[Rhonda]: So thinking about what's actually, you know, causing Parkinson's disease, you're talking about this overlap between the cognitive issues and the motor dysfunction. And there may be like, you know, a big connection there. From what I, you know, read is that, you know, Parkinson's disease is associated with a loss in the dopamine-producing neurons in the substantia nigra. And I had read somewhere that like you lose anywhere between 50 percent to 80 percent of them before you actually have a clinical manifestation. Is that...

[Giselle]: Right. So, you're right. I mean, so the idea is that there is a special phenomenon with Parkinson's, and essentially, dopamine loss is a big component with the manifestations of Parkinson's disease. We think about is actually about 40 percent. Forty, let's say to 50 percent cell loss and 60 percent to 80 percent dopamine loss. So there's a bit of a disconnect between the amount of cell loss and dopamine depletion. And the reason that's important to say it that way is because the idea that Parkinson's is cell loss, for sure, but it's also cell dysfunction. So remaining cells that are still there are also having some problems as well. And that that's important because it may play out in terms of some issues that happen over time with how those remaining cells handle dopamine. Things like wearing off and dyskinesia and these sorts of things that manifest later on may have some role to do with cell dysfunction as well.

I think the other point to bring out is, you know, we tend to think of the behavioral features of Parkinson's disease as sort of being this one-to-one with dopamine cell loss, the idea of being like, "Oh, you know, I've lost another cell now I have tremor." You know? So I want to clarify a couple points. So dopamine loss is clearly important, but what we're recognizing more and more is that behavior, at the end of the day, it's circuit, right? So the idea is that dopamine is actually impacting circuitry. So when dopamine loss occurs, one of the fundamental things it does is disrupt circuitry, and it's that disruption of circuitry that causes behavioral problems. So where is the circuit problems that are underlying these behavioral issues? Well, we can take the motor circuit as an example. And in the motor circuitry, we know that there's a couple big areas of circuits that are involved in motor control.

The biggest one we talk about is that of the basal ganglia, right? So the basal ganglia to the cortex, corticostriatal, and that's essentially responsible for what we call automaticity, automatic movements. So this is movements that have been learned, practiced over time. I mean, so you don't come out of, you know, mom's womb, like walking around and dancing, right? So you have to practice this over time. And so, there's this element of practice, multiple practices that get you good. Dopamine is actually important for facilitating synaptic plasticity there. And there's a couple of forms that are developing in that striatum. LTD is the predominant form that's thought to be occurring there in the striatum, particularly in motor control. The issue though is that fundamentally, it's practice. So it's practice with dopamine as an enabler. So when dopamine levels are dropping, you're losing functional and physical connections, and we see that. We know that that's happening.

So the behavioral issue is probably that, the circuit itself. Now, the reason we care is because there are other circuits involved in motor movement moving through space. And one of those things is a frontostriatal circuit, as an example. And I'm going to kind of keep that simple because there's other circuits, you know, interacting with the prefrontal or frontal system. But the idea behind the frontostriatal is sort of volitional movement, so my ability to kind of update movements, my ability to move into new spaces, and actually my ability to learn new movements. So that's sort of what we call a volitional aspect of movement. So, you have the automatic movement, you have the volitional acts of movement, and they're happening together all the time. Right? And so, if I'm losing my automaticity, if I'm losing that circuit hard because of dopamine depletion, I can compensate. I can absolutely compensate by kind of adapting towards a more volitional type of movement.

And if you ask patients with Parkinson's, they all do that. They'll tell you, "I have to think more about movement." And so, the reason that's also interesting is because that same circuit, many of those same circuits have sort of dual behavior. I mean, it has a cognitive-behavioral aspect of it of what we call the executive function, which is planning, processing, all those sorts of things that you're also kind of doing day to day. So there's sort of a saturation effect happening here. I'm now dependent on it more, and I'm also using it to plan my day. So is that sort of the tipping point right there? I've saturated and now that I can't do it anymore, now that I can, you know, it doesn't take much for me to fall because now I'm using it already, all cylinders are firing and now I have, you know, now I have to hold plates and walk to the kitchen or something like that. I kind of supersaturated that frontal system, and now I'm falling, right? So that's why this whole idea of compensation and threshold, if we bring it up to the circuit level, that may also begin to explain this, if that makes sense.

And finally, on the back end, the idea of the world of cerebellum. So the cerebellum also plays a pretty important role for motor control, for motor planning, has a cognitive aspect to it as well. And the idea here is there's a lot of good data that shows, for example, in Parkinson's models, that when we have an animal, just in the beginning aspects of learning exercise, that cerebellum is on fire, it's lit up like a light bulb. So we have two other circuits that are trying to, what? Adapt. And so, these are kind of principles what we're going to talk about in just a bit, but the whole idea of what neuroplasticity is in the fundamental aspects of brain change and homeostasis, which is reaching a new level of balance or homeostasis so that the brain can function, if you will. And what's interesting about that is that you begin to see like those are all sort of contributing to the Parkinsonian features, right? So the dopamine depletion with the loss of automaticity and then these other compensatory circuits, is that good or not good? Is that contributing some symptoms or not contributing to some symptoms?

So brain changes that happen in the brain because of injury or in this case dopamine depletion leads to a lot of adaptation, some of which is good in terms of behavior and some of them may not be desirable. So it has a kind of an interesting concept for the point of view that it may be accounting for some of these compensatory strategies, it may be allowing for some threshold. At the same time, it may be causing some problems down the road.