Stanford Accelerated Intelligent Neuromodulation Therapy

Welcome to Huberan Lav Essentials, where we revisit past episodes for the most potent and actionable science based tools for mental health, physical health, and performance Hi I'm Andrew Hberan and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Nolan Williams. Thanks for joining today m really excited to have this conversation. I have a lot of questions about differentifferent compounds, psychedelics in particular. Yeah. But before we get into that discussion want to ask you about oppression, broadly speaking I heard you say in a wonderful talk that you gave that Depression is perhaps the most debilitating condition worldwide, yet in contrast to other medical conditions like cancer We actually have fairly limited number of tools to approach depression, and yet The number of tools and the potency of those tools is growing Depression is the most disabling condition worldwide. What's interesting about depression is it's both a risk factor for other illnesses and it makes other medical and psychiatric illnesses worse, right? So Recently, the American Heart Association Added depression is the fourth major risk factor for coronary artery disease, right? So alongside The risk factors that we know, hypertension, high blood pressure, hyperlidemia, high cholesterol, and diabetes, you know high blood sugar, those three have been on the list for a long time and depression and de you know being added to the list is the fourth one. A lot of what we're doing in the lab actually is is measuring kind of brain heart connections and we can actually with transrcranial magnetic stimulation, a form of brain stimulation. we can actually decelerate the heart rate. We can capture that heart rate deceleration over the mood regulatory regions. and so actually a direct probe of that connection We've been very interested in a very particular clinical set of problems around the most severe and the most high acuity settings that folks with depression end up being in and that's in, you know, emergency settings where they go into inpatient units. The field really hasn't developed a way of, you know, of consistently being able to treat that problem. and folks end up getting the same standard oral antidepressants that they've been getting patient. And I came to this because you know, dual trained as a neurologist and psychiatrist went back and forth between neurology and psychiatry. saw that in neurology we have all of these ways of treating acute brain based problems and really wanted to emulate that in psychiatry and find ways to develop an engineer New you know, brain based solutions. Many people out there probably think of the relationship between the the heart and the mind as kind of woo or kind of a soft biology. But here you're talking about an actual physical connection What area of the brain is it? You know, the first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's kind of the sense of control kind of governor of the brain And then and then what we know is that when you use a magnet, kind of what we call Faraday's laaw, this idea of using a magnetic pulse to induce an electrical current in electrically conducting substances. So in this case brain tissue, but not skull or scalp or any of that or hair, you avoid all that, just the brain tissue then you have a direct depolarization of cortical neurons you know, the surface of the brain's neurons in this dorsolateral prefrontal And if you do that in the actual scanner, which we can do You can see that that distributes down into the inter singulate in the insula and the amygdala and ultimately The tract goes into something called the nucleus tract of solitarius and ultimately into the vagus nerve into the heart so that the heart U very consistently seems to be the end organ of the dorsolateral prefrontal cortex. And If you do that over visual cortex, you don't get that or motor cortex, you don't get any of those findings. It's really specific to this control region of the brain. And so Yeah, it seems to, you know, it's our work. other folks work Martin Ares in Europe, the Netherlands work showing the same connections. I think it's been replicated like four or five times. where I think TMS is really interesting actually. We've heard a lot of patients who' have told me like my therapist told me that I wasn't trying hard enough in therapy. These are know moderate, pretty severe depressed patients And as soon as we get them well with with the TMS approaches, you know, kind of rapid you know, five day approach and the next week we come in and see them And they'll say, you know what I did all weekend is I looked at my therapy books and now I can understand it And so, you know I actually see TMS as a way of having kind of exogenous sorts of Cognitive functions that in milder forms of depression we can pull off with psychotherapy you know, this idea of being able to kind of turn that prefrontal cortex on and have it govern these deeper regions and depression, the deeper regions govern prefrontal cortex. In one case, it's like the coach telling the player what to do and's like a player telling the coach what to do and you you restore