Technology vs. Pain and Addiction: Neuromodulation

Technology vs. Pain and Addiction: Neuromodulation

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Although I'll be spending a fair amount of time discussing some of the advances in neuromodulation, spinal cord stimulation for chronic pain, especially back in late pain, I like to actually expand this discussion to include a bit more on addiction and opioid epidemic and even a little bit of COVID epidemic, as well. Hopefully it all pulls together for you. I do have some consulting arrangements with a variety of companies that are listed here.

When I gave this talk initially back in 2016, Barack Obama was President, Joe Biden was Vice President and Nancy Pelosi was Speaker of the House. Now, Joe is president. We have Kamala Harris and Nancy is still there. Major difference here seems to be the mask. Seems that this is the first time we've seen that in State of the Union.

At that point in time, we were in the midst of what seemed to be the worst of our opioid epidemic. Things were escalating quite a bit. There were lots of initiatives, federal and state level initiatives to try and address ways of managing pain, minimize the opioid exposure to address the opioid epidemic that we were experiencing at that point in time. Unfortunately, COVID hit two years later and our opioid epidemic continue to escalate record pace. We're now on track for having well over a 100,000 deaths in 2021 and possibly exceeding one million people who've died from opioid overdoses since the turn of the century.

Now, I just want to explore some of the intersections between the COVID-19 crisis in the opioid crisis and how neuromodulation fits into this. Now, let's look at what the effect of pandemic has had on the opioid crisis. Now, we certainly have seen a data showing increases in opioid deaths as a result of COVID.

Many patients are more isolated and depression and mental health concerns have been skyrocketing, as well. In addition, we've had highlights of opioid over health care disparities, both in terms of treatment of COVID as well as opioid addiction and chronic pain, as well. These are all the things that are coming together to give us the problems that we see today. Certainly, we saw prior to the COVID epidemic, the institutionalization of the mentally ill, huge numbers of folks living homeless and living on the street. That certainly was right for spreading COVID even more drastically throughout our various communities.

This is an image of encampment around the corner from the Costco that I use in Santa Cruz. This baggy syringes you see in our far left here, it is a daily collection of syringes that my auto mechanic would pick up in front of his shop every morning. Certainly, things were already right for problems, for spreading disease and expanding the opioid problem even before COVID hit. We look at the distribution of the opioid epidemic and the drug overdose, we see that West Virginia was number 1 and that'll be relevant later on in the talk with a significant increase between 2010 and 2016, 60 deaths per 100,000. California is closer to the bottom here at being number 44 out of 56.

But still, I'm seeing changes and increases over time as well then COVID hit. Initially, it was curious disease. We heard about coming from overseas, but within just a few days, every week, there seem to be a rapid increase in the number of deaths from COVID until it became clear that it was a pandemic that we would all have to be addressing for the next few years here.

When we look at the disparity issues, we see that COVID also had obvious health care disparity concerns. We see here in this article in New York that there was a significant difference in the COVID-related deaths depending on race and median income. The folks at the lower socioeconomic part of the ladder had less access and less availability to care and as a result, had higher death rates. Similarly, we find that although our opioid death rates in California overall was not among the highest in the nation, if we broke it down by county and looked at some of the counties that had lower economic access, we see that those counties also had higher death rates due to opioids. This year, I was able to join in with a number of my colleagues looking at the racial and socioeconomic disparities in spinal cord stimulation among Medicare patients. That study showed that among those receiving spinal cord stimulation procedures, African-Americans and Hispanics had the lowest access and availability.

With those who had both Medicare and Medicaid eligible had the even lower access to spinal cord stimulation. Unfortunately, this year hasn't been good on a variety of fronts. For the first time in my career, the only pain therapy that requires prior authorization for the treatment of our patients in the pain clinic is Medicare patients is spinal cord stimulation. That's one of the first times ever Medicare has required prior authorization for treatment of any sort.

For us in the pain center, it's quite a shock to find out that that was going to be spinal cord stimulation procedure that we use quite a bit for patients with severe neuropathic pain in the trunk and extremities. Let's review again. This is part of what I discussed back in 2016, but neuromodulation is the focus. Treatment using technologies at the neural interface, sometimes that includes electrical stimulation of a peripheral nerve, portion of the cells outside of the spinal cord, and sometimes the spinal cord itself and even more recently, we've begun using brain stimulation for the treatment of pain as well. All of these are aspects of neuromodulation. Mostly it's electrical, but as we'll discuss later, it includes magnetic stimulation and sometimes drug infusions directly into the central nervous system as well.

