Hello and welcome. I'm Amy Cohen, Associate Director for SMI Advisor and a clinical psychologist. I am pleased that you're joining us for today's SMI Advisor webinar, Neuromodulation Treatment for Treatment-Resistant Psychiatric Disorders, Transcranial Magnetic Stimulation, TMS. SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to care for your patients. And now I'd like to introduce you to the faculty for today's webinar, Dr. Ian Cook. Dr. Cook currently directs the Los Angeles TMS Institute and is an internationally recognized expert on neuromodulation. He is a professor emeritus at UCLA, both in the Geffen School of Medicine and the Samuel Lee School of Engineering, and was also Chief Translational Innovation Officer at the UCLA Neuromodulation Institute, as well as Director of UCLA's Depression Research and Clinic Program. Dr. Cook was the first physician to treat depression with transcranial magnetic stimulation at UCLA, as founder of the TMS Clinical Service in 2009, and he led the early growth of that program. Dr. Cook has worked to develop non-invasive and invasive neuromodulation methods to treat depression, PTSD, ADHD, and epilepsy. Dr. Cook, thank you so much for leading today's webinar. Thank you, Dr. Cohen. It's my pleasure to speak to the audience about neuromodulation and TMS in particular as things that I'm very, very keenly passionate about. Here we have my disclosure slide where LATMS is my private practice. I have these other activities as well. And just to highlight that today, some of the uses of products we will discuss will be off-label, and some of the devices are not yet available in the U.S. for clinical care, just to highlight that. So our learning objectives today are to really focus on what is meant by TMS, what it can be used for, and for depression and other conditions. I'd like you all to come away with a sense that you can really identify who would be right, who might benefit from this kind of treatment as an evidence-based practice, and then, critically, to be able to help you to educate patients and your fellow colleagues about the differences between TMS and other kinds of treatments that use electricity or magnetic energy rather than molecules, because there is a lot of confusion out there about what this is about. People still confuse it with other kinds of modalities, and it really is rather unique, different, and I think very well tolerated. So let's focus first on what is meant by TMS. So let's parse it out. So transcranial means, of course, that things are going across the cranium or the skull. Magnetic implies that a magnetic field is used. And stimulation, it really gets the idea that the neurons are stimulated to fire or to discharge. Medical devices that allow us to perform TMS first received a thumbs-up from the FDA in 2008, but it really traces back to the mid-1990s when they were the first reported cases of TMS being used in mental health, and in particular in treatment-resistant depression. The current state of the art is that TMS is an evidence-based treatment for major depression for major depression, and now also for OCD in adults who are ill despite treatments using medications and psychotherapy. So how does TMS work? Well, there are a series of steps. The first thing is that a strong electric current flows in a coil, a coil of wire, producing a magnetic field. It's important to remember that the skull and the scalp are both transparent to magnetic energy. They don't block or attenuate the field at all. So this is a great way to get the neurons to fire. In contrast, electrical energy applied directly to the scalp is blocked to some extent by the scalp and the skull, and so the amount of energy that would actually get into the brain is less. This is one of the original inspirations to use magnetic fields as a way to stimulate the brain. Anyway, the rapid changes in the magnetic field induce currents in the brain, and because my undergraduate degree is in electrical engineering, I get to use an equation here from Maxwell's equations that speaks to this. But basically, the idea is that magnetic fields that change are able to generate or to induce currents in conductors like the brain. The neurons then react to this current by discharging, by firing. And as neuroscientists have known for many, many years, when you have a circuit in the brain and you encourage it to fire as an ensemble again and again and again with this repeated stimulation, this induces neuroplastic effects. And the catchphrase here is that neurons that fire together wire together to convey this idea that we are able to change the connectivity within a network by repeatedly exercising it, by repeatedly encouraging the neurons to fire together. This reorganized, or if you will, retrained brain circuit then appears to lead to the symptom relief and stress resilience that we observe clinically. For those of you who are more graphically inclined, here we depict a coil that's placed over the middle part of the brain. The current flows in it. There are little arrows there that show the current in the coil flowing, the magnetic fields there in the dotted lines that penetrates into the brain, inducing a