00:00Then when we injected the micropropeols in the first experiment and sonicated and I saw the first image I exactly knew why it worked and why oh yeah, 20 years everybody will have ultrasound device in their home for both entertainment and for sleep help or whatever it might be. But sometimes it worked, sometimes didn't work, it just wasn't working and we spent like a year trying to get the experimental demonstrations that you can focus through the skull with the imaging. I had published another paper before saying that you can get the thickness from MRIs and it focused in that skulls, but it was not universal. And then it was in one of the Uto-san meetings, 01:01I was sitting there and thinking this problem and listening to the talks, and then I suddenly understood, okay, yes, this is quite... Welcome to Stimulating Brains. Dr. Kulervo Hinenen is Vice President of Research and Innovation, a full professor in the Department of Biotechnology and senior scientist at Sunnybrook Research Institute, and he's most widely known for essentially inventing MR-guided focused ultrasound surgery. 02:02His research has focused on studying the effects of ultrasound beams on tissue and their utilization in therapy. He's investigating the use of focused ultrasound for non-invasive surgery, vascular surgery, targeted drug delivery, and gene therapy. I think it's fair to say that without his pioneering contribution, we would not be able to carry out MR-guided focused ultrasound surgeries today. For some of you that might be more interested in exactly what these contributions were, there's a beautiful website by the Focused Ultrasound Foundation that shows a timeline of milestones in FUS therapy, and you will see his name pop up a lot of times. Just to mention some examples, in 1991, he proposed the first use of FUS for brain tumors, in 1992, he proposed the use of non-invasive focused ultrasound using MRI guidance and monitoring tissue damage, 03:00and hence in the same year, he coined the term MR-guided focused ultrasound for the first time. In 1996, he published the first application of FUS to open the blood-brain barrier. In 1998, he demonstrated the feasibility of using a large-phased array applicator for through-skull focusing, and he also proposed the benefits of using cavitation for through-skull treatment, and maybe finally, for this list of examples, 2001 was a year of breakthroughs in brain research. He determined that focused ultrasound combined with micro-bubbles can cause localized and reversible disruption of the blood-brain barrier, which of course was historically a major obstacle in the treatment of brain diseases. In the same year, his group also demonstrated non-invasive focusing through the human skull using a phased array and CT-based planning algorithm. In the same year, he published the first application of MR-guided focused ultrasound for the first time. of MR-guided focused ultrasound for the first time. At Sunnybrook, Dr. Hinunen directs a huge group of around 50 to 100 members that fluctuate 04:00and do a lot of things across the entire landscape of focused ultrasound in animals and of course also in humans. For me, it was a big honor to talk to him today, and I really understood a bit more about the origins of MR-guided focused ultrasound, how it all started, what were the problems, and even going back before I was able to do that, I was able to do a lot of things before his time, who were the pioneers that used this technique even as early as 1942, although without going through the skull. So I hope you enjoy this conversation as much as I did, and I thank you for tuning in to Stimulating Brains. Dr. Hinunen, it's a great honor to be here with you today. And pleasure to talk with you. It's really great that you take the time to talk with us about focused ultrasound therapy. 05:00I will have already introduced you more formally by now, so we can directly start with the interview. And to break the ice, before we get into science, I usually ask about free time and hobbies. What do you do when not involved in research? Well, I mean, I'm married, so I spend time with my wife. But personally, I like running and exercising, walking and hiking. So those are kind of things. And then reading, of course. Reading is one of my hobbies. And then I also spend lots of time in community service. Okay. What do you do there? Well, I'm involved with my church, providing service there and whatever is needed. Great. And for reading, do you get to read prose or is it mainly science books these days? 06:04I like prose, but mainly historic books. So I like history especially. Great. Try to learn from history and mistakes that people have made. That makes a lot of sense. Great. And going into the science, who were your key mentors in your career and what were the critical turning points to get where you are now? I think one of the first, the first one was my supervisor for a summer project when I was an undergraduate who kind of opened my eyes a little bit what research is like. And then, I think I had a lot of colleagues when I, during PhD phase, I had other students, more advanced students. 07:02And then when I was junior faculty, there were some professors who were very helpful and that's a role I want to... Do you want names or I just... If you want to share, sure. Who, you know, was there somebody that stuck out maybe that, that you think if I hadn't met this person or so then, then I would be a different scientist or something like that? Yeah. So for my PhD supervisors, of course, David Watmore, I learned lots from him about ultrasound and then Professor Mallard, who was kind of my supervisor, but I met him. I met with him like once a month, but he kind of gave the higher level idea. And then when I was in Arizona, at University of Arizona, 08:03Bob Grover was one of them. He hired me and he was kind of mentoring me. And those were the people that had big impact. Great, great. So you, I think you were the first person to come in. Yeah. And I think you were the first person to coin or like your lab, at least to coin the term MR guided focused ultrasound. And I think you are widely seen as key person methodological inventor, even of that technology, even though focused ultrasound has a lot of history before that. This April, we both attended, attended a meeting on focused ultrasound surgery in Boston. And I think two years ago in 2021 focused ultrasound surgeries surpassed the brain surgery. And I think since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, 09:00since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, since then, it is it is very rewarding um there are kind of two sides of it so one is that it has taken a long time okay so it feels that okay well you have run a marathon and there is no much joy left anymore when you reach the goal line yeah but then when you see a patient procedure and see how grateful the