order to the game. You restore order to the game. And what it looks like is depression is a bunch of kind of spontaneous content that's semi volitional that's being kind of generated out of this conflict detection system, the singulate in depression, it looks like the left orol lateral does not sufficiently clamp down on it and what P appears to do is to kind of restore that we see with TMS over that region is that we just exogenously do the same sort of thing. We restore the governance of the left oror lateral over the cingulte area. and that is correlated with treatment improvement. So the degree in which you can re time re reggulate in time, the left or soateral over the cingulleate the more of an antidepressant effect you have. TMS is almost like exercise for the brain, right? You're kind of exercising this region over and over again with a physiologically relevant signal. kind of turning that system on And what's interesting for this show is you know we had a couple of folks, probably five or six folks that have actually told me this where if they remit early enough in the week, we have this very dense stimulation approach where we can stimulate people really rapidly over a five day block. Byednesday, they're like totally zero down the depression scales, you know, even better than most people walking around, like really no anxiety, no depression or anything by Thursday The first guy that told me this he came in and he said, you know I was driving back to my hotel and I decided to go to the beach and I just sat there and I was totally present in the present moment. hour And he's like, I read about this in my mindfulness books, but I experienced it last night and I've never experienced anything like this before. And I was like That's interesting. We kind of wasn't sure then and then I didn't tell any, you know, obviously any more patients about that. And then about five over the last couple of years They were metant early in the week. By the end of the week, they're like going to the beach and they're like totally having what people describe as a pretty mindful present moment sort of experience. is really interesting, you know, what that is. I mean, I don't have full on scientific data to tell you, but it It's just It's it's an interesting anecdote, right? that folks, when you push them through this point of of feeling kind of clinically well some people end up reporting this additional set of features. So I'd like to take a quick break and acknowledge our sponsor, Function Function provides over one hundred and sixty advanced lab tests to give you a clear snapshot of your bodily health This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. 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My understanding is that the SSRIs are powerfully effective for certain forms of obsessive compulsive disorder and may also be effective for treatment of depression. Is that right? And how should we think about SSRIs? Are they useful? Are they not useful? SSRIs clearly work Um, you know many, many meta analyses kind of proving that out, right? that that in a subpopulation of individuals they achieve great benefit For depression or obsessive comppulsive disorder generalizing anxiety disorder, panic, you know all these things, you can see an improvement in those symptoms with what we call SSRIs or selective serotonin re upptake inhibitors. the issue is that they don't work immediately, right? So they don't work Like the same day you start taking them And that suggests that probably it's not. exactly the serotonin being in there that's directly driving it, that it's much more likely that it may have some brain plasticity effects, right? There's not a deficit of serotonin. You're not born with u what people call a chemical imbalance and psychiatrys known this. This is not actually new information to anybody, you know, it's kind of a rehashing of a bunch of information we've known for a while now, but In the Lay press, it's kind of hit in a way that It didn't seem to grab attention before with previous publications But this idea that this chemical imbalance idea is wrong. I really think that part's important because I think that what I'll call psychiatry one point zero right, this kind of idea of Freud and psychotherapy and its origins Um It was a lot around you know, your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out or and you know, show you being able to see or people hear you so that you can eventually come to the lusion of certain cognitions that aren't helping you, right? Things like the schizophrenogenic mother and all of that, you know, that was a concept at some point, right? so We've transitioned from that to the, you know, for a long time, the chemical imbalance, which I'll call Psychiatry two point zero You know, this idea that there's something chemically missing. The trouble there for a patient, right is that it's telling it's sending a message of there's something missing with me whether it be my experiences I had no control over when I was a child or a chemical in my brain What I think's really powerful with TMS U, you know reallyally powerful TMS and a level even powerful the psychedelic story Is