 I'm delighted to welcome you to the first session of this year's interdisciplinary lecture series on the topic of neuroethics. I welcome you on behalf of the McLean Center for Clinical Medical Ethics and the Grossman Institute for Neurosciences, Quantitative Biology, and Human Behavior. The series that's about to be launched was organized by John Moncel, who is here in the front, the director of the Grossman Institute, by Peggy Mason, Professor of Neurobiology, and Dan Salmezzi from the McLean Center, working with an interdisciplinary faculty committee representing more than ten university departments, clinical departments like psychiatry, neurology, neurosurgery, as well as non-clinical departments, including the Committee on Social Thought, Philosophy Department, and the like. Recent advances in the neurosciences have raised and continue to raise important ethical issues, some of which are of such magnitude as to have given rise to this new field of neuroethics. Our speaker today, I'll introduce Professor Ilis in a moment, was one of the early pioneers in the field. This year's McLean Faculty Series with the Grossman Institute will examine many of these issues over a series of 22 lectures. Some of the topics, of course, you can see if you pick up a brochure for this year's sessions. But the lectures will draw upon the expertise of an international and interdisciplinary group of scholars representing the neurosciences, philosophy, psychology, history, law, and medicine. It is now my pleasure to introduce our speaker today, Judy Ilis. Professor Ilis is a Professor of Neurology, the Canada Research Chair in Neuroethics, and the Director of the National Corps for Neuroethics at the University of British Columbia. Dr. Ilis is a founder, a governing member, and the President-Elect of the International Neuroethics Society, and I just want to tell you that the International Neuroethics Society will be holding its annual meeting in Chicago on Thursday and Friday, October 15 and 16. The Thursday session on October 15 is a public session, as I understand, open to the public, and then there's a more formal session on Friday the 16th, which will be at the Art Institute. Yes, and the program I've looked at is quite extraordinary. For registration, go online to the neuroethicssociety.org. Dr. Ilis' research focuses on ethical, legal, social, and policy challenges, specifically at the intersection of the neurosciences and biomedical ethics. These include studies in the areas of neurodevelopmental disorders, incidental findings on imaging, clinical research, addiction neuroethics, stem cells and regenerative medicine, dementia, and on and on. Professor Ilis' most recent books are in 2015 on the use and overuse of antipsychotics in children published by Elsevier, a book on contemporary ethical issues in behavioral neuroscience published by Springer in 2015, and a book on the addiction neuroethics issues published again by Elsevier in 2012. Today, Professor Ilis will speak to us on the topic Aligning Human Values and Neuroscience in the Age of Neurotechnology. Please join me in giving a warm University of Chicago welcome to Professor Judy Ilis. Thank you. Good afternoon, everyone. Thank you so much for being here with me. I have this inaugural lecture of the McLean's Neurethics series, and Dr. Siegler and Dr. Samansi, thank you for honoring me to give this first lecture of this series, and thank you to those of you of the program committee for bringing me here to Chicago. So I'd like to talk about neuroscience and human values and neuro-technology. As an introduction to neuroethics to you today, I always begin by acknowledging my team in Vancouver, those who work with me, those who collaborate, those who advise us, and of course our participants and our funders, and you will meet some of my team members through this neuroethics journey the next 50 minutes or so. So I want to begin with some first principles. And perhaps the most important one in our pragmatic approach to neuroethics is that for the sciences of the central nervous system, so there's the brain and the spinal cord, to be applied well for the benefit of people in society, it's really critical to identify ethics challenges at the earliest stages. Now, I'll show you quite a bit of work that we've been doing in Canada and around the world, where people say, well, in some cases, she's ahead of the pack, and in some cases the horse has already left the barn, and that's okay, because it's better, in a sense, better late than never, and certainly the earlier that we can be in addressing ethics challenges in the neurosciences that we're doing today, the better. The other perhaps first principle, and it's really where I'm going to spend most of my time today, is how important it is to bring the voice of all stakeholders to our neuroethics story. We can do all kinds of different kinds of neuroethics. I'm going to bring two studies today that have really brought the voice of stakeholders forward, those of physicians like yourselves, patients, researchers, neuroscientists, philosophers, and so on. This is not to show off how busy we are at the University of Bratka-Lange, but how busy, and this is just a rubric of some of the studies we have going on under six major categories, and you see them here. The topics that I bold-faced at the top of the slide are those that I'm going to touch on today. I just also want to show you at the bottom of the slide the wide array of methodological approaches that we use in approaching the neuroethics problems that we tackle on a daily basis in Vancouver, Canada. And if the sound tech could see if you could make the feedback go away a little bit, that would be helpful. I'm having a little bit of a cognitive challenge with my own voice. Thank you. So this is a bit of a Duinian chart. I'm not a philosopher. I'm a neuroscientist by training. I grew up doing imaging, but I love this simple pathway, and it really defines what it is we seek to do. We seek to identify ethical issues around neuroscience discovery. Maybe before they occur, maybe as they're going on, and maybe in response, but we try to be proactive rather than reactive. We take a very empirical approach to what we do, which is that we collect data, we reduce it, we interpret it. We deliberate over the data that we acquire, and then at the end of the day, we try to deliver solid guidance, evidence-based guidelines, guidance that's solution-oriented in a way that achieves best practices and maximizes benefit for all the constituents with whom we work. And to this end, and I love this quote from Anne Glover, came out a couple of years ago in science, ultimately what we're doing is injecting science into policymaking. So we're really taking an internally-driven approach to policy and health policy in particular, rather than an external approach to neuroscience where sometimes we have to do a lot of iterative adjustment because when it comes from the outside in, it's not always as well-matched as it is when we actually can push the understanding in an evidence-based way out to our policymakers. And so I'm going to take this introduction, and I'm going to ground it