Neurosurgery, Blood-Brain Barrier, Ultrasound Technology for Brain Diseases & Disorders | Nir Lipsman | #181

About the guest: Nir Lipsman, MD, PhD is a neurosurgeon and neuroscientist at the University of Toronto.

Episode summary: Nick and Dr. Lipsman discuss: neurosurgery; the blood-brain barrier and how it works; using focused ultrasound technology to non-invasively treat patients; regulatory impediments to clinical research; costs, constraints, and future applications of ultrasound tech for treating psychiatric conditions; and more.

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*This content is never meant to serve as medical advice.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Nir Lipsman 1:31

Sure So I'm a neurosurgeon. I work at Sunnybrook Health Sciences Center at the University of Toronto. My specialty is something called stereotactic and functional neurosurgery. And I am also a scientist, a senior scientist at Sunnybrook Research Institute, where our group and our interests are in developing new technologies to influence the brain. So

Nick Jikomes 1:55

you're neurosurgeon, you're cutting people's skulls open and doing brain surgery.

Nir Lipsman 1:58

You got it? Yeah? Brain surgeon, yeah.

Nick Jikomes 2:01

What did you have a kind of specialty there or focus area in terms of the types of things that you treat? Yeah? So

Nir Lipsman 2:07

I got into neurosurgery because I was really interested in human behavior and really interested in psychiatric disease, actually. So it's interesting because it's a kind of a niche area of neurosurgery, using surgical strategies to treat mental health conditions. So but there is a subset of neurosurgery, a subspecialty of neurosurgery called functional neurosurgery, where the goal is really to treat diseases where you may not necessarily see anything abnormal on a CT scan or an MRI scan, but things are fundamentally wrong with the circuits driving certain behaviors. So typically, things like movement disorders, Parkinson's being most common. So movement disorders, pain conditions, epilepsy and mental health conditions. So again, these are diseases where not always something very obvious on a scan, but something profoundly wrong with patients and and that's, those are the kinds of diseases that we treat.

Nick Jikomes 3:04

So it sounds like what you're saying is that, you know, we often make a distinction between psychiatric brain issues and neurological brain issues. And to a first approximation, at least when someone has a psychiatric condition, as you say, there's nothing necessarily wrong with their brain that you can see macroscopically and like a scan, there's not necessarily a tumor or a chunk of the brain that's malformed or something, you know, there's just functional problems at the level of synapses and cells and stuff in the brain. Whereas neurological problems are, you know, more classically associated with surgical intervention. Someone has a tumor pushing against a certain part of the brain. You can go take it out of that part of the brain. What are some examples? What are some of the biggest examples, the most common ways that sort of, this approach, the surgical approach, is used to alleviate something that's psychiatric condition. So

Nir Lipsman 3:49

it's a great I mean, you're asking sort of, you know, really fundamental question about our field, which is, you know, the difference between structural conditions and, as you said, functional conditions for me as a neurosurgeon, and you know, being interested in sort of where the fields come from, it's really a matter of scale, too. So you know the tools you're only as you can only see what your tools allow you to see. So for example, when we did not have any CT scans or MRI scans, you know, about half a century ago, everything we maybe could have considered a functional condition or a structural condition, etc. But now that we have CTS and MRI scans, we can probe these things in much more specific ways. And as our ability to to to establish very fine resolution with MRI scans really improves, we can probe even deeper. So maybe some conditions where, in the past, we weren't able to see maybe what was structurally wrong, and we just assumed that the brain was structurally normal. It just a matter of scale and resolution. Now, with these fine tools, we can look, we can look really finely. So in this psychiatric space, actually, neuro. Surgeons have been involved very early in some of the very earliest indications for surgery were psychiatric conditions, mostly mood and anxiety disorders. And this goes back all the way to the 40s and 50s, and even earlier, where there was an early recognition, dating back, really from the 30s, that there are important circuits in the brain that govern mood and that govern our ability to make a decision based on emotional feedback. And we've known that. Neurophysiologists have known that from animal models going back again, you know, almost a century now. So the surgical strategies that we developed to treat those essentially tried to sever or influence that circuit in very specific ways. So we know, for example, where mood disorders or where mood in the brain may arise from or is influenced by, and in patients with severe and significant depression, we may influence that in very specific ways. The way that we influence it has evolved hugely in the last 50 or 60 years, but the principle driving that is very similar, which is that, you know, we want to influence that circuitry in a way that influences the behavior. So we have circuits, structural circuits, that are driven by biochemical and other factors, but ultimately manifests as behaviors. And to influence the behaviors, you need to influence the circuit.

Nick Jikomes 6:21

What, what are some of the more common surgeries that you actually perform on people, and what are you treating with those?

