Chapters Transcript Video Beyond the bladder - Non-invasive brain stimulation for LUTS and NLUTD Rose Khavari, MD Uh, thank you so much for coming or being on Zoom with us today. And, uh, so this is Rose Caveri, so she is coming from um Houston Methodist and joining us from there. Um, today, so she, uh, has been in Texas for a long time, uh, so she did her medical school at um University of Texas in Galveston and, uh, then went to Baylor for uh residency and completed her fellowship in Houston as well, um, but, uh, she's well known in our Sufu world, um, for. Her robust research, uh, in functional neurology, um, particularly in the neurourology space. Uh, so she really is on the cutting edge and, uh, we, um, really look up to her with all of her, um, uh, um, new, um, data and, um, new techniques that she's looking into so that she'll touch on today. Um, so welcome. We want to give you a very warm welcome today. Thank you so much for being here with us. Thank you, Doctor Emin. So, um, first of all, I just want to thank everybody at the department, uh, at the the site at the Institute and um Uh, Doctor Emin, Doctor Sayan, Doctor Wean for inviting me, the leadership for inviting me to be here this morning. So, um, I'll go ahead and share my slides and we'll get started. All right. So this morning I'm gonna talk a little bit about functional neuroimaging, where we are with that in the world of urology, and then how, what are the implications of functional neuroimaging? Where are we with using this modality as a treatment or potential treatment option for some of the disorders that we see in our field, whether being uh neurogenic bladder or lower urine tract dysfunction. So here are my disclosure. The most important thing that I have to say is that I'm a urologist by training. I really have not done any neuroimaging or PhDs in, you know, these um uh amazing uh analysis. Um, uh, this is what I do. I augment patients that I take out stones out of their bladder, so. A lot of um help is needed from my standpoint, from my collaborators who are experts in neuroimaging, neuroimaging analysis, biomedical engineers. I saw Doctor Ying Zheng Cheng and the audience, so he was here in Houston. He was also one of my collaborators. So a lot of smart people around me have helped me build this uh research uh portfolio. One other thing that I want to highlight is that the therapies that I'm gonna mention today or the studies that I'm gonna mention today, they're maximum 20 years old, um, or the therapies are mainly maybe about 5 years old, 3 to 5 years old. So really in their infancy, when you compare them to Um, sacral neuromodulation or tibial neuromodulation, which has been around for 30, 40, 50 years even. So, just take that with a grain of salt, know that we're really just learning at this point. So a lot of things can change as we move forward and learn more about uh brain and supraspinal control over the bladder. Uh, for those of you guys who are interested in this field, there is a group called Neurogenic Bladder Research Group, which is, um, like about 15 or 20, um, uh, urologists and physiatrists that are part of this group, and our goal is to improve the care of neurogenic bladder patients, so you guys can take a look at that. We have a bladder Buzz podcast. Which is for patients and also for clinicians, and it focuses on um uh journal clubs, uh, different informations uh for the patients and, and any clinician who's interested. So you guys, if interested, you can kinda use that for your patients as well. And we meet uh once a year. We met last year in Houston and we actually focused on um how engineering and neurogenic bladder can help each other to improve patient care. So, Every year we have a theme and we publish on that as well. So a little bit about um kind of where we are in the landscape of neurogenic bladder overall. So the structure of the talk today is that I'm gonna briefly discuss neuroimaging in um healthy individuals and also in individuals with diseases such as lower urine tract dysfunctions and see if there's any um any way we can use. functional neuroimaging for diagnosis, for phenotyping prognosis, and also for therapy, um, and then touch base on some of the more, uh, newer uh terminologies or concepts more than terminologies um in our field. The world, the, the world of neuromodulation is really just exploding, and it's not coming from neurology. It's actually coming from the spine world, from uh neurology world, and you can see any part of the central nervous system. This is just central, not even peripheral. We're more familiar with peripheral neuromodulation in our world, but central nervous system, at any point of it, there is a way that we can intervene, um, uh, and see if there's an effect. So again, it's really exploding. It's an exciting time to be involved, uh, with this, uh, with the neuromodulation world. And I'll along the way, kind of share a little bit of how I got involved. So where did we start? Like 50 years ago, 60 years ago. Mainly what we knew about supraspinal control of the bladder, so brain, uh, brain stem by lesions, people would present with tumors in their pituitary area. With stroke, with aneurysms, uh, or little cystic lesions in their like spine, and we would use that information, let's say, or like ponting areas, and we would use that information to make um assumptions or decipher that as far as bladder control. So a lot of lesion studies, a lot of even in animals would create lesions in the spinal cord or or in their brain, and then we would look at their bladder function. Um, and that's how we would learn about supraspinal cord uh control over the bladder until the development of uh uh functional neuroimaging. So earlier on, we learned about Barrington nucleus host such contributed to our understanding of the medial regions of that and then that's when the very first studies of