it saying something different You know, TMS works and there's no serotonin coming in or out of the brain, right? And we're doing a rapid form of TMS that works in one to five days. there's no's it's very unlikely that there's some long term kind of up regulation of serotonin that's driving that. So our work actually kind of pushes back on this serotonin hypothesis as being kind of the center of depression because it says, lookook, we're not giving anybody any serotonin We're simply turning these brain regions on And we're focused on the circuitry. And that's psychiatry three point zer. It's not just like neuromodulation. Nurodulation is a really nice you know use case for psychiatry three point zero because it's a way to focally and directly perturb brain regions and whatever modality you're using You know, there are a lot of a lot of groups that are actually doing neuroimaging before and after and they're able to see circuit level changes for something like psicybin or ketamine long after the drug is gone R? suggesting in those same brain regions converge So the subgenual default mode network connection that we see is changing with our Stanford neur mododulation therapy technique If that same set of brain regions that ketamine and psilocybin seem to act on act on these connections between brain networks that seem to shift And so it refocuses the story on something that's highly correctable. And it's basically electrophysiology And it's basically kind of re calibrating a circuit that is recalibratable instead of I have something missing or I have some set of experiences early in life that are that are going to forever trap me in these psychiatric diagnoses. and so it kind of challenges that idea. And I think that's what's so powerful about psychiatry three point zero this idea focusing on the circuit because it gets us get's us sin into thinking about psychiatry and psychiatric illnesses is something that are recoverable peopleople can get better. people, you know, we've seen with our MS techniques, we've seeen it with some of thesychedelic work that we've done where people actually in normal levels of mood for sustained periods of time or within five days. withithin five or less days and in the case of of the psychedelics within a few days, right? So We can get people out of these states. They're totally well. There's no drug in their system at that point in the case of psychedelics, there was never a drug in their system in the case of of TMS And it just tells us that that it's it's fixable. It's just like an arhym in the heart. It's like a broken leg. We can go in and do something and we can get somebody better. then I think what's what's empowering and what a lot of patients have told me is they say You know, I've gotten to, you know, some people will relapse and need more stimulation or need more psychedelics or whatever it is, but Bill tell me, I don't fear that I'm chronically broken. I don't fear that the chemical Ibalance is still imbalance. I don't fear that these things that I couldn't control in my childhood you know, are going to be there and drive this problem forever. And I think that's That's what's so powerful about this. And that brings me to this question about psychedelics and the frrankly the altered thinking and perception that occurs in in high dose psillocybin clinical sessions. many people do report improvements in trauma related symptomology and depression, as I understand it, from my read of the clinical trials, after taking psilocybin because during those sessions, something comes to mind spontaneously, they will report, for instance, a new way of seeing the old problem That The the old problem could be the voice that they're no good. they'll never, nothing will ever work out or could be even more subtle than that. Why do you think brain would ever hold on to rules that don't serve us well. I think it's it's an It's an evolutionary neurobiology answer, right? I think that we end up being a result of probably a lot of biology that's not that useful in the modern era. And I think in the brain for For say let's say PTSD, right? a lot of veterans come back and they experience these PTSD symptoms and they're not at all useful back home, right? They hear some loud noise and all of a sudden they're behind a car or they're behind You know, I've heard of folks you know jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise But if you put them back in the battlefield, ly adaptive. That's highly adaptive, right? We hold on to those things from I think an evolutionary neurobiology standpoint, but what seems to For whatever reason. alleviate that are these Um, are these substances, some new, like MDMA, some that have been around for thousands of years like psilocybin seem to have a therapeutic effect that seems to be pretty long lasting for these phenomenon. And so It's just curious, right? It's curious that in the absence of that, these things will keep going on and on, but in the presence of that, exposure Th then all of a sudden, you see a resolution of the problem. And we have some work now. We're treating folks with Navy seEALals. The anecdotes that we're getting right are folks are coming back