Nir Lipsman 6:29

So you can classify the disorder, the surgeries that we do in functional surgery, as what we call ablative which are precision strike lesions in the brain, permanent lesions in the brain that are able to have circuit wide, network wide effects on behaviors. So for example, we can do a procedural known as a thalamotomy, which is a precision strike lesion in the thalamus that influence things like tremor, essential tremor being the most common condition. You can also use a thalamotomy to treat very troublesome tremor of Parkinson's disease. You can do a procedure known as capsule automate to treat patients with severe anxiety related to OCD, and we know that you can do that effectively, and the newer tools that we're using can even do it even less invasively than more traditional approaches. Other tools include something called Deep brain stimulation, which is a kind of pacemaker. It's a pacemaker for the brain, where electrodes are inserted in specific targets in the brain, and their electrodes are tunneled under the skin to a pacemaker battery that's placed underneath the clavicle, usually on the right side. And the idea is that electricity will small doses of electricity generated by the battery will jam the circuitry of the brain. And in a way, you can achieve the same influence on those circuits without making a permanent lesion in the brain, without damaging the brain. You can do it in a kind of reversible, reversible fashion. So those two procedures, ablative approaches and stimulation based approaches, I would say those are the workhorses of our field.

Nick Jikomes 7:57

And so, of course, these are highly invasive procedures. There are probably, probably things that happen when there's no other options. There's no other treatment that's available for someone, they have to go and talk to a Brain Surgeon and get cut open, have something installed in the brain, or have part of their brain literally disrupted for therapeutic purposes. You're also involved, it seems, in the development of new technologies that are basically allowing surgeons and scientists to use technologies that have been around for a while to actually modulate brain activity, deliver drugs, do other things in a more non invasive fashion. Can you talk a little bit about the setup for that stuff?

Nir Lipsman 8:38

For sure? Yeah. So I mean, big reason why I got into the field is because it's it's very much. It's evolving, and as we learn more about the circuits of the brain and the tools that we have, you know the tools that we use today are very different than what we used 10 years ago, and we fully anticipate will be very different a decade from now. So even though the central premise is to influence brain circuitry. How you do that will constantly evolve. So we're actively using something called focused ultrasound, for example. So Focused Ultrasound is a helmet like device, and the idea is you use sound waves to influence the brain. And we've been using ultrasound in medicine for decades, for many decades. And in fact, ultrasound is used throughout the body. And everybody knows, you know that you can use ultrasound in different ways, but the idea is that if you harness the power of ultrasound coming from different sources and focus sound energy onto a very discrete point, you can, you can have very specific biologic effects on tissue. So if you use high frequency ultrasound, you can generate a permanent lesion, just like a magnifying glass, harnesses the power of the sun's waves onto a raise onto a discrete point and generate heat. The same principle applies to ultrasound energy. So we can do this non invasively. We can focus sound waves through the skull onto discrete. Points in the brain, guided by an MRI scan, and generate those permanent lesions in the brain to treat patients with tremor and OCD. If you use low frequency ultrasound, you don't generate heat. But what you can do then is temporarily open a kind of window in what we call the blood brain barrier, which is an invisible to the naked eye barrier that invests the very fine blood vessels of the brain so that you can allow therapies into the brain that ordinarily can't get in. So this is, you know, a real game changer, potentially for a lot of diseases where that barrier is a major obstacle. So new, new techniques, for sure.

Nick Jikomes 10:35

Okay, so ultrasound, the most familiar use cases you know, when a pregnant woman goes into the doctor and gets those images of her baby. So we're using sound waves to generate an image in that case, or in the case you just mentioned, to actually manipulate the brain. So if you use ultra high frequency ultrasound, you've got very, very high frequency sound waves that are being generated that generates heat, and you can use that and focus it inside different parts of the brain to actually ablate or physically disrupt different parts of the brain. Yeah,

Nir Lipsman 11:08

that's exactly right. And when you think about an ultrasound being used to look at babies, or look at looking at, maybe our arteries in our neck, that's a single transducer that somebody holds up. So they're holding, and they're holding basically looking at the belly. What we're talking about here is harnessing the power of over 1000 transducers that emit ultrasound waves so that we can, we can focus them through the skull. Now I'm saying it, and it sounds like it's just, you know, you know, simple to do, but this has been sort of the to be able to focus sound waves through the skull onto the brain. Has been sort of the holy grail in the field for many decades. So people proposed this back in the 40s, using ultrasound to influence the brain. But the problem has always been the skull, but ultrasound can't travel through bone very easily, the bone will absorb all of the energy, and you don't get anything on the on the other side of it. So it required a lot of smart people and a lot of physicists and engineers, several key people, one of whom is one of my partners here at Sunnybrook, Calero hinnan, who's one of the pioneers of the technology, requires a lot of people to sort of say, You know what? How can we overcome the so called Bone problem? How can we develop a device? And in this case, it's a helmet like device that is able to, again, harness the power in a kind of spherical fashion around the patient's head, so that we can get ultrasound through, through the skull. And that's exactly what we've been able to do for the last 10 or 15 years in patients for different kinds of conditions. So overcoming that was a major physics and engineering problem, and a lot of key key advances had to happen in order to make that happen.