functional neuroimaging first with PET CTs and then with functional MRI came about that we actually were starting. To look at regions that really control the bladder first in animals, um, and then later on in humans, like map them out beyond the lesion, um, uh, kind of pathology that we were basing a lot of our uh information on. So. Although there's been many contributions to our understanding of brain, brain stem control over the bladder, based on the lesion studies in humans or animals or a lot of animal studies, personally, I think now that we have neuroimaging, it's really, really important to look at humans, um. How the bladder function, lower urinary tract function is in humans. So human studies are really critical because we do store differently, we do void differently, we have a different intent to urinate. The sensation of fullness is different in humans. So we really need to expand our knowledge um on that. And, um, functional neuroimaging or functional MRI that we commonly use now because it's noninvasive compared to PET CT. It's um it's an interesting technology. Basically, the oxygenated blood is picked up differently in the MRI versus deoxygenated blood. So this is an indirect measurement of a part of the brain that's active or not. Let's say if you move. your finger, that motor critique is involved with motor with moving that finger uses oxygen to become active and it shows it shows differently on the FMRI and that is like a spike of a bolt activation, blood oxygen level dependent activation. So there's simpler tasks, like as like moving your finger, and then there are very complex tasks, starting from like memory, you know, thought processes, from bladder control, bladder emptying. So there are multiple different regions in the brain that are involved with these more complex task tasks versus just a motor cortex. Um, and that, and that's when you have multiple regions that come on, uh, together or they're inversely related and that creates the concept of connectivity. There are two different connectivity. Uh, concepts, or one of them is structural, which is we understand a little bit easier. These are the areas that are connected with white matter tracks, axons connect A to B to C. We kind of can clearly see that. We know these tracks. We use diffusion tensor imaging to find them and locate them, very easy to understand. I think a little bit more. Difficult concept is the functional connectivity. So regions of the brain that are activated or deactivated together, but they're not necessarily at the same time, but they're not necessarily structurally connected. So that's called functional connectivity and creates these networks. So you'll hear these terms in my talk throughout the talk. So imagine, I'm gonna pause this for a second, so imagine somebody takes the cap off of off of your skull and takes a look at it. Uh, during MRI and while you're also having a catheter in your bladder and your bladder is being filled. So this is what it would look like if you could really paint, uh, put color on the brain as far as activation being more red, deactivation being more blue in a healthy individual as the bladder is filling, you. You can see more prefrontal cortex starting to feel and process the sensation of fullness, and then you make the decision to void, you have a lot of contraction and then the void occurs. So here, here is like a fast kind of activity in the prefrontal cortex so you can see the voiding and then you back, you go back to the, to the baseline. And if you create the functional uh connectivity between these regions, again, not structural, and use augmented reality, you can really see what regions are activated and connected and even kind of like make it fun and cool and walk through your regions and kind of see how it looks like really up close. Um, these are just some examples of what we've done in the labs. So, who were the pioneers in looking at functional neuroimaging? As I mentioned, this field is really new. It started in the late 1990s. Berto Block really has been giving a lot of credit for his studies, um, first in men, then in women, look at bladder filling and and voiding matrition. Um, and then he compared it a lot to cats because that's his bed, that was his PhD in, and he did a lot of his work in cats, and he said, interesting enough, looks like we have similar, uh, you know, activations uh compared to cats as well, um, and another a little bit earlier than that that. I just want to mention it, it was from um Japan around the same time that also published about identifying uh let's say Barrington nucleus ponds, nutrition centers for the first time in imaging, kind of like histology as opposed to lesion, um, studies that we were doing our animal work. Couple of other people, I think they need to. Be highlighted in the field again, because they were pioneers and helped us, uh, explore this area. One of them is not a urologist, is uh Doctor uh, Derek Griffith, who received the ICS, um, Lifetime, uh, Achievement Award. He's a geriatrician. He's really contributed to our field, uh, with, uh, uro. Dynamic uh understanding, he's a and and nomograms and then, um, and also he got involved with a lot of functional MRI imaging specifically on older populations and patients with overactive bladder urgency and urgent continence. So he really, uh, University of Pittsburgh and him and his group did a lot of those earlier studies, um. One of the individuals that helped us put it all together also is not a urologist, uh, Doctor Claire Fowler, that you guys know, uh, as Fowler syndrome. She is actually a uroneurologist, uh, so she put, uh, she and Derek Griffith actually really reviewed a lot of the literature and started putting these regions that we found in functional imaging. Together, um, I created, uh, basically created these maps or these networks or algorithms, then now we can understand what