This is one of the more common forms that we use in our clinic and across the nation. It's a couple of electrodes, couple of wires with individual contacts on them and that's attached to a battery pack that's implanted underneath the skin, which is like a pacemaker. These are used have to disrupt the pain signals that travel from the rest of the body up through the spinal cord and to the brain. If we can disrupt them before they get to the brain then a person doesn't have much pain and hopefully, they can reduce their usage of opioids and prove quality of life and resume some of the normal functions that they couldn't when they had severe chronic pain.

The hypothesis up until the last couple of years, for 50 years we've been using spinal cord stimulation. Some of the first studies were actually done here at UCSF, by Dr. Yoshio Hosobuchi in 1971 and 1972 and that proposed that the electric field would stimulate the dorsal part of the spinal cord like you see here on the right screen, the green asterisk. It allows as you stimulate those fibers and those fibers will travel into the cord, activate the inhibitory GABA fibers you see here on the diagram on the left.

That would reduce the sensitivity and the activation of the pain neurons that would transmit information to the brain. This has been the working hypothesis for the last 50 plus years. Unfortunately, we begin seeing in the last few years that long-term success of spinal cord stimulation wasn't the same as we were seeing with other forms of neuromodulation. Here we see a deep brain stimulation for Parkinson's, VNS stimulation for seizures and depression. We're maintaining their therapy over the course of 10 years which is the solid line, even if the battery pack diminish over that period of time and need to be replaced, the battery pack could be replaced in therapy continued.

However, when we look at spinal cord stimulation, we see that the therapy itself is diminishing. Actually were having the device is removed because it wasn't providing them with benefit for the entire 10 years. That rate was almost up to 50 percent over the course of 10 years. On average we've seen this about 10 percent per year. Still are unclear exactly why that is the case but some new research that I've been involved with might lead to some insights to that.

Well, the static nature of stimulation was the mode in which we thought the spinal cord simulators were working. It wasn't until we started looking a little more closely that we found that spinal cord stimulation actually is extremely variable and is variable based on the activities of normal daily living: breathing, sitting, standing, coughing, talking, laughing will cause motion of the spinal cord within the fluid that the spinal cord floats in it, therefore the electric stimulation is sometimes appropriately stimulating at the green asterisk, but sometimes stimulating at the red asterisk which is site that causes more pain. There's a lot of variability that occurs and this is something that we hadn't really recognized and took into consideration in our field for the last 50 years. In essence, we didn't really know what was happening to the neural tissues that we were stimulating. If we compare this to a pacemaker, a pacemaker will activate and stimulate the heart and then record the EKG of the heart to make sure that it's responding appropriately and then make a decision as to whether to stimulate the next heartbeat or not and which part of the heart, is it the atrium or the ventricle.

All of this is what pacemakers have been doing for the last 50 years and therefore, there's some physiological feedback that controls the output of the device. The only feedback that we currently have even today in the commercial marketplace, is the patient's response to how they're feeling, and they can either turn up or turn down their stimulator and that's it. We had no real indication and what was actually happening to their nervous system or more importantly to their spinal cord. It's not as though we didn't understand this from animal work however, in animal work, we have known for well over half a century that there is activation of a neuron, which is a pain cell or any neuron for any purpose but it is called an action potential and you activate it and that creates an electrical current and that current can be measured. As you're inside the cell, it goes up like this, comes from minus 70 to positive, as you're on the outside of the cell, it's just the reverse of that.

Well, it turns out just like with the EKG that has electrodes on the chest and recording the compound muscle potentials of the heart, we can use the electrodes on the outside of the spinal cord to record the evoked compound action potential of the spinal cord when it's being stimulated. That's something that is not been available before, it's not available in the United States yet but it is under investigation here in the US and by doing that, we can now have an output from our stimulus and to let us have some insight on the neural activation and the spinal cord response to see if we're stimulating too little, too much or just the right amount. We correlate that by increasing the output of the device, but recording the response to the patient's spinal cord, not just with their response so they tell us that they're feeling better with the stimulation but we'd compare that to how the neural responses that we're recording off of their spinal cord and correlate the two so that we know that their particular neural response that correlates with their pain relief will be the target that we're aiming for, not necessarily just the output of the device. When we do that, we see the huge variability in just normal daily activities occurs with the activation of the spinal cord and if a person's going to manage this and adjust it accordingly, they would have to adjust it so that it stays in that white bar. When they're doing activities like laying down or deep breathing, they had to adjust it down because it'll be too high and if they're laying on their stomach, they have to adjust it up so it's not too low.

