Neuroplastic Promoting Medications for Cochlear Implant Recipients

Brian Taylor 0:10
Hello and welcome to another episode of This Week in Hearing. My name is Brian Taylor. And our guest today is Dr. Rene Gifford, who’s a professor in the hearing and speech sciences department at Vanderbilt University. And along with Dr. Gifford, we have a MD PhD student Ansley Kunnath and I want to welcome both of them to the to the broadcast. Thank you for being here.

René Gifford 0:34
Thanks for having us.

Brian Taylor 0:35
Yeah. And our topic today we’re going to talk we’re going to be discussing with both of them, neuroplasticity promoting medications for cochlear implant patients. And before we dive into our topic, I thought maybe I’ll start with you, Dr. Gifford. And I hope it’s okay if we go by first names here. But if you could kind of share with us your role at Vanderbilt and some of your research interests.

René Gifford 1:01
Yeah, thank you. So I’m René Gifford. I’m a professor of hearing and speech Sciences at Vanderbilt. I’ve been in the field for about 25 years now started out really as a pediatric audiologist working with hearing aids and cochlear implants. I went back and got my PhD in psychoacoustics and then moved on to cochlear implants, Speech Science and kind of just evolved from there. The work I do here is primarily focused in children and adults who have hearing loss who are using both hearing aids and cochlear implants together. So combining electric and acoustic stimulation, that’s kind of been my research focus for about the last 20 years, it’s really exciting, because it’s a very large proportion of the population that we have out there that are utilizing auditory implants. But unfortunately, we don’t know a lot about it, we know it’s effective. We know that, of course, if you program these systems, and you verify and validate the fittings that these individuals do very, very well. But we don’t really fully understand how the brain integrates these two very disparate signals, we don’t necessarily understand perhaps maybe the very best way in which we can optimize the you know, the programming of these two systems, or allow them to work a little bit more seamlessly together, kind of preserving queues across the two ears where, you know, two very different systems aren’t necessarily doing that, or at least not doing it very well. So this is kind of the focus of my work. Within that I’m very interested in, of course, how the use of these technologies influences, for example, a child’s auditory development, ultimately impacting their speech, perception, auditory, visual, auditory-visual, as well as ultimately speech production, which is really an important thing that we don’t always necessarily kind of think about in audiology per se, as well as language, ultimately literacy, academics success, socialization, etc. So these are the types of things that we do here, we look a lot in terms of spatial hearing ability. So how do these systems allow individuals to pick out sounds in their environment, able to pick out for example, a target speaker in a very diverse, diffuse noise, environment, reverberation, and so forth. So these are the types of things we do we use behavioral measures, electrophysiology, functional neuroimaging with functional Near Infrared Spectroscopy, or fNIRS, which we’ll talk about a little bit later. And we just do a lot of different things really across the lifespan. And I do also since I have moment to introduce our one of our MD PhD students, and so Ansley Kunneth, who is here with us, it’s a great pleasure to have her with us, she is working across two labs. So she’s in my lab, the cochlear implant Research Lab, as well as working with one of my direct collaborators, Mark Wallace, who is really a multi sensory neuroscientist. So she’s really doing a fantastic job of bridging those two disciplines. And she brings just a great perspective, that we don’t necessarily always see more on the neuroscientific PhD or students or our scientists.

Ansley Kunnath 3:57
Thank you.

Brian Taylor 3:59
It’s great to have you both here, Renee and Ansley. And before we get into the details of your work on neuro plastic promoting medications, I thought it would be helpful to kind of step back back a little bit at the beginning here and talk more broadly about the topic of auditory regenerative medicine. And I know Rene that a year or two ago that you were a guest editor for a special issue of JAAA that was dedicated to that topic. And I was hoping that in a nutshell, if you could give us a little bit more details about the topic or the subject of auditory regenerative medicine. And then secondly, if you could tell us a little bit of how how you see that shaping the way audiology is practiced in the future.