these regions are, how they work together. So now we think that when the bladder is distended, the sensations are passed through aer nerves, they go to the periaqueductal gray, not PMC that we all have read in our textbooks. They go to periaqueductal gray, which is also a very difficult area to image, and then that um uh uh those signals are relayed to hypothalamus and thalamus, and then they go to insula to uh an anterior cingulate gyrus and insula, so we can sense the bladder fullness. Is it full? Is it the first sensation, is it? The strong desire, where we are with that sensation, and then the prefrontal cortex really processes all of that decisions and, and all of those sensations, and he says, OK, we're full, but we're not in the right place. We're sitting in a conference room. No, we should not go urinate right now. So there's an inhibitory block to the PAG, um, and I always tell the residents PMC is just a switch. It really doesn't do anything. It's a switch. All the decision making is above and beyond PMC. So there's a lot. A lot of activity going here, as I showed you in that video, processing. Should I go? Should I not go? Is the bladder full enough? As I, am I in the right place? Is the bathroom door locked or not? So, let's say that is happening, the bathroom door is locked and your bladder is full and you're sitting down comfortably, and that's when the prefrontal cortex inhibits, uh, releases its inhibition or lifts its inhibition from the periaqueductive gray, and then periaqueductic ray just sends a signal to PMC and is just a switch and the switch goes down, the sphincter relaxes bladder contracts and the voiding occurs. So again, a lot of activities now we're trying to really make sense out of these uh uh areas and um uh we've been able to actually even create circuits. So we've created circuits that we know are active in the default mode so when we're sitting here comfortably, we are, we've created um uh networks or circuits, we've made sense out of it that. What circuits are active during um uh saline networks, and what circuits are even uh abnormal during a disease pathology such as overactive bladder patients. So, um, are we there to be able to use some of these neuroimaging, uh, techniques and technologies or our understanding to phenotype some of the diseases to, to phenotype better, and then in that same um spectrum are we there to be able to use that phenotyping to individualize our treatments? Can we find better targets? I picked a few disease pathologies that I think we are almost there or we're really making some progress. One of them is the bladder pain syndrome. Um, you guys have heard of the multidisciplinary approach of, uh, pelvic pain network, the map, uh, network, which really, uh, one of the components of it over the past 15 years has been looking at functional imaging, uh, because bladder pain syndrome. The spectrum, there's so much heterogeneosity in this group of patients and they have shown that yes, there is a different um uh you know, brain signature, you may say between different patients who present with with uh pelvic pain, um. And that difference is highlighted and can separate patients who have bladder centric symptoms versus patients who have symptoms beyond the bladder. And could that in turn guide us in therapy and looks like it can. This is a a group, this is uh uh Doctor Kutch and Doctor Larisa Rodriguez group and she was at USC. Is that for patients with pelvic pain, they picked 3 men and 3 women, and they use a technology called TMS transcranial magnetic stimulation. So it's a figure of 8 coil. I have an image of it later in the slides. It's like a magnet stimulation that we put on the brain. This technology has been around for 30 more years and used. Commonly in depression, it is FDA cleared with depression, used in many other uh uh disorders such as gait disorders, stroke recovery, other disorders, and they use this stimulation technology to stimulate and strip of the brain called um supplementary motor area, which is right next to the motor cortex, and they focus on the pelvic region. But again, in our field, we don't know, are we supposed to use high frequency stimulation, which is excitatory or low frequency stimulation, which is inhibitory. So they basically did a trial and error. They use high frequency and low frequency, and interestingly enough, they had um EMG sensors in the pelvic regions when they use high frequency stimulation, excitatory. They saw decreased pelvic floor activity and vice versa. So this gave them the framework to create a larger trial in um using transcranial magnetic stimulation for patients with uh pelvic, uh, pelvic pain, and possibly using a high frequency, uh, stimulation to be able to decrease. The pelvic floor tone or pelvic floor activity in patients with pelvic pain. So there are basically two studies currently that I could find that are using neuromodulation um for uh ICBPS. So to answer that question, that can fMRI help with phenotyping can we eventually used some of these understandings over the past 20. 