reflexive electric current in the brain tissue itself. And again, the idea is that the pulse field induces a local current, which causes the neurons to depolarize, which leads to action potentials and the release of the chemical neurotransmitters. And then this changes the synaptic connectivity patterns. Before we go further, let me lay out a little bit of the conceptual framework for neuromodulation broadly, of which TMS is one example, but there are other things out there that one should be aware of as well. First off, it's important to underscore that neuromodulation at this point remains primarily used in the treatment-resistant situations that we find ourselves as clinicians. There are some studies of using it as a first-line treatment, but it's not always the case. It's used in the treatment, but that is not where it is most commonly deployed. When it comes to thinking about the landscape, it's important to, I think, divide things into neuromodulation techniques that are convulsive, where seizure induction is central to the mechanism of action, and those that are non-convulsive, where we don't expect to have a seizure be part of what's happening. ECT, electroconvulsive therapy, going back to the 1930s, is the prototype of a convulsive sort of neuromodulation therapy. There is an investigational approach now being pursued called magnetic seizure therapy, or MST, which seeks to overcome some of the cognitive and other side effects of ECT by constraining the extent of the brain which has the seizure. But that's investigational, and while we all look forward to the results of current and future research projects coming forward, it is not generally available. When it comes to the non-convulsive kinds of neuromodulation therapies, TMS is the one that we'll focus on most today. This has got FDA clearance for use in major depressive disorder and in OCD, but there are some other ones to be aware of as well, and this is a non-exhaustive list, but there are some cranial nerve stimulation methods, vagus nerve stimulation that has been around for a number of years, and now trigeminal nerve stimulation that is a newer technology. There's cranial electrotherapy stimulation, or CES, which encompasses a number of grandfathered devices that we'll talk about in a handful of slides. And then deep brain stimulation, DBS, which has a humanitarian device exemption approval from the FDA for use in treatment-resistant OCD. And until last year, when the FDA granted clearance for TMS to be used in OCD, that was really the neuromodulation option for that condition. But now the landscape is very different. Another bit of background, I think, is the question of dose and what we mean by dosing in TMS or neuromodulation more broadly. So, you can think that when it comes to medications, the biological activity of the therapy is really determined by the molecular structure of a drug, what it will bind to, how strong is the affinity, how it is metabolized, all these things really relate to the structure. The analog in neuromodulation is to think about stimulation parameters. And here in this table from a 2014 paper, we wrote about really the way to divide it into the ones that are spatially focused, about where in the brain, and then temporal ones, about how this plays out in the time dimension. And so, when it comes to anatomical features, we think about what was often called the target. Is there a target structure like the anterior cingulate, like the dorsolateral prefrontal cortex, like the substantia nigra for people getting deep brain stimulation for various neurological conditions? It's important to know whether the stimulation is happening on one side or the other, or if it's bilateral. And then there's a lot of variation in the estimated size of the stimulated region. This can range from just a few millimeters for deep brain stimulation, as might be used in Parkinson's disease, or it could be a whole hemisphere, or both hemispheres when it comes to things like electric convulsive therapy. Turning out of the temporal dimension, this is not something which we usually think about in psychiatry, in mental health care in general, because we give medications, we have people take medications, and expect that their effects will be lasting all day long. Or for at least a well-characterized period of time. But when it comes to these signals, we think about what is the waveform? Is it a pulse? Is it more sinusoidally shaped? What's the frequency? How many pulses per second? Because it's become known that some frequency of stimulation are associated with increasing activity in a targeted brain region, whereas other pulse frequencies may be associated with decreasing the activity in that circuit. Pulse width, how wide are the pulses if it's a pulse thing, so-called duty cycle. Very often you'll see that the stimulation is not continuous, but rather it is on for a period of time and then off. And whether this is for safety to protect the neurons that are being stimulated, or for other reasons, it's an important parameter to keep track of. And then, of course, there's a signal amplitude. How strong is the signal? And this can be measured in voltage, or