 Thank you all for coming to the third of our seminars in the NeuroEthics seminar series. My name is Tos Cochran. I'm the director of NeuroEthics at the Center for Bioethics, and in a moment I'm going to introduce David Fisher, who is responsible for organizing the seminar tonight called Hacking the Brain Neuro-Enhancement with Non-Invasive Brain Stimulation. But first I'd just like to take a moment to thank our partners who are helping to fund the endeavor, and they include the Harvard Brain Initiative, the Harvard Society for Mind, Brain, and Behavior, and the International Neuro-Ethics Society. The International Neuro-Ethics Society is specifically supporting our ability to webcast this tonight, and we'd like to thank them for that support. And during the Q&A segment tonight, I'll be monitoring the Twitter feed. The handle is at HMS Bioethics, and anybody who's watching via webcast can tweet at that handle. I'll be monitoring it. And if you've got a question, I will try and get it included in the Q&A session. So with no further ado, I'd like to introduce David Fisher, who is a senior HMS student who is responsible for the talks we're going to see tonight. All right. Thank you, Dr. Cochran. So I'm David, a medical student here at Harvard, and thank you for coming to this or streaming online this seminar on neuro-enhancement and non-invasive brain stimulation. As Dr. Cochran said, this was made possible by several groups including those listed here. And we're accompanied today by several great panelists, and I just want to take a moment to briefly introduce each of them. So the first is Dr. Alvaro Pasqualeone. He's a neurologist at the Beth Israel Deaconess Medical Center, where he's also the director for the Berenson Allen Center for Non-Invasive Brain Stimulation. He's also the associate dean for clinical and translational research at Harvard Medical School, and he's a world leader in the field of non-invasive brain stimulation. He's published several over 900 scientific articles on the subject matter, several books, and his focus is on the application of non-invasive brain stimulation in healthy individuals and in disease to study brain plasticity, for example. Our second panelist is Mr. Hank Greeley. He's a law professor at Stanford Law School. He's the director of the Center for Law and the Biosciences and of the Stanford Interdisciplinary Group on Neuroscience and Society. He specializes in the ethical, legal, social implications of biomedical technologies and has recently developed an interest in non-invasive brain stimulation, asking questions about regulation, safety, and the ethical application of these new technologies. And thirdly, we have Dr. Jamie Tyler, who's the co-founder and chief science officer of Think, a company that manufactures stimulation devices that are designed to modulate mood. He has a research interest in brain modulation and has helped to develop much of the technology that Think device uses. He's also an associate professor in the School of Biological and Health Systems Engineering at Arizona State University. So really, you're here to hear these panelists talk, but I just want to say a few brief words about what neuro enhancement is and what non-invasive brain stimulation is. So neuro enhancement in the most general possible kind of conception is the improvement of brain functions such as cognition and mood in healthy individuals in contrast to, say, the treatment of disease. And this is the question of neuro enhancement or cosmetic neurology has come up now for many years, but has recently started targeting this issue of non-invasive brain stimulation as opposed to, say, drugs. And when we talk about non-invasive brain stimulation, there's two major forms that we typically talk about. The first is transcranial magnetic stimulation or TMS. And the way that works is a plastic device is applied to the scalp, and within that plastic device is a metal coil of wires. And when you pass a very strong electrical current through those wires, what you do is you generate a magnetic field. That magnetic field passes into the brain and can activate neurons within a particular part of the brain. Based on the configuration of those coils within that plastic device, you can actually kind of intensify that magnetic field in a particular region of the brain. And so you can really have pretty focal effects on the brain using TMS. But these TMS devices cost tens of thousands of dollars. It's not like anyone can go out and just buy their own TMS device. And so recently attention has started turning to an alternative form of non-invasive brain stimulation called transcranial direct current stimulation or TDCS. The way this works is you apply electrodes to the scalp and pass a very weak electrical current from one to the other. There is a positively charged electrode or anode and a negatively charged electrode or cathode. And the way this is thought to work is that a portion of that electrical current is thought to pass through the brain. And the positively charged electrode or the anode is thought to increase the excitability of the underlying brain, whereas the negatively charged electrode or the cathode is thought to suppress excitability of the underlying brain. And TDCS has been studied in lots of different cognitive functions. And there's been lots of evidence to suggest that you can actually enhance lots of different human functions, brain functions with TDCS, including language, attention, learning and memory, many different things. And because of this, it's garnered a lot of media attention, New York Times calling it a jump starter kit from the mind, as well as the Atlantic and the New Yorker. And also, companies have also taken advantage, creating their own commercial devices that anyone can just go out and buy for their own enhancement for gaming or endurance athletes. And Dr. Jamie Tyler will talk a little bit about a device that he's helped come up with to modulate mood. Also because a lot of the components of TDCS are cheap, you can essentially construct your own device for under $100, there's been this emerging community that's just taking it upon themselves to do it themselves. And so there are examples of these online communities sharing tips about how to stimulate your brain, the configurations of the electrodes necessary to improve memory or attention, and also trading tips on safety. So before we had the seminar, I also passed around a survey to kind of assess what people's attitudes were towards neuro enhancement with TDCS. These were eight cases, which I'll go through briefly, and I told people who responded to this survey that TDCS is the passage of a weak electrical current through scalp electrodes and that there's some evidence to suggest that you can improve attention with TDCS. And I've also said that TDCS, when it's applied correctly and with appropriate current levels, is relatively safe. And I asked respondents to rate the appropriateness of each case. So we had 131 respondents total. About 45% have tried TDCS before, 55% hadn't, granted this was not an unbiased sample. These were people who were interested in noninvasive brain stimulation and also circulated among these online do-it-yourself communities. Of those who have had tried TDCS before, about 20% of them were acquired from a company. About 10% of them built it personally or acquired it from a research study. This computer is struggling a little bit right now. Yes, these are all cases of TDCS. The mouse is going rogue. Okay, so there were eight cases. There were all cases of TDCS and there were two sets of cases. So in the first four, there were all about this 20-year-old college student who wanted TDCS to improve attention. And in the first set of cases, he wanted it for different reasons. In the first case, he had ADHD and wanted treatment. In the second, he wanted it for a final exam. In the third, he wanted it to be at the top of his class. And in the fourth, he wanted it to be the best at gaming among his friends. And in the second set, he wanted TDCS for attention for school, but it either required the TDCS device from a doctor, from a research study, from a company, or built it himself. So I separated respondents into those who have not had TDCS and those who have had TDCS. And for ADHD treatment, there was a general consensus that this was typically appropriate, particularly so among those who have had TDCS experience in the past. For those, for the case where the student wanted it for a final exam, both groups were a little bit less enthusiastic about this. And the subjects who have not had TDCS experience actually reversed their opinion, thinking in general this was more inappropriate. When it comes to being the best in school, those without TDCS think it's even less appropriate. And those with TDCS experience still think it's generally appropriate, although less so. And then lastly, when it comes to gaming, respondents without TDCS experience thought this was the least appropriate scenario. And respondents with TDCS experience thought it was still appropriate, but of them less appropriate, for example, than treatment. When it comes to where they got the TDCS devices from, when it comes to getting it from a doctor, both groups again thought it was generally appropriate, especially those who have had TDCS experience. When it comes to getting it from a research study, both groups still generally thought that this was an appropriate place to get TDCS from, although those who had the TDCS experience, again, were more positive about this. And when it came to getting it from a company, both groups were less positive about this, but the respondents who had no TDCS experience showed a reversal of their opinions. They now in general thought this was inappropriate. And those with TDCS experience thought this was still appropriate, but less so. And finally, when it comes to building your own TDCS device, both groups thought this was the least appropriate of all scenarios. Without TDCS experience thought this was in general definitely not OK, whereas those with TDCS experience still thought it was in general acceptable, but of all the scenarios was the least so. So with that, I'm going to switch over to hear our panelists, and we're going to first start with Dr. Alvaro Pasqualeone. Can I maybe try to