Non-Invasive Brain Stimulation: What's Possible? What's on the Horizon?

Podcast Transcript

Intro: Neuro Pathways, a Cleveland Clinic a podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: The appeal of non-invasive brain stimulation, like those of transcranial magnetic stimulation and transcranial direct current stimulation is tied to the promise of safe, simple, and straightforward application, more so than their invasive counterparts. In today's episode of Neuro Pathways, we're surveying the current landscape of non-invasive brain stimulation and what lies on the horizon. I'm your host Glen Stevens, neurologist, neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Dr. Ela Plow join me for today's conversation. Dr. Plow is a researcher in Cleveland Clinic's Department of Biomedical Engineering and Neurological Institute. Ela, welcome to Neuro Pathways.

Ela Plow, PhD: Thank you, Glen.

Glen Stevens, DO, PhD: So transmagnetic stimulation, I'm just going to refer to it as TMS is FDA approved for major depressive disorder. So my first question to you is how did we get to where we are? Is it serendipity, a patient with major depressive disorder and a prior stroke was being treated with TMS and went, holy cow, my left side is getting better, or was it not that and it was just, hey, we can stimulate the brain, let's look at other things that we can do? I'd like the first story, but it's probably the second one.

Ela Plow, PhD: Serendipity is a great way to put it. I wish it was that interesting, but it was a little bit staggered. And so in the first case, the stroke was becoming as a new indication on the horizon because it was easy to target with this non-invasive extracranial, if you will modality, areas of the motor cortex that are quite superficial. They sit at the top and the flat side of the head, so it's easier to reach them. So, that became the first indication. But when people started to see in research that, oh, you could target a motor region, you could target a brain region just from outside of the head and make the underlying neurons jump, if you will, and twitch the arm, hey, what else can we do? Right? So that's when they started to realize that if they started to pattern these pulses of stimulation to the brain and go to different areas of the brain, they could target the unique functionality of those regions.

So I hate to say it, but the psychiatric indication actually evolved a little bit later. It's just that it was a beautiful body of grunt work done by investigators across the United States and even across the world globally, to pair together, to go through strategic phase two and phase three efficacy trials of using this patterned form of stimulation. I'm going to keep saying pattern because then it has a frequency to it. It has different modes of frequency attached to it and that can have “therapeutic indications,” where it can alter the activity of the targeted region. If you give it to a visual, visual phosphenes, for instance, can become manifest. If you give it to the dorsolateral prefrontal, which is what you're talking about, then the issues related to psychiatric illnesses can be potentially alleviated. So therapeutic pattern, I'll keep using these terms a little bit interchangeably, but that's how it happened. They just got their work together and then got through the FDA strategically and very well.

Glen Stevens, DO, PhD: Yes, kudos to the psychiatrists for sure, for doing that. Hopefully, well, we won't be too far behind. So I've been doing a little bit of reading on this, and I know that you're going to explain this to myself and our audience, but I need you to explain the Bimodal Balance Recovery Model, which is sort of one of the tenants of how this is thought to work, right?

Ela Plow, PhD: Yeah, it is a loaded term or a loaded few terms, but what it really entails is in the aspect of unilateral stroke, we believed for a very long time that in stroke, we have this competition from the intact hemisphere, the good hemisphere as in the weak hemisphere is already damaged and the intact hemisphere has free rein. And it takes over all functionality and tells the poor, weak hemisphere to stay down regulated, to stay depressed, if you will. And that theory lasted for a very long time. It was developed by some colleagues at the NIH and was ratified by a few other groups, but it took people by surprise, but still became the framework theory of stroke recovery.

So what we've done in conjunction with, and in follow up with certain investigators from Europe, is to propose a more nuanced theory. It is not as if the good hemisphere just wants to beat and bully the poor little weak hemisphere. We understand human body and especially human brain doesn't just quite function that way. Nature's not afforded it to be a binary situation. So of course, there was going to be something more bimodal, something more non-linear, if you will, right? Rather than the linear relation of more severe, so more competition in the brain. Instead of that, we made it more nuanced.

So our colleagues from Europe and us then later in follow-up studies realized separately and completely independently that the influence of the good hemisphere is just not present or absent, good versus bad. It is nuanced in the sense that if patients have just a minimal, mild stroke, sure, the intact hemisphere, the good hemisphere, it just kind of maintains its hold and it can be a little bit competitive. And that happens in the milder populations, but in more severe stroke where the more damaged hemisphere has nothing else that remains, that's where the good hemisphere can take over functionality in a more favorable way, because that's the only primary hemisphere of control that remains. So that's the bimodality, if you will, right? It's not just linear good versus bad, it's it can be good and it can be bad, but across different ranges of severity. I don't know if that clarifies.

