Transcript

SUSAN AMARA: Thanks, Dan. And I also want to thank the panelists and previous speakers for providing such a compelling and exciting vision of the future. I think it’s given me a lot of optimism for the future. So, thank you all. I’m Susan Amara. And I’m the scientific director at NIMH.

And it’s really my honor and pleasure to introduce Dr. Kafui Dzirasa. Dr. Dzirasa is the A. Eugene and Marie Washington Presidential Distinguished Professor in the Departments of Psychiatry and Behavioral Sciences, Neurobiology, Biomedical Engineering, and Neurosurgery at Duke University. I had to have notes to remember [laughs] all that.

He received his M.D. and Ph.D. in neurobiology from Duke in 2009. And completed his residency in general psychiatry in 2016. Dr. Dzirasa really has been at the forefront in the development of state-of-the-art approaches aimed at revealing the circuits and brain states that underlie neurological and mental disorders.

Through elegant studies using in vivo electrophysiological recordings in animal models and together with machine learning approaches. His work has really explored the changes in the large-scale patterns of brain activity — brain network activity that can be linked to the presence or absence of depressive states.

His overarching goal is to combine his research, medical training, and community experience to improve outcomes for diverse communities suffering from neuropsychiatric disorders.

Among his many awards — and I really mean many — and honors, he’s received the Presidential Early Career Award for Scientists and Engineers. He’s also received the Society for Neuroscience Young Investigator Award.

And in 2021, he was elected to the National Academy of Medicine. Please, give a warm welcome to Dr. Dzirasa.

KAFUI DZIRASA: Well, good afternoon. It’s a tremendous pleasure to be here. In many ways, this is home for me. I grew up not too far down the street, in Silver Spring, Maryland. And spent a ton of weekends at the Air and Space Museum. So, this is like it right here [laughs].

I met the NIMH in 2009. I was in my last year of medical school and I wanted to figure out what translational research was. So, I signed up for an array rotation at the National Institute of Mental Health. And I was in the laboratory of Carlos Zarate.

And while I was there, I got to meet the director. I emailed him and said, “I’d love to talk to you about futures and, you know, where neuroscience is going.” And Tom took me out to lunch. And he played such a remarkable role in shaping much of what you’ll see today.

He convinced me to do psychiatry residency. I see a bunch of other friends here from Maryland. People I’ve met along the way who have really shaped how I think about research. And how to bring a bunch of different disciplines in my experiences to bear on how I think about treating mental illness.

I’ll warn you in advance, this talk is going to wind through a lot of different directions. My goal is to solve a massive problem. And I’m an engineer, which means I grab from all kinds of stuff to solve that problem. I’ll do my best to orient you to the different disciplines and spaces that we’ll move into as we go along.

All right. This is my status slide in here, but I’m working on it [laughs]. All right. So, this slide needs no background here, right? These illnesses impact people. Our whole country is totally familiar with them, particularly, as we’ve gone through the pandemic, the impact they have on individuals’ lives.

If you haven’t experienced these in a deep way, you see them in your kids, your family members, your loved ones. When we look at our young people, they’re suffering tremendously. These sorts of plots on — this is particularly looking at persistent feelings of sadness in our young people. These sorts of plots are alike all throughout the world.

And so, these illnesses are impacting people tremendously. Now, as Brittany talked about during her talk, I think this mental health model of preventing illness is something that’s central to how we should be thinking about things. And [unintelligible] sort of that triangle outlined that way.

I didn’t get an M.P.H. [laughs] in my many years of school. But I love this idea of prevention. And I got obsessed with it as an early career faculty member as well. Can we actually prevent mental illness? And there’s sort of two things that I anchored the idea of preventing mental illness around. The first one is, can we predict who’s going to get sick, right?

So, we need some sort of prediction mechanism. And then we need some sort of intervention, right? So, the talk is going to center on this idea of risk prevention or prediction and intervention.

All right. I hit this concept when I was in residency at Duke, how it was my chair at the time. And I had this observation that folks kept coming into the inpatient hospital. And there was this precipitating factor that showed up whether you had depression or bipolar disorder or schizophrenia, there was like stress, right?

And so, stress seemed to be there at the onset of illness, whether it was you sending your teenage — emerging adults off to college. Or whether you’re having some major family trauma. And again, we all get this as we’ve gone through the pandemic. So, stress was this major participating — precipitating factor.

But not everyone who experienced stress has a major psychiatric illness, right? And so, what I really became interested in were, what were the biological factors that determined who, when they were stressed, would ultimately decompensate or have illness?

You see that the red squares there. And who would ultimately not develop illness? And we’ll call that resilience through the top, right? And so, our idea was basically to track individuals. And those individuals not being humans. I’ll get there in a second.

And see if there was a central biology that mediated vulnerability. So, vulnerability means not being resilient to future stress. And we’re able to do this. We published that work in 2018. But we were able to find a biological signature — in other words, a biomarker associated with vulnerability to future stress.