patients are and what impact it has to those people who are observing it because it every time it's almost like a miracle it's instantaneous relief in patient symptoms with the trauma treatments so that is very very rewarding and i get a good feeling every time when i see that 10:01i i can imagine do you see the procedures yourself quite a lot at sunnybrook or i i used to be you know most of them and but now i don't see them that many i go okay and see and enjoy it and you sounds good so the history of using focused ultrasound to interact with the brain goes way um before your time so we can maybe briefly touch upon that too um goes back i think as i understood back to john lynn and colleagues who published a paper in science as early as 1942 and i think in that first paper they were able to lesion the bovine liver and a bit later in carefully designed animal experiments they they produced focal lesions deep inside the brain and spinal cord without damaging collateral non-targeted tissue using haifu um while initially trying to sonicate brain through the intact skull they um i think they they did damage 11:02the skin and underlying tissue by producing burns to the scalp muscles and even meninges so um that that resulted from extreme strong attenuation of the ultrasound beam while passing through the skull bone so they were able to And it was very important because it demonstrated the ability to focus ultrasound. They observed that the bone will hit too much and that it needs to be removed. 12:00And kind of recommended that technique and using multiple beams. And then Fry Brothers followed that advice and did lots of basic work while removing the bone, but studying the interactions of the ultrasound beam on the brain tissue. So then the work was very important, although it don't set the barrier and people believe it's impossible to treat with the scalp. But it was very important for the Fry Brothers to have, I think, 10, 15 years of work that looked into very, very basic things with ultrasound interaction. And then there was. In Boston, Dr. Lely, who did also lots of work. He was working at MIT at the end, looking at basic interactions and understanding the thermal interactions and the cavitational interactions with the brain tissue. 13:04So those were kind of the basic ultrasound interaction brain tissue and demonstrating the ability to use it for surgery. And then, of course, Frank Fry's later work with the preparation through bone so that you can get some ultrasound through the bone. And when I saw that paper as a graduate student, I realized, OK, we can go through the bone. And that's when the idea stuck my head and. And try to figure out how to do it in practice took many years. But eventually it moved forward. But those were the key people whose papers I read very, very carefully and learned these months. Great. Yeah. So you mentioned the Fry Brothers, I think William and Francis or Bill and Frank Fry. 14:02And they were in Illinois in 46. And then I think also did first partial ablation of the basal ganglia in 55. And then what I heard is that the first therapy. And I think that was the first one that I heard was that the first therapeutic use in humans was maybe by last Excel in 1950 for psychiatric indications. And then Russell Myers in 62 in Parkinsonian patients. But that was all with craniotomy. So so not through the skull. So. Was very limited. And I think, for example, last Excel went away from Haifu. Soon after. Right. And then sort of copied it into sort of 15:13where we developed, scanned focused ultrasound. So I was originally involved in developing hyperthermia systems where we scanned the focused ultrasound to hit the tumors and post cancer treatments to sensitize them for radiation therapy. And we did, it was external to brain initially, and then we did brain also, but it can scalp flap off. And then when we worked with GE to develop a system for MR guidance, it was first breast tumors, because that's easily accessible. And then the idea came that jitter and fibro is a big problem 16:00and that would be something that is commercially interesting for first for GE and then for MR. And so that was the first thing that clinical indication that we went after, and maybe because the market and the ease of the targeting brain is more complicated. Yeah. And so, okay, go on. So can you, so I know a few landmark points. So for example, in 1991, you proposed the first use of FUS for brain tumors. And then in 1992, you proposed the use of non-invasive focused ultrasound using MRI guidance and monitoring tissue damage, which I think was also the same year where you used MR guided focused ultrasound. And then I think in 1993, 17:01you joined the Brigham Women's Hospital. So the hospital I currently work in as faculty, where you reached the rank of full professor at Harvard Medical School. And you were the first person to be able to do that. And then you joined the Harvard Medical School in Boston. And I think as I understood here in Boston, you carried out first trans skulls on occasions, using skulls from Harvard Medical School. So it is a bit hard for me from the outside to unpack the history of, you know, what were the key steps that were necessary before. And then maybe also, if you want to talk about how the companies were involved in this. So, so yeah, getting through the skull, I think, was always the biggest problem. And what was, what were the landmarks for you or the stepping stones to unpack this part of the history a bit? So, so I had NIH grants for using this focused ultrasound beams with short pulses for cancer treatments 18:03and mainly like outside the brain. And then I, and then I, and then I, I sent out $25,000 proposal to ask money to do feasibility experiment with going through the bone, a skull bone. And the reviewers said that no, not possible. Okay. And I had a, one of my graduate students was in an anatomy class and said, well, you can get that skull fragment there too, because I was discussing him about this problem. And I said, so he got a skull fragment there. And I said, well, you can get that skull fragment there too, because I was discussing him about this problem. And I said, so he got a skull fragment there. And I said, so he got a skull fragment there. And I spent about a year doing experiments. I got the build a little phased array and experiments in the lab, demonstrating that you can actually correct the focusing through the skull with the large phased array and then applied for the NIH grant. 