That clearly is quite a challenge for patients to do that requiring that throughout the day. One possibility is let a computer do that and by identifying the ideal response that the patient has on their own spinal cord can understand either that that's the response that they say correlates to their pain relief, then every subsequent stimulation needs to be compared to that one and have the computer make those adjustments. Because the computer needs to meet those adjustments and the patients moving and doing their daily activity, it turns out that they're going to need to adjust that several million times a day. Clearly to much for an individual to push up the amplitude and lower the amplitude with their thumb on their little remote control device. Let's see how this works. Here's a patient in the open-loop boot, meaning that she has the control to go up and down but if the computer is not turned on to control that, this is what happens to her.

Try that little cough, smaller. Did you feel anything then? Respond to intensity. You want to try a bigger cough? Yes.

That'll be your biggest cough. You can see there as she coughed the pressure from just the cough pushes the spinal cord closer to the electrode and she gets an over shock with that very uncomfortable, " Oh yes, that's too much." You can see on that second line there.

This is the way every device is currently available in the United States is currently used. You set the output and then you keep that output constant unless a patient changes it but trying to change it just for a cough is virtually impossible and she ends up with overstimulation, as you can see here. Now when we turn the computer on so that the computer understands the amplitude at that top line that is comfortable for her. We'll see what happens.

Let's try the coughs again. Bigger cough. Do you feel any changes there? Not much, no change. You can see the reason why she didn't get overstimulated is that second line there could take up the fact that the spinal cord is closer to the lead now delivering more energy and being absorbed by the spinal cord more.

Therefore, for her not to be overstimulated and to have the appropriate neural response. The device had to be turned down. This is occurring at 40 times per second.

This is a very fast feedback control mechanisms that allows her to have more comfort. This is one thought that this might be the reason why we've been having some trouble with long-term access and by ability to stimulation in some patients. As a result of that, we initiated a multicenter trial. I was part of a group of over 13 sites in the US that compared the open loop, which means patient-controlled level of activation versus closed-loop, which was the computer-controlled activation.

These patients were identical in every other way. The most significantly they had the most severe pain back in late pain for more than 11 years. They could not be enrolled in the study.

If you didn't have at least a minimum of severe disability or considered crippled the Oswestry disability index. This is the most severe set of patients we've seen in any of our settings. What we find is that both of them did fairly well for a long period of time, over two years. We're currently submitted the two-year data for publication that when your data was published last year.

But nonetheless, the closed loop still did significantly better. But remember these are the first people ever program with their own neural responses in both groups. Just like we saw before in the earlier studies that advocacy starts to wane for some overtime and patients end up with exoplanets.

We're already starting to see the exoplanets in the open-loop arm. Sorry, that's the patient-controlled only. But no exoplanets due to loss of efficacy in the computer controlled or closed-loop arm. Yet other things that we noticed in this study was an increase in the number of patients who are responsive. We use to say that spinal cord stimulation was able to help 50 percent of the patients, 50 percent of the time.

Now, with this steady, we're seeing that the number of patients responsive and it's up to 84 percent. Those with high response activity getting greater than 80 percent benefit was at least 50 percent as well. We're pushing the envelope bond who actually benefits from [inaudible], by recording their own neural responses. Here you see in the red and dark red or brown, that's 100 percent of the patients were severely disabled or crippled.

At the end of 24 months, 78 percent of those patients were in the minimal to moderate range, and only 22 percent remained in that severe range. As you're all quite aware of CPS, extremely important. Here we see that with both the open and closed loop, they did better with sleep.

But the closed-loop computer-controlled does significantly better, and people actually improved to near close. Many of them ended up with close to normal sleep patterns. There's only three percent at baseline. By the end of this study, greater than 30 percent had normal sleep patterns and all had improvement in their sleep quality. As we look at the opioid epidemic, understanding the impact on opioid usage is also important. Here we see a 66 percent reduction and the patients using opioids during the study as well.

These are all good signs that we're getting some ideas on how to improve and spinal cord stimulation, making more effective and last longer and hopefully help eliminate our dependency on opioids for managing chronic pain problems. We call that while we're talking about hundreds of thousand of people dying per year from opiate abuse. We still have 15 million suffer from chronic pain. It's a balancing act trying to help all of those patients. Well, its expand our discussion today into other areas in neuromodulation for pain and other related things.

