[Rhonda]: So one of the probably most compelling lifestyle factors that at least from my reading, and certainly from research like yours, that seems to impact Parkinson's disease in a positive way, meaning decrease risk and also seems to be associated with, you know, modulating the severity of the disease is exercise. So there is literature that has linked to decreased risk of Parkinson's disease with people that are more physically active. Correct.

[Giselle]: That's correct. Exactly.

[Rhonda]: And I mean, exercise is pretty much...it's like a panacea. I mean, you're talking about decreasing the risk of Alzheimer's disease and, in fact, it's been shown to help, you know, with recovering from traumatic brain injury. In a way, Parkinson's disease is kind of like a traumatic brain injury, you know, like just extended out, right?

[Giselle]: Yeah. No. You're right.

[Rhonda]: That's not something that's just...

[Giselle]: Yeah. And I think that's also why... So yeah, so exercise, obviously there's a lot of interesting data, compelling data certainly from an epidemiologic point of view that it may lower risk for Parkinson's disease. I like to kind of think about exercise and lifestyle in general. Obviously we're going to talk a little bit more specifically about exercise. It's sort of the counterweight to everything we talked about before. So the idea that, you know, multiple things, genetic risk factors, environmental risk factors, and disuse, if you will, of lifestyle factors kind of contribute to brain injury, brain changes over time. So sort of an insult, if you will, to the brain that bring out diseases, Parkinson's is an example of that. And it sort of plays out fundamentally at a circuit level, meaning behavior is what is underlying circuitry. So if we see behavioral issues, then whatever that damage is occurring is happening because of synaptic connection losses, either physical loss or functional loss of connections, right?

So then you can think of lifestyle, exercise as an example, as sort of being the counterbalance of that, where whatever those mechanisms are, which we can talk about a little bit more detail are promoting, right? Are promoting these sort of synaptic connections, maybe keeping them healthier, facilitating them, or maybe driving some of these compensatory circuits that allow me to function day-to-day. So I think the kind of cool thing about exercise is to think about it in the idea that it is a type of counterbalance, right? And so, it may not be necessarily targeting every specific mechanism of every toxin or whatever those insults are. It provides a type of repair model that allows some type of resilience, so the idea of resilience. And I think that's important because it gets kind of to the idea of aging, if you will and these insults, if you will. As sort of a part of life, kind of a spectrum of life that is ongoing, right? So the idea is that we don't live in bubbles. We're always going to have some type of exposure.

So exercise and lifestyle sort of gives us this continual spectrum, if you will, of kind of a repair, ongoing repair, kind of the ongoing counterbalance that allows me to deal with this sort of better so that the modification and/or be sufficient enough for me to not even hit the threshold of the diagnosis. And what's interesting about that too, is there's also a bit of a disconnect, if you will, between the pathology load and some of these circuits as well, circuit impairment, for example, or circuit repair. I give the example of Alzheimer's, right, and amyloid. It's an example where people have looked at, for example, in the nun study where nuns had basically been given writing samples over time and showing, you know, their level of education and cognitive capacity, if you will, and yet having a fairly significant amyloid load.

So it makes you think about how much of whatever these lifestyle factors interact with some of these protein aggregates, Parkinson's being another one, either directly or indirectly. So, you know, it may not all be about removing protein load, but it's still able to do something beyond that in terms of maintaining some type of synaptic integrity or function. And I think it also gets back to the idea that when we think about, you know, kind of benefits of exercise, there still could be, even though I'm able to function better and stuff like that, it doesn't mean that my brain doesn't have some changes. You know, what I mean? So there could still be some evidence of injury. All I'm saying is that nothing's all perfectly lined up in terms of pathology, behavior, and circuitry. It's what we're trying to understand. So in the context of exercise, the model that exercise offers is sort of the counterbalance to all the injury side. So exercise offers us this model to understand all the reparative mechanisms, all the resilience mechanisms that we believe at the end of the day are playing out at a circuit level. Does that make sense?

[Rhonda]: Yeah. So basically, you know, what you're saying is that in a way that the exercise is activating all these resilience pathways, it's activating pathways that are involved in maintaining connections between neurons, making them stronger, and repairing damage, and, you know, just a variety of growth factors that are important for, you know, all these signaling. And so, because the... I mean, the exercise in a sense is a type of stress on the body. It's something that we actually evolved doing before we were in our, you know, industrialized society where we sit in our office and cubicles, we were out hunting, gathering, getting our food and moving a lot, right? We're moving. I mean, we're meant to do that. But it is a type of stress that activates all these resilience pathways. And so, in the face of another type of stress, whether that's Parkinson's disease or Alzheimer's disease, or just the stress of aging, you're going to be more resilient to that stress. Like you're going to deal with it better. You're going to have more of this brain-derived neurotrophic factor that helps repair damaged neurons than you would, you know? So even though you're not going to take away that challenge, the challenge will be there. I mean, we're all aging. You're just going to do it better because you have more of these, you know, resilient pathways that are being activated.