19:00And then I, a regular R01 and then I got that. And so that, that was a key piece to demonstrate that you can get it done. And then the second piece was that, try to use imaging to calculate that correction. And I was lucky to find Craig Clement as a postdoc came. He had all the skills for calculating ultrasound fields. And, and so we started developing these models and looking at CT information, looking at thickness and using this skull measurement, speed of sound measurements, and using this skull measurement, speed of sound measurements, which were copied from 20:10And then it was in one of the meetings I was sitting there and thinking this problem and listening to the talks. And then I suddenly understood, OK, yes, this is this is quite. Quite a blind side that I didn't understand, OK, for the speed of sound depends on density of the material. So we need to take the density, not just the thickness of the city, but the density and not just the structure, but the density structure. And so we did measurements and try to correlate and decide to correlate well. But then I had a student, Chris Connor from MIT, who was a computer science major. 21:00And he said because we had this optimization problem, it's kind of density varies. So. Along the thickness. So you put an ultrasound beam and you get one measurement, but there are many values. So how do you get the real density dependence? And he used by machine learning techniques. So we used machine learning at that time already to get the density dependence, the speed of sound dependence and the density of the bone. And that allowed. And he also got that innovation dependence. And so those were the key measurements that allowed us to go through the. To the. Scalpel, and then we waited for a year to file the patents before we published the result. That was at that point, it was clear it's going to work. Interesting. And when was that? 22:00What year roughly? About 2000, 2001. OK. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. . the arrays right the hardware um engineering and so on and um we have a i think philip jason white is uh is here in boston still was in your lab now a professor at simmons university and runs a biomedical ultrasound lab there at the time as as we heard in that meeting and i think greece kosgrove said he was a struggling uh classically trained musician who needed a job to to make ends need and um well he said it himself i think he phased out of music and into science um you had funding um i think he did play a role in the early days and then his wife 23:01tonya giesecke um apparently created as a tech the first hemispheric array so is that i think as i understand that was the first fuzz array to be used on the brain um and i also heard the device now sits in toronto and apparently it was a interesting story can you can you tell that how that um interaction came about yeah so i had a good good at that point i had a good amount of funding and i was looking uh technicians that could work and uh but jason's background was very interesting so he knows acoustics so i i hired him so he did lots of basic measurements and uh kind of uh explored the use of uh shear waves through the skull which make it possible to do a larger volumes and i kind of key component now and uh other things and i encouraged him to uh do his phd and and he 24:02eventually read through the papers and was able to get the phd at penn state so i i think my contribution for his him was i was pushing him to get the degree but um so and then and the other technicians that i hired was uh tonia and um and she was uh very good with her hands and so um together we looked at okay well i wanted to build a semi-spherical array and uh we couldn't buy it from anywhere um before that we had smaller like 10 centimeter arrays that we diced and then made them uh faced arrays but uh 30 centimeter diameter nobody could buy it so we had a very good relationship with the manufacturer so so we bought lots of uh small uh 64 smaller transducers and then the question as regularly of transducers and the question was okay well how can we assemble this so then uh 25:04tonya looked into the shapes how could we how can uh do them and then cut them into the shapes with the diamond wires or an assembled the array um so it was only 64 elements but it uh could put uh four kilowatts of acoustic power out so uh um so taking that power out and having this we had to have a face that driver we can buy it so we built that also i had uh mark kukannon in the lab who was electrical engineer and got his masters under me in arizona and then came and he built the drivers with others to uh be able to drive that kind of high power and we used that array to demonstrate you can go to the scalp bone and the the idea of which we had simulated that okay taking the whole area of the scalp bone you can go through it without overheating and it worked 26:05quite well in the experiments and and what's the next step to build the bigger race so 64 um arrays you said only um how many do modern devices have so the modern uh devices clinical device uh one 1024 elements okay well that's of course uh order of money our experiment area is now four thousand four thousand okay okay wow and um I think another um player that that is still here the Brigham uh is Nathan McDonald and he now works closely with Reese Cosgrove of um our functional neurosurgeon um and I think he also was key in in the beginning um and I've seen many papers from that time together with Nathan um what was his role there in these early days yes Nathan was a keeper he he was a student in 27:05uh Tufts University and I couldn't find anybody to do medical physics so he called me and I was always looking for um students so I said yeah sure um and initially he was he was very keen on MRI um so he was doing the experiments with me to uh using thermal ablation with MRI uh both in in a brain and other other areas and he tested the concepts of how can we use the MRI thermometry and and uh and how how can we use it to uh control and uh uh to treat the tumors precisely so he developed MATLAB interface for the treatment uh monitoring and control and uh that kind of form was the basis for the commercial uh interface uh eventually great yeah so that was how 28:08we started in it then he got involved in the animal experiments with the MRI uh for praying and then so he was not building the skull propagation uh platforms but uh in those experiments uh later on we started looking into uh modulating the blood brain area thermability and uh so it was we spent like five years trying to get some parameters that would modulate blood frame barrier and uh then in one day let's try it micro bubbles and that's when we was okay that's how it's going to work so Nathan was there with me and that we spent uh those experiments uh were done with him and he then he continued has done beautiful work on 29:02the animal side and then uh now involved in the human side also so micro bubbles um I think if you apply them uh that that is um they they exploit the effect of cavitation can can you can you ex explain a little bit in lay terms what how that works or what that does so cavitation so so what what um when you use ultrasound the ultrasound is pressure wave which has high pressure and low pressure and when