for you in three-case examples that I'd like to share with you today of research from our group. And I also like to ground the research in the human values that I would most closely associate with these studies. So the first one will be stem cell trials and spinal cord injury. And I want to talk a little bit about autonomy with you as we think about that science. Then I'd like to talk with you about neuroimaging and disorders of consciousness and the impact on self. And finally, a little bit about neurogenetics and dementia. And again, these capture our goal today. Neuroscience discovery, human values, and neuro-technology. And I've chosen them from among the others. I could have chosen my big chart that I showed you because I think that they really do highlight some of the issues at the intersection of neuro-science technology, neuro-technology, and values. Timeliness and relevance, I think, to an audience like yours and to this amazing McLean Center for Medical Ethics. And as well, they have each had a significant impact where we've been able to take our results and push them out into the real world. And they also will have, and I'll show you very specific future trajectories that we've linked onto the original studies. So just as a last way of introduction, this is our analytic approach. You mostly discourse data. So these are data from interviews and focus groups, for example. And I just want to emphasize that our approach to this kind of social science data is very rigorous. It's every bit as rigorous as when I used to do imaging experiments or run rats on a mage or make single unit recordings from cells that went boop or boop. It's just a different kind of science. And so you just see here, it's an analytic approach. It's taken from Stousson-Cobain where we collect data and we start to reduce it into meaningful units until we can put it together both from individuals and across individuals and groups and we can provide rigorous explanatory accounts of the data that we acquire. It's an iterative process throughout the analysis, unlike some of us who do other kinds of hypothesis-driven research where you start and you don't start looking at your results until all the data have been collected. This kind of approach applies both to discourse data that is narrative data as well as to other kinds of content analysis that I'll show you a little bit of. For example, analyses of peer-reviewed literature, media reports and other kinds of content analyses. So let's begin with our story about stem cell trials. And stem cells in particular are a huge focus for us in Canada and of course all around the world. Here are some basic statistics on spinal cord injury. We know that in the United States alone there's new 20,000, 12,000 new cases of paraplegia and quadrupedia alone. 80% of the SCI patients are males. They're usually less than 30 years old and they're almost, they're not almost almost, but they're largely from traumas, car accidents, sports injuries and so forth. And as you well know, the tensions between the science and society and divide are enormous in this space. We've been seeing and hearing about the promise of stem cells since the 1960s for a wide array of applications. We've seen trials like the Geron trial that was started and halted, but we are still very much at the bench as well as in clinical trials. And we're very interested in hearing and filling a gap of what are the stakeholders actually thinking about stem cells in the science society divide at the bench and for clinical trials. And here are just two members of my team, Dr. Kwan and Marlene Eicholt, who've been working with me on this topic. So I'm going to share with you very superficially on a surface three phases of work in this area rather than going deep, which I think the other speakers in this series are going to do. But it's nice for me to give you an overview across a sampler of neuroethics. So in 2008, one of the first things we did was we went to basic scientists and we said, if you were to think about the ethics of stem cells, have you been thinking about it? And what would you think? What would you prioritize for us? And in a small group of 11 neuroscientists, mostly on the West Coast, we found these priorities, everything from ensuring that vulnerable people, particularly those such as traumatic spinal cord injuries, give proper informed consent, we have to foster public trust in all that we do. I was delighted to hear that they prioritized that we develop experts that are versed not only in the science or not only in the ethics, but that scientists scholars who are versed across both and that we develop rigorous criteria for moving preclinical data and preclinical trials into clinical studies. Very important groundwork, very important insight for us. And we took this guidance and we moved it to the next level now at UBC. And I want to ask this audience, what do you imagine to be the ideal time point for a clinical trial intervention for somebody like, for somebody with a spinal cord injury? Give me a time, I'm going to give you a time window. You think from an ethical point of view, is an intervention maximum at zero to three days? Those of you who think yes, please raise your hands. Seven days post-injury, six weeks to three months post-injury. You're either very shy in Chicago or you're going to give me some data I'm not expecting. 12 months out and even further out, really late out. So you're not responding. Those of you in the back of the room, maybe you're eating some lunch. Thank you. Minus two days. We have to talk about that afterwards. I'm not sure how you do that. Well, so we run a very large study of more than 200 neuroscientists and clinical scientists. We asked the question and the responses we got from them is that the ideal time window would in fact be six weeks to three months out post-injury. Important data, but when in fact you look to see when the clinical trials are being conducted post-trauma, you find out that they're actually being conducted within a seven to 14-day time window. So ethically it odds with what our own experts are saying. So then we turned people with spinal cord injuries themselves and we conducted a large study both with patients who were quite a long time post-injury shown on the left side of the slide and those who were just subacute a few days out. And we asked them questions about their spinal cord injury, their understanding of stem cells and also their receptivity to enrolling in clinical trials. And we found some both unsurprising and surprising data. Unsurprising was that the patients who were chronic post-injury, oh that is not good, there we go, were somewhat well versed in the signs of stem cells compared to those who were just recently post-injury. But what I want to draw your attention to here is the lower two quadrant of this table and it has to do with risk tolerance and change tolerance. And we hypothesized that the individuals with cervical injuries, chronic cervical injuries would be the most prone to a stem cell intervention. We thought they had the most serious injury, therefore they would be the least risk averse. And I want to tell you that we