Glen Stevens, DO, PhD: Yeah, well, you're helping me, so that's good, that's good. So does it make a difference if it's your dominant versus your non-dominant hemisphere that you stroke?

Ela Plow, PhD: That's just an excellent question. Our colleagues in stroke neurology will tell you that patients with dominant side paresis just have a harder time with reaching the outcomes as the non-dominant side paresis. And now, if you add to this, the layer of natural bi-hemispheric imbalances that you and I possess, and everybody possesses, even before in premorbid state, you realize that the situation gets more complex.

Glen Stevens, DO, PhD: What about if it's a deep basal ganglian or lacunar type stroke versus a cortical stroke?

Ela Plow, PhD: What we're realizing is that there are many different factors, clinical demographics of our patients that dictate what type of influence the good hemisphere would have. And that dictates what types of neuro restorative treatments you can provide. Should you ask them to shut off the movement of the good hand for the time being while they restore function with their weak hand, or should they use both hands together, all of that, right? So this theory dictates a lot in terms of treatments.

Now, when you come to what dictates which side of the bimodal spectrum would patients fall in, one of the things that we're realizing is that if you can quantify in a simplistic way, the level of damage at the level of the internal capsule, especially the posterior limb of the internal capsule, in the case of upper limb motor impairment, voila, you have something there, which you can tap into and start to now define patients who are mildly damaged at the level of the internal capsule may have a more competitive, if you will, role of the good hemisphere, whereas patients who have just a huge knockout of the posterior limb of the internal capsule of the internal capsule, they may have a more forgiving influence. So in terms of imaging, that's a site of interest, and it's a little more simplistic as you know, a DWI is a part of the stroke workup, right? So it can be captured a little more in a straightforward way.

The other one, and I can't leave that out, especially in the context of this podcast is the viability of the pathway. So in your language and mine, it's not just the structural integrity or the piping, but actually the conduction near the piping that matters. So even if, sometimes we see patients may have quite a bit of damage to PLIC, the posterior limb of the internal capsule, but the viability via TMS-related neurophysiologic testing is available shows patency, now that's another type of baseline characteristic that can help define the types of influence from the good hemisphere and the treatments that follow.

Glen Stevens, DO, PhD: So based on the homunculus, is it easier to treat certain areas than other? I'm getting the sense that upper limb probably easier than leg?

Ela Plow, PhD: Yeah, it has received so much interest. It's also, I think it started, I believe because the corticospinal tracks are more preferentially dedicated to the upper extremity, especially the fine motor aspects of the distal extremity. And what TMS would do generally is sensitive at picking up the fast-conducting axonal potentials that generally are offered by the Betz cell neurons, for instance, in the primary motor cortex. What that means is it allows us to access the fastest conducting pathways, which are generally dedicated to the hand.

Glen Stevens, DO, PhD: Well, good. And if you are using diffusion tensor imaging, can you see a difference or is it too gross, a level to see a difference after someone's treated? Could you visually see a difference in the DTI?

Ela Plow, PhD: In the context of having received a neurotherapeutic brain simulation treatment?

Glen Stevens, DO, PhD: Yes. Yes.

Ela Plow, PhD: The evidence about that is quite early. As you know this quite well, the DTI-related integrity metrics that we have, like the FA, the MD, and all of that, especially FA just because it's straightforward and more popular, those changes take a while to become evident. In more acute stages and more subacute stages of recovery studies have revealed the changes in FA metrics. But in chronic stages, FA may remain unchanged, but what may happen is the pathway physiology gets augmented. So the piping remains the same, but it gets faster.

Glen Stevens, DO, PhD: Can you walk us through your typical simulation methods and targets? You've discussed it a little bit, but I come see you, just walk me through how you treat a patient, what you do.

Ela Plow, PhD: Sure, so let's take stroke for example, because we have a large population here at the Cleveland Clinic. So we're specialized in the area of severe strokes. So these are patients who can't be participating in regular clinical trials of rehab. They're generally excluded. So a patient is quite impaired, has severe upper limb hemiplegia, comes in. And our goal through, for instance, in this case, the NIH clinical trial that we're performing is to tap into what target their intact or good hemisphere as a means of potentially promoting any recovery that may be possible to achieve. Right?

So a patient comes in, we have a workup with the neurologist, a therapist and also an imaging-related workup that defines where the stroke lies, what areas are remaining, what areas in the intact hemisphere with functional imaging and resting state functional connectivity imaging are likely candidates to act as substrates of recovery. With all of this imaging and clinical and therapy workup, then we are able to start our treatments and those treatments then involve the pattern, I come back to pattern, the pattern of therapeutic modes of transcranial magnetic stim, which we call Repetitive TMS or rTMS, many different types of frequencies. But basically the patient sits down. We have their MRI. We have the functional imaging available from their own brain. And with that, we also have them surface EMG placed on different muscles on their paretic side and the non-paretic side. And we're able to evaluate how much conduction are we still able to see. This is done with, let me just say simplistically, just simply TMS, but this is not the pattern. This is just single pulses of TMS.