Nick Jikomes 12:51

Well, so it's a physics it's a device. It's like a helmet or a net like device, and you've got a bunch of little ultrasound probes, and because you've got so many of them pointed at different angles and stuff, that allows you to have a quite a bit of spatial precision, I would imagine how, what's the spatial temporal resolution here

Nir Lipsman 13:08

exactly, we can achieve sub millimeter accuracy actually. And and the more transducers you have, the more control you have, the more accuracy you have. So initially in the 40s, was four transducer models. And then in the 90s, it was 512 and now it's 1024 and future iterations will be more and more. So the more ultrasound transducers and sources you have, the more control over spatial and temporal resolution you can get. And also, the more and also, the more you know. So in order to get ultrasound across, you need to use high powers. So, you know, and we divide that, if the denominator is higher, you can use, you can, you know, it influences the amount of power that you use. So obviously, more transducers, the same amount of power gives you more more control. And

Nick Jikomes 13:53

so how, how intensive are these procedures from the patient's perspective, how long does a typical procedure take? Do they have to be anesthetized to be put so that they're still Yeah,

Nir Lipsman 14:03

so I you know it's interesting, because you one has to sort of have a comparative course. And the most common indication for focus, or percent today is tremor, essential tremor. And 1000s of patients around the world have had this done. Now, the standard way of treating patients with tremor, and again, these are patients who have reached the limit of what medical treatments can offer them. So they're all surgical. So considering all the surgical patients, the standard approach is deep brain stimulation. It's the pacemaker approach, where electrodes are insert in the brain and there's a stage procedure that's done. So compared to that, it's definitely more tolerable. So usually patients are awake during the procedure. There's sometimes an anesthetist or a nurse, you know, administering some small doses of sedation to keep them comfortable. But usually we need them awake because we follow the tremor in real time. So the procedure is done in an MRI scanner. It takes approximately an hour and a half to two hours, including the image. That's done during the procedure. We use ultrasound to heat the part of the brain responsible for the tremor, and we we ask patients how they feel. And one of the key, I would say, value adds of this procedure is that it is done awake, because real estate is everything in the brain, geography is everything. So immediately adjacent to where we make these lesions are very important structures responsible for motor function and responsible for sensation and things like that. So you don't want to make a permanent lesion in those areas, because you get significant side

Nick Jikomes 15:32

effects. But the awake can give you real time feedback. They give you feedback exactly,

Nir Lipsman 15:35

so they're awake, and they can say, oh, when you did that, I felt some numbness in my hand, or I felt a little bit of numbness in my lips. So, you know, to change the target, we can make millimeter changes to the target and then find the sweet spot and make a permanent lesion. I

Nick Jikomes 15:49

see. So it sounds like you can, you can sort of lightly probe the brain so that it's not causing permanent damage to get the exact spot right before you sort of turn up the That's

Nir Lipsman 15:59

exactly right. And we actually call that a sub lesional temperature. We can raise tissue temperature to levels where they sort of knock out the neurons in the area, but they don't permanently kill them. It's a temporary process, and it's you are mapping the brain, sort of we're mapping saying, you know, what, if I were to make a lesion here, what would it be? And we want to see effect on the tremor in this case, and absence of side effects. If we see that, then we can turn up the power.

Nick Jikomes 16:26

And so this brings us to another important area, which I think is interesting, which is, if you're using, you know, if you're using the ultrasound at one frequency, you'll heat the brain enough to actually ablate neurons, you know, destroy tissue, which can be beneficial for, you know, like the use cases you mentioned. But are there, is there anyone looking into developing sort of the lower frequency ultrasound, so that you can actually modulate the activity of neurons in a therapeutic way, where you're not actually destroying neurons, but you're helping circuits become more or less active as a way to functionally correct something,

