Rhonda: Hello, everyone. I'm sitting here with Giselle Petzinger who is a clinical neurologist who specializes in Parkinson's disease. She is at the University of Southern California where she splits her time between clinical care and research. One of the reasons I reached out to Giselle is because I'm particularly interested in some of her research on the role of exercise in Parkinson's disease.

Giselle: Excellent.

Rhonda: So, can you talk a little bit about what Parkinson's disease is maybe just from a like basic standpoint?

Giselle: Absolutely. So Parkinson's disease is a progressive neurodegenerative disorder. It's a disorder that affects individuals that are over the age of 50, generally speaking, so we consider it a disorder of aging. And generally speaking, we think of Parkinson's disease as a problem with mobility. In fact, clinically, that's how we tend to recognize it. And most people, when they're trying to...or feeling that something's changed, it's often because of mobility problems. And what I mean by that is slowness. People will describe feeling slow or dragging a leg and/or stiffness. So it has a kind of, as I said, kind of a motor movement, big strong moving component. And then, of course, there is tremor. I think one thing though, that people, in general, don't realize is tremor isn't necessary. So tremor definitely brings people in to see a neurologist, and certainly, it can be Parkinson's disease, but tremor can have other causes besides Parkinson's.

So generally speaking, it's really more, I would say about the slowness and the stiffness, and it can affect any part of the body, meaning it can affect the legs and therefore cause slow walking, as an example, but it can also affect the hands and arms where people can actually feel that they can't use the arm as well, they feel that things are taking longer to do. And sometimes that might even be associated with some pain, an element of pain. So as I mentioned, Parkinson's is sort of recognized as a motor problem. What we're realizing and recognizing more over time is that there's what we call a non-motor issue, many non-motor related phenomenon that occur. And some of these non-motor phenomena can occur even before the motor and people don't connect it necessarily with Parkinson's. Examples of that may be loss of smell.

Now, again, some of these other features are not specific, so none of these are specific. We're kind of evaluating everything together, but the non-motor features, as I said, could be the smell, changes in smell. Other non-motor, so that means things that aren't affecting mobility could be mood, for example, so anxiety and depression. In fact, we're now realizing or recognizing...there are a number of papers that have come out now years ago, that anxiety and depression may even predate motor symptoms by two years. And that anxiety and depression may manifest in functional things like not being able to drive in a car on the highway, feeling really anxious about that. And even family members may comment that the person just seems a little bit more depressed. So those things are now really well appreciated and recognized.

Other things that are non-motor that again may precede the motor features are even what we call the autonomic nervous system. So the autonomic nervous system is part of the nervous system that involves or innervates smooth muscle. So this is things like your gut, your heart, your sweat glands, and those smooth muscles are a part of your, as I said, your gut and your blood vessels, when they're not acting normally or behaving normally, it can cause disruption in your gut like constipation. So constipation, again, in retrospect, we find people may have problems with constipation even before they describe and note problems with movement. Blood pressure, changes in blood pressure may be dropping in blood pressure or heart rate abnormalities because of changes in the innervation to the heart. These are all kinds of examples of non-motor that aren't necessarily specific to Parkinson's disease, but kind of come together...once we see the motor features, we can say, "Oh, yeah, before that there were these other sorts of non-motor features that were really predating it." So the point is, is that Parkinson's is certainly more than that. And we're appreciating that more.

And then finally, I would say now, really coming out in the forefront again, even more, is the cognitive issue of Parkinson's. And I think what we're recognizing is, again, cognitive issues are pretty predominant in Parkinson's. The literature's sort of all over the place, but essentially, they are reporting about 40 percent even upon diagnosis may already have some cognitive issues. Now, that's not the same thing as dementia. So this is called mild cognitive impairment, and mild cognitive impairment is defined by the idea that a person may be noticing some memory-related issues or their family members are noting that, but they're not functionally impaired, meaning they could do all their ADLs but they themselves are noting this. And we can actually pick that up on some diagnostic testing as well.

So these things, again, happen quite early. There's some understanding of why this may be happening but they're certainly part of Parkinson's disease. And also the idea that they are very much interrelated. So motor and cognition probably have some relationship too in terms of the idea that cognitive issues can sometimes contribute to more motor problems or cognitive issues can contribute to more mood-related issues. So they're not really separated. They're very much interrelated and we're beginning to understand how and why that may be happening either from a neurochemical point of view or from a circuit point of view. Yeah.

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.

Rhonda: Right. Yeah. Definitely. You're kind of touching on things that seem to be important with exercise and practicing certain type types of goal-based sort of exercises, but I kind of wanted to ask you a little bit about before we get into that, just, you know, how many people, I mean, worldwide, in the U.S. have Parkinson's disease and maybe some of the environmental versus genetic causes of Parkinson's disease or what we know, what the field knows about that.

Giselle: Right. So, I mean, I think in general, so the idea is that 1 in 100 over the age of 50 have Parkinson's disease and don't know the exact number.

Rhonda: So it’s the second leading neurodegenerative disease behind Alzheimer's?

Giselle: Second leading. Yeah. Definitely the second leading. Right. Behind Alzheimer's. And I think in terms of genetics... So, in general, we think that genetics play an, you know, certainly there are genetic risk factors, but in terms of strong genetic contributions, most of that data seems to be in young-onset. By young onset, I mean, younger than 35, for example. Not as common over the age of 35, although now certainly we're recognizing that there are these risk factors like LRRK2, for example, where there may be running in certain ethnic groups where there may be some higher predisposition.

Rhonda: LRRK2 is a gene.

