Self-administration – 2

The Substantia Nigra Story

In the previous post we looked at the practical aspects of taking levodopa. We saw that it was important to have stable levodopa levels in the brain and that timeliness was important but that presents difficulties for everybody.

In this post we will learn more about how the nervous system works and what we are trying to achieve with Levodopa.

Fundamental Concepts

A muscle can only contract and not push. So muscles always come in pairs. One to pull the pull the muscle to a position x say, and a matching muscle to pull the muscle back again.

The one muscle has to relax while its partner is contracting otherwise the would be competing against each other.

In practice they are often working at the same time to ensure a delicate maneuver. For simplicity sake we will illustrate the action as a simple, single command being sent to the muscle.

But usually a complex pattern movement involves several muscle pairs, as well as visual and auditory information. Much of the work will be done without involving the cortex, the thinking you, where you decide to play C.

The Motor Pathways

It will take too long to describe these pathways in text. You can watch Armando draw it on video. People have different learning styles, I like to visualize things. So when I teach a complicated topic, I end up making sketches and would often fill the whiteboard with my drawings. My students loved it, but the would ask me to tell them in advance how much space my illustration would take so that they could allow space in their notes 🙂

I tried doing it with Word. I can do very fancy things with Word but it it still takes too long. I discovered Armando on YouTube, he likes to explain things visually like I do. So I add a link to one of his lectures on YouTube. His style is good but I would have emphasized different aspects of neurons that are applicable to the points I’m trying to make. UI hope you’ll find his talk useful.

You will notice that many neurons connect to various other neurons, but in essence the command originates from the Cortex and eventually goes to the muscles via the spine or brain stem.

But strangely, there is a set of neurons, that come and connect to the main pathway neurons almost like an afterthought. These are the neurons from the substantia nigra. They are not part of the main pathway but they are there to ensure smooth movements.

Feedback Loops

To understand the use of levodopa it is useful to take a look at feedback loops. I was watching the war in Ukraine on YouTube. There were tanks rushing across the field shooting at each other. This would make a good example. The one soldier says “enemy at 11 degrees west” So the turret has to turn through 11 degrees and fast because the enemy is shooting!

However the turret is made of special fortified steel and ways 5 tons – no soldier is strong enough to move that by hand. Instead the gunner has a dial which he turns to 11 deg. Then powerful motors kick in and starts moving the turret.

Attached to the turret is an electronic device to measure the position of the turret. The turret position is fed back to the control box and as soon as it reaches 11 degrees the motors are told to stop. But you don’t stop 5 tons just like that and it overshoots and the motors kick into reverse to try and stop the momentum and bring the turret back. The result is the turret oscillates several times before settling down at the dialed-in 11 deg.

That’s very accurate, but it is not so great when the enemy is shooting at you and you have to wait what feels like an eternity for your turret to steady before you can shoot back.

Fortunately the tank designers knew that this was a common problem with feedback loops, whether in military equipment, industrial systems, and indeed also in medical systems.
You want the system to reach a setpoint as quickly as possible (in our case 11 deg) as quickly as possible so you increase the system gain (really powerful motors in our example). Then the overshooting of the setpoint happens. What you need to do is add some dampening, in our case shock absorbers. With just the right amount of shock absorbers, the turret will move smoothly and fast to the setpoint and come to controlled stop at the setpoint of 11.

1) In powerful control systems if you have sufficient damping your system would move fast to the setpoint and smoothly come to a stop at the setpoint.

2) Not enough damping and the system would still move to the set point accurately but would oscillate a few times before settling down.

3) Low or no damping the system would move to the setpoint, overshoot, move back and overshoot in the opposite direction and end up oscillating continuously!

Try driving your car over a corrugated road surface with worn shocks, your wheels will oscillate out of control and it would be difficult to control the car.

Likewise try painting details in the watercolor painting that you are working on, when the damping in your hand’s control system is low – your levodopa medication has not kicked in – you will be very frustrated!
If the levodopa comes totally late, the damping drops too low and the hand oscillates – the tremor is back!

The neurons that are located in the substantia nigra are different in many ways from their collegues. Their task is to produce dopamine so the ganglion (also called the substantia negra, not fancy names like the other ganglions) where the dopamine is made, is placed a bit out of the way.

Why is that? Because in free form dopamine is toxic to neurons!!! Yes, toxic means it will kill you. Like eating toxic mushrooms, it will kill you.

Melanin is used during the manufacturing process to prevent the neurotoxicity. The melanin gives the ganglion its name of “black substance”. Because it was located out of the way it was often spotted first during necropsies. The researchers had no idea what they were for, stuck away here at the back of the brain so they simply called it the black stuff, in latin of course because then it still sounded smart.

Too hot to handle
The dopamine is produced in the cell body of the neuron and then packed into very small packets or vesicles and then safely transported down the tube (i.e. the axon) to site where it is to connect to in the striatum, either a D1 or D2 receptors. It is only when the vesicles are at the synapse, that the dopamine is released from the vesicles.

The dopamine is released in a very confined space but there still is a mop-up crew (enzymes) on the ready to clean up and recycle any spills or excess of dopamine. Understanding the function of these enzymes are very important as they have an important influence on the timing of the medication delivery and the effectiveness of the treatment. Its a big subject and we’ll discuss the work of these enzymes in more detail later in separate document.

At this point I need to make the point that this long discussion is to show that self-administering of my medication is medically an incorrect approach and even dangerous.

To conclude the self medication story there is one more short page to read…

Pathways for more detail.