Nir Lipsman 16:59

for sure, for sure. I think that, you know, it's probably, it's probably one of the most exciting areas of the field. So two specific areas, there's the using ultrasound to temporarily permeabilize or provide a window into the blood brain barrier in a safe way. And then there's the neuromodulation approaches. So where there you're not opening the blood brain barrier and you're not lesioning, but you're still influencing the brain circuitry in a meaningful way. Now, there are challenges there. One is mechanism. You know what exactly is happening at the neuron at the synapse, whether it's chemically or whether it's physically electrically, remains to be seen. And I don't think anybody really knows right now. And I think it's an area of active, really, you know, exciting, but active investigation. The other thing is, you know, the sustainability, the effects, if you are the one of the advantages of something like dBs, which we do all the time for patients with movement disorders and psychiatry, it's at the stimulation is always there. You know, the battery's providing stimulation all the time with something like focus, ultra modulation. You may only be influencing the circuitry when the ultrasound is on, and that may be effective, for sure, but we need to figure out how to sustain that effect over a longer period of time. Do you need to sustain it, or can you only you only need it for some time, time, some parts of the day, or for some parts of the month, etc. So, so I think mechanisms, long term sustainability, those are the key things that people are actively looking on, looking at to see what indications ought to be. But that that's the next step for sure. So we were looking at ultrasound across all of these different mechanisms, and there are others, or at least a dozen different mechanisms, different ways that ultrasound can interact with the brain, and that's definitely some of them, but

Nick Jikomes 18:46

it sounds like, you know, as opposed to other ways of doing transcranial stimulation of the brain, which we which we can do today, in principle, the ultrasound approach offers a much sort of finer, finer scale. You know, it's got a finer spatial and temporal resolution. In principle, you could modulate neurons in very specific parts of the brain in particular ways,

Nir Lipsman 19:05

for sure, for sure. And when you look at I mean, there are other ways, as you said, ect, transcranial magnetic stimulation. There's something you know, tax alternate occurring stimulation. So we're in a renaissance right now of brain stimulation, brain technology that is geared to influencing brain circuitry, for sure, one of the things with ultrasound that is a value add is the ability to modulate that resolution. So you can look at things like frequency, you can look at amplitude, you can look at Pulse Width. You can look at all these different parameters to try to fine tune exactly what part of the brain, how deep you want to go and what you want to target. So ideally, you pair it with imaging so that you can see it in real time. But I think as we get better and better at it, and depending on the indication, you may not even need real time live imaging to do that, you may be able to use the ultrasound and the feedback that you're getting from the device itself in order to target. It so, so I think that's definitely, you know, one of the value adds. And we've had a lot of experience with ultrasound in the brain. We use it still to this day, and brain during surgery, sound waves pass harmlessly, through, through, through brain tissue. So we know that, you know, standalone is pretty safe.

Nick Jikomes 20:15

And can you give us a sense of and I don't, we're obviously not here yet. But where could this go in terms of, you know, the technology and the application? So, for example, is it conceivable that at some point in the future, someone with a psychiatric condition that develops symptoms intermittently, say they could have an ultrasound helmet at home, and when they need to use it, they sort of just sit in it when their symptoms come on. Or is this something that you think will always be like you have to go into the into the clinic to do this,

Nir Lipsman 20:50

that that's the goal. That's the goal for sure. I mean, I think that, you know, we have to assume and ultimately aim for as personalized and comfortable approaches as possible, and then, yes, having a portable helmet, if you will, or a portable device done, obviously, under the you know, guidance of healthcare professionals, that that will ultimately be the goal. But I think we have a ways to go. And I think that we were very much figuring out we have so many levers to press with this technology, and I mentioned just a few of them, in terms of the technical parameters, but in terms of indications, and in terms of drug delivery, what it is that we want to deliver, where in the brain do we target and for how long? But, but, yeah, I mean, I think that what you're describing is the ultimate goal. It's highly personalized, it's effective, hopefully it's safe. Because we know a lot about this technology, and a lot of diseases are episodic, you know, and they are, you know, things that we just have to get people over the hump, you know. Another A good example is postpartum depression. You know. We know that this is debilitating condition. We know a specific period of time that it could develop. Could it be that in conjunction with pharmacologic and psychotherapeutic approaches, you may use something like ultrasound or other forms of stimulation to augment the effects of those treatments? So I'm a really firm believer in complementary approaches, and I really and that's how we sort of a structured, our center, a structured our approach that absolutely, if you have a hammer, everything looks like a nail. But if you have an approach where you're supplementing, you know, just like you the same approach used for cancer, we supplement surgery with radiation and chemotherapy. If you take something as complex as major depression or brain cancer, it's not going to be one treatment. It's not going to be one single approach. It's going to be a complimentary approach that's coming at the same disease from multiple different angles. Ultrasound needs to figure out where in that algorithm, what role it's going to play. Okay, it may not be the absolute, definitive role, but it may be a central role, a key role that helps improve or enhance or augment other kinds of strategies, and that's really going to be the way we make a difference in these really complex diseases. Yeah.