This was an event study. It looks at a percutaneous vagal nerve stimulation, that load device, there is public electrodes and the end of that device in that now has FDA approval for the treatment of headache. All you need to do is use it when you have a headache. I place it on the neck there and stimulate the vagus nerve for two minutes, two or three times, and see if you're a headache results. The steady looked at how many headache days they were in a month. You can see on the graph here.

The period of eight months, there was precipitous drop in the number of headaches per day or per month. That's why it achieved FDA approval. Then COVID came along. It turns out that prior studies have been identified that the vagus nerve is important for inflammatory diseases. It can inhibit the inflammatory flares.

We recognize that part of the problem with COVID was the immune response. The immuno storm that happened as a result of the infection. With startup at trial and some initial preliminary data, the FDA allowed emergency usage of the vagus nerve stimulator for the treatment of asthma to prevent patients with COVID from hopefully preceding to intubation and decreasing their cytokine storm as we call it. Further data on this is currently being worked out, but it's just another way how neuromodulation be used for pain for one indication but another medical indication as well.

To get a more a sausage discussion about the usage of neuromodulation for inflammatory diseases and inflammatory diseases. This is a wonderful article, I highly recommend. It's from 2015, but it still sets the stage for how things like vagus nerve stimulation can be used for rheumatoid arthritis, inflammatory bowel disease, and a variety of other things. It's a good read, is a little ahead of its time.

Yet here we are five years later actually treating inflammatory disease with vagal nerve stimulation. How about other things we're doing for pain? This is something that has been used in recent years. It's called transcranial magnetic stimulation. It's currently FDA approved for the treatment of depression. However, a number of centers are using it to treat addiction and pain as well. A number of us worked with the lead author on this document looking at the usage of TMS for pain.

Currently, the two investigators here at UCSF, Dr. Motzkin and Dr. Shirvalkar are working in collaboration with our colleague, Dr. Leung at UC San Diego on the uses of transcranial magnetic stimulation for pain. He was studying at San Diego primarily headache, but the protocol experiments that we'll be getting started here soon at UCSF will be expanding that to other neuropathic pain disorders as well.

I welcome you to look for that study enrollment and recruitment in the very near future. Other studies being conducted here at UCSF include the use of deep brain stimulation, where you put the electrodes actually in the brain for the treatment of pain. The neurosurgeon in charge of this is Dr. Edward Chang and the lead neurologist is Dr. Prasad Shilvalkar,

looking at this as a way to manage the most severe issues of pain. For example, the pain that occurs after a stroke can be extremely severe and include large portions of the body, makes it difficult for any other type of neuromodulation to manage. But with EEG recordings and recordings from the electrodes in the brain. More of that closed-loop concept they're able to find appropriate targets and stimulate those targets to reduce pain. I think they have enrolled at least half a dozen or so patients so far.

I think enrollment is still occurring. We're sort onto that. As they learn more about the sites that they need to record from to key onto their DBS stimulation. In the pain, we're also trying to utilize that information by seeing if those same areas can help us feedback control into future spinal cord stimulation.

A little more advanced brain mechanism feedback for spinal cord stimulation. This is still in the very preliminary stages, we're collecting data on EEG for all of our spinal cord stimulation patients during our trial periods so we can compare our EEGs to how they're doing. I'll look forward to seeing that progress over time as well. Let us shift gears a little bit, as we talk about the opioid epidemic. We should probably discuss neuromodulation for addiction as well. In the last few years things have really picked up in this area as you can see here, there's been a spike in both treatment of addiction with the brain stimulation as well as TMS.

These are the number of publications that show up in the medical literature. Certainly very few at the turn of the century, we're on an exponential rise in the number of publications being published for this in recent years. This is a good review of that. In addition to using deep brain stimulation and TMS stimulation, which is non-invasive, there's additional new technologies looking at ultrasound for the treatment of addiction as well. A number of these studies looking at alcohol, heroin, nicotine, cocaine, all the various types of neural stimulation.

You can see here on the left column, there's transcranial magnetic stimulation, low intensity focused ultrasound, deep brain stimulation, direct current stimulation on the transcranial, vagus nerve stimulation, auricular stimulation, and trigeminal nerve stimulation. The field is exploding on various ways to address addiction with neuromodulation techniques. When we look at how one would employ these techniques, there are certainly limitations of each individual technology.