So this helps us diagnose the potential, if you will, of the remainder of the pathways that these individuals have. Once we know that we have a readout on the baseline, then we're able to begin treatments. So if the patient is assigned to receive the treatment to the good hemisphere, then we target certain higher motor regions of the good hemisphere based on again, the imaging workup and also the neurophysiological workup received with TMS. So with a combination of this, we will run those patterns, stimulation paradigms, and immediately the patient is treated with upper extremity rehab exactly and pretty much similar to everything that we do in the clinic here in standard of care. After completion of that rehab, we do certain questionnaires to make sure that everything was safe, there's no neck pain, scalp pain, et cetera, which again, are based on reports of minor, slightly uncomfortable responses to any type of brain stimulation.

Glen Stevens, DO, PhD: And how many treatments would someone typically do? And what's the timeframe.

Ela Plow, PhD: We are working with a severe population, so we do have a longer paradigm than usual. So three months, this involves two times a week coming to an outpatient setting in our lab, which is what we kind of try to duplicate. And they see a neurophysiologist where we provide the treatment. The neurophysiologist exits, the therapist enters, the patient receives treatment and goes back home. So that's twice a week for 12 weeks. In another study, we're doing a six-week treatment of a similar frequency, which is funded by the American Stroke Association. So it's between six weeks to 12 weeks, so very similar to the dosing that we give in standard care rehab after a stroke.

Glen Stevens, DO, PhD: They keep saying that, "I may need a booster for my COVID." Do patients need a booster for their TMS? I mean, is there a possibility that six months bring them in, do another series? I know this is way in the future, but what are your thoughts?

Ela Plow, PhD: That's a great point. We do understand that, especially you understand, the plasticity of brain doesn't abruptly stop, right? I mean the functional repair mechanisms continue and the intrinsic repair mechanisms continue. So in subsequent studies, and I know some groups are trying to explore whether after about a series of patterned therapeutic stimulation sessions, whether maintenance at home potentially, or even in a less invasive outpatient setting, such as with direct current stimulation, which is, if you look at it as quite low profile electrical stimulation modality previously applied to the rest of the body, especially in therapy services, but now applied to the head, whether that's something that can give patients that boost they may need in follow up in retention phases.

I think what I'm really excited about, and I think Cleveland Clinic provides that opportunity and we're ready to embark in this area is the diagnostic potential of the single pulse or the innocuous bi-pulse stimulation, which is not patterned because of the potential of revealing the pathway conduction, which is so primary to a typical MCA stroke, which leads to upper extremity paresis. We understand that's one of the more common deficits. So being able to diagnose that, evaluate that potential of remaining pathways and then monitoring that, we are now at that position where we all have the machines. It's ready for bedside and it's ready for outpatient. So we're ready to tap into that potential here at the Clinic. And we're very excited about that.

Glen Stevens, DO, PhD: And the negative of TMS. What's the risk?

Ela Plow, PhD: So risks for patterned stimulation is a rare risk of seizure. And it's a one-time seizure during or after. Again, it's rare to the point that they've recently completed studies and documented across all the seizures, because we have to report any seizure that happens in the world to certain journals and they're published really quickly. So when they have done this math, they realized that the risk of being hit by a car when you leave your house is much greater than the risk of a seizure with patterned TMS.

Glen Stevens, DO, PhD: So this is a nice segue because I now wanted to ask you about the role of TMS in epilepsy not causing, but treating.

Ela Plow, PhD: Right, right, right.

Glen Stevens, DO, PhD: Thoughts about that or a discussion about work you're doing in that area?

Ela Plow, PhD: Yeah, so I'm pairing with an epileptologists and colleagues here who I know have recently acquired their clinical grade TMS device. Right now, TMS is approved for neurosurgical mapping, not so much for therapeutics, but mapping in the case of an epileptic foci and determination of the intact areas around the focus. And that's very exciting because it's not just, again, going back to, they do receive very high-grade DTI information, but that again, is structures, the piping. So in addition to that, they would want to get their readout of the pathways that surround the speculated focus, right? So, that's where the high resolution neurosurgical mapping becomes... it's more comfortable to do that with an extracranial or a transcranial magnetic stimulation.

Glen Stevens, DO, PhD: So it sounds like that'd be very helpful in surgical pre-evaluation for these patients.

Ela Plow, PhD: Right. Exactly. And I know in certain parts of the world, you would know this way better than I do, areas around the glioma, areas around brain tumors are being monitored with neurosurgical profiling, with TMS.