connect the slides? I can try, right? Will I succeed? It should be OK. So thank you, David. Thank you for the panel and for the opportunity and the invitation. I think it's a very timely topic, and I was excited to see it come to reality, particularly in this format of a panel with arguably three different vantage points that hopefully will make the subsequent discussion sort of interesting. I think part of my role is to make an argument from the point of view of, quote, science slash medical applications. And in that context, I think that both TMS and TCS, transcranial current simulation, be it in the form of direct current simulation, alternating current simulation, or random noise stimulation, both of those sets of techniques have both diagnostic and therapeutic applications. The diagnostic applications are particularly obvious to date with TMS because of the type of more assumed focality that David was pointing out. And I think what is most appealing is the possibility of developing translatable biomarkers, translatable phenotypes of given disorders, be it in the form of cortical reactivity, connectivity, the type of measures of cortical plasticity that a number of groups, including ours, has developed. And of course, the hope is to come up with metrics of characterization of brain physiology that comes closer to the manifestation of the symptoms of the patients. I think that in the therapeutic realm, there is at least growing promise for the techniques that revolve around transcranial current simulation because of their ease of application, because of their ease of combination with other approaches. And that makes it particularly appealing, even though, to date, what has really been substantiated with experimental data is really only TMS. And there is a need for the TCS to catch up. So in terms of the diagnostic applications, I think of the approach essentially as schematically illustrated in this little cartoon, where the notion is there is some neural substrate for behavior, whatever behavior it is, that involves activity in certain nodes of a distributed network. And even in the absence of knowing the exact neural substrate of those components, if we had a way to do a control activation of different nodes, we have a way to characterize that distributed activation in a way of ultimately relay the changes in that activity to the behavior. Think about it as a sort of complex systems approach to characterizing brain behavior relations. And arguably, that is what non-invasive brain simulation allows us to do, do a control input into specific targeted nodes of a network, characterize the dynamics, capture the responses physiologically via EEG or MRI or near infrared spectroscopy or microstate modulations, any number of different measures or a combination thereof, and ultimately related to behavior. From a neurological point of view, I would argue that what that allows us to do is actually flip the traditional way of approaching translational science. So we generally expect science to develop some insights that we can then ultimately translate into a benefit for a patient. And we know that for the most part doesn't work, certainly hasn't worked very well in neurology and psychiatry. And we can discuss why that might be, but there is the opportunity of approaching it in the opposite direction, starting with the patient, characterizing a phenotype that is closer to the disease manifestation, to the symptoms, and literally reversing engineer the research based on the clinic that requires clinicians being at the forefront of the effort and requires tools that allow us to do just what I'm going to argue, non-invasive brain simulation allows us to do, which is in a controlled way as I've tried to discuss, modify, perturb the brain to measure the impact, while at the same time potentially helping patients. And that's what I think is the big appeal and promise of these techniques, with the promise of doing so in a very individualized way. But for the most part, it remains a promise at this point, and it remains a promise in part because that complete loop of getting the basic research informed by the clinical need hasn't quite happened. And so we're still in need for a much greater level of understanding of what the neural substrate, what the mechanism of action of these techniques are. And I'll talk about that a little bit in a moment. But before doing that, let me just remind us that the field is moving very fast and that, in fact, it's so fast that this slide is out of date already. So TMS devices, two of them, in fact, now three of them are approved for the treatment of medication refractory depression. The last one just being cleared on Friday. And they are quite different. They're covered by insurance. They're covered by Medicare. And they are making a difference in people's lives. We can talk about it in a variety of different metrics. But perhaps the simplest one is to do a sort of back of the envelope calculation given the amount of devices that are in clinical use in the US today, about 600. Given how many patients are treated, there's about 750,000 treatments per year. Given the number of treatments that patients require for response and the response rate in terms of remission for medication refractory depression that has been shown by a number of trials, including the FDA approval trials. Currently, TMS is leading to about 25 patients with an otherwise untreatable condition to go into remission, not into a response, but actually into remission. And that makes a difference in people's lives in ways that in neuropsychiatry I think we've hoped for for a long time. There are a number of other applications in the horizon, but they are nowhere near being established or supported by this. That includes applications for TDCS. There are a number of applications for TCS that have been supported by positive Cochrane reports in pain, neglect, and stroke recovery. Depression is supported by two fairly large, well-powered studies, cognitive restoration, including in dementia, there is support from ongoing studies. But what seems pretty clear is that we still really don't know the answer to the question of how effective this really is, because having an effect in a small group of patients or in a number of small studies may make it possible to get a positive endorsement from the Cochrane report, but it doesn't establish the capacity of extrapolating to the general population based on the data that we have, and more importantly, from the general population back to the individual. And I think that is a really ongoing and outstanding question, and there are many, but one of them is who might really benefit 30% going to remission, but who of the patients that you treat will do so with TMS? What are the reasons why some do and some do not? And the question is much larger with TCS, where the data are less to draw from. But there are a number of other questions. What is the duration of the effect? What is the pattern of the maintenance that would be ideal to maintain the benefit? I think particularly important, we've come to realize that there is great value in combining therapists for in simulation with other interventions, but how, when, and with what other therapies to combine are things that we still don't know. We don't know how to optimize a protocol, or for that matter, a brain target for a given patient. And there are outstanding questions of long-term safety, not just efficacy. What is the cumulative dose or the lifespan that is appropriate to use? And some of these questions we can only address over time, which makes it even more challenging. So I was saying, I think that the evidence that combining therapists is the way to go, I think, is growing. We can start thinking of brain simulation as priming. Some brain circuits enabling the benefit from additional interventions or vice versa, with either behavioral interventions or pharmacologic interventions or a combination thereof. So that makes, as I was saying at the beginning, TCS particularly appealing, because as David was mentioning, it is relatively simple, relatively straightforward to apply. I think that's both a benefit and a curse. It is deceivingly simple, meaning it makes you think that you actually know what the heck you're doing, when in fact you really don't. You're putting two electrodes somewhere, and we are talking then ultimately about this electrode having the effect on this part of the brain. When in fact we know that, it's just not true. At the best case scenario, there is a current flow between two or more electrodes, and it's somewhere in the path of current that is generated that you have the effect. If you want to believe that the effect is coming from the brain, I'm sort of brain centric, but the truth is that the effects of brain simulation by definition, sorry about this, are always multimodal. There's always an itching. There is always a sensation. There is always with TMS a tapping. There is always a clicking. There is always something plastered on you that is exerting some degree of tension. There's certainly always the expectation, be it positive or fear of what the heck is going to happen to you, and all those things are going to have an impact on the effect. In addition to whatever effect the simulation has on CSF and the diffuse effect on the brain, plus the local effect on the brain, and which one is it that is more critical, I don't think that we know. I think we believe, and there is data to support, that there is a possibility of an effect on specific brain structures, but most of the studies don't actually establish that link in terms of showing that the clinical or behavioral effect is really true to the engagement of a given substrate. I think we need more understanding of the substrate. We need designs of trials that capture the engage substrate in addition to asking the question of what the behavioral effect is. We have the tools to do that, but the research has to catch up. Now, before wrapping up, I want to address one of the things that David mentioned, sort of in passing, there is this transcranial direct current simulation, and there are really a whole family of techniques that are involved in that. You can apply alternating current in different frequencies, this TACS, you can apply random noise with a mix of