were dead wrong. Maybe I'll tell you we were dead wrong. So my computer has frozen. That is a bad thing. Let's carry on. So what we found was in fact quite the opposite of what we hypothesized. That individuals with chronic cervical injury were the most risk averse to stem cell trials. Completely the opposite of what we predicted. We predicted they would be the most tolerant to risk. And in fact we found it was those with thoracic injuries in the chronic stage. And here are just some quotes to illustrate, some selected quotes to illustrate these viewpoints. And what we learned in fact from these patients at the end of the day is that those with the most severe injuries thought they had the most to lose and therefore they were the most risk averse. And of course we always recognized those in the middle who were a bit on the fence. Very interesting data. So what we learned in fact from them as we probe further into this rigorous analysis of tens of thousands of data points and hours and hours, tens of hours of data is that the spinal cord injury individuals were quite well aware that clinical trials were taking place in this very early time point. When they're still in the hospital bed they have no idea what their quality of life is going to look like. And what they told us in fact is that an ideal time point like many of you in the audience would be post one year injury after they had a period of adjustment to understand where they are, what their quality of life is. But we know that neurophysiologically waiting that long is not ideal. And what we learned when we take all of our data together is that there really may be a sweet spot at the four to six, four to eight week window post injury. And we've shared that, if I tell you how we've shared that, we also learned in a parallel series of studies that individual spinal cord injury are really suffering from lack of adequate decision support. And we learned from them that there are three obstacles. A lot has to do with the personal dimensions of risk, personal dimensions of human values, limited insight to their own recovery. But very interesting, I'm going to say the budding of the heads of family members in individual support networks and the physicians who treat them. And when we talked with each of these constituent groups, we learned that the doctors would say, well it's up to the families to support these individuals with spinal cord injury. And the families would say, but it's the doctors who know the science. And what we have to do is bring these networks together in a way that actually helps the decision support for these individuals. And when we take all of this together, of this first example in our neuroethics journey, we've accomplished the following things and delivered the following recommendations, which is first to shift the target time points in preclinical trials. And Wolf-Tetzlaff at UBC and Brian Kwan are doing just that. They're now doing some trials with skin-derived stem cells and actually showing efficacy in animal models at four to eight weeks out post-injury when they've previously only been looking at the same week out time window. We're very optimistic that these data will hold, that we may be able to start pushing out trial windows for human subjects to those later time points in response to what they've told us through neuroethics research. We also have developed new partnerships, models of consent and educational resources, both through the stem cell network, which is a Canadian resource for stem cell research, the new Canadian Stem Cell Foundation, and I'm sure many of you are familiar with the International Society of ISSCR. And here just is one model of consent which actually needs to be funded now so we can test it because we'd like to see whether pure consent support as well as staged consent support might be more effective than the kind of consenting that we're doing for these individuals at that time. So if we can bring together better support networks, better consent, and better intervention time points, we may be able to propel stem cell science in the context of spinal cord injury at least forward in a very, very positive way. So where has this taken us? I told you that for each of our studies, I'd show you some future directions. We are taking our stem cell research further as we look for some more funding to think about the further issues in spinal cord injury. We've also started to look at stakeholder opinions around stem cells for neurodevelopmental disorders. We don't believe they are effective yet, but we do know that they are widely publicized in the press, both for autism and cerebral palsy. We know of many cases, both in the United States and Canada, of families taking their children abroad for stem cell interventions that are billed as therapeutic. We've also started to look at clinical trials for neurodegenerative diseases. So if we think of spinal cord injury as a disorder of the central nervous system that has a trajectory and then an asymptotes, we're very interested in understanding what happens in individuals with multiple sclerosis Parkinson's, for example, whose trajectory is actually that on a decline. And where are the answers to some of these questions going to lie in terms of values, interventions, and so forth. And just to show you some data, these are clinical trials of amyotrophic lateral sclerosis, MS, badminton's disease. If you look at the data, these are just articles that have covered them in the press. Even though many of these are only in safety trials, there's a huge covers of efficacy, which is sort of inconsistent with the fact that they're really mostly go to clinicaltrials.gov, mostly registered at the early phases. And we're also looking at timeframe projections. If you just look at how news press is covering timeframes for stem cells for neurodegenerative diseases, you see here most prominently in black, where black is imminent. We're going to see an imminent cure for Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis. But in fact, if you look here on this side of the implementation side of the histogram, these black bars are all but absent. And we know that the actual implementation is soon at best and in the distant still at worst. So some real contrast there in terms of what the public is seeing in terms of seeing and reading about stem cell trials for a variety of diseases, whether they're asymptotic or neurodegenerative and what is actually going on in our laboratories at the bench in clinical trials. So let me go on to my second example for you. And this is one that Nico Schiff will be speaking in a few weeks here. We'll talk with you about. He'll tell you a lot about neuroimaging and disorders of consciousness. I'm going to tell you about how I think we need to think about the ethics of it and implementing it into potentially actionable intervention in hospitals like this one and what it means for the self. So just some basic background like we did for spinal cord injury. Traumatic brain injuries are a major cause of death and disability worldwide with millions of people with permanent disability today in the United States and in Canada. Today, clinical