Glen Stevens, DO, PhD: So other indications for TMS, any other little things you guys are doing?

Ela Plow, PhD: So right now, the FDA-approved ones, as you know, for therapeutics are for depression and then for diagnostic and pre-surgical mapping is in the area of epilepsy. Other things that we would really like to take this to is, of course, the potential, as I spoke about, in any condition with upper motor neuron, integrity loss in the context of upper limb or lower limb motor impairment, which can come from stroke or multiple sclerosis. So there are a lot of groups across the country and across the world that are working together, because there's so much data, especially with stroke, there's so much data. It is unbelievable.

Glen Stevens, DO, PhD: And I'm just curious, do you see, as a side effect of the treatment that people have elevated or improved mood? You're treating them for a completely separate reason or is nobody really looking at that or it's not directly targeting those areas? I'm just looking at an additional benefit, I guess.

Ela Plow, PhD: Right, right. And you can imagine that people have tried to use this, use is probably the more correct term or politically correct term here, use this as a feature for improving mood. The more challenging situation, which also goes into the ethics is with transcranial direct current stimulation. I'm sure people have read those articles published in Science and others where people have applied these even more innocuous techniques such as the direct current stem, because you could buy it over the counter at this point or order it online. It's sold out for mood elevation, right?

So it is interesting to talk about it. It is also challenging because, again, it is the borderline of the ethics of having younger adolescent kids picking up these treatments and trying to apply them in their parents' garage. Right? So there are issues related to mood and changes, which are still being explored. But in the context of well-controlled clinical trials, what we do based on the advice from our psychiatry colleagues is we do capture changes in mood, right after treatments, before treatment, of course, to compare to baseline, but even over the long-term to see if there's an association between the side of the head that was stimulated and over time, the change in their PHQ-9 scores, for instance.

Glen Stevens, DO, PhD: Does it generate heat?

Ela Plow, PhD: It does, but it is insulated quite well. We have thankfully evolved in science and created physics around it that helps us not pass that heat on to an individual.

Glen Stevens, DO, PhD: So Ela, just moving away from the brain here for a second, spinal cord, obviously another big area that needs a lot of rehabilitation. Talk about the application of TMS and spinal cord injury.

Ela Plow, PhD: So the most humbling experience in working here in clinical research is to work with patients with spinal cord injury because we are seeing a large number of individuals who have a longer disability in their life years. We all understand the major population that gets affected with cervical spinal cord injury damage is younger, generally male, adults. And so then they have a long lifespan with associated disability and we all understand the context of cervical spinal cord injury, which is the population we study, i.e. leads to paralysis from neck down, putting it in very lay terms, right?

So extremely challenging population to work with. Bringing them into an outpatient-like facility is hard enough. But what we are trying to study here in these individuals is tapping into the restorative plasticity mechanisms that they have available from the brain. So generally as we understand, generally, the brain is left intact in these injuries, right? Even if the injury is quite severe at the level of the spinal cord injury, previous animal studies have demonstrated the ideas of sprouting or rewiring of pathways. We all understand the intrinsic mechanisms that are available afforded by nature to these individuals. So what we're trying to do is boost what the brain provides to the remainder of the spinal cord and the pathways in very simplistic terms and have the pathways work around or loop around, bypass or rewire as much as possible in trying to duplicate what the animal studies have repeatedly shown in rodent and non-human primate models of the repair mechanisms. So using the brain as the major viable organ, if you will, to help restore plasticity and function in these individuals.

Glen Stevens, DO, PhD: So, Dr. Plow, really learned a lot from you today, and I appreciate your being here. Any closing comments you'd like to make at this point in time?

Ela Plow, PhD: If there are any colleagues listening who are interested in using a technique that helps them close the loop, you know, imaging, we have advanced imaging, we have structural, we have functional imaging that gives us a great, great read into what remains. I think what TMS is able to add to that is it show us that how does what remain really function. And once we have that, we can close the loop on understanding the true potential that a patient may have. This may help us with adding value to their care, adding resource utilization to the equation, helping us understand if patients don't have these criterion pathways remaining, are we really just banging our heads against a wall with these standard treatments, or should we think of something unconventional?

So in being able to prognosticate and predict the potential and allocate people into the right types of treatments sooner than later, that to me is most appealing. While I value all of the information I receive from imaging, I think the idea of functionality of what remains is really critical to me and I know that it is to a lot of my clinician colleagues as well.

Glen Stevens, DO, PhD: Well, Ela, we're very excited to see where this work leads us. It's an exciting time in the field. That's for sure. Thank you for joining me today.

Ela Plow, PhD: Thank you so much, Glen.

Closing: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/podcasts/neuro-pathways, or subscribe to the podcast on iTunes, Google Play, Spotify or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter at CleClinicMD, all one word. And thank you for listening.