frequencies, and I think the evidence is pretty good that all these have different mechanisms of action. In doing that, they have potentially different applications and different opportunities offered, but also different challenges, and so to think of it as one technique, to think of TDCS or TMS or TACS, ISR is not good for Alzheimer's disease or for depression, I think is fundamentally the wrong way to think about this. These are tools, these are techniques to modulate specific networks, perhaps in addition to other non-brain derived brain-focused substrates, and I think it is that level of broader effect that we need to consider. We need to do so, however, accepting the fact that these techniques, particularly, for the reasons that David was saying, are already in the hands of a lot of people that believe that they have a need, that we in the medical community, I think, have failed to provide, and we need to now deal with the fact that we want the use of these techniques to be done in a way that is both safe and appropriate, and I think that's the welcome opportunity of this colloquium and the discussion, I think, and it was part of the focus of a recent IOM meeting. I think that the fact is that people are getting devices and applying it to loved ones or seeking opportunities to develop clinics around these tools and applying it of label, and there are both challenges from a regulatory point of view, but from a clinical science perspective, there is the need to engage those communities and those users, be it over the counter with the industry developed or be it do it yourself, communities in such a way that at the very least, we continue to learn from that application and prevent potential damage because some of the things being done are frankly not safe, and so I think there is a reality to contend with, including the fact that from the medical establishment, these techniques offer hope, and we need to develop the studies to provide that support while facing the need of helping patients today. So just my final comment is that I think we're faced a little bit with the same situation as in education, I've made that argument before, but in the absence of detailed knowledge of how to do best mathematics training in high school, it'll be the wrong thing for us to respond to parents with the expectation that they take their kids home and bring them back three generations from now when we have the time to develop appropriate ways to teach mathematics. That is not the way that education works, and it's not because we know everything about how to best educate, it's because there are needs and realities of individuals. I think the same is true highlighted by the development of these techniques. Pharmacological applications and other interventions don't work well enough. Patients with neuropsychiatric disorders face significant disability. There is the hope that this technique can help, and it is on us to develop the research and the support and the understanding to optimize those interventions, but it'd be absurd not to face the need of these late patients and help them to use the techniques appropriately. And I'll stop there and pass it to you, Hank. Still away. Been to this rodeo before. I have no slides to worry about. I just think this is one of the greatest areas around to be interested in. I want to talk about it. It's the area in neuroethics and neuroscience that I find most interesting right now. For a couple of reasons. I want to tell you a little bit about the context, both general and specific for today's, that I see today's issue being in. And then I want to talk about the three ethical issues I see with respect to cognitive enhancement through neurostimulation. Those issues are safety, fairness, and coercion. But to start with some context, what I find so exciting about this on the one hand is the issues around non-invasive neuro... I prefer modulation to stimulation because sometimes you may be repressing neurons rather than stimulating them, but you're changing them, you're modulating them. And as Alvaro pointed out, there was an Institute of Medicine workshop on March 1st and 2nd that we were two of the organizers of. They looked at a variety of modalities and a variety of uses, from medical uses to non-medical uses, mood, cognitive enhancement, a variety of things. And it is, I think, one of the most interesting frontiers right now for neuroscience and for psychiatric disease. Part of that is a message of desperation. Things haven't worked very well for us with respect to psychiatric diseases for the last couple of decades. We've had some successes, but not nearly as many as we hoped. The drugs have not turned out to be the panaceas that they were at one point hoped to be. Non-invasive neuromodulation, things like deep brain stimulation, work for some things pretty well and have some indications of working for others, but doing the neurosurgery to stick electrodes deep into a brain, that gets a little pricey and has its own set of problems. If you can do something like that non-invasively, it opens up lots of potential and there is at least enough evidence that some of this works for some things to make it really intriguing. It also remains a little bit mysterious because nobody as far as I can tell, frankly, has any good idea about how any of it works. There's a lot of hand-waving speculation, some of which I suspect will turn out to be true, although not necessarily, but something's going on with this and it's a bunch of different thises too. Alvaro talked about transcranial magnetic stimulation as well as transcranial electric stimulation and the electric can be direct, it can be alternating, it can be all sorts of different current things from nine volt batteries to electroconvulsive therapy which has miraculous results on some patients with depression. We also have focused ultrasound, a completely new modality with a different sort of approach that's also showing some signs of doing things to people's brains. So the science on non-invasive neuromodulation is expanding quickly. It has the potential, which may not be realized, to do great things in a context where we've had a shortage of great things and so looking for something new makes a lot of sense. That's one context. Second broad context is human enhancement. We've had lots of discussions and they're continuing discussions about human biological enhancement, whether it is from giving people inborn, ingrown night vision to changing the germline of the human genome, to giving people powered suits that make them iron men, to giving college students Adderall so they do better on exams or at least they think they do better on exams. It's a whole to performance enhancing drugs in sports which may be the area that's gotten the most attention. All of these are subsets to the broader question of human biological enhancement which raises a lot of concerns for people. Today's topic is the intersection of those two. We're not gonna talk about performance enhancing in sports although TDCS might help some sports but we are going to talk about biological enhancement on the one hand, non-invasive neuromodulation on the other. That's general context. So both of those fields are fascinating. The scientifically and medically fascinating the non-invasive neuromodulation, ethically, legally, practically fascinating the questions of human biological enhancement. You take fascinating and you multiply it by fascinating and I think you get fascinating squared although I haven't had math in a long time. You get something that's pretty cool to look into. Concrete context. If we're talking about transcranial direct current or transcranial electrical stimulation for purposes of enhancement, giving good ethical analysis requires some good facts. Thought experiments are very useful. They've got their place but if you wanna give practical advice you gotta know what's going on in the actual world and what or at least what's likely to go on, what's likely to be happening. And I think the context pieces that are most important with respect to these issues are questions like how effective is it? Is it effective at all? Is it effective for everybody? Is it effective only for some people? Is it effective for certain behaviors and not other behaviors? If it is no more effective than a good cup of coffee that's an interesting thing to know. If it turns you into the guy who wins Jeopardy, I guess it's a computer now but Ken Jennings or whatever his name was, that's also interesting to know how effective it is makes a difference in the ethical analysis. So does how safe is it? So does how expensive is it? Most of those things we don't know the answer to yet but they're important considerations to keep in mind because that context affects the ethical analysis to which I shall now turn. I think there are three big ethical issues with this. All of which I think are the three big ethical issues with respect to human biological enhancement in general. I do not think one of them is should we enhance ourselves? Because as far as I can tell, since we came out of the trees or left the savannah, those of us who did leave the savannah, Northern California is looking more and more savannah to desert-like with every passing drought month. All we have done as humans is try to enhance ourselves. We've enhanced ourselves physically and we've enhanced ourselves cognitively. I would argue that the single greatest cognitive enhancement ever in humanity is reading and writing. Allowing you to pass information on much farther in space and in time than we could before. And that changed things. And there I'm sure are people who are unhappy about it. Imagine the poor Greek bards who had spent years memorizing the Iliad and the Odyssey and some young schmuck comes along and starts reading it off a scroll? Unfair competition. Clearly they would have been upset. Enhancement is what we do. So I think the idea that enhancement overall is wrong is silly. That doesn't mean that some sorts of enhancement might not be wrong. But on what grounds? And I think there are three big issues to think about. Safety is the first. Safety is really important. Not necessarily the absolute amount of safety, whatever that means, but how well we understand the safety and the relative safety to the games. And that's why