For TMS, stimulation of the cortex is possible to be targeted, but any deeper centers you can't really get to. However, if you use focused ultrasound, you can bypass the superficial layers and focus your stimulation with focused ultrasound into the deeper layers. These are very new ultrasound machines for the purposes of stimulating neural tissue.

I believe we just acquired one of these at UCSF in our beginning, our set of experiments with them. It's a relatively new field that's very exciting to be able to stimulate the brain regions without surgically implanting the lead in the deep brain area. I think this assumption and look forward to more as well. When we look at the treatment of addiction we have to look at all the various complex regions that are involved.

It's not just one or the other, but it's this circuitry of addiction. Understanding which sites and, the pathways to stimuli and critically important sometimes will mix a cortical stimulation with a deeper stimulation like here at 1, 4, 3 areas versus the more superficial areas. We're not doing this quite yet at UC, but this is work that's being worked up at West Virginia University at the Rockefeller Neuroscience Institute looking at a simulation for the top-down approach from the cortex down and from the deepest centers up. This work is being led by Dr. Ali Rezai at West Virginia University as I mentioned earlier.

This is quite impressive that West Virginia was the highest number one area of addiction per 100,000. Their university decided to make this their highest priority and do it a lot of attention to trying to solve this problem using neuromodulation techniques. Part of what they're looking at is looking at the triggers for addiction and craving. Looking at brain signals that correspond to those responsive triggers, pictures and prayerfully, and whatnot.

Seeing how the brain activity changes and trying to modify those changes in the brain by something as simple and non-invasive as TMS. TMS is something you can do, 15, 20-minute treatments, 30-minute treatments. The clinic, non-invasive, you don't take off your clothes, you just put a magnetic stimulator with the focus being on it. It targets the appropriate centers in the brain. Initial studies have shown that this is a significant impact on craving for both patients addicted to heroin and cocaine.

This is a study of this series of publications out of their center. There's a lot of coverage there in neuromodulation of variety of things but what I really wanted to focus on at the end here is to recognize that in spite of all the great new technologies and abilities we have to treat various disorders, both pain, addiction, COVID, whatever the case might be. It's clear that we have to really understand in order to provide adequate care for all of our patients in the entire public health. We have to understand the issues related to health equity as being important over health equality. Making sure that everyone has appropriate access will be an important endeavor that we have to pursue, not just the technology.

With that I'm going to end my talk and open it up for questions, because I'm sure there's a variety of things we can go into more depth with. Thank you Dr. Poree, that was an excellent talk. One of the questions asked, will the idea of 5G interfere with any of these devices? I don't think so. As a matter of fact, I think, let me expand on that a little bit. Many of these devices are currently being evaluated by the FDA, not only for what they can do with communication between their handheld control devices and the devices that are in the patient, but also allow us to remotely manage and program them, and using 5G might be a part of that.

The FDA has gathered together a group of experts, and two things are high on the list to solve, one is data security, and the other is going to be, that's actually more of an issue probably than the electronic interference. The discussion of frequency that communicate among communication parameters or medical parameters, those have been said a while back by the FCC, as they're being very different areas of the frequency bandwidth that is available for those two different things. But interception and security of that data as it transmits through our space and Internet is actually even more concerning, and many people are working on solving all those problems as well because this is growing so fast that without those proper safeguards it could be a problem in that respect. Very interesting, I can see how HIPAA compliance to protect it is very important. I can see how that would be something that the FDA would be interested in as well.

Can you talk about any limitations with any of these devices with respect to perhaps travel or other scans like MRI or ultrasound? There are limits, and so recognizing that patients and appropriate candidate would also mean that you recognize what other medical devices or interactions they might need to have. Just like we just talked about interference with communication devices, early on 30-40 years ago, there was a discussion and concern about interference between a spinal cord stimulator and a pacemaker. Back in those days the battery was oftentimes one of the electrodes before both pacemakers and stimulators, so those had some interference. But that has been solved many years ago, and so that's no longer an issue there.

MRI however was not available to give us spinal cord stimulation up until maybe 10 years ago. MRI would heat up and it became a problem, and so new technologies need to be developed shielding around the leads, different electronics, making them more resistant to MRI, and so now that they are mostly, not all, but mostly now are conditional MRIs at the 1.5 strength magnets. Most of them are not conditionally approved at the 3.0 magnets at this point in time.