you increase the amplitude enough and you uh have a beam in a tissue eventually the low pressure wave it will pull gas out of the tissue and those gas that gas is of course very compressible and so you have these small bubbles and they expand and during the rare fraction of the wave and then they collapse during the high pressure phase of the wave and that collapse is um very 30:03violent and it can break tissues it also enhances the ultrasound attenuation so you get much higher temperatures so traditionally people have thought that it's a it's a bad thing um actually there was a resolution in uh in one of the international ultrasound meetings saying you should avoid cavitation because the people felt that it breaks the tissue and causes cancer spreading and metastasis um so it enhances bio muy muy sort of sort of sound what is these bubbles that we are talking here is these are bubbles that are injected in bloodstream these are two to three micrometers in size they are engaged in a lipid cell and when they come 31:00to the ultrasound field they expand and contract with the pressure wave and of course gas is much much more compressible so that the motion is much bigger than it is in in the liquids or in the tissue itself so they are very effective energy concentrators now when they are in the capillaries they expand and they stretch the capillary expanding and then when they collapse they pull the capillary balls tighter so that lumen gets smaller and that happens to ultrasound frequency so for example if you use a half micrometer that's a half a million times a second so you have this fast pushing and pulling and that causes the antiretroviral cells in the blood brain barrier to come apart a little bit and open the tight sanctions so that that's kind of what's 32:00happening with how we are utilizing them because they compress and not to let the bubbles to collapse because once they collapse they rip the vessels apart and you get bleeding but if you are just exciting them enough to have this makeup on your calf force then you can manipulate the blood brain barrier great and i think you also just to mention that your importance in the field in 1996 you were again first to publish on this application of or the idea even of um using fuss to open the blood brain barrier so um you know if if you look if you read through the history of focused ultrasound there's a lot of uh your name appearing in many milestones so um really really impressive um i think right now in the history we are at the stage where it worked right but then applying it in patients is a big another step and i guess the company played a role but that's really a mystery time for me so probably you just have to tell us a bit how how did you end up um treating the first 33:04patient and then was that at the brigham or where did that happen what was the process to go there in the brain so uh so thermal place and it happened in uh in 2015 uh we not 2005 yeah 2005. we treat the first patient for thermal application first trying to apply tumors um not not very successful but we could see the temperature elevation and we got almost high enough to upload um so that that was the first milestone seeing okay you can do this in the patient with the blood brain barrier modulation uh it was quite tough people were kind of saying oh you cannot do this in any patients and so when i came here i tried to see if it can be done um and i think that the 34:08this the inside they had a system low frequency system which was designed to utilize bubbles to enhance uh heating of the application so you can apply more so and enhance the sun absorption and um that my my studies that that would be good frequency for um for blood brain barrier modulation so we worked with the company okay can we modify it so that we can use it for blood brain barrier and they agreed to give us algorithms that we can do simple experiments in in animals so we did cakes um and so that okay yeah yeah it could work and then natan did work in non-human primates uh showing that it indeed can be done and 35:03then i talked to neurosurgeons and they are more aggressive than radiologists so uh they were eager to do it in the patients took us first patient was very impressive we knew that it's going to work but it took us the first three patients took us i think well like two or three years to recruit because this was not really benefit for a patient we have a modulating part brain we opened a blood brain barrier with chemo and then the patient went to surgery and they took the tumor out and so not too much benefit and then when we move to a phase where we can uh the surgery is up front and then we do the chemotherapy afterwards and that then we start to recruit more patients but it was 36:01very quite a quite um interesting experience because we saw how to control it and humans and human uh skull and uh lots of people and uh none of us quite knowing what we are doing so yeah and that was at sunnybrook i think much later so when when was the first uh yeah 2015 was that 2015 okay so going back to the ablation um piece of it um in the brigham um the like how what is needed to translate something like that into a human it's very invasive right you you destroy tell uh cell tissues um the first inhuman was it still you know with um was it already with the insight tech array or was it um via an fda grant uh nih grant with fda approval or how did that work to get it yeah no no it was um 37:00it was inside the synthetic array we had um worked with amazonics to get 512 channel array and uh did all the experiments animals going through human skull and demonstrated works and then the company took that array integrate with their system and uh they came back and then at that time we had used like face mask radiation immobilization device to keep the patient in the stationary it wasn't very comfortable with the patient but that was the first start and uh it turned out that this this system wasn't not we didn't have enough power so we got almost there but not quite there and then the company developed the next array with thousand 24 elements and the first system went to churic 38:00didn't come to boston unfortunately and they were able to apply there for pain treatments and then the university of virginia was uh studied the essential tremors so i tried to i got the system we bought a system here when i came and uh i asked invited all the neurosurgeons in the city to come and discuss okay we have the system but what can we do with the place and it was interesting because lots of ideas but it felt to me like the ideas were not the patients that they were treating but it's somebody else's patients and we had the approval was to treat tremors so tremor came out essential tremor and we had the approvals to treat for a year but for some reason we didn't get going with it okay until uh the virginia treated the first patients and then uh cfis