diagnosis is largely relies on behavioral assessment reports tell us that they're incorrect in accurate as much as 40% of the time in terms of where somebody is on the spectrum of consciousness from permanently vegetative state through locked-in syndrome or minimally conscious state. And we have wonderful imaging technology to give us structural images of traumatic brain injuries, of course, functional images both using MRIs and using EEGs. And we have some classic studies that I'm sure you're familiar with by Stephen Lorries in Belgium and Nico Schiff. Again, he'll be hearing about it from Adrian Owen who's now in Canada about how potentially certain individuals with severe brain injuries who are minimally conscious state may be able to modulate their brain to offer responses to external stimuli. So without belaboring this too much, just to show you here on the right, this is a study by Adrian Owen, some stimuli of asking people who are behaviorally unresponsive of a very small sample to imagine playing tennis and imagine navigating for a person's home. And these activations here in central sulcus, some out of supplementary motor area and so forth, proto-cortex, are interpreted to be very similar as those of controls. And if you accept these data at face value, you would say these individuals' average data are responding, although they are behaviorally unresponsive, just like healthy controls. So I don't know if those are signals of consciousness, and I very deliberately put a question mark there. But what I can tell you is that for people who are interested in brain and ethics, this is a good place for me to be, a good landscape for me to be playing in, because there are lots of questions. So what if we can have a signal of consciousness from somebody who is unresponsive? What's that person's quality of life going to be like? What's Dr. Siegler going to say, or Dr. Samasi is going to say to a family who you put into a scanner once, you have lots of scanners in the United States, maybe you could put them into scanners more often than I could in Canada where our wait times are six weeks. Cool, but so what? There's a big so what question here. So we sought to map the landscape of the literature, develop a conceptual framework for probing questions of actionability and establish some evidence for translational priorities, at least in our national health care system. And again, I invite you to meet some of the members of my team here on the right. So the first thing we did is we did some bibliophilic informatics studies and we created this map from the literature of everybody who's playing in the MCS-PVS space. And so it's very beautiful. I'm not sure you can see the details here, but I'll tell you what's important was that the ethics inquiry as much as us in the audience here may be well familiar with ethics discourse in the brain injury space. It's tiny compared to what the big guns are publishing about their results of imaging for traumatic brain injury. So we have a lot of work to do to make this little bubble of us talking about brain injury as big as the bubbles of people talking about the physiologic and imaging interventions itself. And it's also, I've got to tell you, a small group of people who are always citing each other, although there's quite a bit of that going on in our biothic space as well. The next thing we did is we took this literature and if my computer doesn't freeze, I'll be able to show you a framework that we created from the literature about priorities for actionability. And we had two notes, two major notes. Yes, it will be actionable and know it won't be and we probed experts in the field. Good, thank you. Whoever said that, thank you. We mapped the field. I know this will be hard to read, but I'll give you some basic notes for you and refer you to the article that we published in the Canadian Journal of Neurological Sciences. We went to experts and we said, really, is this really actionable? If we get this right and we solve the ethical issues, will we be able to bring this into clinical care? And we had no. And we queried about whether we should carry on if the answer is no or yes. And I have to tell you for all the experts we probed and there was more than 20, the answer was uniformly yes. But then the question was yes, but we haven't answered the so what question. So we divided our framework into seven notes that affect people, individuals and their communities, their families and institutions and we probed for all of these notes. And through extensive interviews and focus groups with experts in ethics, neurology, neurosurgeons and others, we have these priorities. I'm going to show you three slides on priorities from the experts. The first one has to do with research. What do we need to do in our research laboratories to bring this technology to be clinically actionable? There are five priorities here. Correlate Neurology with Behavior. We don't have that yet. We know what we think are the associations, but we don't have real correlative data. We don't really know the incidents and prevalence of newly conscious states and vegetative states. Somehow we have to figure out what the probability is of not detecting covert consciousness in these patients, whether they're 15 or 20% of the tire cohort who may be a target for our audience. We absolutely on an international plane have to harmonize our methods, our paradigms and our selection of stimuli and harmonize our language. We are using internationally different words for the same conditions and the same words for different conditions. That's not going to advance us in our science. And we have to consider some quality of life metrics, although I think that's going to be a difficult challenge. On translational priorities, you see these here. We feel of utmost importance to specialized communication tools for every stakeholder involved in this landscape that are practices and standards of care. What you do in Chicago should be the same as what I do in Vancouver with these patients, as well as harmonize technology, again, focused on covert consciousness. And on priorities for the self, if this technology is going to be clinically actionable, we are now going to have individuals who are going to be expressing their selfhood in however a rudimentary way, brain activation patterns to some either diverse or harmonized kind of stimuli. What is that going to tell us about them, about who they are, about the decisions that they might be expressing to us, end-of-life decisions, decisions about quality life in their hospital rooms, about competence. We have to solve these issues and it is a wide open space right now. And at the same time, I think we have to today, not tomorrow, start thinking about laws around this space. Will somebody be able to change their advance directive through activating their brain patterns in response to Peggy Mason's stimuli in a brain scanner? Are they going to be able to say, I'm done, I really, I want to go. California just passed a physician-assisted suicide law yesterday. We do that in Canada as well. Is a brain activation signal a signal of competence? How are we going to deal with