Neuroprotection, Neuropriming & Exercise

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

The goal of the global health initiative Exercise Is Medicine, is to make physical activity assessment and promotion, a standard in clinical care, connecting healthcare with evidence-based physical activity resources for all patients. While the value of exercise is clear for areas like cardiovascular medicine, applications to neurologic disorders has not been formalized. In today's episode of Neuro Pathways, we're discussing the use of exercise to combat neuro degeneration and provide neuroprotection. I'm your host Glenn Stevens, neurologist, neuro oncologist, in Cleveland Clinic's Neurological Institute. Joining me for today's conversations are Drs. Jay Alberts and Susan Linder. Dr. Alberts is Vice Chair of Innovation in Cleveland Clinic's Neurological Institute and researcher in the Department of Biomedical Engineering. Dr. Linder is the Director of Research in Cleveland Clinic's Department of Physical Medicine and Rehabilitation, and a researcher in the Department of Biomedical Engineering. Jay and Susan, welcome to Neuro Pathways.

Jay Alberts, PhD:

Thank you. Thanks for having us.

Susan Linder, DPT, PhD:

Thank you.

Glen Stevens, DO, PhD:

So Jay, it's my understanding that the investigations you've undertaken in recent years are the direct result of personal experiences you had with exercise, and like a lot of discoveries, serendipity plays a role. Take me back to where all this started for you.

Jay Alberts, PhD:

Glenn, this really started in either a cocktail party in Atlanta or the fields of Iowa. Back in 2003, I was in Atlanta at Emory and Georgia tech, and was a early cyclist. And there was a individual who was in some of my studies who had Parkinson's and we met, were friends and started cycling with her husband and we were at a party and she said, "I want to spend more time with my husband." And I said, "I have a great idea. We should ride a tandem bike, or you guys should ride a tandem bike across the state of Iowa for this event called RAGBRAI, the Register's Annual Great Bike Ride Across Iowa." Think of RAGBRAI as Woodstock on wheels with worse music, but better food. So anyway, we got there in 2003 and Ralph and Kathy being the PD patient were going to ride the tandem bike across the state and really just to raise awareness for Parkinson's, right?

Because before that I had some friends and colleagues who had been diagnosed with Parkinson's and they really viewed it as a death sentence. They were told you have Parkinson's and in five years, this is going to happen, eight years, 10 years, you're going to be in a chair. And that really wasn't our mindset. And so our real goal was to go to Iowa and raise awareness for Parkinson's that it's not a death sentence. So Ralph and Kathy were going to ride tandem across the state. And just be examples of that. We got halfway through the first day. And again, riding in a tandem with your spouse is always a challenge. I said, "Hey, tell you what, why don't I ride with Kathy the rest of today, and you could ride my bike." So we did that and we had a very nice time.

And so turns out we rode the rest of the week together. And a couple things happened while we were in Iowa. Kathy had micrographia. So micrographia in Parkinson's is the smallness and an illegible handwriting. And so when she sat down, she wrote a birthday card out and it said, "Happy birthday, Gary." And her handwriting looked beautiful. And I said, "Who wrote this?" And she said, "I did. Isn't it amazing?" And it was because that micrographia was gone. And so it was really after that that she said, "It doesn't feel like I have Parkinson's when I'm on the bike," and things like that. And so that was really the first first that we sort of observed it, but I quite frankly, sort of was very much focused on deep brain stimulation at the time. And so kind of pushed it to decide thinking, well, we're in Iowa, that's kind of God's country.

And maybe she's just feeling better from the pie and ice cream. And then in 2007, we went back, we had gone back a number of years, but we went back and we had a patient who had deep brain stimulation. So something I was very familiar with and he said, one day he wanted to ride with me. And I said, great. And he said, "Well, let's test this whole exercise thing." So he turned his deep brain stimulation system off and he's a movement disorders neurologist himself. And so he had Parkinson's, he turned his DBS off and he had standard tremor and things came back as soon as he turned DBS off. And then we went on this ride on a tandem bike and we stopped and had a doughnut or something. And he looked at me and he said, "Where did my tremor go?" And I said, "I'm not sure." So we hopped back on the bike, finished it. And we have some very striking video to show his pre and post.