came here with you the first patient uh uh and so that's how to do it and 39:08after the first base now our neurosurgeon i don't we're not convinced after the second basis they were convinced so that's how it started and so the emergence of insight tech i think they also started outside of the brain but then at some point um you know now focus quite a bit on the brain were you part of the company or did they license patents from you or what how how did that um originate so what what happened uh sort of the brain so we i had started working with mr guided form in Arizona and then I came to Boston they gave us the system that we could treat fibroadenomas in the breast and then breast cancer and then 40:00InsightTech was created so they span off InsightTech with Elpik Medical and we continued being their main we did animal experiments and had ideas and designs and did the phase array work first fibroids and they developed the system and we did the first treatments and gave feedback and so forth so we worked closely with them and on the same time I was working with my NIH grant going through the skull and then when we demonstrated and demonstrated how we can go through the skull the company wanted to do that so they licensed the patents going through the skull and unfortunately now the patents are expiring so unfortunately royalty income is kind of late with these kind of devices 41:00so that's how it happens and so that's and when I left so I worked with them very closely and they gave us research grants when I was in Boston when I came here the relationship stopped we bought the system and we were treating patients and that relationship continued and I have continued with my NIH grant and other grants to develop the technology outside which gives us freedom to do research that sounds great okay very interesting and so you are currently if I remember your talk correctly you are currently building the next generation focused ultrasound you mentioned it may have up to 4000 arrays transducers I mean and it it does involve custom made head cast is that 42:00do I remember that correctly that you have to personalize it for each brain a bit or yeah that is correct so we what we have we have an idea of using rapid prototyping based on the CT and MR information of the patient so the helmet design is an optimization process where we use numerical models to optimize the helmet what would work for the target that we have for each patient and that allows us to not to have pin fixation and also to use pre-existing imaging and so on so we don't need to put the base in the MRI scanner and what what we are doing we are using acoustic feedback we have very large array of acoustic receivers and from that we can create the acoustic field and see how the bubbles oscillate and where they are so we can localize them so this allows us a very precise control 43:02on the volume this is for for blood brain barrier modulation mainly or neuro neurostimulation and potentially could be ablation also but that's not been our goal right now but the idea is that get away from the MRI online MRI make it something that you can do in a clinic if you need to do daily chemotherapy treatment or something like that interesting very cool I've always wondered since you mentioned blood brain barrier and neuromodulation you know the idea of being exactly at the cusp of maybe doing something with the cells but not destroying them or lesioning them sounds like you know you have to be as a layperson you have to be exactly at the sweet spot to you know not go over the intensity do you think in in neuromodulation applications also let's say with this Insightech device or other devices 44:00do people like are we confident enough that there's really no lesioning of small cells or single cells or is there a way to do that? or do you think there will always be some alteration maybe of the microstructure around the cells when applying this? that's a very good question of course there could be alterations that depends on the level of level of exposure and like with the blood brain barrier it heals so we have blood brain barrier modulation it heals but there is inflammation that develops for the temporarily it got too high and then it becomes causing damage but but yeah we see very interesting results with neuromodulation and reading the literature seems that it is actually the one that you go too high and then you don't get the same effect there is a sweet spot so how to control it 45:01it's still still an open open question I think I think we can get the calibrate the pressure amplitude well enough in the brain so we can get precise exposures with the device that we have but do we know enough about the brain to know exactly what's happening? no yeah there are still a lot of questions yeah absolutely I also thought about exactly this question recently when I read a recent biological study in a psychiatry paper by Ali Reza's group they used HIFU modulations or neuromodulation with the Insight-Hack array 2D nucleus accumbens in patients with addiction and it was a single sonication treatment not ablative and they had very long lasting effects and I think I talked to part of the team and they were also very surprised 46:00by their own data you know that after a single treatment I think if I'm correct six months later there was still a good effect in many patients on remaining abstinent so that's what where I thought you know maybe we don't lesion but maybe there's still some there must be some sort of structural change in maybe some aberrant circuits which would you know could be a gold mine or a potential amazing thing if we kind of disrupt maybe local circuitry that leads to aberrant over activity in the nucleus accumbens or so any thoughts on that study or that that concept yeah no it's it's the results are surprising but it's very very intriguing so and it's it's not isolated results so there is literature emerging that there are some sub threshold 47:00events and impacts and and then then then then then then then then then then then then then then then then then then then then then then then then then then then then there. And I've seen pictures. So you have a big group, right? How many members do you have there? And maybe also what's the philosophy of the group to bring solutions into the clinic, which is, you know, a very challenging thing to do from research to practice, but you've been so successful at it already. So what is the secret? How big is your group? You know, what's the philosophy there? Okay. So yeah, my lab, my lab that I work in the lab is about 50 to 100 people, depending on 48:07the year and how it is. Lots of undergraded students, even high school students during summertime. So that's kind of my core. Then we have a clinical team. I don't know the exact number, quite, quite large also now. And then we have, team who works with the biology team who is looking