safety I think is more important for enhancement than it is for medical treatment. If you wanted a drug, if you had metastatic pancreatic cancer, which I hope none of you has, you have a life expectancy of less than a year and a really painful and unpleasant year at that. If I could offer you a drug that would cure half of the people with this instantly and kill the other half instantly and painlessly, that's an incredibly safe and effective drug in that context. If we were to do the same thing for something that would make you better at math, not so good. With medical things, the risk that you're trying to overcome, the deficit you're trying to overcome tends to be more significant, not always, teenage acne, for example, not always, but tends to be more significant than the plus you're looking for, the benefit that you could get from enhancement. So safety is particularly important in the enhancement context. And safety, frankly, I worry about a lot here. I worry about efficacy a lot. You have to balance safety and efficacy. And I think right now, the answer with efficacy and all of these forms of cognitive enhancement is unproven, unclear, interesting, but not yet sure. The safety issues also need further investigation, I think. More than the FDA seems to thus far have been concerned about, not so worried about short-term efficacy, except maybe for the guys who go to Radio Shack and set up the thing wrong when they follow the schematics off the internet, which happens. But the longer-term efficacy we really don't know very much about. The longer-term safety we really don't know very much about. What happens if somebody uses this every day for a year? Maybe it has bad effects, maybe it has good effects, maybe it has no effects. I'd be interested in learning that before we push this on in a big way. So I think the safety issues are really important. They can become even more important in some of the other contexts. One of the other contexts is fairness. If this turns out to be no more than a cup of coffee, I'm not very worried about fairness. I'm not too worried about somebody getting an unfair advantage because she can use TDCS before going into her exam if her classmate can get the same effect with a good cup of coffee. If it turns out to be really effective, then fairness becomes more of an issue. I would note it's not unique to this. I think every society, but maybe particularly our society, is unfair in lots of ways that affect cognition. If you can get SAT tutoring, you're likely to get a better score on the SAT than somebody who can't. If you chose your parents wisely and chose well-educated, stable couple, your odds, not that it's impossible, but your odds of getting into a very good school and doing very well academically are better than if you were born to a single poor young mother who had no education and didn't value it very much. These are unfairnesses that already exist, but you wouldn't necessarily want to add to them. So depending on how effective it is, the question of fairness can be important. It doesn't mean that that's a slam dunk, yes, no, stop, start issue though. There are ways we could, if it's unfair, try to deal with it other than banning it. For example, you could make it available to everybody. Let's say this works great on organic chemistry. And so all of America's pre-meds, who for reasons that have nothing to do with their future practice of medicine, my wife just retired after 30 years of medicine during which she never had to remember the Krebs cycle, despite having memorized it five times in order to get into and get through med school. Let's say that it really helps pre-meds do well on organic chemistry. And it might be unfair to make the line as who gets into bed school and who doesn't depend on who had good drugs. One solution might be make the drugs available to everybody. Another solution might be have separate curves, have one curve for the drug group and one curve for the non-group drug group. Or you could have drug tests make everybody pee into a cup before they take organic chemistry. And then you can have a question on the exam about how exactly that urine is going to be analyzed biochemically. There are ways we can try to mitigate the fairness issues. They're not perfect ways, but they're ways we should think of. It's not just we should ban it entirely to prevent unfairness or we should allow it entirely and just live with the unfairness. There are intermediate positions. Last issue, coercion. Coercion worries me a lot. If somebody doesn't want to do this, should they be able to be forced to use it? The military currently quasi could coerces pilots into using amphetamines or provigil or other things to stay awake. They have an argument for this that I think has a certain plausibility. If you've got somebody who's flying for 12 hours, you'd kind of like them to be awake unless you can actually have enough crew that they can take turns sleeping, et cetera. They say it's not exactly ordered. You've given a choice, but your choice is either take the drugs and fly or you don't fly. And if you're a flyer, the answer is always you do what you need to do in order to fly. That's what they live for. That's what they do. That's coercive. Stanford could order me, I hope they won't, to take remedial teaching classes. Really, your ratings have been slipping. We think you need a little bit of help. We need you to take this and even though I've got tenure, if I didn't do it, unpleasantness could ensue. They certainly require me to listen to various seminars on all sorts of exciting topics, exciting there being an ironic, did I get the ironic expression? Could employers require you to do this? Could the government require you to do this? Could parents require their kids to do this? And I think in some respects, that's the hardest. I'm a parent, 27 and 23, so 26 and 23, both past teenage years alive. So successfully, when you're a parent, your job is to coerce your kids into being enhanced, to try to coerce them to be better people, to teach them how to be social and how to be nice and how to end the care about learning and all those things, that's your duty. On the other hand, do we want parents doing TDCS or other things on their kids when the kids don't, the kids can't say, yes, I want to do this. Even if they say it at age four, we don't believe them, we can't believe them. And so I think this intersection between parental authority and children's autonomy with respect to enhancement, particularly if there are some significant safety, efficacy or fairness issues, maybe one of the hottest topics of all. So I think those are the main issues. There are a bunch of interesting FDA and other regulatory issues. I commend to your attention, the Journal of Law and Biosciences at Oxford University Press online journal that's now published, I think, in its four issues, six or seven different things about enhancement through transcranial direct current or other methods and has another big one coming out that's actually a survey of people who've used it and how they've used it and what they found out and what they thought about it. It's a fascinating issue and I think I will shut up and let Tim tell us something about what may be coming, what will be coming down the pike very soon. Thank you. That's Tim. Jamie. I know it's Tim Tyler, but that's not you. Okay, thanks for organizing the event and inviting me here today. I'm gonna say hi to our offices out in Silicon Valley. They're all notified me that they're watching for me to smile, so hi. So I am a co-founder and CSO of THNK. We are on the verge of launching the first product that we feel is a very serious product in this category that enables people to ship their mental states on demand, literally via a switch. First, in keeping true to our academic background within HMS in the interest of full disclosure, I am the co-founder and CSO board member of THNK. I'm an inventor on pending and issued patents related to non-invasive brain stimulation, systems, methods, and devices. So the first question, I think this has been brought up a couple times already today, is how do you influence your brain? So we all influence our brain and it was, I think, kind of poetically stated that since we left the Savannah, we've been trying to enhance ourselves ever since then and we'll continue to do that throughout time. People use caffeine, alcohol, pharmaceuticals, off-label prescription. You could probably argue, we could do the same survey and ask how many people have taken Adderall before the medical exams. I'm not sure we get honest answers, but the numbers might surprise you, they'd probably be quite high, or studying for medical exams. So about four years ago, Izzy Goldwasser who's the CEO of our company, and I got together and we decided to start a company and the fabric of our company, the DNA of our company is really, we're scientists. We pride ourselves in science. We had a couple of monsters that we followed by, that we would develop a safe product and it would be a product that people could experience and feel and it would have a big impact on their lives and it would be a consumer product and not a therapeutic. The reason we did this is we looked at, if you look at the history of non-invasive brain stimulation dating back to the 60s, depending on whose accounts you read, this dates back to the late 19th century. But you can see there's an exponential gain, exponential increase in the number of, these are peer reviewed studies per year, right? And so you can look in 2014, there were 1,400 papers published that year on non-invasive neuromodulation methods, right? TMS was introduced by Anthony Barker in 1982, TDCS was kind of reintroduced in 2000. And if you look at that in parallel, driven by parallel advancements in the wearables field, the wearables market, fitness trackers, other wearables that people have, most of these tend to fit in the fitness tracker category. You can see that there's a convergence where the two will meet, right? And that's really what Think represents. We really are a company that's trying to bring modern neuroscience to the consumer world by practicing solid science, sound engineering, to deliver safe products that will allow people to do what they've been doing since the beginning of time. So that was our