And it was really then that I said, okay, there's something going on here with exercise, because I had seen the effects of DBS many times. And now, basically exercise despite not being on DBS, his symptoms had been mitigated. And so that's really, again, very serendipitous that we ever stumbled across this concept of forced exercise for Parkinson's.

Glen Stevens, DO, PhD:

I love the story. Just love the story. I guess we just all need to pay more attention to what's going on around us, right?

Jay Alberts, PhD:

Yeah. For sure.

Glen Stevens, DO, PhD:

The answers are there. You know, physicians often say to me, I've never seen that. And what I often think is you've just never recognized that. And I think that we just all need to pay more attention and these serendipitous things are in front of us. Susan, do you want to add anything to that? Do you think it had anything to do with the cycling motion itself, would running on a treadmill have done the same thing, do you think, or any thoughts about the entrainment?

Susan Linder, DPT, PhD:

Sure. It's really difficult to know exactly what the cause was, but what Jay has found in his studies, and if you look at animal literature, we've seen that that high intensity aerobic exercise is what is likely needed to cause that upregulation of proteins in the brain that might have this neuroprotective effect or neuro restorative effect. So that really launched not just additional studies in Parkinson's, but then looking at other disease populations to see how we could potentially harness these similar effects. And not looking like that was a hammer and everything else was a nail, but rather how could we customize the prescription of aerobic exercise to different disease populations to really optimize its ability to potentially have these neuroprotective or neuro restorative effects.

Glen Stevens, DO, PhD:

So Jay, take us through some of the nuts and bolts. What were you thinking about trial wise after this experience. Did you formulate right away for you or what'd you come up with?

Jay Alberts, PhD:

No, that's a great question. So as soon as I got back to the lab, what we did first was we brought a DBS patient in, evaluated them using the same assessment. We had an early version of an iPad if you will, to measure movement function. And then we brought a PD patient in with DBS, turned him off for four hours and then had him do the same activity. And that's where it was very striking in terms of their movement patterns were very different. And so the next trial, right, we tried a lot of applications to NIH and other places to do a trial, to look at the effects of forced exercise. And the reason again, we're calling it forced is because the person on the back, the PD patient, they have to pedal at the same rate as I was pedaling on the front.

So in some ways, I pedal at 80 to 90 RPMs and Kathy and Dave, et cetera, they were pedaling at 50 or below. And so I was forcing a pedal at a relatively fast rate. So this, again, 2007, 2008, the view of exercise was very different compared to now. I still have reviews from NIH, that say I was foolhardy and I was going to put these people at great risk and someone was going to die because they can't do high intensity exercise. So we sort of begged, borrowed and stole parts and built our first tandem up and did a initial clinical study with Jerry Vitek, who was here at the time. And that was our first study looking at forced or tandem cycling versus voluntary.

And we found there was a significant improvement in those patients who were on the tandem with riding with compared to people who exercised at the same cardiovascular level or effort, but they weren't pedaling as fast. And so this is where it seems like maybe this fast peddling plus elevation cardiovascular response is contributing to these changes or these increases in neurotrophic factors that we think is the mechanism. But again, it wasn't until we published that that NIH finally gave us a small RO3 to do a feasibility study.

Glen Stevens, DO, PhD:

And what did that show?

Jay Alberts, PhD:

Yeah. And the feasibility study was very positive in the sense of it showed that first of all, that nobody died, that PD patients can actually exercise and they can show cardiovascular benefits or have a cardiovascular response. And second, that the individuals with forced exercise actually had a improved level of improvement on their UPDRS, their clinical ratings. And importantly, that was a very important study because we also partnered with Mark Lowe and Mike Phillips in imaging. And we showed for the first time that high intensity exercise actually used the same pattern of activations that anti Parkinsonian medication did through MRI studies.

And I think that was the study that really put us on the map in terms of, here we are, doing a lower extremity exercise and we have improvements in the upper extremity, despite the fact they weren't doing anything with their hands. And we showed improvements or changes in brain function that looked very similar to what you get when you administer anti Parkinsonian medication.

Glen Stevens, DO, PhD:

So I'm just going to take a slight deviation here with you. So if you have a Parkinsonism patient, that's a dopa unresponsive patient, have you looked at any of those patients, do they respond or have you not looked at that group?

Jay Alberts, PhD:

Yeah, no, that's a great question. So we haven't looked at that systematically. I can tell you that again, people have tried this on one-offs and people in the field have, and they report back to me that it's effective. But I have no real systematic data or any studies to look at those individuals be nonresponsive.