at different effects in the brain. So I think, I think that part of the success is that we have physics background, imaging background, and those expertise, you can develop devices. And then we have the biology, the collaboration, the collaborators who can look at, in animal models, different ways of developing, to interact. And then we have the clinical collaboration. So I think that all those three, 49:04three are important and working together allows us to do things. I think that the main, one of the main reasons why we have been successful in some of these things is, is that we have had good reviews on our grants. People have been having faith that we can deliver on our grants. People have been having faith that we can deliver on our grants. People have been having faith that we can deliver on our grants. People have been having faith that we can deliver on our grants. People have been having faith that we can deliver and we have that money to do it because that is a key. Otherwise, you cannot hire people. And the philosophy for us is that anything we do, we want to see to benefit patients and then commercialize. So we are happy to work with companies because it benefits us, but for patients, it's not a big impact, but it needs to benefit a lot wider. Yeah, that makes sense. Great. 50:00So you have talked about MR thermometry before and also Nathan's role in that, which to me is a very different field to acoustics, right? It's MR physics-based, I assume. Yeah. Is it, and I think at that time, around maybe 2001, that was, I think, a key year with two breakthroughs. One was the blood-brain barrier. It was a very interesting paper you had. And then the other one, I think also this CT-based planning algorithm. So how were you able to bring such diverse knowledge together? And then if you want and possible, could you briefly explain how MR thermometry works? Okay, so yeah. So to my interest with the MR guidance and thermometric game, from my interest, I was very keen to do the ultrasound on the brain. 51:01Yeah. I knew that in order to put ultrasound beams in the brain, you have to have the best imaging. So I was very keen to integrate the ultrasound transducers with the MRI scanner. And when I talked about if people, we don't know, that probably doesn't work and interferences, and we built the transducers and we saw it works. And so the first aim was, okay, can we aim the beam the right place in MRI? And so that was the aim. And then we knew that, okay, well, T1 is temperature sensitive. So can we localize the hotspot there before we cause damage? So that looked okay too. And then there was Japanese paper that, Keihei Kuroda, who also was working in pre-combat labs when I was there. He came up with the idea, of using the proton resonant frequency 52:00as an indicator of the temperature. So the proton resonant frequency depends on the molecular environment of the binding forces of the molecules to one another, how, what that frequency would be. And when you elevate the temperature, those connections becomes looser. And that's why the resonant frequency is shifting. So that's how it works. And so we just be able to measure the frequency and the frequency is slow, but Keihei Kuroda came up with the idea of using phase imaging, which also tells about the proton resonant frequency and do subtraction, subtract the phase images and see the phase angle and that is calibrated both to the temperature change. So with MR temperature, we can see how much the temperature is changing 53:00and it's fairly precise, maybe half a degree or so. So you can see small temperature elevation. So you can use it to aim the beam to the target location before you apply. And I think that was a key in brain, especially. So that was, so it was the brain stuff getting it all together. It was quite interesting. We had this multiple projects that we were doing and all thinking that future they'll come together and luckily it worked that way. Yeah. That's really so impressive. So when I first heard of MR-guided focused ultrasound quite a while ago, I, as a young person thought, oh, that's so cool. You will be in the MRI. So you could, while you do the lesions, scan fMRI and see the functional changes. And then most experts told me that's not true. So I was like, okay, that's not true. So I was like, okay, that's not true. So I was like, okay, that's not true. So it's told me that's not possible probably due to while you sonicate, you cannot really scan or, 54:02but you, I think people have told you a lot of times, something is not possible and then you made it work. So do you see a potential application of seeing the function brain functioning brain while the lesion happens, or is that something you explore in the lab at all? Or is that completely not possible? No, no, I think that it's possible. I think it's sort of like, I think it's sort of like, I think it's sort of like, I think it's sort of like, I think it's sort of like, I think it's sort of like, I think it's sort of like, I think it's sort of like, So with the current device, it is difficult, but not impossible. And with future devices, absolutely it will be possible. So it's not, something cannot be, yeah. Usually when somebody says something cannot be done, I think that's like, okay, challenge. Challenge accepted. Yeah, great. And I mean, especially for neuromodulation now, speaking about it, it would be so great to see live what, you know, how the fMRI networks change and so on. 55:01So I think there would be even, you know, neurofeedback applications and so on. So it's, the big advantage is you will already be in the MRI and for example, for most DBS cases, we are not, right? Or we then cannot with the electrode implant while we scan and so on. So yeah, this is really great. Then one other small, more technical question. What are typical limitations for applying ultrasound? So I know sometimes the skull is too thick, so we cannot even do it in some patients. And then also we can only reach regions in the center of the brain, center region of the brain. Are there, is this correct? And then also are there other limitations of how this, you know, is not just applicable for everything? Yeah, so that is correct. So some cases patients, it's not suspect skull is too thick. Like sometimes it's always easy to go through, 56:01but yeah, it's just, there's something there that makes it difficult. And that's known from diagnostic ultrasound. For many years, people have known that there are certain skulls that you cannot go through as well. So, so yeah, I think in the future it's getting better. I think we can do a better job focusing. It's not, the focusing is not perfect yet. So it could be improved. So that will help a little bit to increase the envelope, how far you can go and get more cases where you can go through the skull. But I think the eventual solution is to use these microbubbles to enhance the