Nick Jikomes 23:07

So it's conceivable that you know, if you have an episodic condition, especially where the patient can sort of feel ahead of time that something's going awry. Someone, say has epilepsy, they get that pre seizure aura. Someone has bipolar disorder, they can sort of feel themselves. Feel themselves starting to become manic. You can imagine using something like this to prevent that, for

Nir Lipsman 23:27

sure, for sure. Migraines is another example. Epilepsy is a great example, which you mentioned and, and, yeah. I mean, you we have conditions like bipolar mania, Bipolar depression, depressive episodes where you know things you know, we may be able to anticipate things happening. You may be able to intervene at an earlier stage. So, yeah, absolutely. I mean, I think it's aspirationally the goal.

Nick Jikomes 23:50

And so you mentioned previously that another application here for this technology is to use the relatively low frequency ultrasound to temporarily open up the blood brain barrier to assist with drug delivery. I want to get into that before we get into the nuts and bolts there. I want to paint a picture for people who don't know much about the blood brain barrier. Can you give us just a sort of simple Crash Course and how it works? Yeah,

Nir Lipsman 24:12

sure. So one can think of so our brain is in spinal cord, but if we talk about our brain, it's what we call an immune privileged organ. So it's an organ that is evolutionarily designed to keep bad things out of it and to keep to allow good things that it needs to flourish and survive into it. And as a result, we have something called we have a physical barrier known as the blood brain barrier, the BBB, and this is a layer of cells as well as other kinds of factors that invest the very fine blood vessels of the brain, so that whatever is circulating in the bloodstream, whether it's consumed or injected or what have you or experienced in the world, it can't get into the brain. So. So the barrier is a physical barrier. It's a size barrier, predominantly so very large compounds can't get into the brain. Smaller compounds, oxygen, glucose, things like that. Some medications can get into the brain because they're designed to be small. They are small, but as soon as you start getting into more designed therapeutics, antibodies, monoclonal antibodies, chemotherapies, growth factors, stem cells, things like that. Those are too big. Those are much too big to get into the brain in significant amounts in order to have an influence the body's own immune system, the body's own immunoglobulins, can't get into the brain in significant amounts, and that's where there are some infections that can only occur in the brain, because the body and the body kills it everywhere else, but not inside the brain, so it's immune privileged. So we've known this for a very long time, and as a result, we've known that there are some things that, for example, like cancer, that can be relatively well controlled systemically throughout the body, but cannot be controlled intracranial inside the brain, and that's because chemotherapies can't get in. So a way to overcome that has been long sought in our field, for many decades, a way to overcome that blood brain barrier, and many different approaches have been tried. Unfortunately, they've either been too risky or not effective, so ultrasound, early on, was proposed as a potential strategy to overcome that.

Nick Jikomes 26:31

So, okay, so, so the brain is immune privileged. We don't want anything that's flowing in the blood to get into the brain. That makes good, common sense, I think, to most people. And in essence, if something's small enough, it's got at least a decent chance of getting the brain but most things that we might want to put in there, like a medication, are usually too big. So the basic idea is, Can we somehow temporarily open up the blood brain barrier to let things in that we want to get in there, and then it closes back up so that we're not just flooding the brain with anything else that might come after, how, how is this working? Now, in practice, what is the what is the ultrasound actually doing to achieve the opening? Yeah,

Nir Lipsman 27:08

so I would say, in the early 2000s scientists, including clever hinnen and who I mentioned, that Sunnybrook began to experiment with ultrasound, low frequency ultrasound, and micro bubbles. So what are micro bubbles? So micro bubbles are microscopic gas filled bubbles that exist in contrast agents that we use to image things like the heart and in other parts of our body. What we know about micro bubbles is that when they absorb energy, they can oscillate. They can vibrate very, very quickly, increase and decrease in size. So what was hypothesized, and what has since been borne out in hundreds of animal models, is that if you inject micro bubbles intravenously, the micro bubbles will circulate throughout the body, and they'll get to the brain about 30 seconds after they're injected. And if you expose those micro bubbles to low frequency ultrasound, the micro bubbles will absorb the energy and start oscillating. So when they oscillate very, very quickly, what they'll cause is a physical pulling apart of the cells of the blood brain barrier. So remember, they exist inside the blood vessels, but the blood vessels themselves will start to separate, and the cells making up the blood brain barrier, we're still to separate as long as those micro bubbles are exposed to ultrasound. It's a physical process. It's a physical pulling apart of the cells that takes approximately 12 to 24 hours for it to come back and reconstitute. So it was discovered that micro bubbles plus low frequency ultrasound leads to a temporary window in the blood brain barrier in a very focused way to wherever it is that you're directing the ultrasound to. So just like with high frequency ultrasound, we can direct sound waves to discrete parts of the brain. We can do the same thing with low frequency ultrasound, and we can target a brain tumor, or we can target a part of the brain that's important for Parkinson's or for Alzheimer's disease, and temporarily open the blood brain barrier. And the idea is that if you are also injecting some kind of chemotherapy agent or a nerve or a growth factor or an enzyme or something that you want to deliver, then whatever it is that you're co circulating will then be exposed to that part of the brain that otherwise you can't get in. So again, temporary and permit temporary Permeabilization of the blood brain barrier is what ultrasound can