So, I’m going to show you how we did that now. We’re going to sort of force into neuroscience and then into machine learning. So, we record electrical activity from many sites in the brain at the same time in mice. That’s our model organism that we use.

And you’ve seen brain waves like this. You’ve seen them throughout the day. Antonio showed some slides with brain wave. Nicole showed some slides with brain wave. We’re recording electrical activity from the tips of individual wires inside the animal’s brain.

And then we can do standard engineering analysis. We can ask how much activity is there in that wave of electrical activity. These waves represent populations of neurons firing together. We can look at activity across different frequencies, which — in each of those brain areas.

And then we can take advantage of engineering principles that say, “Things that change together over time tend to lie within the same system.” So, we can quantify how much these brain rhythms in different brain areas change together over time.

And you’ll hear me use the term synchrony or coherence, right? I’m just showing you two brainwaves here. And you can see how the red tends to align the peaks together, right? So, that’s synchrony.

Then we can borrow from our friends. This is used in weather forecasting or in the stock market. It’s essentially statistical forecasting. And what you can do is actually infer how information is moving through the system.

So, if the current activity in one brain area, let’s say hippocampus, aligns with future activity in prefrontal cortex. In this case, you can infer that information is moving from hippocampus to prefrontal cortex. So, that’s directionality. Or you can do the same thing and calculate that information in the other direction and infer that information is moving in the other direction.

So, for each mouse, we’re recording about 10,000 data points per second, right? We’ve got activity in each of the brain areas. We’ve got activity across frequencies [laughs]. And then we’ve got these frequencies interacting with each other, basically creating a really big data problem.

And so, we started acquiring this information, and then we actually didn’t know how to make sense of it. And so, one day, I found myself talking with a colleague. He was the chair of computer science and electrical engineering. And his graduate student at the time, now — who’s now a tenured faculty member at Duke, about this challenge of how you make sense of all this data.

And they were working across multiple disciplines, including like weather forecasting. And they said, “The problem you have in neuroscience sounds a lot like the problems we have in geothermal imaging.” And so, they took their models. They built this model out, which was to make sense of our brain information that we were gathering.

And I’ll explain to you what you see here through an analogy, right? So, when you hear music, right, you’re basically hearing pressure waves traveling through the air, about 10,000 oscillations per second.

So, think of your LFPs as music, right? So, brain music — you’re hearing music. And what we’re going to do is we’re going to take that music and then we’re going to chunk it up into notes, right? And those notes are going to be the oscillatory amplitude measures of power that I showed you, the synchronization or the leading and the lagging.

So, we’ve got all this music. We’re going to break it up to notes. Makes sense? And then we’re going to ask how those notes change together over time. In other words, we’re going to figure out the chords that are playing and the instruments that are playing through a process called, using machine learning, a supervised auto-encoder.

And then we’re going to relate those chords to behavior. So, what the animal’s doing, right? And we’re going to build one final piece onto this model that I think is the most important piece. We’re going to ensure generalization.

And what that means is when we learn a network, we’re going to make sure that that works more than just for the network, the animal that we’ve learned it on, right? And the principle here that you can appreciate when you’re a clinician is if you have any sort of measure, like an EKG, when you go in the emergency room, you want to make sure that it works for the new person that comes in the door. Not just everybody that came in the door before.

So, we’re going to build on this piece that makes sure if you hear that music with a new tempo or a new set of instruments, you still know it’s the same music, right? So, we’re going to ensure that it generalizes.

Okay. So, here’s a paradigm that we’re going to do this in. We’re going to take a bunch of C57 mice. This is an inbred strain of mice. And then we’re going to implant them with electrodes across a series of brain areas that have been implicated in stress behavior.

So, for the neuroscientists here, infralimbic and prelimbic cortex, nucleus accumbens, ventral hippocampus, amygdala, and ventral tegmental area. Everyone else ignored those words [laughs]. And we’re going to record brain activity.

And then we’re going to take these mice and we’re going to put them through a stress paradigm. And the way the stress paradigm works is we put them in the same cage arena with an animal that’s about 50 percent bigger. And these are going to be retired males, which makes them really aggressive.

And then we’re going to pick the 10 percent most aggressive of these aggressive mice, right? So, if anyone has an older sibling, it was just like that growing up. So, this doesn’t go well for the little mouse. It gets beat up.

And then after 24 hours, you put it in a new cage with a new older sibling who also beats it up. So, it gets 10 days of this in a row, getting beat up by different mice. This work was published, led by Rainbo Hultman, who’s now in a faculty at Iowa.

All right. And what’s fascinating about this is if you take these genetically identical animals and you put them through this paradigm, about 40 percent of them look just fine — mostly fine. Sixty percent of them don’t sleep well. They don’t like rewarding substances. They don’t like other mice. So, they have the stress-related behavioral problems, right?

