Daniel I. Simon, MD (Host): Hello everyone. This is Your Science at UH host Dr. Dan Simon. Today I am happy to be joined by Dr. Stanley Bazarek, Co-Director of the Peripheral Nerve Surgery Center at University Hospitals and Dr. Jennifer Sweet, Director of Movement Disorder Surgery, Co-Director of Pain Surgery and Neuromodulation at University Hospitals Cleveland Medical Center, the Sheila and Sandy Fox Master Clinician in Neurosurgery at University Hospitals and Professor of Neurological Surgery and Psychiatry at Case Western Reserve University School of Medicine.

Welcome Stanley and Jen.

Jennifer Sweet, MD: Thank you.

Stanley Bazarek, MD: Thank very much.

Host: So before we begin, I want to kind of back up just a little bit to set the stage for our listeners in the sense that we're kind of represented here by two parts of the brain. We have the central nervous system with Dr. Sweet and the peripheral nervous system with Dr. Bazarek. So Jen, maybe you could start out and just tell our listeners what does a Neuromodulation Neurosurgeon do exactly? What are the diseases that you treat? And in simple terms, how do you actually do it?

Jennifer Sweet, MD: Okay, well thank you for having me. In simple terms, what we do is we place electrodes in the brain or different parts of the nervous system, and we basically modify the behavior of neurons of different cells in the brain and we allow things to function more normally. So for different diseases, for example, Parkinson's disease or essential tremor, some of the cell behavior is abnormal. And that manifests as different symptomatology. So when we place these electrodes, we're modifying those cells. We're not injuring brain or lesioning brain. We're just modifying it. And, usually our electrodes connect to little batteries like pacemaker batteries. And essentially we give electrical stimulation to change the behavior of cells and restore normal symptomatology.

Host: So it seems sort of magical. How good is the imaging and how quickly can you do this in the operating room to place an electrode for Parkinson's disease, in a very precise manner? How do you do that?

Jennifer Sweet, MD: A lot of planning. Our surgeries really begin way before the patients come to the operating room. We do a great deal of planning with preoperative imaging, different types of neuroimaging to look at the various locations in the brain. And, we do a lot of planning with our neurology colleagues, our neuropsychology colleagues, and we really establish that patients have a specific disease that would benefit from our electrodes.

And after many, many months of intense detail and planning, we then bring the patients in for surgery. The surgery itself is really the simple stage. We really just can do things in a slightly minimally invasive way where we make little openings in the bone and pass these electrodes into the brain and then connect the electrodes to the batteries, and then afterwards there's a lot more work where we actually program the patients and watch them postoperatively to get the right settings. So it's sort of a long-term relationship with these patients that we have, but the results can be life changing and, and really gratifying.

Host: That's great. Okay, so Stan, you're the peripheral nerve guy. Tell us a little bit about a typical procedure for peripheral nerve injury. How do you repair of the nerve or is it stimulation or is it actually surgical repair of the nerve?

Stanley Bazarek, MD: Right. Yeah. So I mean, we do your typical releases like at the elbow and the wrist for entrapment syndromes, tumors in the nerve. But injury unlike the central nervous system, does have some regenerative properties, although it's not as robust as everyone thinks, and really you try to look for any natural recovery that's going to happen. So we typically wait a little while and then once we see that it's probably not going to recover, then we have to go in and either, cutting out a scarred neuroma and using a graft or trying to direct re repair things, which is the most ideal. Or we can rewire things, to try to redistribute existing function for the greater good, I would say.

Host: That's great. So several years ago, a research team from UH and Case Western developed a system of muscle stimulation controlled by a brain computer interface that allowed a paralyzed person to move his previously immobile arm. And an upgrade to that system is in the works, which allows really unprecedented reanimation of paralyzed limbs, under direct control of the brain. I understand that you've received a $3 million grant from the Department of Defense to upgrade the system, now known as ARehab for reconnecting hand and arm to brain. What makes this such a significant effort for patients recovering from traumatic brain and spinal cord injuries?

And, and can you explain exactly how the system, really decodes motor intent, let's say, and reanimates movement through stimulation? Maybe Jen, you could start and Stan, also weigh in there.

Jennifer Sweet, MD: So this is just a phenomenal project that I'm really lucky to be a part of. Just as a, bit of background, we are part of a, a larger consortium with many centers around the country, namely Stanford, MGH, Brown, and then, Case Western. And we were part of this consortium where we, implant electrodes in the brain and help patients who have spinal cord injury or other forms of paralysis move a robotic limb so that they can finally feed themselves with a robotic limb.