René Gifford 4:44
That’s such a great question. I’m so glad that you’re bringing this up. I really believe we’ve reached a point that we’re going to be seeing truly a paradigm shift in our approach to hillbilly dative and rehabilitative audiology really in just the next few years, which really has not been the case for the last 20 to 25 yours. So I do want to recognize that hearing aids and cochlear implants and all auditory implants, I mean, they’re highly effective. And we know that these can transform people’s lives. But of course, the primary issue with these hearing technologies is that they’re just not addressing, you know, the underlying physiologic and pathophysiologic changes that are resulting from the hearing loss itself. And so for this reason, hearing aids, auditory implants, they’re they work well, but they’re not able to completely restore, you know, normal auditory fidelity. And so that’s one of the reasons I’m so excited about auditory regenitive therapeutics. Of course, another reason is having worked in clinical audiology and research, the research space for all these years, I’m always getting questions, particularly from from families of children, you know, should we wait, do we need to wait until there’s hair cell regeneration or gene therapy, should we not proceed with a cochlear implant, and I don’t believe we’re at that point yet, because of course, we do know that there was a very critical period during which we need to be providing that auditory stimulation to allow for auditory development, as well as Speech, Language Literacy, and all of those downstream effects. But I do believe that there is potential for that to be something that we see in the future where we’re not necessarily waiting, but maybe it’s paired therapeutics, so you’ll see maybe use of an auditory implant and then paired with it, whether it be you know, genetic therapy, or some sort of molecular or pharmaceutical form, you know, agent to help with that, that system. But right now, that’s why I really was interested in having a special issue, because I get this question all the time from families, and of course, adults as well. So what’s right now there really are a number of therapeutic options that are available or will soon be available. So including molecular pharmaceutical, and stem cell based therapies, all of which are aimed really at kind of hair cell regeneration, or gene therapy. So we know this area of investigation is really active, it’s active both in academia as well as in an industry based science labs. And in fact, there’s even ongoing approved human clinical trials right now. So for example, there are some that are looking at acquired hearing losses and adults and applying a molecular agent to help improve hearing through stem cell regeneration, as well as there’s a human clinical trial looking at gene therapy in individuals who have oterferlin mediated sensorineural hearing loss. And so this is really, it’s a very exciting time to be in this space. And I do want to recognize that a lot of people have brought to my attention, they’ll say, Well, do you have any concerns, you know, about how the future of audiology or specifically, you know, my own career, the fact that I work with hearing technologies, basically, am I concerned that my job and my skills are going to go away? And absolutely not, if anything, I think it’s going to really allow us to ultimately practice at the top of our scope, and you know, utilize our our skills and our knowledge of the auditory system, specifically auditory physiology, and that interface between, you know, the difficulties that our patients are presenting with which of course, speech understanding and noise, understanding individuals when a number of people are talking, or if there’s reverberation and difficulty with music, perception and appreciation, these things are not going to necessarily go away simply because we can restore, for example, regrow hair cells, those connect those synaptic connections are going to need to be formed, we’re going to need to kind of teach those individuals to reuse this new information. And I truly don’t necessarily believe that hearing technology is going to go away entirely anyways, like I said, we don’t know if this is something that it’s going to be a one, you know, one shot, for example, that that’s going to be all that’s needed, or it’s going to be something that’s going to need to be delivered over time. And then paired with hearing technologies, it’s still a little bit kind of up in the air. But audiologists are going to be absolutely critical to this space. And I think if anything our our practice, and our field is going to expand and grow with this this area of restorative medicine.

Brian Taylor 8:56
I’m glad that you said that. Because we’ve had a few other guests on this topic, among some of our most popular episodes that this week and hearing have been representatives from some of the pharmaceutical companies that are researching in these areas that we’re talking about today. And I think one of the common threads through all of those interviews is that they’re seeing what I would say kind of a synergistic effect between the therapeutic and the devices, and they sort of complement each other. And it sounds like you sort of have that same opinion.

René Gifford 9:29
Absolutely. And in fact, one of my primary areas research of courses with that electric acoustic stimulation with cochlear implants and hearing aids. And specifically, I’m really interested in focused on individuals who have cochlear implants but have acoustic hearing preservation in the implanted ear. So of course, years ago, we thought this wouldn’t even be possible but now surgeons are implanting these relatively atraumatic electrode arrays preserving those delicate and cochlear structures and that neural substrate and my thoughts are how much better could This work, if we have, you know, some pharmacologic molecular agent to help with that hearing preservation and ultimately allow that individual take better advantage of that electric and acoustic stimulation, both within the implanted ear, and then of course, across the ears as well. So I’m, I’m just thrilled. I’m very excited. Yeah, that’s

Brian Taylor 10:19
great. Great to hear. Let’s go ahead and dive into the details of the clinical trial that you’re involved in right now that are investigating the neuroplastic effects of donepezil, am I saying that right?

