Mechanistic Pathway Through Which Saphenous Nerve Stimulation Can Modulate Bladder Function - Paul Yoo
April 24, 2022
Paul Yoo, Ph.D., PEng, Associate Professor & Associate Director, Professional Programs, Chair, Biomedical Systems Engineering Major, Division of Engineering Science, The University of Toronto
Diane K. Newman, DNP FAAN BCB-PMDUrologic Nurse Practitioner, Adjunct Professor of Urology in Surgery Research Investigator Senior, Perelman School of Medicine, University of Pennsylvania
Diane Newman: Welcome everybody. I'm Diane Newman. I'm a nurse practitioner and Adjunct Professor of Urology in Surgery at the University of Pennsylvania in Philadelphia. I'm also an editor of UroToday, and today I have with me, Dr. Paul Yoo. I had been at the SUFU Meeting and had listened to his presentation, and I thought it might be of interest to you, who are watching. Dr. Yoo currently holds cross appointments as Associate Professor at the Institute of Biomedical Engineering and the Department of Electrical and Computer Engineering at the University of Toronto. He also serves as a review editor for the Frontiers of Neuroscience Journal. His research interests are in the field of neuroengineering that encompasses neurointerface technologies, neurophysiology, and clinical translation. So Dr. Yoo, can you give us a short presentation on what you talked about, about the saphenous nerve stimulation?
Paul Yoo: Sure. Thank you, Diane. Very excited to be here. Give a very brief overview of the research that we've been working on and it focuses around a novel neuro target that we've discovered in my lab. And, in this particular study, we're interested in the mechanistic pathway through which saphenous nerve stimulation can modulate bladder function. It's a very important question because it seems quite difficult to wrap one's mind around how a peripheral nerve can modulate bladder function and it turns out that there is a very specific pathway, and so this study provides that. And so, in this slide, what I'd like to briefly talk about is actual preclinical model that we are using. And so, as you can see on the right here, the animal study that we're using is an anesthetized rat, where we've implanted the bladder with a suprapubic catheter, and we continuously fill it such that we have repeated bladder contractions, bladder filling, and bladder emptying, and that just repeats over and over again.
And so, the idea here is that we provide electrical nerve stimulation, and there are specific parameters that we use, and when we do that, we see changes in bladder function that correlate with inhibitory responses. So, on the left side here on the bottom, this is a sample figure from one of our published papers and this is the first study where we looked at short duration trials. So these were 10-minute trials, we stimulated at a very low amplitude, 25 microamperes, which was about slightly less than two times the nerve activation threshold, so it's a very low level of stimulation. And what we found was that we could increase the intervals between bladder contractions which, if one were to interpret that, it means that we're increasing the bladder capacity and we're increasing time between the contractions and, hence, there's a decrease in bladder contraction rate. So that is consistent with a bladder inhibitor response.
In a subsequent study, we increase the amplitude, so we wanted to get a stronger response to see what was happening, and we increased the duration as well. So now it's 40 minutes instead of 10 minutes. And when we did that, what we found was that the bladder, all of a sudden, exhibited these transient inhibitor responses, and these are known as overflow incontinence. And the reason why it's called that, is because the bladder is continuously being filled, but since it stopped contracting, it just distends passively and you have dribble through it, and that's why it's called overflow incontinence. But the main point here is that we see these transient periods of inhibition of bladder function. The bladder stops working. And we think, based on this evidence, that perhaps these could be translated to patients with overactive bladder.
So, in this current study, as I mentioned, we wanted to know how exactly the saphenous nerve, which is this new nerve that no one has really talked about, how that connects with the bladder. And it turns out, through this study, it connects indirectly through the brain stem and back down to the bladder. And so, in order to prove that, we used the same animal model, and so we have a control group with 10 animals, and then we compared that with a spinal cord injury group. And so what happens when you transect the spinal cord, and this case we're transecting the spinal cord at the level of T6, what happens in these animals is that over the next couple of weeks, following the surgery, they recover bladder function, but it's a different type of bladder function. In other words, it becomes overactive. It's a neurogenic overactive bladder, but other studies have shown that you can inhibit this bladder function by, for example, stimulating the pudendal nerve.
So it's a model where neuromodulation has been shown to work, and so what we wanted to see, was in the same animal model and the same spinal cord injury model, could saphenous nerve stimulation achieve the same things? And if it did, then it would suggest that it's not a super spinal mechanism, it's a spinal mechanism. So in these two models, in these two groups of animals, we applied this the same stimulation parameters, and in this particular study, we looked at intermittent stimulation. So 30 minutes of stimulation on, 10 minutes off, 30 minutes on, 10 minutes off, and we repeated that six times.
And so the data analysis, in other words, the quantitative measure of changes in bladder function, were compared to our baseline, which is prior to stimulation and then we compared changes in bladder function during stimulation, and also after the stimulation was turned off. And the reason why we were looking at post stimulation is because we know, at least with tibial nerve stimulation and what we were seeing with saphenous nerve stimulation, is that the effects of the stimulation persists after the stimulation is turned off. So this is very different from sacral or pudendal.
So just to highlight the main difference differences between these two groups of animals, on the top trace is bladder activity from the control groups, so these are healthy urethane-anesthetized animals, and in the baseline period, you can see we have periodic bladder contractions, so the bladder's filling, emptying, everything is fine. And then we start stimulating, and then what you start to see is that, in this particular case, after the first cycle of 30 minutes, we see that the bladder sort of goes quiet and then it starts to fill. And then when we stimulate again, it continues to contract, and then when we stop the second cycle, now that fill ends up being longer, and what we actually see is no flow incontinence episodes. So, this is something that we've seen previously, but now we're seeing it in a much more consistent manner.