this in the legal system? And in our personal systems, and I think the implications here for self are tremendous. So our deliverables from this work, and it is still ongoing, is again, we've developed very close partnerships with advocacy in the brain injury space, as well as the disability space, who become very interested in the potential of bringing out the self through this kind of neuro-technology. We're working with Health Canada to provide evidence-based resources for the kinds of policies that Health Canada needs to be thinking about. And as well, we are very interested in doing some continued research with family members themselves and potentially with recovered patients as well. So where has this research taken us? We continue there, and we've gone down some new trajectories, and we've moved some of our work from traumatic, from severe brain injuries to mild brain injuries. And this is, I'm going to say, a dirty little study that's just ongoing now. We just looked at policies around concussion, a very crowded space, both in the ethics side and in sort of the sports medicine side. And we asked the question in four countries, Canada, U.S., U.K., and Australia, just in four major sports, what does policy guidance look like out there? Here's a very pretty map of the... So you dominate the number of policies that are out there just so that you know, and Australia and Canada follow that sort of usual fare. But I immediately think about some ethics questions there. If I'm a mom and I have an elite 17-year-old who wants to play football or soccer, and we're seeing some repeated concussions and head injuries, and what do I do? I go to the internet. You know, what's the policy du jour? What is the NFL saying or your National Hockey League? Well, I'll tell you, you're going to find a really messy landscape. So we've started to actually look at this, apply the neuroethics lens to the concussion policies that are out there just in a tiny little poster stamp. And we're looking at how policies are coordinated. What is the evidence that goes into the policies? How are policies implemented and how are they adhered? How are there sunset clauses? Because the science is moving incredibly fast. And of course, a topic that's of great interest to me is the management of incidental findings. You have a kid and an adult who is seen for a concussion or even repeated concussion. And we see in that individual an unexpected brain finding. And if we report that out, that might well be the end of that individual's elite career in that sport. And so there are some issues around that, not only in clinical medicine but in research, of course. And here's the team that's been working with me on this project. And so I'm just going to show you, and this again is a question, clarity or confusion, on the left-hand side of this slide, you see the number of new policies that have come online for concussion for four sports in four countries. That looks like a lot of policies coming online all at once. And if you look on the right, that's the number of existing policies today. If you go on the internet and you do some simple surges, concussion, mild head injury, sport. And in the dash line, we see those that are self-described as recommended. We recommend that you get three days of rest. And those that are mandatory. And for the same sports, for the same regions, we actually have colliding policies existing at the same time. So we think that from an ethics point of view, a neuroethics point of view, we have a gem that really requires some serious attention. It's affecting our adult population. It's affecting our youth. We know that repeated concussions, even the slightest concussions, can lead to chronic traumatic encephalopathy, where the tau protein actually embeds itself in the sulci of the cortex, and leads to what seem to be early onset forms of dementia. So this question's about return to play. Who makes decisions? Who's self-propelled to go back on the field? Who's coerced? And maybe we should be thinking about safe sport in addition to revised policies and our harmonizational policies is an important place for people interested in neuroethics to consider contributing to. I'm going to go to my third example for you now. And it is a departure from the one that we have been focusing on and it has to do with neurogenetics and dementia, predicting Alzheimer's disease in our population. Our now healthy population, our now not so healthy population, but our population that's aging. And what is the impact on community as this neuro technology comes online? So what are our basic principles? We always start with those. The population is aging, we know that. We know that Alzheimer's and vascular dementia are the most prominent diseases of the aging central nervous system. There's a tremendous cost and burden on the individual and on the community. And we know that we may be able to predict, but we cannot cure. So what are the challenges of prediction? Well, one of the challenges I think has to do with the individual is that the dementia is really very so much. They vary with the biology. Where does the biology start? What's the course of the degenerative trajectory? What's our sensitivity and specificity in predicting disease? When is it going to start? Can we predict when it's going to start? Can we predict how fast somebody's going to decline? Some cases yes, some cases no. What are the implications for third parties? How are we going to manage our resources as our population ages? And fundamentally whom to test and when. So with my colleagues, Lynn Beatty, Howard Feldman, and Kevin Peters, we started to develop some models for looking at disease prediction trials and prevention trials for Alzheimer's disease. Just in the healthy, I'm going to say, European-based population. And what you see here, the lights are a little bit bright, is basically in the top left of this slide is a predictive model for people who are essentially don't have the carrier for Alzheimer's disease. And so the risk of prediction in them is quite high in terms of what benefit we can offer. And at the bottom of this slide are those who have a high genetic risk, and I'm about to share a story of a population that we've been working with you that have a high genetic risk of Alzheimer's disease. Where the risk for dementia is very high, but so is the benefit-to-risk ratio. Whereas for when there's no identifiable genetic risk, the risk for prediction is high and the benefit low. Here it is quite the opposite. So I want to talk to you about culture and where culture and neuroethics come together. And it comes together particularly when you have a world view of researchers, like myself and Dr. Beatty here, differs from the world view of the research community. And my story here is that when I came to UBC from Stanford in 2007, UBC researchers had just identified this NLN1 gene in a family very, very far north in British Columbia, about 2,000 kilometers north. It's actually very cold and very hard to get to. It's a charter plane to get there. And they were perplexed that the people from this nation were not flocking to UBC for genetic testing. And they