Giselle: Right. LRRK2 is a genetic mutation. But still, in general, I think the idea is that most of these genetic predispositions are happening in younger-onset people and that in the older, and again, older being anybody over the age of 35, as an example, or over the age of 40, at least, that there's probably a mix between as, you know, environmental and genetic factors. And we've heard that again by some work by a number of very important investigators who've been able to show us, you know, some of that epidemiological data, which is the idea that there's been some higher risk in rural settings than in urban settings, the idea that environment does seem to play a role. And so, in general, we would say, still in Parkinson's disease, that it is sort of there's a number of different risk factors. Some may be genetic as we get older, those genetic influencers may have some specific role in certain populations in general, but that we would say that it's environmental risk factors and maybe even things that play a role in genetics that are related to metabolism, how we metabolize, for example, herbicides. And also the other genetic aspect of it is still questions related to, you know, plasticity itself, repair mechanisms, is another example.

So you can see that it gets complex pretty fast in terms of what genetic risk factors may be and what environmental factors may be. And I guess the point is people are beginning to recognize that Parkinson's may be kind of a common final pathway of a number of different mechanisms, which kind of makes it challenging in a way because trying to isolate every single one of those targets can be hard because there may not be one single risk factor, for example.

Rhonda: Right. Exactly. Yeah. I was talking to you a bit before we started rolling that basically the field seemed to really advance back in the 1980s when, you know, this precursor to a neurotoxin, MPTP was, you know, like found to basically cause parkinsonian symptoms in people, I guess, chemists that were synthesizing it, or even I think IV drug use.

Giselle: Yeah. The IV drug users. Chemists seemed to not get the problem, but the IV drug users, right? Exactly.

Rhonda: And basically this, you know, this neurotoxin essentially inhibits mitochondrial function and it crosses the blood-brain barrier. It can, you know, affect all sorts of, you know, brain regions and dopamine neurons. But the thing that was very disturbing was the similarities between some of these insecticides and herbicides, like rotenone and paraquat that essentially have the same mechanism of action, also can cross the blood-brain barrier and are used in animal models...

Giselle: Exactly. They're very effective, aren't they? Yeah. I think the thing about it that, you know, obviously that the finding of the MPTP in the 1980s, so to clarify essentially what happened was in the 1980s, there was a sort of an outbreak, if you will, of Parkinson's and what was so unusual about it is that these particular individuals, and there were about eight individuals that say that presented around the Bay area in various emergency rooms had essentially developed parkinsonian features overnight, and nothing like that had ever been seen. And there was sort of some really interesting investigative work that had been done to try to identify what was the commonality between all of these individuals and what they found right off the bat was they had been heroin users and that they had gotten some access to some, you know, synthesized heroin, essentially that had been tainted with this protoxin, if you will. So MPTP is sort of a protoxin. It gets delivered to the brain and there it gets converted to MPP+.

But in essence, they were not aware, of course, that this was in the kind of the heroin itself. And it had been synthesized inadvertently by these chemists because they had changed the kind of the protocol, if you will, in how they were synthesizing this compound by changing the temperature. Simply changing the temperature of the reaction had brought out this particular toxin. And when they injected it directly into their vein, they essentially blew out their nigra, so killed dopamine cells. And we know that for a fact because for some of these individuals who passed on, the brains were looked at, and also they had gained access to some of the same material and used it in primates and were able to see replicate, Parkinson's essentially be able to see that they had killed cells that caused dopamine depletion, that it disturbed circuitry, and that it caused motor impairment like Parkinson's disease.

So the difference was this was acute, right? But I think what was so important about that was that, one, it created a model that we could study, two, it validated the whole idea that there are environmental products or environmental exposures of toxins that could absolutely contribute, right, to a neurodegenerative disorder. And so, that kind of reconfirmed this epidemiological data that rural aspects of where you live may influence, you know, or contribute at least to this kind of disease of aging, may be accelerating it, or certainly in this situation, bringing it out even faster. So, you know, again, affecting how fast people may get it.

Rhonda: Right. You mentioned earlier how there's a, you know, probably a lot of combining factors, perhaps additive, in some cases, you know, so you may have higher exposure to some of these pesticides, if maybe you're a farmer. In fact, farmers have been shown to have a higher incidence of Parkinson's disease if they're working with paraquat. So, you know, in combination with other things, maybe being sedentary and having a lot of inflammation, and just like the, you know, the perfect storm of environmental factors that can, you know, increase your risk.

Giselle: Right. Exactly. And I think that's the point. It's hard to, you know, necessarily always pick out one thing. And what happened to that MP..., you know, obviously would tragically happen to these individuals, fortunately, we've never seen an outbreak like that since then, you know? But it does sort of point out the idea that, you know, right, that there may be a contribution of things either over time or a number of different risk factors that can certainly contribute to this. Right.

Rhonda: I think with those two, in particular, those two, you know, rotenone is an insecticide and paraquat is herbicide. And I know that rotenone I think is really only used now in the U.S. to kill fish, like a piscicide or something. I don't know how much of it's in the water. I mean, it's kind of like, you know, all these things to think about. But paraquat, I think it's like pretty much phased out. It's restricted use in the U.S. maybe in developing countries and stuff. But, you know, the question becomes, "If I have a, you know, my produce is not organic, but I'm exercising and I'm, you know, I'm avoiding refined sugar and I'm doing everything else. Maybe it's not such a big deal. I don't know. Maybe I have a genetic risk factor, maybe I don't." There's a lot of things to consider. Maybe you don't want to have a complete fear. I've decided I'm eating organic just because I do eat a large quantity of them and some, you know, but blending them in smoothies and stuff. But, you know, it is one thing to consider of many different, you know, possible risk factors.

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.

Rhonda: So the skillful exercise that you're describing, it seems really independent of talking about something else which would be the intensity of your exercise, the vigorousness, like that's another aspect. What you're talking about specifically has to do...I mean, you're getting some physical activity, but it's a very specific type of activity where you're focusing on something, you're getting that feedback of learning, and, you know, you're basically engaging your brain a lot more than just like...