idea. The way we look at our company is, we're not a company that works on any type of cognitive enhancer, right? We don't work on cognitive enhancement. We really are a company where our technology mission is to impact brain health. And what I mean by that is there's certain things that we think about, we engage in every day that impact brain health. Some of these are obvious, some are not so obvious. One is reducing stress, improving the quality of sleep, increasing energy, promoting smart choices, boosting motivation, enhancing focus, and encouraging socialization. Even if you have all these things, many people tend to forget this one, right? But even if you have all these things, you get great rest, you have low stress, you have good energy when you need, you make smart choices, but if you don't have friends and family to support you, you're really not a balanced individual. And I would argue that you probably don't have a healthy brain, right? So this is where we focus our energy. We will focus our efforts. Our first product really will focus on this area, reducing stress and increasing energy. And I'll talk a little bit. I just wanna show you some of the science behind the type of science that we do. We have two offices, one is in Los Gatos, California and the other is in Boston in the Prudential Tower. We conduct studies, IRB approved studies on human subjects all day long. Studies, the types of studies we do are wide ranging, but so I'll tell you a little bit about that. The way that we see these two initial modes, this is what we call them, we have calm vibes and we have energy vibes, right? So there's an energy mode and a calm mode. I'll talk about the science behind it and exactly what happens with each one of these in a minute, but the way we see these doing is really what you're doing is you're optimizing your psychophysiological arousal for a given task, right? So when you want to be more calm, we can help you become more calm. When you want to have more energy or a boost in motivation, we can help you do that as well. And if you think about this, this goes back to, this is kind of a classic curve where on the x-axis we have levels of arousal and on the y-axis we have physical and mental performance. We have energy vibes that we will introduce to the consumer market soon and calm vibes will also be introduced. But if you think about your performance, there's certain tasks that are low arousal optimized tasks where you have to be very calm to perform well. Surgery might be an example, right? You probably don't want your surgeon jacked up on methamphetamine or a lot of caffeine, say, well, I mean robotic surgery now is a little bit different, but there's certain tasks where you want to be calm to perform well and there's certain tasks where you need a little more arousal to perform well, right? So if you're too calm you're not gonna be able to perform those tasks well. And so we think about the ability to switch between those two on demand will really empower people to be able to utilize their psychophysiological arousal to achieve a certain end. The major principles and mechanisms by which we see this working. So this is the point where I'd like to say, look, we do not, what we do is not transcranial direct current stimulation. Transcranial direct current stimulation is a 1960s technology. It uses typically sponge electrodes saturated in saline. When you see subjects that undergo this they have saline water dripping off their face. It's a bandage wrapped around their head to hold the electrodes in place. So over the past four years we've invested the equivalent of about 17 to 20 R01s in advancing the platform several decades beyond that. We believe the way that transcranial direct current stimulation and transcranial alternating current stimulation work and Dr. Pasqualeone alluded to this is that it's multimodal. We believe that we're activating cranial nerves and cervical nerves, cervical spinal nerves, right? So one of the electrodes goes over to the temple and activates the maxillary and ophthalmic branch of the trigeminal nerve and another electrode for the calm effect goes on the back of the neck and activates C2 and C3 cervical spinal afferents. For the energy vibe the electrode in the front stays in the same place and the electrode in the rear goes on the mastoid and activates the greater auricular branch of C2, C3 spinal nerves. I think this has been overlooked in the field for quite some time. People just assume that there's current passing across the skin and the skull and the CSF when we talk to people who actually put electrodes on the dura the currents that they have to use to generate a response in the brain or about 10 times higher than what is applied for TDCS. And that's directly on top of the dura. That's not counting the skull or the skin. If you look at the pathways and you look at what's been described in the literature it seems to be fairly consistent. Most people describe it, you can get this modulation of psychophysiological arousal, that's fairly consistent. The cognitive effects have not been so consistent. If you look at the pathways and this is textbook anatomy, the trigeminal nerve and the cervical spinal afferents feed directly into the trigeminal nucleus and the pons of the brainstem, the nucleus of the solitary tract. So C2, C3 facial nerve all feed into the nucleus of the solitary tract and the trigeminal nucleus. Those have direct monosynaptic connections with the locus serilis and the reticular formation. So those of you who have had neuroanatomy know that the reticular formation is essentially a seed of consciousness. This is the first place where all sensory information is integrated in the brain for the first time. Below the pons, not conscious, above the pons that's where consciousness begins. And so we believe that by modulating the reticular formation and reticular activating system in the locus serilis and neuroanergic system that you can start to modulate psychophysiological arousal without modulating cortical function. And when you look at these types of mechanisms you start to see, you start to find that you can gain robust effects across populations such that you get these effects in 85 to 90% of the population. If we were modulating cortex and we were trying to understand the way the electric field was affecting brain and considering gyroanatomy and different folds in different patients, this becomes more of a problem and I think that's why people are looking at TDCS and taking that approach and they're not really understanding what's happening and so the results haven't been as consistent. So we spent a lot of time trying to understand the mechanisms of action by the way that our device works and we haven't even launched it yet. Safety is probably the foremost thing that we have concerned ourselves with since day one. We work also on using ultrasound for neuromodulation, particularly for trying to access deep brain targets but we realized very early on in the company that it is gonna be harder to prove out the safety using focused ultrasound for neuromodulation compared to using electrical stimulation. And so our safety margins were about 100 times below any levels that would damage neuronal tissue, right? So we have a pretty large safety margin. Our device has been looked at by independent medical device groups that evaluate medical devices. Our output levels are actually below our peak output level is about 20 milliamps and that's below devices that you can go by off the shelf that are such as TENS devices, right? There's a class of TENS devices that are cleared through a 510K process, they're TENS for aesthetic purposes and these devices actually wear on the face and they stimulate the trigeminal nerve. Those devices can generate a current density of about 46 milliamps per centimeter squared which is incredibly high and the TDCS world, the TACS world, the best practice is to keep the current density below two milliamps per centimeter squared. So there's devices that are out there that already generate 20 times the current density. They've already been approved by the FDA. They've been used, these devices have been used for 40 years with no serious adverse events. If you look at where we are, we've defined as limited output designation. This comes from some language that was developed by the FDA several years ago in which they said that like below this, some of these devices may be considered to be exempt from pre-market notification or 510K process and really here it's below an average current that's 10 milliamps and then a current density below two milliamps per centimeter squared. And so if you look at all these other devices that fall outside, these are all devices that have been cleared by the FDA for over-the-counter use, right? Some of these are, there's a couple in here that are for prescription use, which you can go buy these devices at Walgreens or CVS or anywhere else. We just completed, hopefully by the end of the week we'll post it, we'll probably post it on Buy Archive, which is a pre-print repository that's housed at Cold Spring Harbor Laboratory. We ran what's to date the longest comparison of TDCS and what we'd call transdermal electrical neurosigling or transcranial pulse current stimulation. We did this in collaboration with Merone Bixen at the City College of New York. So we ran a hundred participants in three different treatment groups. One treatment group was a sham, one was conventional TDCS and one was using our technology. They were randomly assigned to each one of these groups and blinded. They came in and we set up a naturalistic environment that was kind of like a library or coffee shop. They came in four to five days a week. They used the device for 20 minutes a day and we had pretty conservative exclusion criteria throughout the trial. We conducted over 1,800 stimulation sessions, 20 minute sessions. Basically what we saw was that our technology outperformed in terms of tolerability, outperformed conventional TDCS and that's because we worked really hard on the electrodes. We don't use sponge electrodes. Our electrodes are hydrogel electrodes that actually are optimized for comfort. It's completely comfortable. There's no irritation of the skin. After someone gets through running a vibe, you can look at the