Our version here is that we were fortunate enough to get new funding. The biomedical engineers here at Case Western are just incredible and they basically incorporated the brain electrodes that we were already implanting with peripheral nerve electrodes that Dr. Bazarek can talk about.

So basically we implanted electrodes in various areas of the brain as well as in the paralyzed limb of the individual. And we're really the first center in the world to help patients move their own paralyzed limb via these electrodes. So basically we're bypassing the paralyzed spinal cord and allowing a patient who hasn't moved his limb in 10 years or so to, to restore that function. And it's quite remarkable. The way it works is we have electrodes in areas of the motor strip and also in areas that are involved with the intent to perform hand grasp or arm grasp, arm reach. And basically the electrodes the signals are recorded and then they're decoded and, through fancy algorithms, ultimately we are able to interpret the patient's intent and desire to move their limb.

And then those signals are then basically delivered to the electrodes that are implanted in the peripheral nerves and in the muscles of the paralyzed limb. And then, this reanimates that actual limb, and Dr. Bazarek can speak more about the limb portion.

Host: So, Dr. Bazarek, your experience, includes performing nerve transfers for upper limb function and bladder control in tetraplegic patients. How do these surgical rewiring techniques set the stage for the broader goals of the rehab project?

Stanley Bazarek, MD: What we're hoping to do at the Nerve Center here is really kind of offer everything, including the most up-to-date technology, which, I think would include, the neural interfacing. So I think each patient is really, has to be tailor made for these applications.

So if you have no bodily function at all, then you really need a brain computer interface. As you move further down the spine, you have more nerve transfer options. So it's really just the idea that we can offer all these tailor-made options. In the meantime, it just learning the anatomy a lot better to be able to help place these electrodes in the right spots.

Host: So, you mentioned that this study is a collaboration between multiple centers, but locally, UH, Case Western, the VA are all getting together. Tell us a little bit, how does this multidisciplinary, multi-institutional partnership team, how does it play for success? Maybe Jen, you could start.

Jennifer Sweet, MD: Yeah, it's incredible to have collaborations with such great colleagues around the country. It's been really instrumental in our success. And then to take it one step farther, the, Case Western and UH partnership has been really helpful. There's something called, the FES Center, Functional Electrical Stimulation Center that's very unique to Cleveland with, multiple investigators, probably more investigators in one center than really most places in the world.

 I wish I had those statistics for you. But it's an incredible center with a lot of investigators and clinician scientists, and really they've been developing these functional electrical stimulator electrodes to restore mobility of limbs for many, many years.

So with our involvement in the brain portion of things, we were able to partner the two and marry the FES center electrodes with our brain electrodes. And that's what makes it so unique here in Cleveland with this particular project, the REHAB study, which is restoring the hand and arm to brain.

Host: So this is all obviously heavily intertwined in biomedical engineering, but Dr. Bazarek, you're working on some cutting edge strategies using stem cells to I guess you would say, repair injured peripheral nerves. Can you walk us through this work? How do these stem cells work? What exactly are you doing?

Stanley Bazarek, MD: Right, so one of the biggest problems we have even with our last patient being a higher injury, is that you can have some muscles that are denervated. So it's really important when assess electrode placement, to know what's denervated and what's not, because denervated muscle doesn't stimulate.

So, and that's actually the, the real problem we have in all of peripheral nerve. And that's just piggybacks on how important it is to have. We have an excellent neuromuscular team to really assess all these muscles and we meet every week, essentially. So it's not just that we're technicians here, we're heavily intertwined with the planning process here with the engineers, which I think is really a, a step forward for something like this.

 You can pretty much generate any cell type in the body now. So the idea is to make the motor neurons, inject them in the distal aspect of the nerve to actually keep the muscle alive, even though they don't have control from the spinal cord or the brain, they now can be stimulateable and can become a live muscle. And that could offer us more options for electrodes in the future.

Host: What are the nature of the stem cells? What is their lineage?

Stanley Bazarek, MD: Yeah, so you can either get these from embryonic stem cells, you can get them from blood cells, turn them into stem cells, and then differentiate them into spinal motor neurons. So, so these are all spinal motor neurons.

Host: Excellent. So Jen, you know, one of the exciting frontiers of neuromodulation is actually, in psychiatric disorders, depression and bipolar. This is extremely interesting because I think all of us have family members or friends where we see the limitations of medication and it's incredibly interesting. I saw some work, related to obsessive compulsive disorder and, neuromodulation that has been game changing. Tell us a little bit about your work in bipolar disorder and how did you get to this spot?