Giselle: Right. And I think fundamentally, you're sort of getting at the two kind of discussions that are going on with exercise. Actually, there's other discussions with muscle resistance and those sorts of things. But I think fundamentally, some of the questions that are coming up are intensity in the context of learning. Someone is learning. More about motor learning, right? Which definitely requires lots of practice and challenge to get good, right? Like tennis as an example, right? And the other type of intensity was the heart rate, getting your heart rate up, feeling your heart pounding in your chest, and sweating. That's also intense. So they can both be very intense, but for different reasons, right? So one more from the aspect of learning and practice and problem-solving to get better at something from a physical point of view. So things can be very physically challenging to learn, you know, like skateboarding, or tai chi, or yoga.

And Parkinson's disease, the bottom line is their gait isn't normal. The balance is not normal. We're starting all over again. So this is not normal walking, right? And this is not normal dynamic balance. They have impairments in that. So we can start at that level where we're concentrating on getting their balance better, the walking stride better, the posture better. All those things are what we call more normal, automatic gait. That's practice to them, to get it good and to make it harder.

Rhonda: And as the disease progresses, those things are dysfunctional or you're saying like from the beginning?

Giselle: Even from the beginning. Right. We're already working on it and making it harder. We can make it harder yet. I mean, we can make it, you know, have you be more accurate with it, make you go through an obstacle course. So we can make it harder yet to get you even better for balance, as an example.

Rhonda: No. What I was saying is when someone is diagnosed, like does their balance, like, for example, if they were just diagnosed, you know, are they going to be having problems with their balance or is that as the disease progresses or is it at very...

Giselle: No. It is as the disease progresses in general, but gait is very common. I mean, not normal gait. So they'll have the slowness in the gait, for example.

Rhonda: And by gait you mean like how they're walking?

Giselle: Walking. Exactly. Yeah. So, I mean, we tend to target, and that's why you see many of the exercise programs really target gait and balance because many times...I mean, so people definitely can have slowness in their hand and stiffness in their trunk, but targeting gait and balance is huge because that's really ultimately probably where the biggest deficits are. And many times in targeting gait and balance, you're really engaging different parts of the body as well, arm swing, posture, and these sorts of things. So it's a good place to start, if you will. Now, obviously, you can add more with things in your arms, boxing is an example that you can add more and make it more complicated tasks.

Rhonda: And if people that are doing this rock steady boxing, as it's called, the non-contact, or they just like doing like a bag or is it like...is that...

Giselle: Yeah. So I have to tell you, I've never gone to a rock steady boxing class, but the idea would be that yeah, they're learning different types of patterns of movements, for example. So it may not just be pure moving of the arm, but it may be a pattern that they have to replicate, for example. So that would make it more skillful.

Rhonda: So the cognitive skill that you were talking about.

Giselle: Exactly. Right. And I don't think anybody thinks that one type of exercise necessarily negates the other. There's no...you know, no one thinks that one is necessarily better. They're just different. You know what I'm saying? And I think fundamentally, the reason we care is we think that the mechanisms which underlie, they may be different. And that's why I think in terms of the work that we're doing, we're very interested in that idea. And some of the work that a colleague, Dr. Holschneider at USC has shown is certainly in the animal models that we've been doing, looking or trying to separate out or tease apart these different mechanisms where one group of rodents with Parkinson's have gone through a type of exercise practice more skillful, meaning they're on a motorized wheel with spokes removed, animals definitely need to pay more attention versus a group of animals Parkinsonian where there aren't spokes removed, so it's nice and smooth. They don't have to think as much about what they're doing, same match for speed, the animals that have the spokes removed have blood flow in top-down circuit cognitive domains much more so than animals that don't. So kind of the proof of concept that, "Okay if exercise is just exercise is exercise, we shouldn't be seeing differences in blood flow to different circuits."

Rhonda: Wow. Yeah. So they were doing the same intensity?

Giselle: Yeah. Right. And so, again, why do we care? I think the biggest thing, honestly, is that it's just beginning to say, "Hey, guess what? The brain is not passive. This is not a passive effect of exercise. The brain is engaged very much in this reparative mechanism and is driving this effect." So it's not just take blood and dump it onto the brain, it's like, no, the brain is an important signal of this effect. And that's huge to think about.

Rhonda: I also think, to some degree, and you know, maybe this is like with the animals, like there wasn't like a dose that you haven't, you know, maybe a dose-response would be an interesting to do as well in terms of intensity because I know from experience, when I go really hard, when I'm pushing my intensity to something like 80 percent to 85 percent of my maximum heart rate... And by the way, people usually aren't measuring their heart rate, like, you know, I have like my watch and stuff and all that, but for people that aren't measuring the heart rate, would you say a good gauge is about sweat, getting flushed in the face? I mean, this isn't like walking your dog. You've got to like push it.

Giselle: Out of your comfort zone. Right. Yes.

Rhonda: Yeah. Push your past. I have to think about what I'm doing a lot more, like even though let's say my spin class, okay? And it's like, if I'm pushing it to my like 80 percent max zone, I am more cognitively engaged. Absolutely for sure than when I am doing like 50 percent, you know? So there...

Giselle: No. You're right. And I think speed. I mean, that's true. So there's a speed component, right? Where, so as you get faster, you are thinking about accuracy a lot more and you are starting to... You're right. Absolutely.

Rhonda: And kind of more...