thought that perhaps by bringing the neuroethics lens to the question, we'd be able to bring some understanding of why there was this mismatch between neuro technology and people living in the cold north of Canada. And my hypothesis was that probably nobody had bothered to bring meaning to this genetic testing to this population. And even if we were to bring meaning to bring the resources that would make that meaning meaningful. So let's just look at this population. There's about 100 effective family members right now. I was just up north in August and we're starting to see some evidence of newly affected members. So this is us guys down here. Most of us, anyway, we're not of this family in the north. We're seeing late onset sporadic Alzheimer's disease. But this is this family up north. They have the Prismillin 1 gene. Their onset for Alzheimer's disease is as early as 50s. There was actually a recent report of somebody with EOFAD in their 30s here in the United States. And there are different Prismillin genes. There's a PS1, 2 that's also been identified. But the bottom line is if you have the gene, you're going to get early onset Alzheimer's disease. If you have a parent who has it, your chance of getting it is 50%. It's a bad disease. So is this genetic testing and bringing it up north where people are still living on reserves, where suicide is a tremendous problem, alcoholism is a tremendous problem, is it an opportunity for this population or is it an intrusion? And how do we address those issues? So we have been traveling up north for six years in what we call the community-based participatory research. We used indigenous methods, and I think I'm the only one in neuroethics who has used indigenous methods to do neuroethics research, including sharing circles, which look a lot like focus groups, but there are some rules, but if you wanted to know what they are, focus groups and individual interviews. To ask the question, what do you understand about Alzheimer's disease, early onset Alzheimer's disease? Have you been talking about it? Do you know what genetics are? Has anybody talked to you about genetics? What do you want to know if you are going to get the disease? Do you want your children to know? And all of this also happens against the backdrop of colonization and residential schools and families, and so there's been tremendous fracturing of knowledge, of intergenerational knowledge in this community. So what did they tell us? In one long phase of work, by the time you want to go up north, you have to charter an airplane, and it can't be when it's winter and it can't be when the moose are running. Some interesting challenges. Oh, we learned about the impact on the community. And what we learned is that there's still some deeply held beliefs about Alzheimer's disease, even though the families have started to understand the biomedical explanation of this disease. But they are not letting go of their traditional explanations, and we learned that to really provide the best medical care, healthcare for these individuals, we have to respect both views on this disease and how those two views interplay in the community and with each other. And this we call two-eye-seeing, and it comes from indigenous ways of knowing and believing. We've learned that knowledge sharing is vital. Because of the bleak history in Canadian, in Canada, with our indigenous people, there was a huge amount of fracturing of knowledge that passed from elders to children because they were taken away from schools. So there was a lot of mystery around the crazy uncle, and who didn't recognize her children anymore. And kids came back into the communities, and now there's been a reconciliation. And there's been a whole flurry of both inter- and intra-generational knowledge sharing that has just begun. And we are trying to come in with this new knowledge around Alzheimer's disease and neuro-technology to bring that knowledge sharing to be more robust and open. We learned fundamentally that testing will remain irrelevant unless meaningfulness is demonstrated. So it may not be cure, but it has to be something more than you have the disease, your anti-headet, your mom had it. You seem to be manifesting some of the symptoms. We were up there, we did a focus group, and a 40-year-old gentleman said to me, the world seems to get smaller every day. And he was there with his two preteen children in a focus group with us. And we thought he'd come to the clinic. He still hasn't come to the clinic. And I think it's because he lives on the reserve, and he may find out he has the gene, but what he's going to do with that information is unclear, and we're trying to provide that forward. And then we also deal with the complexities of community and individual ownership, both of primary data. So what do these genetic data mean, and to whom do they belong? Do they belong to the individuals or families? Do they belong to the community? Do they belong to the nation and the tribe and so forth? And this is really a naughty problem that must be untangled. And it also brings up again the issue of incidental findings. Who owns those data? And I'll just share with you, for those of you interested in research ethics in this audience, for the first four and a half to five years of our project with this community, we had a research agreement that did not allow us to name them in any of the work that we did. And in fact, you see this, I still haven't named them today, because that's been so ingrained in me. And on the one hand, they wanted to be champions of Alzheimer's disease, and on the other hand, they were so afraid of the shame and stigma surrounding this gene and this family that we had to maintain strict confidentiality. So we were really torn as neuroethesis because we wanted to bring this community to others with Alzheimer's disease, to their own community, to Health Canada to bring skilled nursing and better resources to the community, but we couldn't name the community. So we could say up there in British Columbia. Anyway, just six months ago, we changed the research agreement to now have openness about the nation, the Taltan people. And we are able now to go to our government with these data with our Taltan team and bring the data to them that we hope will bring resources, better skilled care, better nursing to the community. And in a departure from our normal academic deliverables, like a paper in progress in neurobiology, we are delivering resources that are meaningful to the community. On the left side, you see a cartoon book that we've published with one of our Taltan collaborators called The Mind Thief, an Alzheimer's familiar Alzheimer's disease that depicts the children. It's a children's book that depicts the children as Taltan children themselves. Where so many of our resources from the Alzheimer's Society don't look like the Taltan people and don't really just don't cut it for them. We've created these resources for them and by them. And this was actually at their behest. It's a book for them. I'm happy to send you a copy if you want it. You can also download it from our website. We want to distribute it widely. And it really