current, or magnetic field strength units, depending upon what kind of technology is being considered. When it comes to TMS, the language to know here is that there's a pulse, and you could string together a series of pulses into a pulse train. And here we have an example of 10 pulses per second that was originally what the FDA cleared back in 2008. And then you string together a number of these pulse trains into a treatment session, and then a treatment sessions are strung together into a treatment course. And each of these needs to be described in the research literature if you're reading about a study, or need to be specified in a course of treatment that a patient is receiving. The technology has changed in some ways a lot over the last few decades, in some ways not much at all. There we have a picture from 1985 of Anthony Barker, the medical physicist at Sheffield University in the UK, who really pioneered the development of the technology that is still the underlying fundamentals of the sorts of machines that we use today. We have coils that are named basically on their geometry, ones that can be a simple circular coil, ones that are two coils that are placed in the same plane, looking like a figure of eight, or they can be bent a little bit. They can be angulated there, as depicted there in the lower right, the so-called double cone kind of approach. Why does this matter? Well, it matters because the geometry helps influence what part of the brain is being stimulated. And that again is our anatomical target question. When it comes to a single circular loop coil there on the left, the magnetic field intensity is depicted there in that colored diagram floating above the loop. And there you can see that the field is really strongest right over where the electricity flows in the coil. It looks, to my mind, at least a little bit like a volcano crater. When you construct a so-called figure of eight coil and really have two loops, you can imagine them as sort of two volcano craters being pushed together, metaphorically speaking, and they summit where they overlap. And so this leads to the so-called hot spot, the focused spot of greatest intensity, which means that that is where you will stimulate most deeply into the brain, that you will be able to affect those neurons much more than those in adjacent parts of the brain. But it is worth noting that it's not a single laser beam-like focus. It's actually got width and depth to it. Plus, there are these side shoulders, the other areas. That's important because sometimes some of the sensory side effects of TMS relate to those, to the simulation of structures in the scalp from those other parts of the volcano crater, if you will, the lower parts. And twisting the coil, adjusting the so-called coil angle can make a big difference for patient comfort by being aware of that. There are a number of devices which use a more complex coil geometry. Here we have what's called the H1 coil. And as you can see from the picture there on the left, rather than the coil being outside the head, here actually the coil windings are placed in what is sometimes described as a helmet design. And the brain is actually inside the windings. And this leads to a very different kind of pattern of where does the current flow in the brain. I can flow more deeply into the brain, but with less anatomical specificity. It's a broader field. Now, whenever we think about the practice of medicine, we should think about what is the evidence that supports efficacy and safety. And there is a large body of evidence about this. The registration trial that supported the initial FDA action to allow this on the market in the US was a double-blind randomized controlled trial of what we sometimes call high-frequency TMS, 10 pulses per second. 10 pulses per second versus a sham. That's the O'Riordan study that was published in 2007. Johnny O'Riordan led that multi-site study. This was then followed by another double-blind RCT, also of high-frequency TMS versus an active sham. And here, this is called the OptTMS for optimizing TMS study. It was not industries funded, but rather was funded by the NIMH. And Mark George was the principal investigator and lead author on that work. These are both positive. A third positive study that showed clear benefit of active treatment over the sham condition looked at the H-coil design, the so-called deep TMS. And all three of these were in treatment-resistant depression. More recently, a very interesting study was done in Canada that was, rather than a sham control study, compared to active treatments, so-called non-inferiority design, looking at the more traditional high-frequency TMS versus what is called intermittent theta burst simulation, or ITBS. And this is a treatment modality that we'll come to in a handful of slides. The essence of it is that the pattern of pulses is different. It is a more efficient way to influence the neurons and to lead to neuroplastic changes. And so, what in the original days of TMS back in the late 2000s, a treatment session might last 38 minutes. Now, in this study, results of similar magnitude were seen in a treatment that lasted only about three minutes. So