René Gifford 10:30
That’s correct, donepezil.

Brian Taylor 10:32
Okay. And I know that’s a medication, I’ve seen it advertised in different places, I know that it’s a medication that’s used to treat different forms of dementia. I mean, maybe Alzheimer’s, you can kind of give us the details. And I know in the trial that you’re investigating its use on adult cochlear implant recipients. So maybe tell us a little bit about this medication, or this drug? And what are some of the questions that you’re attempting to answer with the trial?

René Gifford 10:58
Yeah, so I’m going to start and then I’m going to transfer I’m going to go ahead and let Ansley take over. I do want to point out that first, this is not my area of expertise. I’ve been very excited about this for many years. My first interest in this type of this area was when Emily, Toby and her colleagues published this paper in 2005. That was a placebo controlled trial looking at the effects of auditory training and regular stimulant use on auditory speech understanding as well as cortical cerebral blood flow, and a group of eight post lingually Deaf and adults with cochlear implants. And what’s really interesting about that study, of course, so four of the individuals were randomized to placebo, and four were randomized to daily amphetamine use over a period of time. They looked at functional neuroimaging using a single photon emission computerized tomography or SPECT. So it’s just basically it utilizes a radioactive isotope that allows you to visualize nervous system activity. And of course, it’s not necessarily contraindicated with the implanted magnet with a cochlear implant, as, for example, fMRI would be. So what they did was they looked at cortical cortical activation, as well as a number of speech perception tasks. And they found that following a eight week period of just targeted our auditory therapy, so this was like to one and a half hour sessions a week, which is a lot that the group that had auditory training paired with amphetamine use, they showed significantly greater improvements in speech understanding, as well as significantly greater cerebral blood flow, particularly in auditory cortical and auditory association areas. So it was really I found the study fascinating and and while we wouldn’t necessarily want to look at regular amphetamine use long term, particularly not in our you no more vulnerable populations. I was just really wanting to do this. And in fact, when Ansley came along, you know, as an MD, PhD student, and has this special knowledge and skill set. She was really the one she was the catalyst to really take this forward and the answer, I’d like to turn it over to you and kind of give us a little bit more information, about basically what we’re doing.

Ansley Kunnath 13:03
Thank you for the introduction. So ultimately, we’re trying to see if we can improve their brain’s response to a cochlear implant, cochlear implants can take over the role of the inner ear and activating the auditory nerve. But after that point, your brain has to make sense of all this new information that it’s receiving from the implant, and Donepezil it belongs to a group of medications that we know can increase neuroplasticity, or the brain’s ability to adapt to new information. Like you mentioned, an episode is also known as Aricept and it’s one of the most commonly prescribed medications for Alzheimer’s disease. There’s over a million Americans who are prescribed an episode currently. And we know that Donepezil can improve cortical plasticity, and specifically, we’re trying to see if it can improve auditory cortex plasticity following cochlear implantation. So in this study, we’re aiming to recruit about 50 participants, and 25 of them will be randomized to receive an donepezil and 25 will be randomized to receive a placebo. And then we are targeting a specific window after cochlear implantation, where we see the largest improvements in speech recognition and in cortical reorganization. So, these participants will be taking the medication daily from the time that they turn on the device and until six months after their implantation. And then outcomes from the study that we’re interested in include, of course, speech recognition, so we’re looking at word recognition, sentences, speech and noise, as well as functional neuro imaging with fNIRS like Dr. Gifford mentioned. And then finally, we’re also interested in a number of cognitive outcomes. Since there’s all of this new literature coming out suggesting that hearing loss can increase the risk of dementia where interest So to see whether donepezil may mitigate or prevent some of these effects as well.

Brian Taylor 15:05
That’s really interesting. So just has the has the clinical trial, Has it started yet? Or is it something that you’re ramping up, kind of give us an idea maybe of your timeline and how things are progressing.

Ansley Kunnath 15:18
So we are actively enrolling participants right now at Vanderbilt. And we plan to continue enrolling participants for about the next two years or so.

Brian Taylor 15:30
And I’m assuming it’s a randomized controlled trial. And I know as researchers, you don’t want to get out too far ahead of your skis. But I do have to, I’m really curious, like best case scenario, what are some of the results that you would like to see?