is meaningful not only for this community but for other communities, Indigenous communities and those living in rural remote areas broadly in the United States and Canada. And on the right here is a resource book for adults actually that we delivered that we brought up north. We were going door to door delivering these books to the community in cabins and the wilderness. It was really an extraordinary experience. And then always gathering more collaboration, more voices as we distribute we'd want to learn more. And as another deliverable, again a departure from the usual academic deliverables, we also have created a little movie. It's six minutes long. Here's the link if you want to view it. And for the fellows who I'm meeting with afterwards and want to look at it together, I'd be happy to bring it up. It's six minutes about early onset Alzheimer's disease about doing neuroethics work in rural and remote communities and how incredibly meaningful that can be for all stakeholders engaged in the story. So I just want to, before I conclude I want to tell you that this project also has led us to new and unexpected directions just like the stem cell work did just like the disorders of consciousness work did. We learned as part of the traditional explanations of Alzheimer's disease that the belief that the changing landscape is actually affecting brain and mental health of the communities that live in close proximity to the oil sands, for example to the pipelines, for example. Here's a beautiful quote. I'm part of any environment and if my environment suffers I suffer as well. So we started to go down this path and we said what's going on in the area of brain and mental health as it applies to new kinds of resourcing from the environment and in a way that I like to create new things I've called this environmental neuroethics and we have actually been starting to look at the effects of technological change the benefits of it, industry, economic expansion, even population growth and health and the actual questions about how is all this changing brain and mental health, particularly people who live close to oil sands and pipelines, here's the team on the right. And so we've embarked on a little study, it's just hot off the press on fracking. Fracking affects us in British Columbia, it affects Canadians in Alberta, it's going to affect you because we're going to be sending you oil from up north down here I think to Texas and hopefully the pipeline goes through. So what's in the literature about brain and mental health and fracking, just as one example and we found that there's about a hundred papers that deal with fracking if you do a rigorous search through all ways I'm not going to explain to you now but you will trust me to know that our methods are rigorous found about a hundred papers most of them talk about asthma, respiratory disease skin diseases almost none talk about brain and mental health and if you think about it we know that there are neurotoxins in the environment that change brain and mental health. And we know that the chemicals that are going into fracking some which remain a proprietary but some that are open are neurotoxic. So how is it possible that no one's talking about brain and mental health in this unconventional gas development literature and so this is just one of the many graphs we have of our data where brain and mental health is sort of loosely mentioned in a journal article, you see the graph on the left and you see the example of it on the right and then almost none of them around 20 of them make some brief mention around brain and mental health and actually there are only two papers, one of which is my own that substantially brings the ethics discussion about brain and mental health into this changing environment space and again for those of you interested in neuroethics this is another place where we can all make a huge contribution forward. Here are just some other ethics concerns that we found in the literature as you see the fracking literature as you might expect basically says that fracking and other kinds of unconventional gas development are safe and have no harmful effects on the environment or on people that's the majority here and a little bit of ethics concerns we found mostly had to do with trust vulnerable populations, justice and disempowerment that's really a mental health issue and a little bit around the precautionary principle maybe we should be thinking about the implications of what we're doing to the environment as it affects individuals and society so this is a paper that we were very lucky to be able to publish in the Journal of Lombayan Sciences and as part of a recommendation that we made to the presidential commission for the study of bioethical issues and we were very grateful Dr. Samantha that the commission accepted it and really enabled us to go forward so I'd like to summarize for you now we've talked about neuroethics in the context of neuroscience discovery, neuro technology and human values I've highlighted three principles there are only three there are many many more autonomy, self and community and I've done my best to give you some examples in neuroethics where we started with what's going on now where ought we be going, where ought we go and what lies ahead and I hope that I've showed you some concrete examples of the kind of impact that we can make in a domain where sometimes people think we don't really have an impact but in our very pragmatic solution oriented way we really are making positive change these are just some of the historical milestones in neuroscience and ethics starting all the way back here to Walter Freeman's prefrontal lobotomies, some of the changes we know that occurred after the Nuremberg trials where neurologists and psychiatrists were really the most egregious in perpetrating crimes against humanity all the way through to 2010 we've come a long way a long way in ethics and neuroscience and today we have the international neuroethics society we have the presidential commission on the study of bioethical issues that's devoted so much of its tension to ethical issues in neuroscience and neuroethics we're very grateful for that and we have a long way to go and so this is my summary slide where do we go from here and continue deeply to integrate human values into all aspects of neuro-technological advancement and neuroscience discovery drawing on my theme of how important voices are put to the voices of all stakeholders in there and I would say as one of the pioneers of the field leave no stone unturned as new opportunities arise for us in our scholarship and our science thank you very much things I am confused by is to put it bluntly why we should care what the opinion is of when to put in a therapy why does it matter when the person thinks if there is a that does not make a physiological truth that may make a legal fact but it does not make a physiological truth simply what's the correct scientific timing end of story so I love that question and I thank you for it I would argue that we've been doing science without the human for a very very long time and now we're at a place where we have neuro technologies