20 years or so to for therapy, maybe, I think we're heading that way. We are really making some progress in the world of pain, um, and a lot of it again overlaps with the pain, um, studies from the spinal uh uh uh uh field. So another disorder I wanna touch base on is overactive bladder, and I wanted to give a shout out to Doctor Ween. Um, who actually could uh helped coining this term, otherwise we had to be dealing with this, uh, very, uh, odd and very old term of unstable bladder, bladder instability, but now we have this really cool name of overactive bladder that's really helped us move the field forward with therapy. So many groups, um, I want to give a shout out to all of these groups who've contributed to our understanding, Oregon Learned group, Pittsburgh, uh, Swiss group, the Netherlands the Berta Blocks group. Uh, they really have tried to, uh, stratify your phenotype patients with OAB and, and we've learned now that They are different. The patients who have smaller bladder capacity with really strong contractility maybe different patients who have more sensory, uh, urgencies, more nocturia, more sensory issues, and there is, they do have a different uh brain activity or brain uh footprint. For instance, if you look at some of the therapies, let's say this is a group that looked at pharmacotherapy, anticholinergic. Versus a brain-based therapy such as hypnotherapy, and they realized that their patients actually responded better with hypnotherapy and the association between the prefrontal cortex and the anterior cingulate gyrus, which perceives the fullness uh was uh uh strongly improved, that network was strongly improved in the hypnotherapy group. Um, another group also looked at um anticholinergics, and they saw that there were 18 patients who did not respond to therapy and 21 patients who did respond. And in the group that didn't respond, actually they already had abnormal uh uh uh patterns of activation in the anterior cingulate gyrus. So, so basically some data that people who respond to one therapy to the or to the other therapy may have different footprints and their um supraspinal activation patterns. This is a Pittsburgh group. This is one of my favorite studies because it was designed so well. So we use pelvic floor physical therapy as our first line therapy for everybody, for all patients. This is part of our guidelines. Um, but not everybody responds to this therapy. Um, and this is a good group that, uh, put, uh, uh, patients through public floor physical therapy. There was a responder group and a non-responder group. Everybody got fMRI before and after therapy. So people who responded, you can see in their anterior cingulate. Agilis in their insular prefrontal cortex. They start with really, really active, like their brain is on fire. And then when they responded, that activity did go down. Uh, if it just to like, like a novice eye, you can see that there was a change. People who didn't respond, they started with the really not so active. You know, uh, brain, uh, activity in those regions, and then there was no change. So it's interesting that maybe you can use functional MRI and say, OK, so brain centric therapies like hypnotherapy, like pelvic floor uh pelvic floor physical therapy, maybe. More appropriate for this group, and not so much for this group. So I think we're almost getting there with um uh with phenotyping and using neuroimaging a little bit better, um, in phenotyping for patients and helping uh stratify our our our therapies, um. There is another concept in overactive bladder, and that's cognition, especially in aging. Um, um, I wanna again, I've highlighted collaboration earlier in my talk, but I want to highlight it again, especially for the residents or the junior faculty in the in the group who want to do research, is that really reach out beyond neurology, reach out beyond your little group of, you know, people that, you know, um, reach out to other mentors from other specialties because I think it's the collaboration that will make our field move forward and. Um, you'll be surprised to see how other disciplines, how much more advanced they are in their research and how they can help, um, translate some of the clinical questions we have. So, um, Rachel High was actually a resident gynecology, uh, at our institution. She went and did a fellowship and then came back and we recruited her again. So, um, she started looking at cognition and overactive bladder. Basically, she started this trial and we worked. Together to look at that's, this is a few years ago when there was a lot of discussion about anticholinergics causing dementia. So we did a, a memory test, um, put patients on, uh, blinded, randomized, put them on anticholinergic solafenoin versus Mirbeck rot, um, after a month, and then we did, uh, memory testing in the MRI to see if there was a difference between the, the groups who took either or, and we did not see a difference, but That led to some other projects that she is doing right now using um TMS for overactive bladder that I'll mention. This is another group from the Pittsburgh area group that they use a different kind of neuromodulation called direct current stimulation. So basically you run a current uh through the brain, um, for patients with overactive bladder to randomize them to mindfulness and um uh direct current stimulation and the combination of two, and this was just like just a couple of months ago published uh in in AU journal. So interesting results, some improvement, but the combination therapy. They did not, unfortunately do any FMRI before or after, so we really can't tell why the non-responders were non-responders, but I think it would be interesting to do those kind of imaging when we use uh uh therapies that are beyond the bladder, like brain centric therapy, so we can identify uh uh uh. Contributions to to response, so we can uh select our patients a little bit better. There are two trials right now ongoing using non-invasive brain stimulation for overactive bladder. One of them is at USC and the other one is the one I mentioned with Rachel High. She just completed her recruitment, so we'll see what her data would show uh on using RTMS for overactive bladder. So moving forward to other pathologies, uh, this is a group of patients that I am personally very interested in patients with multiple sclerosis who present with neurogenic lower urinary tract dysfunction. So again, another shout out to Doctor Alan Ween to making this simple enough for us to understand, um, and be able to talk about it, and that's uh when people come in with lower netract symptoms, we say either stored symptoms, frequency, urgency, incontinence, or voiding symptoms, emptying