But this is an ongoing process, as technology advances, the interaction has to be more focused on and pay attention to things that we can need to do. It's an ongoing process. Yeah, there's moving forward in both of these service-wise.

It definitely sounds like it's an evolving field, and I can see that there's talks of now perhaps a 5 Tesla MRI, and now we have some of these other devices that were not approved for that. I can see now trying to always stay one step ahead is really the way to succeed with us. Can you walk through the steps of how a patient might attain one of these, or how do they acquire one? Let's say it is for back pain, how would they go about this process to see if it's the right fit for them? Real easy, just come to UCSF and we'll take care of you. But if you're not able to come see UCSF, there are certainly providers across the nation and across the globe, most of us have a very similar evaluation process, we look at the kind of pain you have. Spinal cord stimulation in particular is very useful for what we call a nerve related pain, shooting electrical sensitivity that runs on the leg after bad back injury, or a nerve injury, or episode of shingles, those are the severe neuropathic pain disorders, and seeing a pain physician that specializes in neuromodulation that can assess you for that is first step. In the United States, all insurance companies, including Medicare, require a psychological evaluation prior to being trialed, and once you are deemed to be an appropriate candidate, because we still are not looking at 100 percent of the people who are trialed on this getting adequate benefit, we still do a trial phase, and in that trial phase you're committing to a needle or two needles directed into the spinal area and the epidural area, much like a procedure that is similar to epidurals that women get for labor pain.

That's the same procedure. Through the needle instead of injecting a local anesthetic as you would do for labor pain, you put these two wires in, you pull the needles out and tape it to the back, and the patient wears that for 5, or 7, or 10 days, and evaluates a variety of the electrical programming to see if it provides some pain relief. After that period of time, is pulled out, put a band-aid over it, and that's the end of the trial. If the trial is successful, then the patient returns, those leads are placed underneath the skin and attached to one of these battery packs.

It's a bit of a process, but that's usually the way most of us evaluate in trial the patients and see if they're appropriate for this kind of therapy. The patient actually get to try this before it was ever implanted. Pretty unique, you're never really allowed to try on a hip replacement beforehand so it is very unique. It's pretty much 100 percent reversible. If you get a hip replacement or a knee replacement, you can't say, "Oh, never mind, give me back my old hip or my old knee." That's also a nice thing about this.

It's something you can try out without cutting at all and then evaluate for a good period of time before you make your final decision. Another attendee asked, can you expound on how ultrasound is able to pass by some tissues and target areas further inside the brain. I would like to be able to tell you I'm an expert in that field, and I'm well versed in it. I would be perfectly honest with you, it's something that is relatively new to me as well. But my understanding is that as it passes through the tissues, it is not focused and therefore does not disrupt or generate a lot of energy in the local surrounding tissues. It only generates energy as it focuses down onto a particular beam.

Like I said, this is really new technology, I've only learned about it in the last few weeks, and I'm equally bewildered by that engineering and technology, but that's what I understand so far, but we're looking forward to understanding it more. Like I say, my understanding is that UCSF just acquire one of these within weeks ago. I think we have a lot to learn about it. Great new technology. I wish I was more engaged with that technology to be able to give you a better engineering answer. But hopefully on our next update we'll have all of that squared away.

Thank you, that was a great response to that question, concerning the fact we just acquired one. It's very exciting, it's new technology. Again, sometimes we don't know how things work either, we just know that they do. We'll see how that plays out obviously. Another question from an attendee: has surgical removing or cutting of nerves, then part of historic attempts to relieve pain? The spinal cord stem seems like a much more elegant solution. Absolutely.

One of my colleagues and friends, Jamie Henderson at Stanford, would often give a lecture on all of the neural ablative techniques that are available through neurosurgical; cutting a nerve, taking out part of the spinal cord, taking out sections of the brain. One of them was tragic. Public stories of this is Rosemary Kennedy. Any of you that don't know, but this story is something you're going to look up on the Internet.

But she had a diagnosis which in today's terms it may have been depression. But any rate, she was subjected to a frontal lobotomy and prior to that, she was an active person, heavily engaged in her life. After that procedure, she have the cognate just still set of a three-year-old and it was institutionalized, and only died just a few years ago.