Giselle: And I think the point that you're bringing up, which I think is so important is it's a spectrum, isn't it? So it's not really often just one or the other, right? There's some that have certain types of activities that are going to have a higher aerobic content, maybe even skill. But, you know, as I've often been reminded by many of my physical therapist colleagues, it's like, it's actually also kind of impossible not to have some level of skill in anything you do. I mean, it's hard to be completely mindless on whatever you're doing, even... I mean, obviously, with weight lifting, even weightlifting is requiring some cognitive loading.

Rhonda: Yeah. You don't want to get hurt.

Giselle: Right. Exactly. I'm not just like throwing weights around. So, yeah. So the idea is that there's always some element of skill, even in biking, even in a stationary bike, because you're thinking about your speed. It's kind of the issue of the degree and also, again, the issue of intensity and that the two are probably, you know, obviously have different types of mechanisms that may be contributing to repair, but the idea is they may be different. And particularly when we're thinking about cognitive circuitry, as an example, we may want to be thinking about how we could add more cognitive loading, right? And what's curious about this sort of idea of cognitive loading, you know, many times when I talk to people about cognitive loading, the first thing they want to do is tell me about, you know, like a crossword puzzle they've done and I'm going, "Well, wait a minute."

You know, our brain has evolved to be pretty effective in movement through space. I mean, it's pretty, you know, pretty on board when it tries to figure out how to get from point A to point B. I mean, it's been important in our evolution. It's probably why we're still living today because we've been able to avoid animals that harm us, we've been able to be successfully going for meals. I mean, the idea of movement in space is huge for us. And the point there is that that's cognitive loading. Myself, just problem-solving movement through space, whether that be because of the skill that I'm engaging or even through a different environment, right? So the idea of mixing that up, changing the environment is going to be another type of cognitive load.

Rhonda: There's been animal studies that have shown that doing that exact thing, like changing the environment and particularly putting an animal in a more enriched environment, it increases synaptic connection and long-term potentiation, you know, all these things.

Giselle: Right. Absolutely. And what's interesting about that field though is even in the context of environmental enrichment, many times, it's also what else is in there like the wheel, or... I mean, there's always a physical component that they find is also important. So I think it kind of, just, as I said, kind of goes back to the idea that movement through space is a big deal for our brain it itself is a cognitive load. We can definitely ramp that up in a lot of different ways. Certainly from a skill point of view, we can. From an environmental enrichment, making it a novel environment for us. Moving effectively through space is also...in a new space, in a novel environment is also pretty big. I know there's a lot of interest now looking at natural spaces and what that does for cognition as well. And there's some really interesting things coming out of that. Again, kind of tying it back into movement though, is really where it gets really interesting. Yeah.

Rhonda: Right. I mean, certainly... So in addition to, you know, all the benefits that exercise...ad I mean, there's been studies showing that, you know, in Parkinson's disease patients, Parkinson's disease patients that do, you know, a certain amount of, you know, 30 minutes of exercise, you know, moderate to high intensity increased BDNF and their plasma and BDNF crosses the blood-brain barrier. It's a growth factor, it's important for maintaining synaptic connections, for growing new neurons. And, you know, it's certainly important for repair of, you know, damaged brains. So, you know, there's definitely lots of factors that probably, as you were mentioning, there's the, you know, the combination of these things, exercise is anti-inflammatory, you're making anti-inflammatory cytokines, and, you know, those things also are doing stuff in the brain. As you mentioned, the brain and body are very connected. They're not disconnected like we thought. In fact, the immune system, you know, these immune factors are getting into the brain. Our lymphatic system is connected, you know? So there's definitely a connection there.

Giselle: Absolutely. I think the one thing and tying back kind of what, again, what you were saying, so this whole idea of how connected, obviously, as you said, we're learning a lot about that. But also, again, the idea that, which I always like to emphasize, that the brain is not a passive recipient of this. Meaning there's a lot of signaling, we're probably just beginning to understand in terms of what the brain needs and the idea that as you kind of create these sort of metabolic demands on these circuits by virtue of how you're using your brain, right? By virtue of the taxing nature of skill and the taxing nature of a cognitive load in the context of movement, that those neurons and those synaptic activity and that high metabolic demand is signaling the need for more fuel, you know. And so, the idea there is all those sorts of pathways that are, you know, metabolic in nature and driving changes in blood flow that are also kind of interesting because like I said, many times we do tend to think about these sort of lifestyle effects as sort of being the sort of global kind of glow, your body glow. I mean, it's sort of like it's a sort of wave over your whole body that suddenly gets better. It's like, "Well, no. No." I mean, these it's very active and it may be even more specific than we think.

And I think as I said, the brain is a great model to begin to understand that because it has some kind of cool repair mechanisms. The question is, how does that signaling start? How much of that is brain driven, right? And top-down. So we're not even talking about, you know, from the periphery in, I'm talking from the brain out. Brain is signaling to the periphery, what do I need now to be able to accomplish what I need to accomplish, reaching my new level of homeostasis? I am asking for a new level of a type of connection that I now need. I'm going to signal for the type of whatever support I need to make that happen. Right?

Rhonda: I was talking with your colleague, who happens to be your husband, earlier about...we were talking about the exercise and the lactate that's induced from exercise. Now, this isn't your...you know, I'm not sure if there's a signal, you know, basically, lactate is being generated and it's crossing the blood-brain barrier and getting the brain. I don't know if there's a reason for that. I mean, your astrocytes make lactate. You know, they're highly glycolytic. In fact, mostly, I think they're using glucose to make lactate and that's shuttled into neurons and used as a very easily used oxidizable source of energy, but also, it acts as a signaling molecule and it's affecting BDNF and other things. And so, I just thought that was very interesting that, you know, there's another possible, you know, mechanism that exercise is like you've got this lactate that's being generated and the brain wants it, you know. And I don't know if it's like, there's some...it goes to other tissues as well. I don't know if, you know, how much goes into the brain. And he was saying quite a bit.