skin and it's not even red, right? There's not even redness of the skin. The incidence of side effects. Oh yeah, okay. So the incidence of side effects, the most common side effects were minor skin irritation and tingling of the skin and mild headache. It turns out that we couldn't distinguish between groups because the incidence rates were so low so they were equivalent to sham. So for example, the sham condition had an incidence rate of headache for about 3.5% and trans-cranial pulse current stimulation had an incidence rate of headache of about 2.7%. So there are people in the population that if you just put a sponge on their head and do nothing else to them, they will develop a headache, right? And that's just kind of a placebo effect. Experimental validation, we run lots of different studies. One series of studies that we ran was basically a quantitative effort. We used quantitative biometrics such as heart rate, heart rate variability, galvanic skin response and we also assayed biomarkers of stress from the saliva. So those of you who know about autonomic function, which I presume most people in this room do, you understand that heart rate, heart rate variability are somewhat controlled by the autonomic nervous system. So the way this particular study worked and we published this is available on BioArchive now, it's undergoing peer review but the way we work, we like to be very transparent with our science. So we like to put the pre-print out and allow people to see what we're doing as it takes the next 18 months to undergo peer review, right? Which that has its own problems we could talk about in another forum. What we found is that when people do the combine, they come in and we expose them to a fear conditioning trial, a classical conditioning trial where they see a series of nature scenes and when they see a bolt of lightning, they've been pre-instructed that they will be shocked and we deliver a mild electrical shock to their finger. It doesn't hurt but it is uncomfortable and then after that they undergo a series of time-constrained cognitive tasks, a strut task, a flanker task and an in-back task. And so what we found is that people who had the calm vibe compared to the sham had a significant reduction in heart rate variability and particularly in the low frequency spectrum. They had significantly reduced levels of salivary alpha amylase which is a biomarker, it's a surrogate marker of the sympathetic adrenal medullary axis as opposed to cortisol which is really a marker of the HP axis. People had significantly suppressed response, GSR responses. So during the baseline they're watching a series of videos when the videos stop and switch to still images, there's an immediate increase in the GSR so this is the sympathetic skin response. This is kind of a classic response but this is an anticipatory response because they know that they're about to begin, the shocks are about to come, right? And then for every single shock they get there's also a little transient increase in GSR. Both of those were significantly suppressed in the condition where subjects received calm vibes compared to sham. We then looked at cognitive performance, it's on the flanker, the strupe and the in-back and there were no significant differences between the treatment groups indicating that we're not affecting cognition per se but we are indeed affecting psychophysiological arousal and those two things are somewhat disentanglable. When we asked subjects, we found that one of the best biomarkers with all the fitness trackers and sensors that are in the world, the best thing you can do is just ask someone, right? You just ask them, how do you feel, right? And there is this expectancy, right? So if I bring someone in off the street and say, hey, this subject's gonna come in and they're gonna be involved in a neuromodulation experiment, there's some anxiousness, acute state anxiety that's associated with that event. And as the person sits down, we put electrodes on their head and after 20 minutes they don't experience anything negative, you can imagine they start to calm down. So there's a very strong sham effect or placebo effect associated with these types of experiments. We spent about a year and a half trying to beat the sham effect through an iterative process. We just kept refining our waveforms, refining our waveforms and getting a little bit better and a little bit better and a little bit better until we got to the point where we were absolutely convinced that we could beat the placebo effect. When you look at these distributions, as a rating scale, it's a scale of zero to 10. We tell people that a five on this scale for the calmness scale is like a single drink of alcohol and the rating scale for energy five is a single cup of coffee. You can see the distributions but there's a significant increase in the calmness, the sensation of relaxation or the perceived or subjective reported sensation of energy that's reported by individuals after they receive either the calm or the energy vibe. So lastly impact and discussion points for the rest of the afternoon. You know there's lots of potential impact with how our technology will impact the world. I think that one thing we're going to do although we as a company are not going to engage in the commercialization of any therapeutic device, we want to work with clinical partners and clinical clinicians who are going to investigate how this may be used to treat anxiety for example. So while we say we're going to reduce stress, a clinician may say this person has anxiety and we're going to study how this may affect anxiety or even PTSD or insomnia versus just not being able to sleep. I think one of the biggest opportunities that's yet to be realized is how this is going to affect the entire effort on brain mapping, right? So everyone in the world is crazy and fixated right now on brain mapping and I actually think we're probably taking the wrong approach because as Dr. Pascholoni talked about when you bring a subject into the lab and you try to understand what's happening to their brain, it's a completely artificial environment and whatever little piece of information you can extrapolate from those experiments is not really meaningful in a real world context. And I'd like to illustrate that by just showing this video. So this is what happens in the real world, right? This is not a laboratory setting. If you think about how you go about your day, you're moving in and out of your labs, you're moving in and out of classes, you're being affected by the sounds in these environments, the smells in these environments, the people that are around you, the people that you see, the people you sit next to on the train, the people you bump into on the sidewalk, every single one of these things affects the brain and they affect the brain in completely different ways and the only way that we're gonna be able to understand this is deploy a platform that's able to modulate neural circuits and record from neural circuits in the real world and right now that capacity is not, it's non-existent but it will be very soon. And so I really think that there's a major opportunity, you know, if we talk about what the brain mapping, what brain mapping really is all about, this is what we wanna understand. We wanna understand the relationship between brain and behavior, whether that's pathological processes or normal processes, this is what we want to understand. We wanna understand how the environment, the body, sensation, perception and cognition all give rise to certain behaviors. This is a huge opportunity, right? We're approaching a world where everything is connected to the internet, right? The internet of things. So we should also connect the brain to the internet of things, both from an input and output standpoint. By the year 2020, the world's population will be 7.6 billion, but there will be 50 billion devices connected to the internet. There's a huge opportunity to collect data and to try to understand behavior and behavioral patterns, especially if you're modulating no neural circuits in the real world. So where we are is we have a platform where we can modulate brain activity, known neural circuits in individuals. It's a wearable neural modulation. We can modulate that in social structures. It's literally scalable to billions, right? I mean, there's 7.6 billion people in the world. If you factor out everyone who's over the age of 18, there's still a couple billion people that we have an opportunity to modulate their brain. We can use this in real world use cases to study decision making, daily performance, communication, physiological arousal, attention, relaxation, memory. We can collect real world data, neurocognitive metrics, biometric sensors, heart rate, heart rate variability, how many times you text your wife, how many times you text your husband, how many times you yell at your child, how many times you give positive reinforcement to one of your employees, biopsychological feedback, geospatial information, where you go, who you talk to, and then use machine learning to develop statistical brain maps and really understand how modulating those known brain networks are affecting behavior. This is what I think there's a huge opportunity here that's being completely overlooked. We're not gonna find how the brain works in a voxel from an fMRI. And so final discussion points. Responsible company efforts can accelerate research and engineering in terms of manufacturing and validating medical grade products that are safe for consumers. This is a costly process. This is not something that you do in your garage. This is not something you have a couple buddies come over and get some duct tape and solder and hack together. It's not for Reddit, right? It requires multidisciplinary teams with deep experience to do this safely. Companies are better poised to tackle regulatory hurdles that face consumer and therapeutic neuromodulation devices. Single academic groups, not even Harvard Medical School can go to the FDA and get a device approved because the amount of money, the amount of effort that has to, you have to have a responsible entity that goes to the FDA and interacts with the FDA or goes to the Underwriters Laboratory or IEC or whatever regulatory agency there is that is gonna take ownership