And so we see this change, so the emergence of overflow incontinence episodes, and we also see some changes in the intervals between bladder contractions as well. And I'll highlight that in the next slide. Now, in thew cord injury group, what you see here is basically stimulation does not seem to elicit any type of response. We don't see overflow incontinence, we don't see any quantitative changes in bladder contraction rates, and so we see this very stark difference in the responses to saphenous nerve stimulation in these two animal groups.
So to summarize briefly what we've observed in these two groups of 10 control animals, and 10 SCI animals, in the control group, we see a 70% incidence rate of those overflow incontinence episodes. In seven out of 10 animals, we see that very strong inhibition, whereas spinal cord injured animals, we don't see any at all. When we look at the bladder contraction rate, so again, the intervals between the contractions, if you follow the healthy group, you see that during baseline and during the first stimulation trial, not a measured difference, but then as we reach the last stimulation trial, and then after stimulation, we see a significant decrease in BCR. In other words, there's an increase in the intervals between bladder contractions which, again, would suggest that there is an increase in the bladder capacity, as a result of this repeated saphenous nerve stimulation.
In the spinal cord injury group, you'll notice that the BCR is a bit higher and that's expected for a neurogenic bladder, but as you see with stimulation, it remains relatively high and there's no significant change. These, I guess, hashtags are indicative of the comparison between healthy and SCI. And what we find is that prior to stimulation, we don't really see a big difference, but with stimulation, we start to see a difference between the two groups, again, which furthers supports that even the BCR is different with stimulation of the saphenous nerve.
So the main findings here is that the differential effects of saphenous nerve stimulation between these two groups provides pretty clear evidence that the brain stem, a super spinal mechanism, seems to play a very important role in eliciting these bladder inhibitor responses that are evoked by saphenous nerve stimulation. As I mentioned, we see in the healthy groups, a definite decrease in the BCR, which we don't see in the spinal cord injured animals, and we see a high incidence of overflow incontinence which, again, we do not see in spinal cord injured animals. So with that said, this novel neural target that we've identified, seems to draw a neural mechanism where it starts in the saphenous nerve, the [inaudible] potentials, which are evoked are then entering the lumbar spinal cord, which is different from tibial nerve stimulation, and then, based on these studies, it appears that it affects the brain stem, which may or may not be the pontine nutrition center. It's a super spinal location, which is controlling the function of the bladder.
And so these are very exciting outcomes, and so we're very looking forward to continuing this work and trying to further nail down what exactly is happening within the central nervous system, and to better understand how this can be used in patients. And so, just to close that, I'd like to thank our funding sponsors, so Mitacs, EBT Medical the Canadian Foundation of Innovation have provided very generous support for our work, so I thank them very much.
Diane Newman: Well, thank you very much, Dr. Yoo. So I can see that you've done this, of course, in animals, but that probably has application for saphenous nerve stimulation in individuals with overactive bladder, right? So that was which, if you inhibit those bladder contractions, and hopefully with individuals who have urgency frequency, we may see some effect by simulating the saphenous nerve. That's basically where the next step would be. Do you agree?
Paul Yoo: Yes, yes, absolutely. And we've actually recently published a paper. It's in collaboration with Dr. Scott McDermott, and this was a CIHR-funded study, it was a pilot study, where it was actually the first test of this idea of saphenous nerve stimulation of patients, and what we found was that ... and this is published in The Journal of Urology in 2018, if I'm not mistaken, and we found that in a small core of patients that percutaneous nerve stimulation. So we used the same device as PTNS, but instead of placing in the ankle, we place it up near the knee where the saphenous nerve emerges. And what we found was that we see significant improvements across the entire spectrum of only these symptoms. And so that was a very promising first proof of principle results and we're continuing to look deeper into that.
Diane Newman: Now you've done quite a bit of work in this area, neuromodulation, kind of with the pudendal nerve, right? The posterior tibial nerve, and now the saphenous. What do you think? Is the saphenous, you think, is going to be better for this than the posterior tibial, or? It's closer, I guess, up to the bladder, but the pathways, is it so very different?
Paul Yoo: The saphenous nerve, in my opinion, I think offers a better option compared to tibial and pudendal. And it's for specific reasons. So compared to pudendal, as I mentioned in this presentation, that saphenous nerve stimulation has a prolonged effect, an effect that seems to persist or get stronger after the stimulation is turned off. And so, for that reason, we don't have to stimulate all the time, such as we would need for pudendal nerve stimulation and to a certain extent, related to sacral nerve stimulation. Tibial nerve stimulation, the physiological responses are similar. Tibial is also a post-stimulus type effect, but the main difference is that saphenous is a sensory nerve, purely sensory, so when this nerve stimulated, the patients only feel a slight tingling, or what's called paraesthesia that travels down the leg, and there's no movement, there's no muscle movement. And so it's even possible that this type of treatment could be provided in a sort of ambulatory setting. I don't know exactly if it will go that far, but it's a possibility. And so there are multiple advantages of saphenous, compared to other neural targets.
Diane Newman: Well, you brought up a good point. So saphenous is more sensory, whereas tibial is sensory and motor, correct?
Paul Yoo: Yes.
Diane Newman: So when this stimulation, they'll feel the sensation down the leg. And the fact that you also saw that it persisted as far as inhibition, right, in your basic science research here, so that's encouraging. [crosstalk]. Yeah, that really is, that it would persist even after the stimulation stops. Well, thank you very much. We really appreciate you doing this, and I know our audience will be interested in this basic science because in OAB right now, the growth really is in neuromodulation, so the fact that we have other options, hopefully in the near future and with the saphenous nerve, I think clinicians will be very glad to see this, so we're looking forward to it. Thanks very much.
Paul Yoo: Thank you very much for having me.