Giselle: Right. Quite a bit. And I think the other thing... I mean, so it is one of the interests of the lab, in general, which is understanding how does lactate...how can we signal the need for lactate in the brain or how is the brain using lactate in the context of exercise and what is the upstream mechanism for driving the signal, there are a number of different pathways that people are looking at, but one of them are transcription factors and hypoxia-inducible factor, HIF1-alpha, is one example of a transcription factor that is known to be up-regulated in the context of hypoxia and now ourselves and other groups have reported some up-regulation of this in the context of exercise. So the idea of a stressor, right? So the idea of this sort of disconnect between what the neuron is doing in terms of activity in the metabolic demand, it itself may be driving transcription factor changes that then may up-regulate metabolism or alterations and lactate transport, as an example.

And that's some of the interests that we have right now which may be metabolically-driven. So the idea is that neurons through activity are, as I said, up-regulating transcripts that are detecting this mismatch, if you will, that may change metabolism, right? And then allowing for better use of glucose or even use of peripheral lactate through changes in transport and blood flow. So that's kind of cool, right? So now you're kind of thinking about peripheral effects, whether that's immunotrophic factors on one hand, and then you're thinking about signaling that essentially driven by stressors. We certainly know cancer can do that as an example. It's kind of ironically kind of an interesting model for us because it kind of does the same thing and it kind of...it changes the demand on the brain. It's changing the metabolic demand that it needs and it's changing blood flow to the tumor itself.

And we're sort of seeing those sorts of things with exercise based on how we're using circuitry which is interesting, right? And I think it kind of all goes back to the idea of what homeostasis is, right? So the idea that homeostasis is sort of trying to reach this new type of balance, this new type of kind of brain change that's responding to injury, that's responding to a new demand on the brain, right? That it recognizes where it's beginning to need more fuel, better blood flow, more support, and that we can influence this to some degree based on what we do, right? Which is crazy, right?

Rhonda: Didn't you also publish...a few years ago, you had a very small pilot trial where you showed patients with Parkinson's disease early diagnosed. I think they were medication-free even. And you had them doing this sort of moderate to intense high-intensity treadmill exercise and it seemed to change the way the sensitivity of their brain to dopamine, or to some of the receptors, dopamine receptors. So like they're basically using it better, you know, the little they have, it's better at it, you know?

Giselle: Right. More efficient. Yeah. So that was another thing that we had seen, which is actually changes in dopamine receptors. Right. So the idea was that we'd taken patients who had not been on anything and essentially...no meds anyway, and, you know, were recently diagnosed and then putting them on a treadmill. And I would argue that although the treadmill, again, so intensity in two ways, one obviously getting their heart rate up, but they were actually also getting a lot of feedback on gait and balance, again, constantly correcting, going up on speed. So they had to become more accurate.

Rhonda: So having like a personal trainer seemed to kind of be very important.

Giselle: Yeah. They were getting tons of feedback. And by going up on speeds, now you're having to work harder to make sure you're accurate. So, again, you're in the zone, if you will. But in any event, yeah. So we were able to show that we saw changes in dopamine receptor levels, with the idea being that the amount of dopamine you have with a better receptor expression, you're becoming more efficient. And that was duplicating what we saw in the animal model. So this was kind of nice to be able to show it in both a rodent model and translate it into humans.

Rhonda: It goes along with the adaptations you were just talking about as well.

Giselle: Absolutely. Yes.

Rhonda: And so, I would ask though, you know, for someone that is, you know, does have Parkinson's disease, it sounds like having a personal trainer may be a good idea because you're getting all of these things that you're mentioning. You're getting that feedback, you're getting someone to help challenge you more. It's that challenge. You don't want to just be in your comfort zone like you would if you were walking your dog. You want to push yourself more, right? And so, it helps to have someone or a group class, you know, feedback and, you know. I mean, it's just...

Giselle: Yeah. And I think it's great. You've touched on a number of different things. I think, first of all, number one, I think in general, we like having patients with Parkinson's have exposure to physical therapy one-on-one periodically. And I think the idea there is what you've said. For a couple reasons, obviously one, you want to make sure you're challenging yourself, you want to make sure you're not hurting herself, but also you really are gaining kind of a toolset and feedback on what you need to be working on. And it is, as I said, you, you know, getting the feedback to be accurate and problem-solve to do it again better, right? And so, you, you know, you definitely want to progress and get better. Number one. And two, you can kind of use those toolsets to, you know, apply now to a class, so you're doing, you know, what your class, but you kind of know what you need to be working on. So I kind of liked that combination. So getting that one-on-one, I think is always great. And I think for Parkinson's, that's particularly true because they have some deficits that they really should be working on and focusing on. Getting that feedback is important. They may not recognize it. So that feedback is important.

The other thing I was going to say is I like people also to kind of mix things up a little bit, do a lot of different things. So, you know, once you try one thing, maybe mix it up and do something a little different. I think that's also important. Doing something you love, the whole idea of self-belief, you know, self-efficacy and self-belief, the idea that you're going to do better, if you believe you can gain benefits from it, and if you enjoy what you're doing are really key. So I think that's also why the idea of obviously getting some feedback in physical therapy, but then doing something you love, you enjoy, you want to learn is good. Mixing it up both from the skill set, doing different things and mixing up from the different environments. I always say, "Look, we live in Southern California. You know, we've got, I don't know how many different types of terrains here. It's not that hard to mix this up." So it's really going back to the idea of mental flexibility, exploration, and fundamentally play. It's play, which is all those things.

Rhonda: Definitely increases compliance that you'll keep doing it if it's something you enjoy doing and like doing.

Giselle: It's play, right?

Rhonda: But to a certain extent, you also want to make sure it's not...I mean, it's play, but you're also like pushing yourself, right? You're not, you know...