That was institutionalized to the rest of her life. This idea of cutting material out of the brain, spinal cord, and nerves, is certainly rudimentary by comparison to our more directed focus neuromodulation techniques today. Dr. Henderson is the director of neuromodulation of functional neurosurgery at Stanford. While he gives an entire hour lecture and all the things that he was trained in to cut and remove to treat a variety of diseases, he basically focuses all his center now on just the neuromodulation because many of those, not all of them, but many of them can now be treated without destruction. We typically will focus our attention on modulating the nervous system before destroying the nervous system, in most cases.

Now, one of the attendees mentioned that they've heard a peripheral nerve stimulation. Is that the same as spinal cord stimulation? Not the same, but in many cases, it is a similar technology. For example, I've placed a number of central nerve stimulators so you don't really need to stimulate the spinal cord itself. One of the ones that I find to be terribly useful is occipital nerve stimulation for headaches and back of the head pain, and the same lead, same batteries. The technology is almost identical, it's just about where you put it.

We also have leads that go into the areas of the nerves and the sacrum, stimulate those nerves both for pain and for function. There are advantages and disadvantages for peripheral nerve stimulation, but it's certainly a viable technique that we use quite readily at the UCSF main clinic in addition to spinal cord stimulation. In general, a big global perspective here, if the pain is focal and as a result of a peripheral nerve injury, and is easily accessible, then peripheral nerve stimulation might be a simpler and easier way to go about it versus having to go inside the spine. But the techniques are very close, same needle, same batteries, same leads for the most part. Some people prefer to stimulate the more peripherally. If the pain is more widespread like a total trunk involvement of shingles, then you'd have to have too many peripheral nerve stimulators make it effective.

That's where it's found the simulation is more effective for that. It's certainly right in the mix of what we use every day for neuromodulation for pain. What do you feel is the future of neuromodulation? Is it a smaller lead, more efficient batteries, or more applications? Where do you feel that they're headed next? I think that in the last 10 years, there has been a tremendous focus on greater indications, some new work coming out on diabetic peripheral neuropathy. Early work was even looking at peripheral vascular disease, arterial problems, diabetic ulcers, and things of that nature. I think there's always been this push to utilize it for a variety of conditions and expand those conditions.

However, I'm very excited that I believe the future will be understanding what we're doing to the nervous system, and I think that's where we're going to have a huge explosion and its utilization. The information I presented, it was just the tip of the iceberg. When we have ideas of things that's just medications which should affect the nervous system, didn't even know that until we started doing these ECAP studies and we're finding huge changes in what type of medications.

Some pain medications make spinal cord stimulation work better, others make it work less well and we didn't know that before we could record the nervous system. Now that we can see that, it'll adjust how we do things. I think the big next boom will be an understanding, how we can modulate it to accommodate the physiological changes, the pharmacological changes, and just the changes of aging that occur to body and understand how to make that change work better with the systems that the patient has. Do you or have you seen an application to be utilized in an acute setting? Such as let's say, post a lung transplant or recovery from maybe a sports injury from a competitive athlete that you don't want to have narcotics and can't afford to have narcotic testing or have a positive test in their narcotics.

Do you feel that this could be utilized in those type of scenarios or have you heard of that? I'd say this has been something I've been on my wishlist for the last 10 years. I think that this is highly underutilized and I think the trouble with the concept is not a physiological or a medical concept problem. It's an economic concept problem. Until we can solve the issue of getting the cost significantly reduced, then we won't see this being explored more. I certainly believe that for many, especially the postoperative neuropathic pain states we see, that sure might recover over the course of a year or two on their own. But if a person has become more functional quicker, get out of the hospital sooner, have less medication on board, I think this is something that we certainly can look at.

Certainly folks have looked at tens units to see how they've been effective for that issue, but we do epidurals for postoperative pain every day of the week. Exactly. Why not just put a lead in instead? The issue is not so much the lead, but the issue is the generator, we need reusable peripheral generators where some of the latest new technologies using RF that are out now don't implant batteries at all. They just have external generators. You just can adhere to your surface of your skin or put in a fanny pack and thereby use that same generator for various patients over a period of time. I think we're really close.

We're not quite there yet, but I think we're very close to being able to treat on a regular basis acute pain without opioids but with neuromodulation. But it has to make financial sense and economic sense for the companies that are developing these and for hospitals and payers who are paying for themselves. We're almost there. That's very exciting. Can you talk about spinal cord stimulation as a possible therapy for Parkinson's patients? This is a great question. I cannot talk about that with any detail, but I can tell you that we expand that question a little bit more and we ask the question, can spinal cord stimulation possibly be used for movement disorders of various sorts? There is a number of studies going on and that includes movement disorders including spinal cord injury.