Glen Stevens, DO, PhD:

Is there an RPM sweet spot?

Jay Alberts, PhD:

Great question. It looks like based on our data, that seems to be about 75 RPMs, 75 and above seems to be the sweet spot. The concept of exercise and treatment of Parkinson's is not new, right? Charcot thought of this concept a long time ago after he had noticed people come to him in a wagon ride or something and they get shaken about, and they feel better. And so he developed the shaking chair, as well as the shaking head thing. Turns out they didn't really work, but there's a history there in terms of trying to understand how exercise might be working here.

Glen Stevens, DO, PhD:

So duration, so greater than 70 RPMs, how long?

Jay Alberts, PhD:

So generally we have 40 minute sessions, so about a five minute cool or warmup and a five minute cool down. So 40 minutes, three times a week. And again, to your earlier question of maybe how we were received, early on that concept was crazy, right? So I remember presenting this data at different clinical meetings, national meetings, and people would stand up and say, oh, I can't believe you want me to tell my patients that they have to exercise three times a week for more than eight weeks. And at first I sort of backed away from it, but then I was like, well, no, that's what the data are saying. And going back to your opening statement about exercise as medicine, we would never think about prescribing some anti Parkinsonian medication for a patient and saying, you know what, just take this two or three times a week at whatever dose you want, or even deep brain stimulation. We would never implant the stimulator and say, you can just use it 14 hours a day, right?

So there is a prescription here, and I would also argue that whether and how effective medication is, or how effective deep brain stimulation is really comes down to how effective your neurologist or your neurosurgeon is in terms of managing the disease or implanting the electrodes. And I think about this, and we've had lots of talks with PD patients, Parkinson's is a disease that really wants to rob you of your control, right? You lose control and it robs you of control. And exercise is one way to regain a bit of that control back because they now can take a more active role in their treatment by exercising three times a week at 40 minutes.

Glen Stevens, DO, PhD:

Yeah. I think that's an important point. Patients always ask me, or families always ask me, what can I do to help myself and allowing patients some degree of control, I think is great. Susan, are you in the weeds with these patients? Are you helping get them going? What are you seeing with them on your side of things?

Susan Linder, DPT, PhD:

Yeah, so I joined Jay's lab in 2010, right about when he was coming out with the results of these initial pilot studies. And most of my work has been in stroke. So I really looked to see how we could potentially adapt this approach to improve motor recovery in people who have had strokes. So like I said, it wasn't a matter of, we have a hammer and everything is a nail, but rather how could we harness these neuroplastic effects of aerobic exercise? So we changed our model a little bit. And in stroke, we use aerobic exercise to prime the brain to improve the motor learning benefits that are associated with traditional rehab or motor task practice. So the model that we developed in stroke, and we continue to investigate in clinical trials is about a 45 minute bout of this forced aerobic exercise. And again, the intent is high rate.

So similarly to the Parkinson's patients, in stroke, we found that the sweet spot was about 75 RPMs. So we encourage that rate of exercise and we follow it up immediately with upper extremity motor task practice. And we have found in our preliminary studies that those who use this model of aerobic exercise to potentially prime the brain actually had more improvement in motor recovery of the upper extremity than those who did not. And in fact, our control group had twice the dose of just task practice. So again, this implies that there might be some priming that is occurring.

Glen Stevens, DO, PhD:

So it sounds like frequency is important, but what about intensity? Frequency more important than intensity, it sounds like it.

Susan Linder, DPT, PhD:

Yeah. So that's a great question. Glenn, both groups exercise at 60 to 80% of their heart rate reserve from an aerobic standpoint, however, that was not one of the main predictors in motor recovery. And in fact, exercise rate was a bigger predictor of motor recovery rather than aerobic exercise. But again, we had patients exercising at this moderate to high intensity.

Glen Stevens, DO, PhD:

Jay, I know it's a little different on the stroke side, but have you seen patients decrease their need for medication?

Jay Alberts, PhD:

Yeah, so we have actually. And again, I want to emphasize that I'm a PhD and not a MD, so I never encourage anyone to change medication. These are all decisions that they do in collaboration with their treating physician. And so we have indeed seen people who have decreased the amount of medication fairly dramatically. And the value of that hopefully would... Potentially could reduce future levodopa induced dyskinesias or other complications associated or side effects associated with anti Parkinsonian medication.