Giselle: Yeah. Hard play.

Rhonda: There was that study. I think it was JAMA medicine, the one that was published in December, 2017, where they did the dose-response and intensity of exercise. They took Parkinson's patients and had a group of them, you know, basically not do any exercise and other group did moderate intense. So they were doing about 60 percent to 65 percent maximum heart rate. And the other one was high intense where they were about 80 percent to 85 percent. Again, people that aren't measuring their heart rate, you know, when you're sweating and you're flushed, I mean, that's kind of a good indicator...when you feel uncomfortable because you're pushing it, you know?

Giselle: Right. Exactly. That's a good example.

Rhonda: This was a six-month trial and the people that did not exercise according to the tests that they measure for disease progression, and we talked a little bit about this. There, maybe, you know, there's some caveats there, but according to that, you know, test they do, the people that did not exercise progressed 15 percent worse over the six-month trial. The ones that did moderate-intensity progressed 7.5 percent, so about half of what the ones that didn't exercise and the people that did high intensity had zero progression over six months, which to me is huge when I think about Parkinson's disease. And a friend of mine, a really close friend of mine who happens to be a neurologist as well. She specializes in motor dysfunction as well. Her mother has Parkinson's disease and I've watched her progress over the last 15 years.

And I've seen it progress from tremor, little bit of the gait problems to now she can't walk, she can't dress herself. I mean, you know, it's progressed now to full-blown dementia. So there's definitely a progression there. And I'm wondering, it's like, if you could take someone and have them in this...sorry, in the study they did, it was 3 times a week, and it was about 30 minutes of the intense exercise. It was a little bit of a warm-up and cool-down. And if you could take someone and have them do an intense workout like that three times a week and slow the progression where you're talking, you know, just having a little bit of a tremor and maybe some of the slowness, you know, maybe just a little bit of that initial stage, but like having their quality of life where they can still dress themselves and put their makeup on and, you know, like they still have their mind. I mean, that's a huge difference in quality of life.

Giselle: Right. That is huge. That is huge. And again, I mean, we still have a lot of room to go. I mean, understanding how this affects Parkinson's disease, we've got some really great promising data. I think there's still gaps, particularly, I would say still in the cognitive realm. We've got a lot to do there in terms of understanding what that cognitive impact really is. And, again, we talked about the idea that cognition impairment is common in Parkinson's disease. Probably is finally the biggest disability over time. So obviously, work to do there, but certainly, we're heading in the right direction in terms of one trying to understand through many different types of studies with clinical and in animal models to try to understand how well they can impact these different circuits, particularly cognitive circuitry, as an example.

And then also, I think the cool thing is you're right. We actually have some data, without a doubt, that we can use now, right? And so, the idea of definitely making sure that our patients are well-informed in terms of the idea that it's important, right? So they need to be using...you know, we always say 50 percent of treatment should absolutely be lifestyle and particularly exercise and all the things we just talked about and making it intense, having a physical therapist that can help you really challenge yourself. We talked about gait and balance because that tends to be the bigger issue. And when you try gait and balance, it's going to incorporate many other different things, making an intense, partly aerobic, partly from practice. Those are all important.

One of the things I have to say though, that I always try to make clear to people is, one, there is no data that it stops disease. So that's the one thing. It's never shown it cures Parkinson's. And two, I also want to make sure that we inform patients that it's not a replacement for dopamine. And the reason that's important is because we also had some experience with individuals who were frightened of dopamine, and I know there's a lot of literature out there that can be very frightening for people, but the idea that they weren't taking dopamine, all they wanted to do was exercise. And what we noticed is that those people really struggled. I mean, they really were not able to get the most out of practice. They have a lot of fatigability when they tried to exercise. And so, the point was they didn't really get the benefits of exercise because they couldn't do it, right? And so, the other part of the equation is there's a reason for dopamine, right? And so, dopamine has a role for synaptic plasticity. Obviously, practice is as important, but dopamine enables plasticity.

Rhonda: Can you talk about little bit about... So there's the standard of care treatment right now, is levodopa, carbidopa, right?

Giselle: Right. So dopamine replacement, because Parkinson's disease, as I said is, causes, obviously dopamine depletion with circuit changes, but the dopamine depletion also, it's driving some of this loss, this loss of connections. We need dopamine back because dopamine is what enables synapses to form as well along with practice and it also alleviates the symptoms themselves. So treating with L-DOPA will help a lot of the symptoms of slowness and stiffness that will allow you to get the most out of practice. I can move better. I can move more accurate when I can, you know, I'm not feeling a slower stiff. So, you know, again, I think of the L-DOPA, which is what we give, Carbidopa/levodopa.

Rhonda: L-DOPA gets converted in a dopamine, so L-DOPA across the...

Giselle: Yeah. So L-DOPA is a pro-drug that I ingest with carbidopa. Carbidopa blocks the peripheral metabolism L-DOPA so it doesn't break down in the blood or make me sick.

Rhonda: The carbidopa prevents L-DOPA from becoming dopamine before it gets into the brain. Is that right?

Giselle: That's correct. But the idea there is once L-DOPA makes into the brain, it gets converted in the brain in those remaining cells to dopamine, and that is now targeting those circuits that I mentioned, the automatic circuits, right? And that's what allowing it to work more efficiently. And then the idea is with adding exercise, it may also drive repair.

Rhonda: So you're saying that exercise is not a replacement for the L-DOPA or carbidopa, but it's in combination, you know, because you obviously still need the dopamine. And I think that the L-DOPA and the carbidopa itself doesn't actually slow disease progression, but it does help treat symptoms, but that's...after a certain time, doesn't some of those become refractory doesn't, is it...