and clinical trials that aren't being well populated that aren't being taken up is why aren't they being taken up so one example I gave you was from genetic testing in a population for whom it was virtually meaningless and the spinal cord population and stem cells put a lot of science into it there's not a lot of uptake yet there isn't a lot of clinical trials yet but if we take the values and we put it together with the science don't we create a more perfect storm one or the other so if we can actually and and won't we actually have better outcomes so if we have a patient with a spinal cord injury totally traumatized with an early intervention they have no idea what their life is going to look like they're confused they have trauma they probably still have some edema everybody's running around and we enroll them in a clinical trial how well would their personal position lend to their recovery or the effectiveness of that trial and I think what we're arguing is that if we could just take that window out a little bit without jeopardizing the science let the acute period pass let everybody settle down we think the intervention might actually benefit from I'm going to say the better participation whether it's voluntary or involuntary from the individual you can argue well let's test it and I'm going to say I'm on board with you let's test it but that's the evidence and then we work with individuals and they say you know it's true when I was on the trauma Dr. Sieger could have asked me to participate in anything and I would have said yes but I really had no idea what I was consenting to nor did my love person my parent and if we could just move that out I would have actually made a better decision for myself and my family and if you put all those things together if the science works outside that window that's my caveat we have to show that science works outside that tiny little window I think we can have more powerful outcomes that's the goal but if we show that the science is most effective in the first 24 to 48 hours then it would modify your position so now people have asked that question so this is giving antibiotics when somebody is acutely septic of course but we don't have stem cells that have that kind of efficacy right now but a clinical stem cell tries a little bit different the problem here is that you're mixing clinical therapy with clinical trials we're talking about experimental medicine in order to do we're not promising these people any sort of benefit we're asking them to be guinea pigs and so of course you need to talk to them about when they would like to become guinea pigs we're not talking about therapeutic any sort of efficacy for them how do you deal with the larger issues like for example the Alzheimer's Foundation whose basic goal is to diagnose everybody in the country with Alzheimer's disease how do you deal with that kind of group when you're trying to do sort of ethical, neuroethical research hmm so I have to unpack how do you deal with what you're what you're after so we we deal with Alzheimer's Association in a number of ways we go to them for funding that's big we try to distribute or disseminate materials that they provide that we think are helpful to the extent that we're with patients who might benefit from them so there's no filtering there and we try to bring our resources to the Alzheimer's Foundation and Alzheimer's Society so these books that we've published for example on early onset Alzheimer's disease we will be giving to the Alzheimer's Foundation for downloading, distributing we're putting them in the clinics across Canada for us those are solutions if Alzheimer's Society is willing to distribute material that we've produced we are grateful for that I'm just thinking there are a couple of kids books out there that the Alzheimer's Society has produced they're quite different from what we produce though they're very basic they don't have an emotional component and they don't have a holistic component because these European people don't really think that way and we're hoping that the kind of work that we're doing with Alzheimer's disease will shift everybody's thinking about the envelope of understanding to be a little bit that much bigger some people might say what do I care about indigenous people in Chicago, indigenous people who live in Canada but you know what I learned a lot from working with them about my values around aging, disease, quality of life brain health so I think we can all benefit I really enjoyed your talk I'm a pediatric ICU doctor so I'm seeing at least the spinal cord injuries I get the four to six weeks but I also get that there are families and there are teenagers that are begging for something in the ICU and so I wonder if moving and I personally from what I've read in the literature I think earlier makes more sense clinically to me but the other thing I'm seeing is five high spinal cord injuries for gunshot wounds for gunshot wounds and fundamentally they have a very different socio-economic background than the person that falls off a horse and and that's the other piece they're not getting the same recovery it's just we've also got the data here that cochlear implants it depends on how many words your parents are talking to you every day they're not getting the same outcomes and so when we're doing the research how are we going to adjust with these very different groups of people so it's a wonderful question thank you so I think we come back to the distinctions between therapy and clinical trials that's number one and we have to respect those distinctions if we could show that in two days you can inject some stem cells straight into the spinal cord and either prevent the progression of the disease even there of course but we're talking about experimental trials now on the one hand we sometimes say that it's people who are of the lowest socioeconomic status who are the guinea pigs for the most experimental trials but actually I've had somebody Scott Atlas actually who was the chief of neuradiology at Stanford argue with me that it's actually the wealthiest who are the guinea pigs because they're knocking on the door the first time something comes out so I think sorry it might be bimodal right so just what I was going to say it might be bimodal you know for me it's all about the science and I include ethics as under that science envelope if the evidence suggests through our clinical trials that through rigorous clinical trials right approved all the way through that outcome is better if you wait we might have to do that but we're a long way from doing that but I think what's what at least from an experimental point of view I was very gratified to work with scientists who are willing to say this ethics result is really important you know we're all hypothesizing acute and subacute time points and knocking off these rats two days after we injure them nobody thought to maybe just wait a little bit and see if we can have as good efficacy from the scientific point of view as from the human value the human values point of view the proof is in the pudding but there's a dimensionality there that I think is important to consider