of that product and make sure it's ushered through to the market. Lead VC-backed companies can set the example for others by delivering medical grade products that are compliant with federal and international safety guidelines versus skirting loopholes and regulatory frameworks. There's been a lot of debate about what a medical device is, right? A Band-Aid is a medical device. A Crutch is a medical device. A Band-Aid is a Class I medical device and a Condom is a Class II medical device. Electrical stimulation is a Class II medical device. Whether it's regulated as a medical device by these regulatory bodies or not depends on the intended use and indication of that device and that is the law. Successful consumer products will draw expansive research funding into this area, more so than other academic efforts because of the total addressable population is large. If you combine all the people in the world who have depression, Alzheimer's and Parkinson's disease together, it's still a fraction of the number of people you can affect and impact if you develop a consumer device, right? And improving consumer brain health from a lifestyle and wellness approach can reduce major burdens on our healthcare system as well as support future clinical efforts and that's all. So are there any questions? Well, just jump right in, right? Yeah, can I? Is that on? So if I can just push on one particular thing because, so you basically presented, I think, an elegant hypothesis of a mechanism of action but it's just that, just to be clear, right? So the fact that you say this is because of the reticular formation, first of all, the hypothesis should be testable. One could image it. I mean, if you believe my chairman, then the answer really is that's a nonsensical hypothesis because you will never find the reticular formation because it's there in the netters of this world but it's no longer really there and nobody really believes its existence. So it's a very good sounding hypothesis but it really is not a scientific hypothesis because it cannot be tested because in fact we've moved beyond the reticular formation to a different conceptualization of brain-stream structures. And so I just want to push it because I think you're doing the right thing by framing a concept of a device in the setting of a scientific approach and a responsible approach but it's still a sort of slippery argument to give people, right? Because most people listening to it would take it as a fact and it sounds really good to say you want to activate the V2 branch, the maxillary nerve because that's something phenomenally unique going to a specific, what was it again? Tractus solitarius, what the heck is that? It sounds really good but first of all, it's not testable exactly and second, maybe it doesn't matter from the point of view of the outcome and so why go there? I think first we have to go there, right? We have to understand how it works to make it better. The world of TDCS and TMS has failed miserably in this aspect. I think if you touch, like you said it yourself, we don't have a good understanding of how any of these methods work in their multimodal. If you touch this location on your head, how does it get to your brain? Trace the pathway. How does it get to your head? But what is the main pathway if you touch this part of your head, if you feel that sensation, how does it get to your somatosensory cortex? Who wants to trace it on the board? It's certainly the maxillary branch of the trigeminal nerve to the trigeminal sensory nucleus. Yes. What is it? What is it? What is it? It's not the maxillary branch. It's it. This is a super orbital branch. And this is the maxillary branch that runs right up to your hair and branches up here. You can look at the anatomy. So when people feel the sensation of transcranial direct current stimulation, when they feel that sensation, if it's on their scalp, I don't know like it doesn't go straight to the somatosensory cortex. That's for sure. Is it carried by some mystical fiber we haven't discovered yet? I don't think so. I think it's probably carried by cranial nerves via the ponds of the brain stone through the thalamus to the somatosensory cortex in root. And it's been known for 50 years that sensory stimulation activates neurons in the local serilis. So I don't think the reticular formation itself is the main responsible nucleus. I think it's part of it. It's a diffused network that's responsible for arousal. That's why when I snap my fingers it alerts people's attention. But aside from the dead, those are... Sorry. Those are testable hypotheses. But what I'm saying simply is that that when you say it's really critical that we get at the signs, I obviously agree with that. But to be clear, it's not critical from the point of view of testing efficacy for any one outcome. There is a lot of medications that we use and we use well. I think it was Hank that mentioned electro-convulsive therapy. We have no freaking idea how it works. None. We can discuss it. But that it works. There is little doubt. It's the best antidepressant out there by far none. And so I think those are two different questions. What is the substrate of function and what is the efficacy, as it were? My commentary was simply because by framing it the way you do, which is very smart from a business point of view and a very interesting hypothesis to be clear. I don't think that you're framing just a hypothesis. You're presenting it as this is what we know to be relevant, which appeals to the population. I think in a bit of a leaning way, right? And that's all. So this could go on forever. But I think we have to, it's hard to imagine a scenario where you can place an electrode on the head and it doesn't affect a cranial nerve and doesn't affect the pons of the brain stone. I can't imagine it happening. I'll pass it on to them, but just to be clear. I agree with that. I've mentioned it myself, but that doesn't establish that that's the mechanism of action. Okay, but that's different than what you presented. That's what I'm saying. Hypothesis is a hypothesis and you can test it. And if you can demonstrate it, it's activating it. Then... No, no, look, this is not a game, right? It's not just a hypothesis. It's a testable one. If one wants to, and that's the point I was trying to make. If you want to establish that that's the mechanism, I think one needs to show not only that it engages, but that it accounts for enough of the clinical outcome. And that's a different type of reason than what you presented. I'm actually just gonna open it up to audience questions. But I was gonna say something. I've been around for a while and I'm older than some of you folks. I got my, what was, 45 year pin at MGH in October. I studied in D.O. Hebb's department at McGill University before I was a psychiatric resident and before I did my medicine at Hopkins and worked in the United States Navy. I cannot think of any time in the history of neuroscience, psychology, and psychiatry that there has not been a new approach to neurological stimulation. One of the first observations that preceded the development of psychotropic medications, which had their very significant limits, but the 30% number is very, that you had up before similar to what you see with the extraordinary number of psychotropics that come along in terms of efficacy. There was some serendipity in looking at people on the Insanitaria for duerculosis and remarkably some of these people were doing pretty well in terms of their mood and this led to the development of monomyne oxidase inhibitors. Psychotropic stimulate the brain. When I do hypnosis with people, it stimulates the brain. When I talk to people in my office or here in this room, I'm stimulating your brains. If you go to the media lab at MIT and speak to Nair Grossman who's leading for King's College and the other folks over there, Dr. Boyden, they've been looking at a milliamp of current and applying it to certain parts of brain. You can do it with the lateral apparently more effective than the medial, sorry, the left versus the right, dorsolateral prefrontal cortex and you can do some wonderful things in terms of attention and mood and arousal and there's been some very significant information about that. The military is very interested in arousal and affecting neural currents in the brain. I remember reading some years ago that the DOD at some point is interested in having chips that can be placed in the brain that will help pilots fly airplanes from the ground. I hope that someday we'll be able to do that to supplement loss of memory in humans. The information here seems so terribly disorganized and I think one has to be very, very, very, very cautious about another among the extraordinary abundance of fads that people get very excited about and one needs to be very, very specific and not think that there haven't been advances in science and that now this great wonder has come along that supersedes everything else when it hasn't been thoroughly researched. I think it's very stimulating. I want to read about your company. I want to read about the Cochrane reports they do wonderful analysis. I want to see what they're coming up with but there was a lot to learn here. Thanks very much. Just a very quick question for Dr. Tyler. So you presented under safety TDCS versus your modification of it versus sham. Then efficacy you showed your modification versus sham. Where did TDCS fit in terms of efficacy? It was in the middle. So it was in the middle and the way we assessed efficacy was with the, it's a state trait anxiety inventory. Stay six is an abbreviated form and we looked at different scores and TDCS was, it was more towards sham than it was towards our neuro signaling approach. When we released the data later this week or the week after, we're first gonna describe the safety and tolerability and there will be another follow on paper after that describing efficacy comparing sham TDCS and TPCS. There is a sham effect. You do see a sham effect across six weeks, right? Like people, I think what happens is people tend to become more relaxed in the environment. They become more comfortable and there's a reduction of the state anxiety. I do think that one of the problems with dealing with this area is a lot of the efficacy testing is testing in laboratory