symptoms, hesitancy, uh, retention. Those sort of symptoms. In MS, majority of patients have storage symptoms. Quite a few have voiding symptoms. And then when you combine them, there's a lot of patients who have both. So you get the whole spectrum of symptoms in multiple sclerosis patients. Not only that, their symptoms actually changes over time. So it's the, it's a very dynamic disease. It's a very, um, You know, moving disease, um, uh, so, uh, very heterogeneous, very dynamic, um, and these patients really need help to help with their symptoms. So our group really started to look at patients with multiple sclerosis about 15 or 1213 years ago, um, and we have the largest group, a cohort of patients in the literature, almost about 50 individuals that we've looked at with different paradigms and have been able to identify regions. Of the brain involved in bladder control. So I mentioned a structural connectivity, um, so it's interesting in MS because it's a myelin disorder to look at axons, right? Um, we wanted to see if these tracts that are involved with bladder control, um, and thalamic radiation or superior longitudinal vesiculus, are these more important when it comes to symptoms or functional connectivities. So basically, the networks that work together come on and off together at the same time. Interestingly enough, in patients who had voiding dysfunction. We realized that functional connectivity was actually more predictive of uh abnormality or symptoms compared to structural connectivity. So again, kinda, uh, it goes to the fact that brain is really very active and very neuroplastic when there's structural connectivity, there are other uh networks that work together to either um as a response or or or um uh to try to help with it. With the symptoms. Another group of patients that we're interested to to study is uh patients with bladder outlet obstruction due to BPH. So this um idea came about um actually at tofu, um uh when uh one of our colleagues kind of approached me and said, do you remember this is Toby Chai and said, do you remember when um Bill Steers from the University of Virginia was doing these studies that he would obstruct the outlet, kind of mimic a BPH syndrome, and then unobstructed and would look at the brain for neuroplasticity. Uh, you guys should do the same thing. You have the platform, work with your, you know, BPH guys and see if, if you can kind of set up the same study because we know that in patients who have bladder outlet obstruction due to BPH, about 1/3 of them, we relieve the outlet obstruction. Avoiding improves, but their overall symptoms don't improve. Their, their stored symptoms still there. The frequency urgency, their bother is still there. They keep coming back. So is there a change beyond the bladder, beyond the, you know, urothelium, beyond the bladder muscle? Is there a change in the in the brain? So we actually did uh partner with our uh BPH uh uh faculty and um set up a study. Sorry about that. Um, to, um, look at, uh, brain changes before and 6 months after bladder outlet procedure. Unfortunately, we're not able to uh recruit enough patients that we wanted. We only recruited 10 men. Um, and I learned a lesson, and that is, uh, up to this point, the majority of my patients were women because I was looking at MS. It's really difficult to recruit men for doing fMRI studies combined with urodynamic. It was just very, very challenging. So that was my, my lesson learned, um, and putting a catheter in them in the MRI was very challenging, um. So I mentioned a little bit about our lab and what we've done for MS patients and the BPH patients and overactive bladder patients. So our lab really wanted to look at uh not only just storage of the bladder phase, but also the voiding. So we needed to do the task of filling and voiding multiple times in the urodynamics, and you're only there for like 45 minutes. So, uh, we had to fill the bladder empty the bladder multiple times. The way to do it is to have a urodynamic machine. To, to fill the bladder in the MRI uh suite. And it's, uh, uh, you know, your dynamic machine is not MRI compatible. We can't take this to the MRI room. So we had to make an opening or a hole in the wall, uh, have uh a tubing that were like MRI compatible, super long. Uh, be able to put it in the patient and, and be able to run the urodynamic at least 4 times to be able to get um data. And again, I wanted to highlight the collaboration because none of this would have been possible without biomedical engineers in our group, without even GI doctors in our group. We have urologists from Europe partnering with us as well. So many groups have looked at uh uh supraspinal control of the bladder in neurogenic bladder uh patient population. Majority of them have looked at spinal cord injury or Parkinson's. Our group really has looked at um MS. So when I was at a meeting a few years ago, I saw the very first study of 6 individuals with a 7 Tesla MRI. This is a European group, this is the Swiss group, that they really were trying to map periaqueductal gray. So we learned a lot, a lot about the brain, um, at this point, we learned how to look at ponds a little bit in more detail, but periaqueductal gray is a very difficult area to image functionally. So, uh, we're really just kind of had a little blob of dots in that location. We really didn't know which areas were involved in bladder control or how, uh, fine tuned, uh, we could look at it. So they use this really very, uh, interesting fine-tuned, um, analysis. And I thought, well, that sounds great. We are getting a 7 Tesla MRI, um, at Home that is. We should do that as well. So we kind of decided to focus a little bit more on periaqueducted grade and cerebellum. Um, cerebellum had always been mentioned in a lot of the studies, um, related to bladder, but it was always like this stepchild that nobody really looked into it, um, carefully. So