Giselle: I would say there are several points. One is that it, you know, because those cells are not storing it as well, you know, you're having to dose more frequently. So that's a cell dysfunction problem. And then secondarily, there were other circuits, cognitive circuits, as an example that are getting affected. And we know cognition plays a big role in my ability to move safely through space. And so, that's going to be a big contributor. And L-DOPA does not do as much. It's not as a factor for cognitive function. It has a role there, but it's one of many different chemicals. Acetylcholine being another one, serotonin, norepinephrine being other ones.

Rhonda: These things are also modulated by exercise. And there have been meta-analyses that have been done looking at various types of exercise and their effect on cognitive function, executive function, global cognitive function, memory, and those things can be improved by high intense.

Giselle: Right. And aging field I'd say is a little further ahead of us in terms of their data. Probably the strongest data in the aging field right now.

Rhonda: Absolutely. It is. But there are some with Parkinson's patients that they have looked at and so, it certainly is affecting cognition as well at the exercise, you know? So, again, it's just like, you know, doing that, you know, I just feel like it's like driving it home. Like, you know, it seems... You know, we hear about exercise and how important it is like every day in the press. I mean, everyone's heard it, you know, the question is like, how do you get your patients that have Parkinson's that may be sedentary, maybe, you know, know, not... There's quite a few people that are sedentary in their late sixties. Yeah. And how do you convey the importance? How critically important it is to do exercise along with their treatment?

Giselle: Yeah. I think one of the first things I would say is education. I mean, I think I, you know, having the data, you know, that's huge. So, you know, it's one thing to say, "Okay, access is important. "The other thing I would say now we have a lot of data and I'm, you know, I think getting the word out, but more importantly, showing the data, what we're seeing, why we think it's happening definitely adds some motivation. I find many times when I talk to my patients about it, they're pretty motivated after I talk to them. I think the other thing too, like anything else, having some goal setting, you know, being clear in your mind while you're doing this right? So the educational piece, what I'm trying to get out of it. Having resources clearly, I think most people like to have things that are close and available to themselves.

So identifying resources that are close to them, classes that are close to them, and then, you know, having other kind of motivators in your life, people around you that support you. So I'm definitely a big believer in community and, you know, that health and wellness started the level of community. And so, having those sorts of support system to help you want to change your life, want to get more active is important. I have to tell you, many times when I'm talking to people with Parkinson's about exercising, I turn and look at the whole family and go, "This is not Parkinson-specific." Just saying, right? "This is about everybody here. So I think, you know, that's helpful because I'm like, "No, no, it's not just Parkinson's. I think all of you could start working on this." So getting a partner out there, whatever is important as well.

I'm not saying it's always easy. I mean, heck, you know, we're talking about changing the whole Western culture here because we're sedentary, right? So small steps are good steps and I, you know, trying to get the word out, keep them motivated by different ways, mix it up. These sorts of things are huge. I think we still have a lot of work to do. Obviously, I think there's a lot of other issues in Parkinson's that make them a little bit more vulnerable. I mean, apathy and these sorts of things. So it's not always easy. I'm not saying that it is. So clearly, something we need to work on in Parkinson's disease, but I would also say kind of our culture in general. Yeah.

Rhonda: It sounds like it'd be easier also to intervene earlier, like if you're, you know, some of that stuff gets worse.

Giselle: It is. But I have to tell you, you know, for me, it's like everybody. I don't let anybody off the hook. Nobody. I’m vicious.

Rhonda: Good. I mean, I think also just communicating like, you know, to the patient, that's like, "Look, there's one thing that is effecting your symptoms. Okay. Yes, there's improvement in symptoms." And they think, "Well, I can get that from my pill." Right? But talking about like the way this disease will progress, like 5, 10 years from now, like potentially like...

Giselle: That should be motivating enough.

Rhonda: That. And go like, "This pill, isn't going to do that." Like it's going to help with your symptoms and stuff, but like that's a big deal.

Giselle: Yeah. And I think those sorts of testimonials. I mean, again, it gets back to the communities and stuff. Having other people talking, what they're doing is so helpful, you know? So it's certainly not just from us, it's from, again, their own support groups and stuff like that. I think it's extremely helpful to get people motivated and making it a community-based event as opposed to PD-specific already, which is not that at all, right? So the whole eye aging goes back into the aging field and trying to think about how to incorporate this into our lifestyle as part of our culture. I think those are things we certainly need to work on more, but, yeah.

Rhonda: Yeah. Totally. A couple of things I just wanted to mention quickly before we wrap up. I know you may not be so familiar with this field, but more like the nutritional aspect. There's been some interesting evidence with the omega-3 fatty acid, DHA, which is an important component of cell membranes in the brain. That's been done. Observational studies have shown like people taking fish oil have a low risk on Parkinson's, but you can never establish causation. Some interesting animal models, both rodents and primates showing in the MPTP model where you kind of induce this Parkinson's-like symptoms, that taking pretty high dose of DHA, specifically, would be a human equivalent of dose of like for an 180-pound man, like 3 grams a day, pretty much, which is like 6 pills of the standard fish oil like. In both in the rodent models and the primate models, nonhuman primate models, lowered the L-DOPA-induced dyskinesias that can happen. And I thought that was pretty interesting because it is a negative side effect that can occur with that levodopa, carbidopa and the fact that it was like, you know, multiple animal species, the same thing was happening. I thought that was a very interesting finding that I kind of just wanted to get on your radar, just get on your radar. Maybe you can look and read in the field a little bit more about that. And, of course, DHA, interestingly has been shown to affect dopamine in the context of traumatic brain injury in animal models as well. So there's probably something going on there.