that is a real game changer in many ways, as far as being able to treat more people per day, get more people well. And that was actually a data set that was submitted to the FDA and led the FDA to clear devices for use with theta burst for TRD. Finally, there was a double-blind RCT of the H-coil design of deep TMS in obsessive compulsive disorder. And this also led to the FDA clearance action for that. And these are just some of the very big studies. There are hundreds of other smaller studies that have been done, some of them controlled, some of them not controlled. And if you look back at the literature, many of the early meta-analyses came up with the conclusion that there wasn't much there. And of course, if you look at all the studies that were done back in the late 1990s, there were many that were negative. And part of this is that some of the studies had pulses that were fast, some that were slow, some that treated only for a few days or a few sessions versus those that went longer. The targets that were used were highly varied. And I think of this really as a dose-finding era, where we learned a lot about what doesn't work. But we also learned a number of important things about what do work in terms of what targets seem to be most likely to be of benefit to patients with TRD, with treatment-resistant depression, and also about how to manage this as a treatment rather than as a science experiment. One of the things that's important to bear in mind are the side effects and the adverse events that we must know as clinicians, but also that we must be able to describe and warn our patients about, inform them about. So there are some common side effects, and this is not a surprise if you've looked online about TMS, plenty of videos online, where people describe a tapping sensation, also what is sometimes called application site pain. The basic idea here is that the magnetic field pulses that make the neurons depolarize also cause depolarization of the excitable tissue of the scalp muscle fibers and of the nerves that are in the scalp. And this feels, frankly, for all the world, like something is tapping on your head. When I got the first device at UCLA in 2009, I thought it would be unethical to make my staff practice on each other, so they all got to practice on me. And you can wonder about the wisdom of that, but it did give me a very direct firsthand experience of what patients go through. And it does feel very oddly like a tapping sensation. I think of it as being more unusual than uncomfortable, but that's in the eye of the beholder or the scalp of the beholder. The other thing that people sometimes report is headache, especially in the first few treatment sessions. And I think the way that I think about this is that when the scalp muscle has its little twitch, when those muscle fibers depolarize, it's making the muscles work. And much as if you had gone, if you were to go to the gym and work out some muscle group that you don't ordinarily use and do a thousand repetitions the first day, that muscle group might feel a little bit sore. And I think that that is analogous to what is happening really in the scalp, since when it does happen, it tends to fade within the first few treatments and over-the-counter analgesics seem to work pretty well for this. Those are the common things that happen. There is an uncommon risk, which is worrisome, but really relatively rare, and that is the risk of inducing a seizure. Now, as context, it's important to actually look at the numbers. And the risk of a seizure from TMS is actually lower than it is with an antidepressant like bupropion. Fewer than three dozen reports worldwide, I believe, is the most current figure on this. And importantly, the seizure ends if it does happen. It ends as soon as the device is turned off, unlike a seizure that you might have from a medication where it could happen at any time of the day or night. In theory, here, if it's going to happen from TMS, it's going to happen while the person is there in the chair being treated, and it ends as soon as you turn off the device. So fairly easy to manage, but it is important for staff to know what to do. Speaking of what to expect people to know what to do, here's some of the things to think about for a treatment session. Again, I put this here because this is unlike a med visit. This is unlike psychotherapy. It's a medical procedure. And at the first session, you have to personalize the device settings for that individual patient. You have to determine what the targets are and what the field intensity should be. The way that we usually determine the field intensity is to stimulate over the motor cortex and look for a thumb twitch in the contralateral hand. And the intensity of the field is varied up and down to really to focus in on what is the strength of field that will cause a thumb twitch about 50% of the time. And then there are different ways of finding the targets, and this is really keyed most closely to what device one is using as to how it is aligned to the target that you intend to treat. But most commonly, that's the dorsolateral prefrontal cortex, and most commonly in the United States. On