and they're saying these set of PTSD symptoms are finally gone And so this idea that for whatever reason going into what's probably a highly plastic state and re experience memories and then as you know, you know, we reconsolidating it in that state for whatever reason mayve drive a therapeutic effect. My business is to find treatments that help people And so I'm much more like pragmatic about it, you know, if if this sort of thing, which has a lot of cultural baggage. But if this sort of thing ultimately ends up being therapeutic, if we can design trials that Convince me and others that it is then we should absolutely use it. And if it doesn't, then we clearly shouldn't use it, right? The work that's been done so far, the first psocybin trial, the first MDMA trial is published in Asure Medicine recently. And what do those generally say? Let's start with psilocybin and MDMA. So MDMA appears to in you know one to a few MDMA sessions have an anti PTSD effect that seems to be you know, outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD, right? So So does that mean that for people that have trauma who do a and again, we're talking about in a clinical setting, they take a one or two doses of of MDM. I think the standard MAapsS dose is one hundred and fifty to one hundred and seventy five milligrams. Again, doing this with a physician, et cetera. control clinical trial, legal. Exactly. They do it once or twice. And Broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma trauma afterward bout two thirds of people had a clinically significant change in their PTSD. That's impressive. And how long lasting was that? It appears to last for a while in the earlier trials where they followed people out. It seemed to last for kind of in the years range for some people. and so it's, you know, it's pretty pretty compelling. In contrast it with ketamine, which only on average lasts about a week and a half for a single infusion. So it's a much shorter. So they have to get repeated infusions of ketamine every ten days or so For some people or they end up getting like L like a bunch of doses for a couple of weeks and then For some people, that seems to last a while You know, that's where I think I think the psilocybin story for depression the in the MDMA story for PTSD seemed more interesting to me. So for psilocybin, what is the rough percentages on and this would be relief not from trauma, but from depression. Yeah, exactly. So it's, you know, in open label studies it's closer to like half to two thirds of people end up getting better depending upon their level of treatment resistance in the In the blinded trials, it was more like a third or so of people. I'd like to take a quick break and acknowledge our sponsor, Better Help Better Help offers professional therapy with a licensed therapist carried out entirely online I've been doing therapy for a long time, and I can tell you that it's a lot like physical workouts. There are times when I want to do it, and there are times when I don't want to do it. But whenever I finish a therapy session I come away feeling better and I have specific actionable items that hadn't occurred to me that when I implement improve various aspects of my life The data tell us that there are just so many benefits that come through effective therapy. 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Again, that's betterhelp dot com slash Hubberman Since you mentioned pilocybin, let's talk a little bit about the neurchemistry of pilocybin. What's going on when one takes psilocybin and, um Why is it interesting in light of depression? Yeah, definitely. So David Nutt and Robin Carard Harris's work around neuroimaging, psychedelics are kind of some of the first folks to do that work and u You know, and to their great surprise, they thought there was going to be an increase in activity on psychedelics and what they found is the opposite, right? There's kind of a an overall decrease in the level of activity in the brain with psychedelics, but they've also looked at activity and there's this kind of small world you know, large world connectivity that you think about. And so You know, small world, meaning there's a lot there's kind of a much more kind of focused kind of cortical function or you know, subcortical function or whatever it is And and what you see is a difference in that in that level of engagement of brain regions, so the connectivity, kind of global connectivity kind of increases. And so it's interesting, you know, I think to kind of have a convergent theory on this. It's still you know, to be determined, there's still a lot of work, I think that needs to be done but it's certainly suggestive that there's pretty profound changes in in brain activity and brain connectivity after and what we found to be really interesting is the antipressant effects of psilocybin particular connectivity change that we also see with our TMS approaches, right And it's this activity between the subjenal anterior cingulet and the default mode network And so when we do this effective Stanford neuromodulation therapy stimulation, we see a D regulation, the connectivity between the negatively valanced mood state in