we thought, OK, we have this opportunity with the 7 test MRI list of cerebellum and periaqueduct are great. Um, and we used this time we actually use noninvasive bladder filling protocols so patients or individuals would drink fluids and then we would scan their bladder. We recruited healthy individuals, at 10 men and 10 women, 20 of them. Um, what I want to highlight in this, um, slide is that these are very healthy young individuals, amazing bladder capacities up to a liter. But when it was time to urinate, Only half of those patients or individuals were able to urinate in the MRI scanner. That's why it's so difficult to look at the voiding phase because it's really hard to urinate lying flat, even if you have a leader in your bladder. It's really difficult to urinate on the scanner with your head bolted down. And then just let go. So I want to kind of point that out, that's because it makes the interpretation of our dissolve our results so much more difficult when patients are not really able to urinate. But that study really led to identifying three specific regions in the periaqueductal gray, which we're excited about. So we kind of added these three points um specifically into uh the literature. Um, we had a visiting a urologist from France, uh, Charles Masou, who was finishing his PhD in neuroimaging and functional neuroimaging, a very bright guy, he's backing Nancy right now as a faculty. And so when he was here, we got him excited about cerebellum. So I gave him the cerebellum project and he really worked on it and um now we have 3 regions in the cerebellum that we know are involved with bladder network. So we hope that we can add these 3 little spots in the cerebellum, 3 little spots in periaqueductive gray to our working networks on our working paradigm. So we feel like this is a little bit of contribution to our understanding. So another um area that our lab has been excited to look at has been spinal cord. It's difficult to also do functional MRI in spinal cord. There's a lot of vessels are on the spinal cord that cause uh artifacts or the spinal cord moves a lot, it's free floating in the fluid, so it's really difficult to look at it. Another um difficulty with it is that you need a task, you need to excite the spinal cord, and we thought, OK, great, we'll do bulbocabiosis reflex, and then we'll, we'll use our functional MRI and see if we can scan the spinal cord, because again, at this point, all our data that we have about spinal cord activity, majority of them are from lesion-based animals or, or human lesion based. So we thought, OK, we should do the same thing for spinal cord. But doing bulbocavernosis reflex for patients, um, or participants in the MRI, you know, it's, it's really challenging. Nobody is gonna squeeze their glands or their clitoris or let us do it or Um, do electrical, you know, stimulation. So we really needed a, uh, simulated, um, uh, kind of device to, to create that. So our biomedical engineers designed and, um, kind of printed or fabricated this, this uh MRI compatible, we call it um uh bladder tapper. To tap the bladder with a very specific pressure, so we can kind of control for all of that in a full and empty uh uh uh time points to simulate the bulbocavernosis reflex. We did that with EMG sensors um into the anorectal region outside of the MRI scanner to make sure that we truly are creating a bulbocabernosis reflex, and we were, so then we started using it with the uh with the MRI to look at the. Um, the, uh, the spine activity. And these were the very early, um, activities that we could get. Um, and then we got, um, we kind of looked at our, uh, 2 subjects. Um, I had their full and empty bladder and we're able to actually show activity. They made a little bit of sense, um, in the spinal cord. This was just recently published also in NAU and really one of the very, very first, uh, functional MRI's. In our world, looking at uh bladder control. So there's a lot of work that needs to be done. Hopefully other groups will do this, um, and we can learn from each other to be able to look at activity areas in the the spinal cord, which would be exciting because we can apply this knowledge to spinal cord injury patients who have a partial uh injury and we can learn about activities and, um, um, uh, and spine, um, function in them. So in my opinion, I think we're learning a lot more about the not only the brain but also the other missing parts, the cerebellum, the, the brain stem, PMC PAG. We're learning more about phenotyping patients and, and we're moving more and more towards um uh neuromodulations beyond the bladder, beyond the spinal cord or peripheral uh nerves, and maybe more into the central uh central nervous system. As I mentioned when I started in this, um, field, I really wanted to learn more about voiding dysfunction because MS patients have difficulty catheterizing from below, and this is one of my patients that I did robotic metrophin off on her. She had visual disturbances and really spasticity from below, didn't want a cath from below. So all we have to give them for bladder emptying issues is a bag of catheter, and we just say good luck, pick the catheter you like and um and, and, and, and here we go. Uh, we have tons of options for storage, but not so much for emptying. So, our lab really tried to identify regions that were different in patients who were voiders versus voiding dysfunction in MS, and, um, created a, a, a pilot study that what if we modulate the brain noninvasively, can we make the networks that are abnormal, more normal looking, and could that Lead to improved bladder emptying. So this is actually me when I was learning about uh TMS. This is a TMS coil. It's a figure of 8 coil. Uh, I went to to Boston to learn and um for those of you guys who remember the homunculus guy here, so pelvic uh uh region for motor and sensory and SMA is right in the