the left, often on the right in other countries. We'll come back to that in a handful of slides. When it comes to the treatment sessions, originally, the high-frequency protocol that was approved back in 2008 lasted about 38 minutes. A few years ago, so-called rapid high-frequency TMS was allowed by the FDA. And there, the off time, remember, we talked about duty cycle, when the device is on versus when it's off. Here, the off time was shortened, which got the treatment duration down to about 19 minutes. And this has now been even further shortened through the intermittent theta burst stimulation approach, where it takes about three minutes to do a treatment that has approximately the same efficacy as the old school stuff. Typically, people get about 36 treatments in a course of TMS. This number comes out of, in part, out of the O'Riordan study, the original registration study that the FDA reviewed. But insurance companies have glommed onto this idea. Now, as clinicians, we know that seldom does one size fit all when it comes to a therapeutic. And some people do get better faster, and some people are slowpokes and may take more treatments to respond effectively to this kind of an intervention. But typically, 36 is what you get from insurance coverage. During treatment, the patient is awake and alert. Unlike ECT, where they're under general anesthetic, here they're awake, alert, fully functioning, depending upon the duration. You may engage them in conversation. They might watch a video on a flat screen TV. You know, there's a lot of variability here in what practices tend to do. Importantly, people, both the patient and other people in the room, should be wearing earplugs for hearing protection. The machine does make a fair amount of noise. Anyone who's had an MRI scan for imaging knows that the machines can be rather loud. And after the treatment, there really are generally thought to be no restrictions. People are able to drive. Again, unlike ECT, people can engage in their ordinary activities. And so it's a very easily tolerated sort of treatment this way. People can come and do it any time of the day that is convenient for both the treating team and for the patient. So who should be a treatment candidate for TMS? And when it comes to what to expect, we think that with treatment-resistant major depressive disorder in real-world patients who stay on their medications, the expected acute outcomes, and this is based on a number of different studies, are that we expect that there should be a response. If you're doing a research project with quantitative rating scales, i.e. a 50% improvement or more, or meaningful benefit for about one in two patients, about half of them will say, yes, this made a meaningful difference for me. We see a full remission. Basically, people who will report that they are feeling like well versions of themselves in about a quarter to a third of patients who have TMS. Importantly, it's a treatment with durability. The majority of patients who responded acutely were still doing well at 12-month follow-up. And when it comes to thinking about who's likely to do well, well, in some ways, it's not a surprise that individuals who have lower degrees of treatment resistance generally have better outcomes. But even those who are highly refractory, who have been on a long, long list of medications, can respond to TMS. Individuals who have not done well with ECT can respond to TMS as well. The response to one does not necessarily predict response to the other. So it is an option for a wide range of patients who have treatment-resistant depression. Now, one word here of regulatory wonkishness. When we speak of TMS devices, the FDA issues what's called a clearance because devices that are in category two, that's what they do. They don't offer approval, they offer clearance for that. Approval is the term of art that is used for category three devices. And these typically are things that are implanted like pacemakers or breast implants, things that are important for sustaining life, like heart valve replacements, things like that. So some people make a big deal about clearance versus approval. This is the FDA's language. And what they offer for non-invasive devices that are not life sustaining, like a bypass pump would be, it's clearance. That's as good as it gets. So they have issued clearance for TMS for major depressive disorder in adults with at least one medication failure as monotherapy. So technically to practice within the labeling, patients should not be on medication. In reality, patients tend to be on medications and they do quite well. So which medications we'll come back to in a handful of moments, but the evidence is that they do very, very well by staying on their meds. When it comes to OCD, this clearance is for adults. And here it's for use as an adjunctive treatment, i.e. it's supposed to be added onto medications. And there is an indication for use of TMS, a single pulse device for migraine with aura, not something which we as psychiatrists tend to be involved with, but just for completeness, that's the FDA clearance. FDA clearance is one thing. Insurance coverage is quite different. Here, the