Jennifer Sweet, MD: Yeah, well, great points that you bring up the neuropsychiatric world, it's really interesting. I won't bore you all with the details of it, but, most people remember the Psychosurgery era, which was really tainted the lack of neuroethics at the time and has really put a lot of stigma in this field.

But there's always been a really focused group of individuals around the country who've looked at the role of doing neuro interventions for psychiatric disorders and that ranges from lesioning procedures where you can lesion parts of the brain, injure parts of the brain, and help these disorders.

That's where a lot of our background knowledge comes from for doing this, for obsessive compulsive disorder and depression. And then as we've become more sophisticated in our neuroimaging technologies, we've been able to figure out ways to use stimulation, primarily the deep brain stimulation that we do for movement disorders.

And so, there have been a number of studies to look at neuromodulation or deep brain stimulation for different disorders. What many don't know is that, obsessive compulsive disorder has an FDA approval via a humanitarian device exemption approval, HDE approval. And so, we can perform this for patients who are very refractory.

The issue is though, the target that's been FDA approved is not usually the target that's really targeted anymore. We know that the more we learn, the more we realize there are potentially other areas in the brain. So if we can identify these networks, these widespread networks and the centers in the brain that would be the most optimal for delivering the therapy, then we can really achieve a lot. So there's been a lot of work in centers across the country, across the world really, where we've looked at it for depression, different areas for depression, and many centers have had very good results of that.

 I came to this because we were interested in this and we had a team of psychiatrists at, UH who were second to none in bipolar disorder. They had achieved so much in terms of their work. Dr. Calabrese and Dr. Gao. And, so I stepped into this from the pocket of there's a need for bipolar disorder. Which is different than unipolar depression. And there are a lot of nuances that make it quite distinct. And so many of the trials that have looked at DBS for depression have included bipolar patients, but they haven't really explicitly teased out the nuances of that disease. So we've really looked at this from a neuroimaging standpoint. We've done a number of studies to look at the brain wiring to see if we can find a target in the brain for bipolar disorder that would be slightly different to that of depression.

We're still going through that data, combing through all the data that we've acquired. And the hope is that if we can identify these neural networks that are really primarily responsible for some of the symptomatology of the disease, then we can put electrodes in the brain and target it. But this is a national effort.

There are a number of groups around the country involved in this, and it's multidisciplinary as well. Psychiatry, neurology, neurosurgery, neuroscientists, the engineers, the industry. So we all have many meetings each year to really figure out how to make this more successful.

Host: This is a rapidly evolving field, and maybe for the final question, I could ask each of you to look into the future and say five to 10 years down the road, what do you think your area's going to look like? So Stan, let's start with you. Five to 10 years from now, what are you going to be doing?

Stanley Bazarek, MD: Yeah. It, and I think even more important than what's going to be there in five to 10 years is really increasing awareness that these things are being done. It's hard to recruit people for these things. And, even for the nerve transfers where have been known to relatively established at this point, only 14% of people are using these for spinal cord injury.

So, really in, at this time, I'm hoping that, I mean the electrodes are, are always going to improve. The computer systems are always going to improve. So I'm really hoping to see these taken advantage of and fully implantable systems in people by then.

Host: That's good. So we'll make sure that we refer you a lot of patients. So everyone listening, Dr. Stan Bazarek's willing to help. Okay. Jen, what about your area next five to 10 years?

Jennifer Sweet, MD: There's so much evolving with all of the improvements in AI and in the technologies and in what we're learning with neuroimaging about wiring in the brain. I'm hoping in five to 10 years we start to make more improvements in the treatment for neuropsychiatric disorders, even neurocognitive disorders like Alzheimer's or different dementias, though I think five to 10 years is a little optimistic.

With regard to our REHAB study, we're hoping to have a take home version of this in the next five to 10 years so that patients don't need to come to the lab to get their devices programmed and to do the signal interpretation. So hopefully there'll be a version where we can access more patients and have it more meaningful for them for use.

Host: That's really terrific. So I'll tell you as a cardiologist, a simple plumber, this is light years. The smarter people in medical school are obviously the neurosurgeons, and so congratulations to both of you on this incredible work. To learn more about research at University Hospitals, please visit uhhospitals.org/uhresearch. Thank you both for joining me today.

Stanley Bazarek, MD: Thanks for having us.

Jennifer Sweet, MD: Thank you very much.