medial part of the, the brain, and that's the area that we really try to focus on. So, we picked 5 regions. Again, a lot of this is trial and error based on the networks that we know. We, um, stimulated excitatory 2 regions and inhibitory 3 regions. Uh, we recruited 10 MS patients and, um, did MRIs before and after, individualized the stimulation to each patient, did a 2 week stimulation for these patients, and, and here's the results. We showed that there's some improvement in the post-void residual, um, we're focused on the voiding. And the percent PVR over bladder capacity improvement in the questionnaires, and here's an example of an individual who voided. Uh, like 60 cc before, had a 125 residual and this is afterwards, uh, where they voided like uh uh 250 and then had very minimal residual. So, uh, 6 out of the 10 patients really improved and responded to the therapy, and 4 did not, um, but that response did did not last more than 3 months. It's a 4 month follow up and majority of them went back to their baseline. So a lot of uh limitations with this pilot study, obviously heterogeneous disease, we didn't have a placebo, but I think it set the stage for us to move forward with a bigger trial, which I'll mention in a minute. Uh, we looked at the liturgy to see what others are doing. Um, this is a, a review that we did to see who else is using non-invasive brain stimulation for bladder disorders, um, and there are different ways to stimulate the bladder. You can use magnet, you can use current, you can use ultrasound. Um, and there were 13 other studies, uh, that we could find that used non-invasive, uh, uh, brain stimulation, very small numbers, majority of them in, uh, pain or multiple sclerosis or spinal cord injury, um, and majority of them used uh TMS or um direct current stimulation. So with knowing that we designed a randomized trial blinded for the patients and investigators for MS patients who had overactive bladder and um this study was just funded by NIH and we we started recruitment recruitment about a year ago, and um we uh randomized patients to placebo sham stimulation versus um actual stimulation blinded to two regions that we care about prefrontal cortex and the SMA, um. And now we have recruited about 17 out of the 29 patients. So if you have any MS patients in the Miami area that is willing to spend 2 weeks in Houston, please send them over. We'll cover almost everything for them. Uh, and if you look at the clinical trials.gov, you see that there are a few other trials going, all of them are actually outside of the United States, uh, so the other three are outside of the United States that are looking at TMS for, uh, uh, bladder control and stroke or um in MS or other disorders. One last comment that I have about neuromodulation is that if you look at cardiac world or spinal world, cardiac pacemakers are not on all the time. Our sacral neurostimulators, tibial neurostimulants are on all the time. It's a very old school way of stimulating. So open loop neuromodulation. Eventually, we want to get to closed loop neuromodulation. We want to be able to receive sensation from the bladder. Is it full? You have urgency because patients don't have urgency 2 and 4 hours a day. Do you have urgency and that that sensation is processed, decoded by a device. And then when needed, the stimulation is delivered. So basically a more advanced um uh uh interpretation of the bladder sensation and um and then delivery of the stimulation. And I think we're moving towards it now that we have devices that can. Um, like this one by by the Cleveland Clinic, Marco Damaster's group, um, the ambulatory urodynamic devices, um, or if we can put EMG sensors on the bladder, can we have an, uh, uh, our, um, our generator decode that sensation and then maybe only deliver a simulation when it's needed. So I think this is the future. I don't know when, but hopefully in the next 1015 years, that's where we're gonna be heading. Um, and, and as I said at the beginning, these changes that we see in the bladder, in the brain, or supraspinal regions, we're not sure if this is, uh, the cause or an effect. Is this a response because of the bladder changes or there are truly some differences in the bladder that lead to differences uh uh in the brain that lead to the differences in the lower urine tract. But we think if we module, if we can modulate some of these abnormalities, we can make this. Work that looks haphazard. This is a MS group with voiding dysfunction and make it more organized, looking like MS patients who can void with deep or superficial neuromodulation, would that in turn improve bladder function. And with that, or, or, or there's a vice versa interaction between the two. Maybe. Again, this, the world of neuromodulation for bladder dysfunction is really new, um, maybe like 3 to 5 years old only. Um, these are my collaborators and are my supporters, um, um, and some of the websites that you guys can take a look at, um, and I wanna thank everybody for their attention, and I'm happy to answer any questions you may have. Thank you so much, Rose. That was really interesting. It was a great um overview of the journey that um of the research that's been on, that's been done in this area. And then also of, you know, touching on what's to come in the future as well and what what you guys are looking at. Um, and I think for the trainees, it was very interesting. I thought, um, with your own journey of kind of coming up with an idea and then applying that to the real world, like avoiding in a functional MRI and uh the trials and tribulations of, you know, what we come across when we come up with ideas that are sound exciting and then trying to apply those. So I appreciate um your honesty with that. Uh, so my question, you know, I think the TMS is very, very interesting, um, and it's kind of, uh, um, has a lot of promising aspects to it. Um, do