coverage for TMS in major depressive disorder depends on the carrier and it varies from company to company, and it may change within a company over time. At the present time, Medicare usually covers it. There are some exceptions. Medicaid generally does not. So as a 2019 example from one of the major insurance companies who will remain nameless for the moment, they require that a patient must have had four failed medication trials with at least two from different medication classes. They have to have at least two evidence-based augmentation therapies and even one trial of an evidence-based psychotherapy with documented rating scale data. And frequently, there are exclusions for comorbid neurological or other kinds of psychiatric conditions. But as you can well imagine, a patient who could do very, very well with this kind of treatment may not fit within the parameters that their insurance company has dictated, even though these are not congruent at all with what the FDA indications are, where the FDA said one medication treatment failure and it's indicated. But this is the reality in which we live. When it comes to insurance coverage for OCD, this is a bit out of step with the FDA language. The FDA issued clearance for use of TMS in treating OCD in August of last year. As of July of this year, private insurers were still deeming it to be, quote, investigational and would deny it as a covered benefit. Just as context here, as one of the people who suffered through the early years of TMS in the United States, the FDA, again, cleared TMS for major depressive in 2008. And yet, many insurers were still telling me, no, we're going to deny coverage because this is an investigational treatment. And they did that for years before finally they realized that going through all the levels of appeals, they started losing appeals consistently and then adjusted their coverage as one would hope to help people get well. When it comes to what we know about TMS gender and ethnicity, and again, this relates to who is a reasonable candidate for TMS. In general, the good news here is that, to the best of our collective knowledge, these are not factors that seem to impact the likelihood of getting well. Gender and ethnicity were not related to outcome in the initial TMS registration trial, not in the NIMH's opt TMS trial or in the deep TMS registration trial. Likewise, the Canadian 3D study that led to the ThetaBurst approval, clearance rather, these factors were not related to the outcomes there. In moderately sized open trials using real-world patients, again, no association. In meta-analyses, gender was not associated with this. To look more broadly, and again, as you can tell here, this is not something that has been studied super explicitly, but for instance, in a study looking at TMS for methamphetamine dependence, a lot of the early studies were predominantly male subjects, so in an all-female subject pool, it was also found to be to be very effective. And in a more neuroscience experimental kind of paradigm, using TMS to probe for exercise-induced neuroplasticity, biological sex and ovarian hormones did not impact short-term neuroplasticity, so it seems to be that that is, based on all that clinical data, seems not to be something to worry about. Likewise, in other studies looking at excitability, there sometimes have been found to be some gender-related differences, but these are ones which probably wouldn't impact the clinical care because the intensity of the stimulation is personalized for each patient's brain's properties, and so one would simply personalize it and overcome any difference, group-wise difference, that would be there. Eric Wasserman's original 2002 study found no differences in cortical excitability on either age or gender, and the study by Yi et al., looking at Han Chinese versus Caucasians, found that there were some differences in cortical excitability, but in terms of clinical care, again, these were things that would be overcome by compensation for, by keying it to the individual motor threshold, which was, which is a measure of cortical excitability in some ways. So the bottom line at this point is, seems like there's not a difference that we need to attend to, but this is an area that is clearly understudied and needs more, more attention. When it comes to contraindications, you know, who is, who should not have TMS? Fortunately, there are relatively few contraindications that would bar a person from receiving TMS. One thing is probably not good is metallic implants in the head within 30 centimeters of the coil, and here in particular things like cochlear implants for people with hearing difficulties, aneurysm coils or clips, stents, implanted electrodes or stimulators or bullet fragments. These are things which we worry about because they might either move in response to the magnetic field, or they might have, they might heat up because of induced currents in them. Luckily, things like dental fillings, bridge work, or single post implants are all okay, according to the instructions for use manuals, which is basically the labeling for devices. As well, implanted stimulator devices in or near the head, such