Glen Stevens, DO, PhD:

And the stroke patients they're able to cycle okay. If they have a significant leg weakness, they're able to do the procedure, Susan?

Susan Linder, DPT, PhD:

Yeah. So with the forced exercise model, after the tandem bicycle, Jay developed a custom engineered motorized stationary bike. So we've transitioned all of our trials to this semi recumbent stationary bike that again has a motor that supplements the individual's voluntary efforts. So they can achieve that cadence that is set by the therapist. So with that motor assisted bicycle, they're able to do that. We've also looked at voluntary rate exercise where individuals are using just a standard recumbent bicycle. And there are several who are able to achieve the intensity that we see with forced exercise patients as well. So there's certainly a component that those who have less disability and can achieve that intensity can probably have similar outcomes as those who are on the forced exercise bicycle.

Glen Stevens, DO, PhD:

And Susan, have you seen any improvements in areas of stroke relation that you wouldn't think would get improved with exercise or not necessarily?

Susan Linder, DPT, PhD:

Yes. In fact, what we're looking at now is changes in walking capacity and gait. And previously it was really thought that in stroke patients task specificity was needed to elicit improvements in other functions. So for example, in order for walking to improve, you have to practice walking. So cycling and walking aren't the same, but they have similar enough characteristics that we're seeing a carryover from intensive cycling interventions to improvements in walking. And we've seen improvements in gait velocity, walking capacity. And importantly, patients are not demonstrating worsening compensatory strategies in order to walk faster, we're seeing that their biomechanics of gait are actually improving as a result of the cycling intervention. So we're finding that the old adage of killing two birds with one stone is absolutely happening here. We're seeing improvements in cardiovascular function, which was already known in previous studies, improvements in motor recovery of the arm. And again, this is with a lower extremity aerobic exercise intervention and improvements in walking capacity. So we feel that this intervention can potentially reduce disability.

So one of the things we're looking at now is the cost effectiveness of this intervention because aerobic exercise is not covered in patients who have stroke yet we see a lot of benefits to it. So if we can show that we're reducing disability, improving community reintegration and all at a lower cost, then we're hoping insurance companies will start to cover this intervention and this approach.

Glen Stevens, DO, PhD:

So one of the most challenging things for patients is if their language is affected. Any possibility of any improvement in language skills, even though I know you're not exercising those areas at all?

Susan Linder, DPT, PhD:

We haven't done formal studies in that, but again, I'll go to what Jay has said that we've had anecdotal reports from patients and their spouses that their aphasia has improved. And in fact, I had one patient literally yesterday whose wife told me that the speech therapist indicated that since she had enrolled in our study, his improvements in speech had improved. This is an area I would love to investigate formally in the future, but we haven't and it's just been anecdotal responses.

Glen Stevens, DO, PhD:

And those are the things that keep us going. And I think that as we mentioned early on, we just need to be good observers.

Susan Linder, DPT, PhD:

Absolutely.

Glen Stevens, DO, PhD:

And look for things outside the area that we're looking at. And that's where really the excitement is. I'm a neuro-oncologist and there's a nice study done. Maybe we need to send some of our patients over and think about doing some studies with you, but there was a nice study done a number of years ago, and it's always the chicken and the egg, but they looked at grade three and grade four gliomas, sort of the glioblastoma anaplastic astrocytoma, the very aggressive high grade brain tumors. And they saw that patients that were able to exercise five days a week at a brisk walk pace for a minimum of 30 minutes on average, lived twice as long as those that did not.

And again, it's always hard to know the chicken and the egg. Maybe they were functionally better. Anyways, maybe they had decreased risk of blood clots. Maybe their blood sugar was better controlled. And that was good. But I think in the brain tumor area, also a lot of potential fruitful data or things that we could look at and maybe we'll have to talk offline at some point of things that we could do in the future for this, but quite excited about your results. So what about outside stroke, unless you want to add something else about the movement disorders or the stroke group before we move on, anything else?