[Giselle]: Right. That's right. And so, in a way, it's sort of a continuum then. So then you kind of don't think of it as before the disease, during the disease or after... It's just always there. And so, you're kind of moving forward through an aging process with all these other risk factors happening that are causing, without a doubt, some injury at some level. And so, I mean, the importance of us understanding exercise as a model or a mechanism, it's really trying to understand better what the brain is capable of in terms of repair mechanisms. What are we really enabling there? You know, what's the counterbalance to injury that we're able to tap into that allows us to compensate at a significant level? And, again, Parkinson's disease, remember, I mean, think about that model itself. There's a threshold there. I mean, I've lost, you know, 40 percent of cells before, I'm showing functional impairment, right? So that's important because it gives us an idea that the brain may be able to tolerate some level of injury, if you will. And through optimization, you know, which we still believe has to happen at a synaptic level, because behavior is synaptic. So to get functional improvement behavior, you need something at a circuit level, right? So it's more than just cells. That's the other important thing here.

That's huge, understanding those reparative mechanisms. And so, I think for people in the exercise field, you know, obviously we're thrilled that we can, you know, be able to understand this better to enable people to do more things and to be more involved in their own care and these sorts of things. I think that other bigger issues, or kind of the field of reparative mechanisms itself it's sort of like, you know, we think about space as a final frontier, but there's so much we don't understand about how the brain is able to drive repair mechanisms. What's the limit of that, you know? Which is very interesting.

[Rhonda]: Yeah, absolutely. And not only just, you know, we're talking about exercise in a general term, but like the specific types of exercise, right? And how they're, you know, maybe differentially improving, you know, there's different repair mechanisms happening when you're doing a high-intensity interval sprint versus resistance training at, you know, 60 percent or 70 percent your max heart rate, or, you know, treadmill walking, and coordination. And so, there's all different types of exercise.

[Giselle]: Absolutely. Absolutely. So there's the issue of the different types of exercise and also kind of getting into that discussion, sort of underlying that is obviously the mechanism question, right? So are they doing something differential? Right? And I think the reason we care about things like that is because I think one of the general early concepts of exercise, in general, has been really more about the body's effect on the brain, you know, as though the brain is a passive recipient of all these sorts of benefits somehow, right? I think when we're teasing apart these different types of exercise, I think one of the questions that come up is we care about these different types of exercise because we do believe that there are certain circumstances where the brain may play a more active role, meaning it's driving some circuit-specific effect. And what I mean by that is this whole idea, for example, if I'm more engaged in what I'm doing, if I'm more top-down cognitively involved in my process of movement through space and learning something, that I may be activating certain circuits, right? And that activation of circuitry by virtue of using it harder may itself drive some of these benefits, right?

[Rhonda]: Can you give me an example of that type of physical activity?

[Giselle]: Right. So, for example, let's say something that would be more skillful, right? So where I'm actually having to get better at it, it's actually quite challenging. For example, I live in Southern California, so surfing, as an example, where I'm not only considering obviously how I'm balancing on the board, but I'm watching the waves, I'm thinking about my speed, getting up on the board, my weight distribution. So there's a lot of different things I'm thinking about as I'm trying to get better on that. I fall off and I do it again and getting through a lot of different practices. So it's a lot of practice, repetition, learning, feedback where I'm really thinking hard about what I'm doing. So that as a skill versus, for example, a stationary bike, right? Where I'm just moving, you know, just moving my legs, trying to get up to a certain speed, but maybe not having to think about balance as much, these sorts of things.

[Rhonda]: What would be an example for someone, for example, that has Parkinson's disease, they probably aren't going to be out surfing?

[Giselle]: So, an example, in other words. So tai chi or yoga, as an example, right? And boxing as an example.

[Rhonda]: So non-contact exercise?

[Giselle]: Right. But also even a physical, you know, many of the physical therapists, what they'll do, as an example, is just even gait and balance practice, making it harder. Anytime you're making something harder, more challenging, whether it's through balance, whether it's through weight change, through dynamic balance, working harder with dynamic bounce, speed, you get the speed up, you have to make them more accurate, all those sorts of things is going to make it harder for you. So the idea would be getting out of your comfort zone, problem-solving how to get more accurate, how to get that speed up, how to become more dynamic on that task. And as I said, that can be done even with a physical therapist working on gait and balance, right? That itself is going to be more skillful over time.