosciences, 23, S28-S33.

Cover and other photo credits: Cover Image by kordula vahle from Pixabay. Man walking in Amsterdam train station Image by Rudy and Peter Skitterians from Pixabay. Amsterdam train station image https://www.pxfuel.com/en/free-photo-jgbmd.