Nick Jikomes 29:26

do. So literally, the blood brain barrier, you've got cells that are tightly packed together. They've got tight junctions and things physically holding them tight to create that barrier. These micro bubbles start to vibrate when you apply the ultrasound after you inject the micro bubbles, and they sort of shimmy around such that these cells of the blood brain barrier temporarily and reversibly start to physically come apart. But all of this is not killing any of the cells or permanently damaging them,

Nir Lipsman 29:52

as long as you're very careful about which ultrasound parameters you use. So it was very early recognized that, yeah. If you, if you use too many micro bubbles, if you apply too much energy, if you leave Ultra standoff for too long, etc, if there are, in other words, if there are no redundancy mechanisms or safety mechanisms in place, you can cause damage for sure, and you can cause something called uncontrolled inertial cavitation, which is basically a collapse of the blood vessels. And if you have a collapsed blood vessel, you can potentially get bleeding and swelling, which are the two things we worry about. So this is not a this is a very fine process, a very, you know, by definition, a microscopic process, but it's one that requires really fine level of control. And when we started doing this and when the device was starting to be designed, a fundamental component were these safety and risk mitigation strategies. So this being ultrasound, we can build in what's called hydrophones into the system that listen to feedback from the ultrasound and from the micro bubbles themselves, so that if there is any sense that cavitation is happening or that anything untoward or risk is happening, the system shuts off. So there are sort of these risk mitigation strategies in place, but it's important to remember for sure that, you know, when we're influencing the blood brain barrier, it's important that, you know, be done in a sort of judicious way. And that's, again, one of those things that we're actively looking into. You know, What? What? What parameters can we use to modulate how much of the blood brain barrier is open, and how big is that opening, and how temporary is it, and how long does it last? And

Nick Jikomes 31:34

so, what are some examples of this technology in use? What kinds of drugs are you able to get into the brain, and for what purpose? Yeah.

Nir Lipsman 31:41

So the first trial that we did was in glioblastoma. So glioblastoma is a malignant, aggressive form of brain tumor, stage four. It's a grade four brain tumor. And unfortunately, Despite rapid advances in our ability to recognize the disease and study genetically, not a huge amount of we haven't been able to really move the dial on, on treatments for the disease. But before we got to delivering a therapy, and I'll get to that in a sec, before we got to that, we wanted to show that it was safe to open the blood brain barrier in the first place. And that's because of exactly what you mentioned, that we're opening very fine blood vessels. We want to make sure that we can actually can actually do that safely, and that it was technically possible to do that. So the first patients were in glioblastoma, where we just opened the blood brain barrier without delivering a therapeutic and we were able to show that, now, almost a decade ago, that in patients who had previously undergone surgery, previously undergone radiation, we can safely open the blood brain barrier, and we can do it reversibly. So after that, we designed a trial looking at the delivery of something called hemozolomide, which is an oral chemotherapy agent that is administered to patients with GBM standard of care. And the idea there was to couple that with ultrasound, BBB opening. And we did, in fact, show that it was safe to do that, we've gone on to delivering monoclonal antibodies, which are very large compounds to treat patients with breast cancer metastases to the brain, as well as doxorubicin, which is a chemotherapy agent used to treat things like sarcomas, but hasn't been used to treat brain cancer, but we're using it to see if we can improve his delivery in pediatric brain cancer as well. So those are the chemotherapies, and we're interested also in antibodies and enzymes for Alzheimer's disease and in Parkinson's so in all these instances, very large compounds where in the past, there may have been a rationale, but the blood brain barrier was a major obstacle. One thing I

Nick Jikomes 33:44

want to ask you about that's also interesting. It's a little tangential, I think, but you know what we're talking about here. We're implicitly talking about people who have a blood brain barrier that works, that has high integrity, that needs to be open, because it's not normally permeable to these things. A lot of people, my understanding is uh, over time for for different reasons, and I'm not sure how much we know about why this happens, but the blood brain barrier can lose its integrity over time. It can become leaky. Can you talk a little bit about what we know in terms of how often that happens and why it happens? It