ultrasound absorption at the focus. So that way you get less, you need to put less ultrasound through the skull bone and then you don't overheat and you can go anywhere in the brain. And in animals, that is working well. 57:02So I think eventually that will be the way. I strongly believe that brain surgery, destroying brain tissue, that focus on the sound is the tool that can do it anywhere, so I like it. Sure, sure. And then I think if you apply sonications too long or even in repeated sessions, Sure, Sure. And then I think if you apply sonications too long or even in repeated sessions, Sure, Sure. Sure, Sure. Sure, Sure. Sure, Sure. sessions, you need at some point higher energy to get the same effect. Something in the skull seems to change, but we don't yet understand what. Is that true? Is that the effect you usually observe? Yeah. So there are kind of two things. One is that we go too high and you can see these lesions develop. So there is an overheating of the skull and you develop necrosis, I think. And the necessary measuring of the protein. So that my guess is that the activation of the skull bone goes up and we have 58:04seen that kind of next people skulls. So, so that will mean you get more energy, but there is also a situation when you sonicate and then you see the temperature go and it starts leveling off. And that in my, what did, what a few, experiments on it and I think the issue there is the skull is heating and now the speed of sound is changing. So your correction algorithms are not accurate anymore. So get blurring of the focus while you go. And if you've, if you go too high in the, in the, in the skull heats up and then you go and repeat it and now you have attenuation changes also, so you get less energy through and now it's scaling even more. And now you blur the beam even more. So I think that that is maybe the explanation. 59:03Interesting. Yeah, that makes a lot of sense. So, so that would speak again, either for micro bubbles to reduce the dose or for maybe thermometry in the skull, right. To then adjust the algorithms. But I'm sure you're, you're at least in experiments thinking about these things. Yeah, we actually have, actually have shown it that you can use the, the ultrasound to pick up the temperature elevation in the skull and use that to correct the phasing. So you have to shift the phasing during, during the treatment, but we haven't implemented that in practice yet. It's the experiment is easy, but the implement in thousand element array is not trivial. Sounds great. Very interesting. All right. So I want to be mindful of your time. I want to. Ask you one more personal question and then maybe some, some, some rapid fire wrap up 01:00:00questions. So you are from Finland, if I'm correct, and you moved to the US. When did you move to the US and why can you talk about that? Yeah, so I, so I'm in, I'm from Finland. I moved to UK in 1980 to get my PhD and I went back to Finland to do my national service. So in the. US Army for, for a year. And then I got an offer to go to Arizona 1984 for, for two years. It has stretched a little bit longer. So that's how it started. You stayed since 84. That that's my birth year. So, so that means you've been there for almost 40 years now. Um, do you feel home in the US or now in Canada? Well, now in Canada. 01:01:00So half of the time it's been Canada. Um, yeah, I, I have been felt home, uh, anywhere I've been actually. I tried to see the good things in every place and forget the bad things. Every, every place has good things and every place has bad things. So Finland has good things and Finland has bad things. And the things that I miss there and things that I don't miss. Yeah. Yeah. That, that makes a lot of sense. Do you ever think about going home to Finland one day to retire or to. No, no, because my, that was my original plan, but, uh, our children are in the US. Uh, so we can grandchildren. It's just, uh, yeah, would not be possible for me to go back to Finland and leave off. Yeah. Yeah. Great. Okay. Interesting. And then again, so to, just to wrap up, um, some rapid fire questions, um, we, we have. We have talked about the fast device you're currently developing, but maybe if you could 01:02:00be bold and think about how will the next generation fast device look like in, in 20 years, what what's the future of fast? Maybe that's a bit better. Um, question. What will we solve in that time? Oh, yeah. 20 years. Uh, everybody will have ultrasound device in their home for both entertainment and for, uh, um, sleep help or whatever it might be. So, uh, Yeah, that, that is interesting. Sorry. I need more information now. Um, what would they use it for, for neuro stimulation? And you said, yeah. Yeah. So, so yeah, I, I think that, um, so what we will, you could have an ultrasound device and then you turn it on and say, okay, well, I want to sleep eight hours and we'll stimulate your brain to let you sleep eight hours. Uh, and you could use it for entertainment. Uh, yeah. You could, okay. Well, what pleasure center you want to stimulate? What, what feelings you want to have? 01:03:01Interesting. So that's kind of, and just for the record, you're not joking. You, you actually mean that. Yeah, actually. I mean, that's great. Love it. We'll see. So, so yeah, that, that will be an exciting future. So I guess what you're saying and how you come to this is probably because if it's safe and, you know, cheap enough, then why not? Right. Probably. That's the. Yeah. As, as soon as there are, um, you know, solutions for it, people will, will buy them. I, I, I probably agree to that. Yeah. The first step probably will be that it is used for like a depression or something like that, where people put the helmet on and get the treatment every day. And, uh, and then I think eventually it will evolve to the entertainment, but, uh, I'm scared of that. So I hope not. Okay. Okay. Yeah. Good to know. Okay. Interesting. 01:04:00Um, then we have talked about Eureka moments or one Eureka moment you had when you thought about the density and, uh, you know, speed of sound, um, other, you know, moments of your career where you thought, wow, now I understood this, or this was a great success or, you know, positive anecdotes you, you may want to share. I'm sure you had many of them, but, um, yeah. Yeah. So there's some, uh, of course, uh, reading that fried paper, uh, remember it being the library and reading it and realizing, okay, you can do it brain, uh, therapy. And then when we injected the micro bubbles in the first experiment and sonicated, and I saw the first image, I exactly knew why it worked and why it, it, it goes massive damage. But I knew how it works and why, why. And I just, again, same with them with the density. Okay. Well, why didn't I think this first before? 