the case of depressed individuals and the self representation of the brain And you see that same connectivity change occur post psilocybin. you know, suggesting there's a convergent mechanism and it makes sense, right? You've kind of got over connected, negatively balanced system, conflict system that's attached onto the self representation people feel stuck, right? And then when you do whatever you do that's effective, it unpairs those two systems. I want to ask you about IBbogain. Is it legal in the US in terms as a clinical tool? Who's using it and for what purposes? IBbuain is one of the alkaloids that you can extract from a Iiboga tree that's u typically growing in the country of Gabon, Africa. So what individuals taking Ibergame will say is that O eyes, they don't see anything, but closed eyes They'll go back through and re experience earlier life memories and they will be able to experience it from a place of empathy, not only for themselves, but from others and kind of detached empathy and being able to see this as almost a third party, even though they were there Ibuogaine is in no way a recreational substance. You're essentially having this what they call a life review. They also call it ten years of psychotherapy in a night. So these are the terminology that people talk about the issue. How long does it last? Is it truly one night? Depending upon how fast you metabolize it, sometimes twenty four, sometimes thirty six hours, sometimes it can be shorter, but it is a long time It's a very long time. So it' defefinitely the longest acting psychedelic substance I know of. And so you know we have over the last couple of years been able to to do this first in human kind of full neurobiological, clinical, neurocognitive evaluation of what Ibain is doing. In this case in special operations, spepecial forces individuals, former Navy SEALs, former Army Rangers, that kind of crew folks and look at the pre post changes that their experienence to be able to totally quantitate all of that. And so we've been able to capture all the clinical scales, you know depression scales, PTSD scales, all that standard stuff, neurocognitive batteries. So how does your executive function work specifically? How does your verbal memory, all of that and then neuroimaging and EEG. So this will be the first human study of Iibogain for those And the reason why is because Ibigain's kind of the bothoth seemingly the most potent and most and most seemingly to me, at least most powerful psychedelic, but the one that has the most risk to because it has a cardiac effect. It seems to be that you can screen people out that have risk off of their electro cardiogram and reduce the risk quite a bit and that's what we all did. but Um, but that's why people haven't really studied it as much and it it isn't as U In addition, there's no nobody goes to rave on Ibergain. There's no recreation at all with It's not fun. People say that it's relieving but it's hard work because yeah, you're you're ree examamining things. So then we see these folks after and I'll tell you, you know, we haven't ull analyze the data, but I'll tell you that from what my folks are telling me, it's pretty dramatic. You know, peopleeople come back and they're doing a lot better. Soldiers experience something called moral injury, right where they Maybe they accidentally blew something up and it had a kid in it or something like that, you know, you know, if they're Afghanistan or Iraq, maybe a you know, child died an accident or maybe maybe, you know, a civilian died or whatever it was, right And they suffer these moral injuries as part of the job, and it's almost one of the kind of, you know, vocational risks They come back and say that they've They've they've forgiven themselves, you know, which is which is huge, right? And and part of that is being able to see themsel in a different light and having empathy finally for themselves and being able to kind of have that experience of forgiving. And so there's this kind of Timothy Leary kind of social cultural construct that ends up being overlaid over psychedelics and what I think is that if you rid yourself of all of those preconceived notions of what it is and isn't and the counter culture movement, all that stuff that neither of us were ever involved in, neither of us are ever partake in, you know is kind of straight scientists looking at this, right? If you can kind of rid yourself of all those social cultural constructions and then re examine this these if we just discovered these today We would say that These sorts of drugs are a huge breakthrough in psychiatry because they allow for us to do A lot of the sorts of things we've been thinking about with SSRIs, with psychotherapy, but bbind, right? Psychotherapy plus plus drugs in a substance that kind of allows you to reexamine these things and so it's That's interesting. it' you know, there's a lot to do to try to figure out if that's true. You know, and I can say that as it stands right now, we don't know if that statement is true, right? There's a lot more work that needs to happen for that statement to be proven to be true. But the hypothesis is if it is true, then it's very