conditions. Efficacy is defined in particularly narrow ways that are not necessarily real world relevant. So the stoop test, stoop test has been around for a long time. It's useful for some things. Is it really what students wanna know about in terms of are they gonna be able to study better or not? A lot of the Adderall work has this problem too. They do short-term cognitive tests like how many random numbers can you keep in your head at various times, but the kids taking it wanna focus better for the space of 12 hours in terms of studying for the test or writing their exams. That's a lot harder to study, but I think that might be a more relevant kind of efficacy study. If I could, the IRB wouldn't let me, I'd take 200 standard undergrads and give half of them Adderall and half of them placebo or half of them think and half of them placebo and follow them for a year and see how their grades changed. The IRB won't let me do that. I do think moving from efficacy as measured in a lab context to efficacy in the real world, it's gonna be a challenge. So just to comment on that, so we started doing a series of alpha studies and beta studies and we thought that we would have a more difficult time getting good efficacy effects in the real world. So what we saw in the lab, we then translated to the real world and we ran a series of studies around the holidays. We brought people in and we said, you're stressed around Thanksgiving and Christmas. We'd like our Hanukkah, whatever, you get around your family. We'd like you to use this device. We took people who went on first dates. There's usually a lot of anxiety associated with first dates. We had people who before they had public speaking engagements on and on and on. And what we found was that the efficacy was actually greater in the real world when there was a need to reduce sympathetic activity versus in an artificial environment in the laboratory where sympathetic tone may be very low. And I wasn't really criticizing your overall energy versus calm and asking patients as well as the galvanic skin response and so on. When you went to the cognitive tests you did, I like those who are a bit artificial. I don't want us to monopolize so I'll make it very short but again I think the critical thing in that setting is what is really your control and perhaps eventually you can expand more because when you said you spent a lot of time as a company sort of defining how to best optimize the waves to go beyond the placebo, the sham effect, that sounds alarms in me, right? In terms of what exactly are you talking about doing? And yet there are fairly straightforward sort of control conditions that one can imagine, right? If you really believe that the waves, whatever they are are different in the pattern for the calm versus the energy, you can just flip them and give the same instruction and actually see whether indeed there is a different effect or you didn't present that. So I think there are things that make it hard to capture in real life that obviously is what we all want to do is make a difference in people's life be it patients or otherwise. But there are reasons why it's difficult to do real life experimentation which eventually will be overcome with the technology, but sorry. So I want to thank the three of you for coming here. You represent very different pieces of the spectrum of this debate. Just three quick observations. One is that each of us has a different identity. Some of us have dual identities. I'm a physician but I'm a neuroscientist so I accept the fact that every day I see people for whom we have inadequate therapies, inadequate treatments, it helps to do something, do no harm. So I think Pasquale Young falls into that perfectly with TMS is a kinder and gentler ECT, bring it on. It may say nothing about how the brain works or it may be the holy grail. And none of us are smart enough to know that right now. It's understandable that sometimes these two sorts of things want to get confused, right? Did Jackson was used since the 1700s in medicine? It was 200 years before anybody had any idea what the molecular mechanism was and probably the Greeks used it because they knew everything. So it's important to sort of think about these different pieces of ourselves when we have these conversations. My first observation. Second is about enhancement. I really appreciate Professor Grayley's really interesting talk. Enhancement is a tricky thing. Yes, we've always been enhancers, but there's no guarantee that the enhancement doesn't end in a species ending apocalyptic nightmare, right? True. I'm willing to bet that in 11 billion years we will not be here. Right, so it's always safe in the short run, but that's my point, right? Climate change, who knows? That was enhancement, carbon. Who knows where it ends? And that relates to my third point. Are we gonna be like the surgeons or the geneticists? The surgeons have done procedures for years, some of which ended up being completely counterproductive, killing their patients, making mortality worse, but they had sort of evidence-based medicine forced upon them in the last two decades and so they've adapted. The geneticists, they're scientists way ahead of where our science is. I mean, we're idiots about the brain compared to them. We really are. But they've been thinking about the ethical issues from the very beginning. They've actually sort of thought about what experiments we can do, what experiments we can't do, where does this head? It's not perfect, right? There are people in Japan doing stuff that jumps over all of the ethical things, but I think it's worth thinking about which path do we wanna follow? The surgeons, and with all due respect, the device people I think are more soulmates. You know, let's get it out there, let's see what happens. I think you're more in the traditional trying to heal model, but I'm really worried if we don't start thinking about the geneticists have really thought about this and they are so far ahead. We have no idea about what the underlying mechanism of consciousness is really. Be a century, probably. Neuroscientists, we love to be arrogant, I'm a neuroscientist. We love to be arrogant, we love to be modest. There's no Watson, there's no Rosalind Franklin, there's no Crick, our metaphors are pre-Newtonian, right? There's no quantum phenomena that's modifiable in the brain. We gotta be really modest. So I'll just say international neuroethics society is not only helping support the webcast of this, but it's a place where scientists, non-scientists, lawyers, ethicists, individual, regular people try to come together to worry about these kinds of issues and our annual membership is cheap. That's my conflict of interest. But I do think the geneticists to some extent had the ethics thrust upon them, in part because the politics were really ugly and Jim Watson, who has many things, is also smart and he basically bribed the ethicists with 5% of their budget. And it worked in terms of limiting the political pushback against genetics research, but it also worked in terms of creating a whole bunch of people who are scientifically sophisticated but ethically sophisticated and willing to examine these things. Well, I think neuroscience needs that. I've been arguing that with Tom Insel for a while. The Brain Initiative is a great, the US Brain Initiative, as opposed to the Harvard Brain Initiative. They're both a great way to kind of make that happen and it might. But if any of you have influence with Tom, push. Well, I was just gonna say one of the things we've done as a company, and I'm not gonna name names, but we have actually sponsored some unrestricted educational grants to look at ethics. And I've actually reached out to Professor Greeley to get advice from him so we can understand the landscape, the future. Are there hurdles that we're taking in the Medicare? No. But we want to understand the landscape. What are the issues? And we're doing that because we are trying to act as responsibly as a company as we can. We're not geneticists, we're not at that level yet because I don't think we understand the problems that we're going to face in the next 10 years. What are the imbalances that this is gonna cause? Genetics is a little more black and white. People understand what some of the issues are. Cloning humans, people say, no, you shouldn't do it. I don't think we can do it yet, right? Like, can we make people five times smarter than they are today? Some people in the neuromodulation world would want you to believe that. I don't think we're there. I don't think we can do that, right? So I think that it's something we're gonna have to continue to monitor for quite some time, but we are paying attention. I just wanted to echo the point of the importance of the different constituencies, actively up front and early becoming engaged in the ethical aspects of this. And I think, you know, nerve simulation, brain simulation, neuromodulation has a long history and it's a colorful one, right? Where Rodriguez Delgado or Hunt or many others did all kinds of remarkable things. And that led to some insights and some remarkable derailments to the tune of the call for a psycho-civilized society. So, which meant inserting electrodes so that we might in fact guide appropriately people or treatment trials of stimulating specific brain structures while exposing people to prostitutes so as to overcome their homosexuality, right? And in the face of that history, I think we have to do better. This is in part because of the fact that hopefully humans have some limited or by real possibility of learning from history and this is one where we have to. The second is because ethics has come a long way and is very engaged in this and very willing to help think through. But I think the last one is because the availability, the relatively ease of these techniques will confront us with the reality that it is being used widely and increasingly so. And unless we address the ethics of it broadly with all the constituencies, we risk losing in historical grounds just like we did with neuro-population in the six months. So I think we actually have to wrap up there. We have a dinner where we're gonna continue this conversation in an informal setting. If anyone's worried that the discussion has been too cordial thus far.