We've been using spinal cord stimulation for pain for a number of years, even in those patients with spinal cord injuries have pain that generates from the transition where their spinal cord injury is, and low behold, it turned out that some of them were able to get up and walk after being unable to walk for greater than 10 years. It was a surprise to everyone and so there are a number of centers that are exploring that. In addition, there is a group out of Australia, looking at cerebral palsy as a dysfunction of descending inhibition from the brain and causing spastic gates and inability to control the lower extremities looking at the usage of spinal cord stimulation for that. The idea for Parkinson's, I know some folks are evaluating that as well as all of this is still not on the label and still on experimental stage, but ultimately the brain sends signals down the spinal cord to control various functions.

If we can tap into that control, one of the studies we are currently doing, just to get a better understanding of how we might utilize it in the future, we're taking those patients who were coming in for spinal cord stimulation trials and at the end of their trial, connecting them to our recording devices and looking at them, moving their limbs. These are patients who have normal physiology. But as they move their limbs, move their various sets of muscles we're getting those recordings off the leads and we're going to be able to use that information to then better understand how to stimulate to mimic that same activity. This is happening on multiple fronts and multiple centers. Movement disorders and spinal cord stimulation is certainly front-and-center of the research field in neuromodulation across the United States and across the world.

Actually, deep brain stimulators as well, which can help with some movement disorders. Another question from the Q&A, do you have a preference for or against paddle leads for spinal cord stimulation? I don't have a preference for or against any neuromodulation device as long as it's for the right patient. The paddle leads have a number of advantages and they have some disadvantages. Matching the appropriate advantage with the appropriate patient is always the key.

You cannot place them. Actually, this might be an untrue statement as of two months ago. I was about to say you can't place him without surgically going in and removing some of the lamina on the spines, that makes it a bigger surgery, more involved surgery. But the reason I mentioned that as in Europe, I heard that there's just a new release of a paddle lead that is foldable and can fit through a needle.

Once you've placed it through the needle into the epidural space, it has water chambers and you fill it up with water chambers and it unroll lays out on the spinal cord. Extremely fascinating. I haven't seen it in real life yet, but the advantages of paddle lead is that they focus their energy on one side of the lead, down towards the spinal cord and so less energy is directed away from the spinal cord so that's a huge battery saving parameter. Migration for paddle leads is possible, but it's a little more stable usually than the percutaneous leads that take time to solidify in.

There are certainly advantages for patients. I send folks off the paddle leads all the time when there's epidural scarring in the area or other major surgery in the area where it makes it untenable to do the percutaneous technique. It's definitely has a place and has a function and we use it on a regular basis.

The last question is very interesting, and this does come up from time to time. Is there an expectation that patients will overtime require less SCS or not at all? How often are these therapies temporary or to develop tensile for access type of thing? Both of those statements are true and we're collecting data and trying to understand why. There is certainly a number of reports that's fine that patients oftentimes we're looking at CRPS.

It has a continuum and sometimes people get better and don't need it. I certainly have explained it in a number of people who've gotten better, just say, I don't use it anymore because that pain is gone now after a few years. The flip side is also true. There are people who would say my pain is still there, but this is no longer working.

That's I think the most important thing in our field to address currently and understanding what's happening at the neural level by recording and understanding the neural activity I think is key. What we have found out through the usage of all the devices commercially available today is that for the first 50 years we were probably stimulating at too high in amplitude. All the companies and all the devices are focusing on reducing their stimulation.

Just like with medications, if you give someone too much opioid for too long a period of time, opioids stops being effective and yet we certainly have people on really low dose opioid therapy for decades not escalating because we keep it at a very low dose and manage it appropriately and modulate it via other mechanisms. This is a therapy like any other. You can't just set it and forget it and not manage the patient. You have to constantly evaluate what changes to make. Sometimes it's change in the device itself, sometimes it's change in something else.

But that number I quoted earlier, between 10 and 20 percent loss of efficacy for therapy in the course at 2-5 years is what we still see and that's a dilemma that we certainly have to solve. By understanding all the parameters that lead to that, I think we're heading in the right direction. That's why the success rate keeps going up over time but we're not quite there to understand all of that just yet.

Dr. Poree, thank you so much for being here this evening. You're a great conversation, great questions. Thank you all for attending the lecture and have a great evening.

Good night.

2021-12-09 20:55

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