you think that it has a big role for like a patient with like DHIC, um, that, that conundrum that we always, um, see when the patient has overactive bladder symptoms, but it also, um, a weak detrusor, so an incomplete bladder emptying as well. So, um, first of all, uh, so I'll tell for the residents and, and the junior faculty who who are interested in research, really pursue your passion. What got me interested is that the image I showed with the urodynamics and the person in the MRI actually was me. That was almost 15 years ago. I was the very first volunteer. It took 4 hours that study. To do your dynamics and MRI, uh, and then it got me excited about it, and I, I kind of decided to look into things. So, uh, really pursue your passion, collaborate, collaborate, collaborate as much as you can. Um, so to answer that question, one of my, again, voiding issues has always been my, my sort of my passion. Um, I, I'm, we're doing this MS bladder with overactive bladder, um, just because, uh, it was, um, we have a lot of more patients with that syndrome, uh, uh, specific, you know, complaints, but Um, underactive bladder, avoiding dysfunction is what I care about a lot. So we actually sent, uh, I've submitted two other ones, they both did not get funded, an underactive bladder, um, and, uh, brain imaging. Um, so, so hopefully one day, I think, I think there's a lot more room actually to use neural modulation for not only, you know, due to so hyperactivity impaired contraactively, patients that you mentioned, aging population with underactive bladder, PD. patient population of avoiding dysfunction. I think there are a lot of these um uh pathologies that we lump them all together, but these are just spectrum of different kind of etiology. Some of these patients really need therapies beyond their bladder and if we just focus on the bladder, we're gonna fail. Uh, but there are other therapies that can be more. Central nervous system centric, that can help some of these patients. Mhm. That's great. Yeah, I mean, I think I always talk to patients and I say we don't have like a magical pill that will make your bladder squeeze stronger. Um, so we have to look beyond that, um, you know, right now we just really have a sacro modulation, but we need something else in our toolbox for these patients. So, um, I appreciate your hard work on that. Of course. Any other questions? What about IC for initial cystitis and bladder pain syndrome? I know it's a very hot topic with sufu right now. Um, what kind of phenotype do you think that this would apply to, uh, for, for those patients, um, you know, when we're trying to tackle that, that diagnosis? Um. As I've done kind of read the literature or talk to people in this field, I've also learned one other thing is that neuromodulation will not be the answer to all of our problems. It will not even fix the things that we think. Uh, are gonna fix. For instance, we had a recent publication in Journal of Neurology and spinal cord injury individuals and tibial nerve modulation would argue samples a tear, um, and the goal for that, and we just got a DOD funding for, for another bigger trial for that. The goal should not be fixing patients urgency and urgent continence with tibial neuromodulation or let's say brain neuromodulation. There's a different way we should look at it. Is it an adjunct therapy? Can we decrease the need for overactive bladder medications for some of these patients? That's a long time, long term, you know, lifelong need. So, is it an adjunct? I think that's where we can make a lot more progress, a lot more success. If you look at some of these therapies, whether it being for IC, for overactive bladder, for neurogenic patients, the more complex patients as an adjunct therapy, then an absolute fix. Then there's there there's more room for success from their expectations from our expectations. So, so with ICU or bladder pain syndrome, I think since there's truly a spectrum, there are individuals that really have a devastated bladder and nothing works except for diversion, like doesn't matter what we do. So those are obviously not, but there are patients that they have other symptoms that is. More generalized, more centralized, more, you know, uh, brain centric. I think having a multidisciplinary approach and having a brain neuromodulation is part of the, the treatment pattern we make it, we may get better results than um just focusing on their bladder or um or even thinking that. Neuromodulation, let's say sacral or brain, would be the only thing that would work. So really looking at this neuromodulation as a, as a um adjunct, um, and then kind of fine tuning our expectations that we're gonna get with it. Maybe it could be just reducing or getting rid of the need for their overactive bladder medication. Yeah. No, that's true. And I think um basically with your um functional MRI and your techniques that you've used with imaging, I think you've done a really good job about um you know, the understanding the PAG, the different um avenues for how bladder function, um, but then that kind of applies for how we can. Treat, um, for synchron modulation, sometimes we, we say we don't really know how it works. Um, but I think, uh, the, you know, when you're concentrating on the brain, we have a little bit more better understanding, so it's, it's very exciting. Um, it's, you know, and nice to know that we know why it works. Um, so, yeah, I appreciate that. Any other questions from the audience? All right. All right. Thank you, everybody. Thank you. Thank you so much. Have a great day. Thank you for waking up pretty early today. No problem. I appreciate it. Thanks. Bye bye. Bye. OK. We're gonna switch gears and have the med student presentation. Um, we have Orlando Diaz, um, one of our cells here with us, um, who's gonna give us a short presentation today. Published October 23, 2025 Created by