as DBS cochlear implants or VNS, are ones where, in general, one may, may wish to think twice or three times before, before doing stimulation there. That said, there are reports of individuals with old VNS devices left implanted who have been successfully treated with TMS without untoward outcome. But, in general, if you think about 30 centimeters from the face of the coil, sort of basketball-sized shape, it's basically things that are in the head or the neck that one worries about, and things that are elsewhere in the body are probably far away. Hip replacements, other kinds of things not to worry about. Cautions are also important when an implant is controlled by physiologic signals, like an implantable cardioverter. And here, very often, the thing to do is, these devices often have a way to temporarily deactivate them, usually by placing a permanent magnet over some part of the stimulating apparatus. And, in general, people, practitioners of TMS will temporarily deactivate the device while the, while the treatment session is happening, and then turn it back on once it's over. If a person has a past history of seizures or seizure risk factors, generally, this is an area to proceed with caution, but is not often an absolute contraindication to proceeding with TMS. While major depressive disorder and OCD are the ones where there are FDA-cleared indications, the research literature is ahead of this, and studies have found benefit for using other conditions, although the research literature is varied, and some find stronger signals than others. Depression in youth is, of course, a very important area where medication sometimes can be problematic, and a number of studies have looked at this, some of them positive, some of them more equivocal. There are positive studies suggesting that this can be useful in generalized anxiety disorder, especially that which has been not well-controlled medications. Post-traumatic stress disorder, substance use disorders, are all areas of hot research where, in general, the data are positive. There's a good deal of information about using TMS over different targets than we use for mood and anxiety, or substance use, for that matter, to lessen the effect of auditory hallucinations in individuals with schizophrenia where that has not been able to be controlled with meds, and in pain syndromes as well, an area that I think will get more interest as the opiate crisis continues to play out. There is a bit of a perverse interplay between FDA regulations and intellectual property law that is worth thinking about because people often say, well, if there's all this research data, why don't we have FDA clearance? And again, the somewhat wonkish explanation here is that the FDA regulations allow for class 2 devices to be cleared if there is what is called a predicate device, which is to say a device that is much like your new device that you want to get on the market, and the device can be shown to be, quote, substantially equivalent to the one that's already on the market. And this is done via bench testing. You don't necessarily need to do any clinical trial work to get the Me Too device on the market. This is somewhat different than it is with medications, but this is the rules for devices. So, once one manufacturer has received clearance for a new indication or a type of stimulation, others can receive clearance without performing the clinical trials. And this is the case, as has played out in the last year and a half, with Theta Burst stimulation, where there was one manufacturer that had the first indication for Theta Burst, and then other manufacturers have been able to say, ah, our machine can do Theta Burst stimulation too. They do some bench studies to show that that's the case, and then the FDA grants them clearance as well. So, device manufacturers are businesses, and so getting a new indication is a sound business decision if one's device has some patented features, some patent protection that can block others from claiming substantial equivalence. So, for example, the clearance for OCD involves a device that has an H-coil, and so the figure of eight coils are substantially different, and so manufacturers of a figure of eight coil can't assert a substantial equivalence, or have not been able to thus far, because the coil geometry is so different. Now, while physicians are allowed to use devices off-label, as the FDA says they don't regulate the practice of medicine, we can offer treatments for people with these other conditions, but insurance companies have been known to assert non-coverage and to limit access for these other off-label kinds of treatments. This, of course, severely limits innovation and clinical advancement. Some people have thought, well, maybe there could be other third parties who would sponsor trials, as actually was the case in Thetavirst, where the Canadian health system and government supported the clinical trial, the 3D study, that was then used to get FDA clearance. So, this is an impediment. There are maybe some ways around it, but it is what it is. How about TMS versus some other kinds of treatments? Well, TMS is not ECT. So, as we talked about earlier with