Nir Lipsman 34:19

happens a lot, and in fact, some of the theories behind Alzheimer's disease is really relating to leaky, leaky BBB. And also we know in brain cancer, the reason we can see tumors on an MRI scan is because the blood brain barrier has been compromised. And in gadolinium, which is a contrast agent that we use, is able to seep in. And gadolinium weighs is twice as big as a typical compound that can get across normally. So the BBB is abnormal in many of these patients. But what we what we also recognize and believe, is that it's abnormal in in abnormal ways. So there's a there's been a breakdown in the normal machinery. So there's a very different when. Morphologically, physically, electrically, the blood brain barrier in a healthy person, if you will, in an uncompromised state is different than in somebody that has a compromised blood brain barrier. Some of the cells are broken down. The tight junctions aren't as strong. And we know that the mechanisms and sort of the more practical aspects of opening the BBB are very different in those populations. And as a result, when we target, for example, a brain tumor, we target beyond the edge of what we can see on a contrast enhancing scan. We know that in those parts of the brain, or centimeter or two, beyond what we can see, or beyond what was resected, that's where most of the recurrences will occur. That's where brain tumor cells live, and we know the blood brain barrier is more intact in those areas. So that's the rationale for doing that. Certainly in conditions like Alzheimer's, we're just learning, we're learning that amyloid itself can, can render some of the can, can have an impact on amyloid, and tau can have an impact on the blood brain barrier. And the goal really is to impact intact, healthier blood brain barrier than than one that has already been compromised. Really the the analogy that often uses an out of control sort of fire versus a controlled, a controlled burn kind of thing, and with, with, with with fuss and BBB opening that is in done in a very controlled fashion. It's more of a controlled burn. You know, the idea is you're able to control the parameters, and you recognize the anatomy is more healthier, more normal, rather than a situation where it's uncontrolled. In some of the basic mechanisms, the blood vessels may be leaky and may not be as effective. And it may be that that fuss may not be as effective in those populations.

Nick Jikomes 36:41

Is there much thinking or even evidence that certain brain disorders might be downstream of a leaky, leaky blood brain barrier? Is there anything you know, whether it's Alzheimer's or something neurodegenerative you know, are some of these things potentially caused by the leaky blood brain barrier, enabling toxins or other things, inflammatory molecules to get into the brain and then trigger the disorder. It's

Nir Lipsman 37:03

a great question, for sure, the neurodegenerative conditions are, you know, high up there, and Alzheimer's? I mean, I think the field of BBB and in Alzheimer's is really active right now, I don't think there are any clear answers. What we know is that there may be an issue with drainage away from the brain. So there's an intense area known as glymphatics, which is an area of research that is really interesting in the neurodegenerative conditions in algebra, specifically, which is, how are, how is waste drained from the brain, for example, how is blood flow moving away from from the brain to carry all these toxic proteins and toxic, you know, collections away from the brain in a normal state, and how is it gummed up in an abnormal state? One of the interesting things that we've shown is that when you open the blood brain barrier, you sort of see a enhancement, and you see increased drainage around the very fine venules and blood vessels of the brain, which for us was the first time they can actually visualize that, potentially visualize that glymphatic system that has only been theoretically posed in the past. So here, because you're kind of, again in a controlled burn kind of fashion, opening these very fine blood vessels, these capillaries, you we've never really been able to visualize after you inject contrast, how is contrast then seeped away from the brain? Well, we think it's now happening around the blood vessels, around these venules, and that may be a mechanism that things are drained away from the brain and and as a result, a failure to do that, maybe may, may be linked to some of the neurodegenerative conditions, again, very early days. But I think an area that that is really quite interesting for us to study and but also think maybe linked to some of the pathology.

Nick Jikomes 38:52

How much do we know about factors that lead to a weekly leaky blood brain barrier, whether that's lifestyle factors related to things like activity levels and sleep quality, whether that's things like drugs that might people might take for other reasons than have a side effect of affecting the blood brain barrier. Are there any patterns that we see clearly that lead to leaky blood brain barrier?

Nir Lipsman 39:17

You know, to be honest, I think we're quite early on this area. I think we've been hampered by, frankly, our inability to visualize what's happening in a real time basis. We know that sleep modulates BBB function for sure. We know that aging does. We know that exercise and cardiovascular health and even sedentary lifestyle influence for sure, the development of dementia and Alzheimer's, but it's linked to BBB, I think remains to be seen. We know from, you know, neoplastic and oncologic conditions that it's intact in most in most patients, or except around the area of the tumor. And there are also regions of the brain that are the lack of blood brain barrier, you know, the pituitary and other in other regions of the brain. So I think that's where a lot of. Insights will come from, but it's very much early days. But again, going back to the very first question about scale, about, you know, maybe we just don't have the right tool to look at this. I think that we're just at the point where we're looking at ultrasound as a therapeutic strategy, but what may be really cool is looking at it as a kind of diagnostic strategy to look at. Well, what is the integrity of the BBB in these different conditions, and how can we modulate that potential?