likely that This will be seen as a breakthrough because It allows you to do these sorts of things that you can't do with normal waking consciousness but also why we have to really think about this and You know, these drugs can't be recreational drugs, It really shouldn't be creational drugs, right? They're really too powerful to be used in the context of recreation because they can put you into these states. and the This generation of psychedelic researchers are really clear about that. you know, I think the sixties folks were not clear about that and they They felt like there was this whole kind of cultural thing that was going on there But I think this cohort of individuals really understands that In order to really make this happen, we have to understand that if you need a prescription an SSRI, which doesn't change your consciousness a whole lot And we we're very worried about that and the doctor has to evaluate you for that every week the idea that some of these substances would go outside of very strict medical supervision is It's kind of preposterous actually. It's kind of It's kind of a dumb moment, I think for all of medicine to say, look, we've You know, if we're going to do this right, we've got to do it such a way that's so protected, thats so safe that we make sure people know. These things are not recreational and they're really for the pure purposes of A reallying powerfully changing cognition for a while and letting people have these what seem to be relatively therapeutic states Tell me about Ayahuaskca and as a plant, is it useful for the same sorts of conditions that we' talked about Thus far, and if you could perhaps tell me a little bit also about the Brazilian prisoner study. Yeah Yeah. Definitely. Ayahuasa is another psychedelic. It's used as a sacrament in In Brazil and in Peru and Ecuador and Colombia, so a lot of the South American countries and u And what they do is they combine two plants together where one plant of the two combination would effectively do nothing two plant combination together is capable of producing this very profound psychedelic effect and what's really kind of curious is that there are As I understand it, ten to twenty thousand plant species in the Amazon and somehow Somebody Ted them all combine these two plants together in certain proportionality to this for five ten hours to the point where you cook out the dimethylptamine out of one of the plants and cook out the reversible monoimune oxidase inhibitor out of the other plant It's such a way that The reversible monoimunine oxidase inhibitor prevents the GI breakdown of the dimethyl tryptamine in such a way that it's then allowed to cross the blood brain barrier and get into the brain. And if you didn't add the reversible monoimmunoxidase inhibor plant derived into this combination then it would never cross the brain If you put people on a standard psychiatry prescribed monoimmune oxidase inhibitor that wasn't reversible, you'd throw them into serotonin syndrome, right? So this kind of Sweet spot that somehow Iyahasa practitioners have found being able to get DMT into the brain from an oral source with this combination of a mononoimine oxidase inhibitor Curious U And so that substance has been explored as an antidepressant agent and some studies have looked at that It also seems to be very safe. there was a there's a psychiatrist down at UCLA Harbor who's done a lot of work with this where where he's looked at children even that have been exposed just to kind of small doses of Ayahuaska is it kind of a sacrament within Amazonian tribes and found no neurocognitive effects, no neurocognitive effects in adults. And so it appears to be safe. It's kind of part and brought into various religions, including kind of merged with Catholicism in South America, which is kind of very interesting And so, you know, in some Sexs of Catholicism in Brazil It's used as sacrament during religious ceremonies And so it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons, right? So they gave half of the prisoners u, you know, some sort of inert substance in half of the prisoners a Awasa session And the recidivism rate or the return to prison rate in the Ayahuasa exposed individuals was statistically significantly lower than the recidivism rate in the in the control group, suggesting that You know, whatever is going on there seems to have an effect on whatever drives criminal behavior or whatever criminal behavior that happened to be. And I don't have the The details on the exact nature of the crime. U you know, no I am also in no way saying that we should just be giving psychedelics to folks And prison and all of that, I think that is a very edgy thing to do and probably not something that anybody should try, but But it does it does kind of bring up this curious question of of what is it about that that would drive people to to change those behaviors. and why why do people make those behavioral decisions As many of you know, I've been taking AG one for nearly fifteen years now I discovered it way back in twenty twelve, long before I had a podcast and I've been taking it every day since. AG one is to my knowledge, the highest quality and most comprehensive of the foundational nutritional supplements on the market. It combines vitamins, minerals, prebiotics, probiotics, and adaptogens into a single scoop that's easy to drink and tastes great. 