René Gifford 15:50
Yeah, so that’s a great question. So one of the things that we know about this drug is that it does result in increased acetylcholine in the brain. And so acetylcholine of course, we know is a neurotransmitter, it can help facilitate long term excitability changes synaptic plasticity, it helps with memory and learning and motivation, arousal, tension, lots of lots of, you know, higher order cognitive processes. And there are literally hundreds of studies that have looked at acetylcholine and drugs that promote acetylcholine binding or release in the brain or areas of the nervous system that have shown significant improvements with targeted activities. Such as, you know, vision, motion detection, and, and other aspects. And we also know that this also impacts auditory processing. So we’ve seen that we the royal we has looked at changes, and for example, reduced latency, increased amplitude of auditory evoked potentials, as well as speech understanding improvements in noise with these acetylcholine mediated agents. Now, the thing about that, however, is none of those studies have looked at individuals who have hearing loss. And so the fact that we know that this is a an effective mechanism in a number of you know, sensory and motor activities, it’s sort of, it’s sort of shocking that this hasn’t been done yet. So this is what we want to do. And so if we can kind of look to those other studies and create a hypothesis, which is what we did, I mean, best case scenario, that over that first six months of cochlear implant use following device activation, which we already know, is the steepest trajectory of improvement in our patients, or adult patients. That is, we’re hoping that when pairing that you know, rapid period of neuroplastic changes, that we pairing that with this medication, that we’ll see even greater improvements, and perhaps faster improvements of faster, you know, plateau effects for auditory based speech understanding. But we’re also potentially expecting to see some changes in neural cognitive processing for the better across this group of individuals. And, you know, best case scenario, this is this is what we’ll see. But of course, this is a double blind placebo controlled study. And so it will allow us to kind of avoid the traps of experimental bias, and you know, all of those things that can be associated with the interpretation of of these types of studies.

Brian Taylor 18:15
Can you give us an idea of when results might be shared with the public or the profession?

René Gifford 18:23
What do you think Ansley? I think, well, obviously, I think we have to wait until all 50 of those individuals have been recruited and then completed, at least you know, that first six months of device use over which we’re going to be following them regularly. So we have approval, this study is ongoing, and we’re enrolling individuals. So we are expecting this is going to take at a minimum likely two years to complete the trial. And as soon as the the trial is completed, and the data are unblinded, we’re going to be sharing these data with all of the communities audiology, otolaryngology and neuroscience, all of them. So we’re really very excited. And quite frankly, irrespective of what the results show, there’s a lot to be learned here. And so we’re very excited to just kind of proceed with this project and see what what happens

Brian Taylor 19:09
right, it makes sense. I guess my last question to both of you is, and you’ve kind of already alluded to this earlier, Rene and how do you see this kind of therapy? How do you see it changing the way audiologists practice with both hearing aid and cochlear implant recipients? What are your thoughts on that?

René Gifford 19:30
It’s a great, I can’t say for sure. Like let’s say we even see a really fantastic impact of the use of Donepezil on auditory outcomes and audio visual plasticity as well. I can’t necessarily pursue that this is a drug that would be prescribed for every single individual. But I think that this could potentially really unleash a number of investigations looking at a number of plasticity promoting medications that we really couldn’t be in likely should be considering in you know, use in our adult population of individuals with hearing aids. In various auditory implants and those that are going through auditory training, what do you think Anlse, in terms of how this might impact like future otology practice?

Ansley Kunnath 20:08
Yeah, I definitely agree. I think we’re only now starting to investigate the role of the central nervous system in our rehabilitative efforts in audiology and otolaryngology. And this is only going to improve from here and we’ll I’m excited to see where the field goes in that aspect.

Brian Taylor 20:26
It’s really interesting. Well, kudos to you and your labs for having the forethought to bring these studies to life. I think it helps everybody that has hearing loss, it helps the profession. So we’re, we’re very grateful to have you on on our broadcast today. Thank you for taking time out of your busy schedules to be here.

René Gifford 20:48
Thank you,

Brian Taylor 20:49
Ansley and Rene at Vanderbilt. Ansley Kunneth is a MD PhD student at Vanderbilt and Rene Gifford professor at I think most people that watch our show, know who Rene is, and familiar at least somewhat with her work at Vanderbilt. So thank you both for being on on our show today.

Ansley Kunnath 21:11
Thank you