Nick Jikomes 40:24

And when we think about the the use and the future use of ultrasound technologies in the ways that that you've been describing, and we think of even, you know, future states where people have portable devices they might be using under guidance from from their own homes, can you give us a sense for the costs here? How much does it cost to create some of this physical technology, and how much does it cost to actually use it?

Nir Lipsman 40:47

Yeah, it's expensive. So currently it can only be done, or it should only be done, really, in centers that have an MR. Dedicated MRI capability, because it's an image guided procedure. So there's obviously the millions of dollars that you need to invest in an MRI and somebody to run the Mr. In a facility, the device itself. And we work very closely with our industry partner, Insight tech, which is the leading manufacturer of fuss technology these days, certainly in the world of tremor. So yeah, these are devices that cost millions of dollars, and that's just the upfront. Then you have the upkeep. You have to make sure that you have the latest tools, the latest technology, software and hardware, and that you have you're able to maintain them. Arguably, some of the most expensive and rare resources are the people. So these procedures require a physicist require technicians and require clinicians to do and that's just the treatment. To say nothing about all the upfront work to select patients who ought to get the procedure, who is going to follow the patient afterwards. How do we assess somebody that, for example, has failed and then needs to be retreated? So all of these costs need to be factored into it. Can we get to the point where, certainly, for the BBB strategies or the neuromodulation strategies, we're looking at more transient, temporary treatments, for sure, and as we do that, the cost will definitely shrink. But what we need is an indication, and what we need to show that it's safe and effective first for an indication, before we get there.

Nick Jikomes 42:22

And so can you sort of paint a picture of where the cutting edge is today, in terms of, you know, what are some of the studies that you've recently done that are published, or some of the things that are pre publication, where, where, where's the cutting edge here?

Nir Lipsman 42:33

Yeah. So, yeah, it's rapidly advancing. So I think that, you know, on if we're talking about the lesional side. So precision strike lesions. I think we have an opportunity to essentially make lesions currently, and I anticipate within the next three to five years, anywhere within the brain. Right now, we're fairly limited to the geometric center of the brain, and that's because, again, the further out you get from the geometric center, the more transducers that we discussed actually need to be shut off because they're too far away from the target. Shut off a transducer, you reduce the power, and you can't make a lesion. So we're really, we're really focused on on the center of the brain. Within the next few years, that geo, that geographic limitation, is going to be eliminated. So that means conditions like epilepsy, like pain psychiatric conditions and movement disorders, the goal is ultimately obviating the need for any open neurosurgical approach. So we just published a couple weeks ago our experience in OCD to long term follow up in our patients that we treated with capsulotomy, so precision strike lesions in the region of the brain known as the anterior limb of the internal capsule, and patients with OCD, showing that in these patients who are truly resistant to treatment, treatment refractory, we saw very favorable response rates at a year, about 50% so 50% of patients had significant improvements in their anxiety having previously failed previous treatments. So that for us was, you know, critical goal, but also a critical moment in the field where we may be able to offer this treatment to patients with treatment resistant anxiety. As the technology improves, we'll be able to do that more and more on the on the on on sort of the non ablative BBB side. One of the most exciting things that we're doing now isn't necessarily showing that we can get things into the brain, and that work is happening, but we're also interested in seeing what can come out of the brain after we open the blood brain barrier. That's because we know that the BBB is a two directional strait. Not only does it prevent things from getting in, but prevents things from getting out. So if you open the blood brain barrier around a brain tumor. Our question is, can you then detect very fine fragments of that tumor in the bloodstream? After you open the blood brain barrier for diagnostic purposes, say, make a diagnosis exactly so patient comes with a brain lesion, you expose it to ultrasound, open the blood brain barrier, do a blood test that maybe you'll be able to make a diagnosis. So we're doing that for things like lung cancer and other conditions called liquid biopsy, but liquid biopsy approaches in the brain have been limited by the BBB. So here's another potential diagnostic opportunity that we can use, and ultimately, neuromodulation is going to be, is going to be, probably the future of this technology, and we're going to see that really coming fast in the next decade or so, and you

Nick Jikomes 45:21

mentioned some of the spatial limitations here and how that connects to, you know, the physics of how this works. We're limited today to, you know, certain parts of the brain, but eventually we'll be able to do the whole brain. Of course, there's, there's a lot of creatures out there with much smaller bodies and brains than us. How is this technology being used for things like basic research?

Nir Lipsman 45:41

It's I often say that I am not aware having done been