ECT, a seizure is central to the therapeutic benefits. In contrast, no seizures are expected with TMS. Anesthesia is required with ECT, but not with TMS. With ECT, cognitive side effects are an issue that many people find to be limiting. In contrast, cognition has been shown in studies to actually improve with TMS. Basically, as the depression clears, cognition improves too. With ECT, a person cannot drive during the treatments and is often unable to work. In contrast, there are no activity restrictions with TMS, and ECT was, of course, introduced back in the 1930s. TMS, in contrast, is really a 21st century treatment. How about wearable magnets? Well, wearable magnets are not TMS either. In this country, magnetic bracelets, shoe inserts, mattress pads, and other kinds of things are marketed in the U.S. with vague wellness claims, but not with medical claims. And so, this means that they are not within the parameters that the FDA regulates. These magnets can't induce an electric field strong enough to make neurons fire. The laws of physics are what they are, and so these things can't make the neurons fire through their magnetic fields, inducing electric fields, and therefore they are just not the same thing at all. And here, very often, therapeutic efficacy evidence is frankly lacking. But again, since these are not medical devices, these are not medical claims, marketing is what it is. Wearable magnets are not TMS. Finally, at-home stimulators are also not TMS. Now, there are a number of low-energy devices, such as what's called TDCS, or transcranial direct current stimulation. They have been investigated, but have not been granted an FDA clearance as a treatment. There are some products that are on the market with phrases like, overclock your brain, or that purport to help athletic training, again, without making medical claims. And so, they are able to be marketed in this way. They're very popular with people who do eSports or online gaming. There are an ample number of online videos that will show you how to make them in the do-it-yourself model. It's a very intriguing modality. There are a number of well-designed, well-blinded, controlled studies that suggest that TDCS may be helpful for some people who have depression or anxiety or other kinds of conditions. But at present, there are no FDA-cleared devices, to the best of my knowledge, with this kind of a medical claim. And without a sponsor, a commercial sponsor, it's unclear who would take this forward. There's another class of devices called CES, or cranial electrotherapy stimulators. And these are based on an old technology, and were grandfathered in for approval under the 1976 FDA regulation changes. And so, these are devices that have never been required by the FDA to show data on efficacy or safety in the way that we would expect a new device to be shown. And so, we're left with a situation where there's lots of publications. Some of them are are better than others. I would direct you to the review written by Shackley and others from 2018. They concluded that there is some evidence here of efficacy, but the effect sizes are limited, and the studies have limitations too. There are a couple of exceptions to know about at-home devices. Trigeminal nerve stimulation is now FDA-cleared for migraine and for ADHD, two different devices from two different manufacturers. And I have a conflict of interest with the one that makes the ADHD device, because I'm one of the inventors of that technology. Plus, there is a single pulse TMS device that is used for treating migraine with aura, but none of these are in the CES category. What is it like from a patient standpoint? Well, very briefly, while I was at UCLA, we were approached by a patient who was a well-known actress, and we offered to treat her under a pseudonym to help protect her identity. And she said, no, if this works as well as I hope it will, I'd like to tell the world. Well, it was Charmian Carr who played Liesl in The Sound of Music. She had a course of treatment and very graciously helped with a video, which is still online, and for which I still get emails from time to time from providers and from patients saying, I watched the video. It helped me decide to go forward with TMS, and now I'm better. Thank you for making this available. And we've got a link there, both from my practice, but also a YouTube direct link. So, to sum up, transcranial medication stimulation is an evidence-based treatment, currently with indications in treatment-resistant depression and OCD. Individuals who have had difficulty in responding to or tolerating medications may be appropriate candidates for TMS. Although it is a covered benefit for most insurance plans, there may be some stipulations that limit access for any given individual patient to TMS. But the bottom line is that it is important to think of TMS as being well-tolerated, and that it can lead to a durable improvement or even remission in a large fraction of patients for whom other treatments have not been successful. Thank you.

Neuromodulation

Transcranial Magnetic Stimulation

TMS

Depression

OCD

Psychiatric Disorders

Non-invasive treatment

Brain stimulation