Giselle: Right. Exactly. Yeah. I mean, the whole diet field, I think, you know, and again, diet and exercise really go together, right? So, absolutely. I think the diet field is tremendous. And it's going to give us a whole another way to think about, again, how these things are interacting. And I have to say for right now, I would say in the Parkinson's field, not as much, I mean, we're, again, probably again, more in the aging field, but I think in general, we, again, we borrow from each other's field, but I think probably the most comfortable thing that we feel safe in saying would be something like the Mediterranean diet, again, based on epidemiological data, and that, of course, includes things like fish and less sugar and higher, and, you know, just green vegetables and vegetables in general, nuts and legumes and stuff like that.

Rhonda: Do people with Parkinson's disease have a higher, like, for example, higher levels of plasma circulating inflammatory cytokines in their plasma?

Giselle: Yeah. So there's some data, I mean, interestingly, you know, there hints here and there. It's, again, not as well worked out is, you know, MS, for example, but yeah, the idea that there is, you know, TNF-alpha, IL-6, so the idea that there may be higher proinflammatory cytokines, and that's something that we're going to try to explore in some of the work that we're doing right now. So we, you know, people do believe that, you know, again, it may not be the cause of Parkinson's, but maybe something it's adding to the progression, which is things like inflammation, what role diet and the microbiome. I mean, they all sort of tied in together there. That may play as a mechanism is going to be important and something that definitely needs to be investigated further. So, again, another place where we may be able to modulate the disorder.

Rhonda: Yeah. But right now it seems as though the thing that's pretty repeatable is the exercise, and that's... Do you tell them three times a week? Do you...

Giselle: Yeah. I mean, most of the studies are about three times a week. So I would say about three times a week, minimally 30 minutes, three times a week, and trying to make it as, you know, intense as possible.

Rhonda: Intense as possible.

Giselle: Yeah. And then we add that... You know, as part of that, that should also have some skill component, particularly involving gait and balance-related tasks. And there's a lot of things that do that. So I don't pick out anyone in particular. I don't, you know, whether that's tai chi, yoga, surfing, whatever they like to do. I think that's important as well. And I think as you pointed out before, having someone to give you the feedback so that you're accurate and challenging yourself is actually quite important. So I think having that one-on-one, particularly in Parkinson's is a smart thing. And we do try to get people into some one-on-one therapy. I usually do at least two times a year. And actually, I start right away. And there isn't anybody that I don't send because we can always make it challenging for you.

Rhonda: Absolutely. That's really key. I think that having, you know, having someone there that's going to really help push you past your comfort zone, give you that feedback, I just, you know, it's really important for people, particularly people that are less prone to push themselves. Like I'm one of those people that I'm pushing myself. I want to be the hardest working girl in my spin class. Like I'm like, you know, that's.. But, but you know, I don't have these neurological problems and apathy and all this other stuff, you know, that comes along with Parkinson's disease and I've been younger and this is sort of my personality. So getting someone to do that, to push themselves, it's so key. Oftentimes, you know, I might say to someone, you know, "Exercise is really important." And they're like, "Well, I walk my dog." And it's like...

Giselle: Yes. I hear that a lot around here.

Rhonda: You know, "I walk my dog." Well, that's good, but are you red in the face and sweating? Are you pushing yourself? And you know, are you running with your dog? So I mean, I just...

Giselle: Right. Exactly. Yeah. Yeah. You got to be tough. You got to be a little tough. And anyway, I try to be pretty tough, but also, like I said, there isn't anybody... I don't care if they're even, you know, been in a wheelchair, I'll try to get them up. We'll see what we can do. You know, we do everything safely, but I think I'm so passionate about that because, you know, when I was in field, you know, it's been a while obviously, but, you know, I was in the field of time...exercise was not thought like that. In fact, it was pretty much thought it couldn't do anything. And so, patients with Parkinson's disease, we may give him a wheelchair or a walker, but there was no plan to make it hard. And I think that's the thing in general, I think people kind of feel like, "Oh, you know, as you're getting older, you know, just chill and like don't do anything." And it's like, yeah, no. No, no, no, no.

Rhonda: People are afraid of falling. They're afraid...

Giselle: No. I think it's this idea that somehow you can't gain something or you can't do it. I'm not sure. But, yeah. So forget that. Yeah. No. Everyone is...

Rhonda: Do you see improvements like with your people that have more severe...they're more...

Giselle: Everybody gets better. I mean, we see improvement in everybody. You know, I think that's the thing, you know. And even small gains are good gains. I mean, so, yeah. And I like them to mix it up by, you know, tell them to play instruments even to get more hand skill going. And I mean, yeah. I mean, I think that's the thing. In a way we're too easy on each other. And as people get older, it's like, yeah, get out there and learn something. Go out there and learn a new skill. Take up racquetball. I mean...

Rhonda: Like is this a common for clinicians in the Parkinson's field? Are they commonly emphasizing exercise? Do you know, is this like something that's been more embraced or do we have to push it more?

Giselle: In general, it's been more embraced, but I have to say, in general, I mean, I'm very, you know. I'm harsh.

Rhonda: You do research on it. You know, you've got the data.

Giselle: I don't let anybody get away with not talking to patients about lifestyle. And I think the data is pretty clear. And this is not just Parkinson's, it's 50 percent of any neurological disorders lifestyle. And I'm very on it, I tell everybody, I tell all my residents whenever I'm educating people or whatever going around with rounds, 50 percent of any discussion of treatment has to be lifestyle. If you're not doing that, you're not giving a fair balance of what we really know. And so, yeah, I think that message, loud and clear and there's no excuse anymore.

Rhonda: And it's never too late. It's never too late.

Giselle: Never too late. Right.

Rhonda: Well, thank you so much, Giselle, for this discussion and for all the wonderful research you do. I mean, very thank you. Thank you.

Giselle: Thank you so much. Thank you very much. Thanks.