Jay Alberts, PhD:

No, not really, but I think to your question to Susan, about where else have you made these observations, or what else has changed maybe that we didn't expect? We had some in Parkinson's for example, who I remember coming in. And one guy said, "Hey, doc, I could smell my wife making onions for the first time in 10 years." And then another guy said, "I never thought I had body odor until I started this trial and now I can start to smell." Right. And we all know that loss of smell, anosmia is one of the very early signs, really, almost a prodromal sign of Parkinson's. And so again, that led us to start doing the [inaudible 00:24:03] at the University of Penn, a smell identification test. And we actually published on that to show that this type of exercise would change, reduced anosmia as well, so I think those are things that give us hope that again, it's not a hammer and everything's a nail, but that we're actually changing for function and the operation of the central nervous system, which is very exciting for me.

Glen Stevens, DO, PhD:

Yeah. we always look at risk benefit and the risk seems pretty low benefit on the positive side.

Jay Alberts, PhD:

Yeah. I would agree.

Glen Stevens, DO, PhD:

So what about work in other areas of neurology, Alzheimer's, MS. You guys doing anything there?

Jay Alberts, PhD:

Yeah, for sure. And so one of them is related to Alzheimer's and this many ways was a combination of the observation of some of our work in Parkinson's, where we showed improvements in executive functioning. And then also the great work that Dr. Steve Rao has done already in some exercise studies with individuals who are APOE4 positive. So Dr. Rao and I just recently got a grant study, the effects of high intensity exercise on decreasing the conversion rate of those individuals who are APOE4 positive to Alzheimer's, right? So there's about a 20 or plus percent conversion rate.

And so what we have is we have two groups of individuals who are all APOE4 positive, and one group is doing usual and customary care and they're fairly sedentary. Whereas the other group is randomized to the home exercise program using a Peloton cycle. And we're monitoring to evaluate, does exercise change that conversion rate. Based on some of Steve's earlier data, we are clearly hypothesizing that it does. And then associated with that, we're doing a tremendous amount of imaging and other neurocognitive testing there, again, to see if we can change that trajectory or that conversion.

Glen Stevens, DO, PhD:

So Jay, I'm a runner, but maybe I need to get back on my bike a little bit more.

Jay Alberts, PhD:

Well, your knees, at some point, they're going to force you to get back on a bike, right. So...

Glen Stevens, DO, PhD:

They're already talking to me.

Jay Alberts, PhD:

Exactly, but that's a great point. We use cycling primarily because we can control a lot of variables and we can measure a lot of things from the cycle. So that's great. But it is by no means the panacea to the mode of exercise, right. Certainly treadmill walking is good, even rowing, things like that. The challenge is safety, especially when you're talking about a patient population. And we're asking them to exercise at relatively high intense rates and cardiovascular parameters there. So sometimes coupled with mobility issues, the treadmill may not be the safest but again, it's not a panacea. I mean, cycling is not the panacea here.

Glen Stevens, DO, PhD:

And what about MS? I seem to recall in my older days that Utah's phenomena, people get heated up neurologically it affects transmission, and the MS patients could get a little bit worse. So I guess if they're exercising and getting too hot, maybe that could be a negative. Are you seeing anything with the MS patients, is that an issue or not an issue?

Susan Linder, DPT, PhD:

No, that's a great question. So in the last summer we launched a pilot study where we're enrolling 20 participants in that, and we were ready with cooling vests just in case that would occur. But in fact, all of them have tolerated the intervention without any negative side effects that way. And the reason we started with this feasibility or this study to primarily look at feasibility was precisely that can this population tolerate the intensity that we think is necessary to result in this upregulation of neurotrophic factors to potentially improve either their symptoms or there are some animal models that are showing exercise can even promote remyelination, which I know we're a long ways off of demonstrating that in humans. But based on some animal models, if we can even look at exercising at an intensive rate with people with MS, then we potentially have some promising things to look forward to.

Glen Stevens, DO, PhD:

Well, you guys have convinced me I'm going for a run tonight.

Jay Alberts, PhD:

Excellent.

Glen Stevens, DO, PhD:

At a high rhythmic intensity.

Jay Alberts, PhD:

Excellent.

Glen Stevens, DO, PhD:

Well, Jay and Susan, you guys made me believers. I'm very excited about the work that you're doing, and I think everybody should be excited out there and I'm really looking forward to extrapolating to other neurologic disorders and hearing the great work that you're doing on this very interesting research topic. So thanks for joining me today.

Susan Linder, DPT, PhD:

Thank you, Glen.

Jay Alberts, PhD:

Excellent. Thanks for having me.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.