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Again, that's drrinkagG one dot com slash Hubberman to get a weak supply of AGZ and a bottle of D three K two with your subscription Before we wrap, I do want to give you the opportunity to talk about the SainT study. S or what we're calling it S andT now. Stanford Accelerated Intelligent neeuromodulation therapy, or we're calling Stanford neurodulation therapy. The idea there is that TMS is a device thatlivers delivers a treatment And the treatment is the protocol And the protocol is stimulation parameter set. in a specific brain region for a specific condition. whether it be transcranial magnetic stimulation or transcranial direct current stimulation or deep brain stimulation, like what Casey Hopperin talked about. In all of those cases, the device itself is a physical layer conduit of a stimulation protocol therapeutic for a given condition in a given brain region We decided Gosh, you know, this problem I talked about at the beginning of the show where You had these You know this problem that we don't have a treatment for people who are in these high acuity psychiatric emergency states, right? This idea that we're going to engineer a treatment where we can reorganize the stimulation approach in time to be much more efficient by utilizing something called space learning theory. And so you probably know about the space learning theories. The idea for the viewers is if I'm cramming for a test, what I do is I write out sixty note cards and I read each one for a minute until I get to the first note card and again, and that's about an hour later, right That's space learning theory. It's this idea that you need to see it about every hour to an hour and a half and that optimizes learning What we found was that the old way of doing TMS, this idea of just doing it once a day every day, five days a week for six weeks didn't utilize the space learning theory. It's like studying for a month or two just a little bit once a day. like you remember some of that stuff, but it's like not as potent as that week where you're kind of cramming, right And what we realized is that if we could reorganizizeed the stimulation in times so that we took the whole six week course, and we actually figured out a way to do it in a day. And then what we also figured out is that people were underdosing TMS because if you just keep going after six weeks to month three, four, five, more and more people got better. So we figured out It's not just one day. We're going give five times a normal dose. We're gonna to have seven and a half months worth and five days using space learning theory So every hour, every hour for ten hours for five days for five days. So it's a fifty hour block. it's ninety minutes of actual stimulation, but spread out through the day in the same way of learning What we've found is that folks will within one to five days, you know, in more cases than not, and depending upon if you're looking at this open label or in trials somewhere between sixtycent and ninety percent of the time They will go into full on remission in the sense they're Totally Normal from a mood standpoint at the end of this And like I said, with variable durability. So that's the part we have to figure out now about dosing and how to keep people well. But for some people, you know, we've had four years of remission, you know, a year of remission And it's really that cramming of the test. It's really that idea that you're laying in that information to exact right spot. and the signal is a simple signal, but it's a profound one, which is Turn on Stay on, remember to stay on. you know, that idea that you're you're sending this memory signal into the brain and you're doing it in such a way that you're telling the system, you're kind of Taking out of the hippocampus your own hippocampus' hand is and you're sending the same signal the hippocampus normally signals out Now you're sending that signal into the prefrontal cortex and kind of utilizing the brain's own communication style to get it to get out of the state And what's very cool about this is that is that people when they when they kind of exit out of that, they end up u They end up saying They don't have any any side effects from it and they feel back to normal. Thank you so much taking us on this incredible voyage through the neurosircuitry underlying certain aspects of depression, the coverage of the different types of depression, the various therapeutic compounds, how they work. We've talked about a lot of things, D, you've shared so much knowledge. and even as I say that, I I very much want to have you back to talk about many other things as well that we didn't have time to cover, but to take the time to sit down with us and share all this knowledge that really is in service to mental health and human feeling better and in fact avoiding often suicidal depression. It's just incredible work and an incredible generosity. Just thank you so much. Absolutely