01:05:02Because it's so obvious now. Um, so that those are a couple of things and then, uh, yeah, then, uh, some, some other quite a few, but those are the two that's paid to this topic. What about the negative, um, uh, moments? Um, I guess. I, I heard that for example, there was the first hemorrhage at the Brigham that put everything on a, on a halt. Um, but it's, I think in, you know, you've been so successful, so it's also sometimes helpful for listeners to hear about maybe the more, you know, negative points or, or even waste of time or, you know, episodes where you feel like, ah, this didn't go well. Can you talk about that a bit? Yeah. So that case, um, uh, so I had, uh, uh, early on in, uh, in our research, uh, in our research, um, in, uh, in our Arizona, we treated hypothermia brain and, uh, patient died couple of years, uh, couple of days later. So that was kind of a moment where you, it was not a treatment mistake, but then, but 01:06:08just a demonstrated the legacy of brain. Yeah. Um, in, uh, in Boston, I, I had left Austin before they, they did that experiment and that was done with the low frequency device. And, um, I would have, so I have mentioned that that is the danger of getting cavitation and causing a bleeding and that, that device. So, um, so I, I think, uh, so I was happy. I wasn't there. Yeah. That makes sense. And, uh, but the other thing, uh, uh, with the blood brain barrier, we spent five years doing test after test. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. Yeah. 01:07:00and new things. Luckily, we didn't give up. Yeah, yeah. Five years sounds like a very long time. And it may relate to the sweet spot we talked about, right? Where, yeah, too much. You want to be probably at the exact, and getting to that exact window is probably not easy, I could imagine. Yeah. It was the introduction of the bubbles that solved it. So now you get the effect in the vessel itself, not on the surrounding braid. That makes sense. Yeah. I have a guest question by Rhys Cosgrove, again, our neurosurgeon here at the Brigham. He has always wondered about where, when, and how you got the idea that we should be able to overcome the barrier of the skull. And you, in part, already answered this, also with the Prye paper. But he specifically asked, were you a high schooler or university student? And what experience prompted this question that you had? And then set you on your life's course? 01:08:02Can you point it to a moment, even? Yeah, no, that was the moment that I mentioned. I was in the library. Yes, library, Forest Hills Library in Aberdeen, and the university library. And every lunch hour, I went there and read the papers, with new papers that's coming out. And I saw that, and I read so many books saying it's impossible to go through. And I saw that I had to go through the skull. And I saw you can get some through. And then I realized, okay, if you get some through, and then you distribute it all over the head, you have big window, you should be able to focus tight enough to overcome the skull. And that was the moment. And so you were a university student? Yes. A grad or? Yeah, grad student. Grad student. Okay, interesting. Great. Then what? Do you have any advice for young researchers 01:09:02that enter neuroscience or academia? Any tips? Enjoy it. It is my hobby. It's not my work. If it's your work, you cannot be successful because of, it takes so many hours, so much time thinking, so you have to enjoy it. And, you have to be willing to work with lots of people. So it's not one man show. So collaboration, collaboration as a team, you can do much better. And don't worry too much about who gets the credit. So it's the goal is the important one. Sounds good. The goal is the important one. Great. The future of the field is, you know, future of the field, we have talked about the future of FAS. Can you think about the future 01:10:04of neuromodulation in general? Do you think more invasive procedures like the brain simulation will ultimately be taken over entirely by FAS? Or is there even something that we don't think of that will come and take over everything? Or how do you think the future of neuromodulation will look like? Well, I mean, I think that non-invasive techniques will be better than invasive techniques. And like I indicated, I think we'll have devices that I use even at home to improve patients' conditions. I think we can do so much with neuromodulation. I think it will allow so many things, good things, and maybe for the future of neuromodulation. Bad things, enhanced performance, for sure, might not be great. 01:11:05But yeah, I think that we are just in the very beginning. And I don't know, there might be something new that I don't understand, some way of getting energy in. But right now, ultrasound is the best because you can do it non-invasively and fairly precisely. There will be new ways how you can make the focal spots smaller and more precise. And eventually, you want to be in cell level. And I don't know how to do that, but I'm sure somebody will figure it out. That sounds interesting. Yeah, I mean, yeah, you could think about something like, you know, in optogenetics where you tag specific cells, you could think of tagging them to make them more susceptible to FAS. So yeah, interesting. Any missed opportunities that the field currently has? You know, 01:12:00what should we be doing but are not as a field? You're talking brain specifically? Main interest is the brain, but anything is interesting. So yeah. Yeah, I don't know. I think the field is developing very, very nicely. Lots of people looking, lots of things. The danger, of course, is that if you don't, if you're not very careful with brain, something can happen that stops the progress for a long time. And it came very close to that in Brigham many years ago. Lucky we were able to move forward. When was that, by the way? Do you remember the year? So I think it was 2006. 2007 when that treatment was done. 01:13:03But so the things, things like that in brain, it's very, very delicate. So and so we don't know. But I think there are things that could have been faster. But that's the nature of research. So I don't think there are too many missed opportunities. People are, the door is open. There are many, many more. But it's not just the Udo-san interactions people are discovering the brain. So it's a great time to be in the beginning of this, some of this career, because definitely a field that will go for 50 years at least. So. I totally agree. So to conclude, is there any last question? Is there any topic you would have liked to talk about or any period of time that I missed or that we missed? I know we covered a lot, but anything else you wanted to mention? Oh, no, it has been good. Nice to talk. Okay, then thank you one more time. This was really, really helpful. 01:14:02A big honor to talk to you. And I know this was a lot of time. So thank you one more time. Thanks for doing it. It's great. Great to talk about all things. Great. Thank you.