So, now you’ve got the groups that we set up in this sort of prevention algorithm. We’ve got everybody before stress. We stress them out. We know how they respond to stress. And so, we can look at their brain activity before stress.

When we do that, we see something that looks like this. And we call these our electrical functional connect domes. I’ll tell you the take home before I explain these. The take home is the picture on the right is different than the picture on the left, right?

[laughter]

All right. So, the picture on the right is the signature that shows up in the animals’ brains after their stress. And the signature on the left is a signature that is there before stress when all the animals otherwise look exactly the same, right?

So, you’re looking around the rim of the circle, we’ve got our brain areas there. If you see color around the tire, it means that brain area in that frequency contributes to the chord. It’s part of the chord that’s playing. The lines through the center means a brain area synchronizing.

And for the brain areas that are synchronizing, you see the information moving through the brain at the bottom. But again, the take home is, there’s a signature that is different that predicts who’s going to respond well to stress and who’s not. So, we achieved the first part.

So, we’re like, you know, nine minutes into the talk, [laughs] and prediction is done. Which means intervention is going to turn out to be way more complicated than we anticipated. This is the fun of science.

All right. So, we love using simple assays in the lab. The former director is probably cringing right now. He is saying, “This is not depression. This is not depression. I’m going to say it.”

But we love using these simple tests. One, because there’s a ton of literature running and other people have used it. And I’m not arguing that this is depression. I just need you to accept two things so we [laughs] — before we move on.

The first is that this is stressful for the animal, right? I can objectively tell you this is stressful because we’re going to measure the [laughs] animal’s stress hormones and it goes up when we do this to the animal, right? So, we just need you to accept that this is objectively stressful.

The second thing is that this assay is sensitive to how much stress the animal has previously been exposed to. So, if I stress an animal out and then I put it on this test, it behaves differently, right?

So, the test is stressful and the assay is sensitive to prior stress. That’s it. It’s not depression. Not depression. All right [laughs]. So, we’re going to take advantage of these two things by putting the animal on the test two days in a row, right?

And so, it’s in the same context. But the difference between the first day and the second day is it’s been previously stressed, which is the stressor of the first day. And what we’re going to ask is, how do computations in the animal’s brain change as a result of the prior stressor, right?

So, is it computing different between day one and day two? All right. And when you do this again to a group of animals — I’m showing you a bunch of animals here. I’m showing you their behavior on the first day and the second day.

As a population, the animals show greater immobility on the second day. That’s what I mean when I say sensitive to this — the prior stress. But it’s not all the animals. There’s some variability across the population of animals.

Okay. So, we’ve got our animals implanted. We’re recording from a series of brain areas. And what we want to know is, do any of the computations in any of the brain areas change? It’s sort of a brain screen of what’s changing as a result of prior stress exposure that computes how you deal with stress.

So, recording all these brain areas, we’ve got day one in gray, day two in red. I’m showing you a bunch of single cells that we’ve recorded. And the thing to take home from here is there are two brain areas that the computation looks a lot different, right?

One is infralimbic cortex, which is in the mouse, what we call mouse prefrontal cortex. And one is in the medial dorsal thalamus. So, the computations in the other brain areas look fine. But these two areas have changed.

Again, we’re not recording comprehensively all the brain areas. But it’s highlighting that something interesting might be going on here. So, now, we’re going to look at each individual mouse, right? We are recording before — we’re pulling a bunch of cells.

Now, we’re going back to the oscillations. And the oscillations, we get an oscillation from every single mouse, right? So, we’re going to ask the simple questions; are — is the power in these brain areas different? Right? Prefrontal cortex, infralimbic cortex, or medial dorsal thalamus? The answer is no.

Is there synchrony between them? No [laughs]. Is the flow of information different? No. This is again — the rabbit hole gets deeper. And we were sort of reminded at the time that there was another interesting pattern of synchronization that could happen in the brain, right?

So, everybody’s thinking of things changing together. You can also have a pattern of synchronization where things are changing across frequency. So, it’s another pattern of synchronization. I practiced to get that right in talks [laughs].

So, it’s another way the brain can synchronize. And this is called cross frequency phase coupling, where you have the amplitude of the higher oscillation synchronized with the phase of the low oscillation.

So, we calculated this property. And I’m showing you a plaque here. The phase of infralimbic cortex is on the bottom. The amplitude of medial dorsal thalamus is on the y-axis. And red is the — is coupling. Blue is no coupling. So, we can actually find coupling between these two brain areas across frequencies.

And this coupling changes between day one and day two. And importantly enough, the amount that this coupling changes is related to the individual behavioral change of each of the animals. So, it looked like we found a signature that we can go after that’s involved in how the animals are adapting to stress.

Okay. So, I’m an engineer. So, I immediately think of, you know, two things, right? Whenever we observe something, it could be the thing, right? So, this is the thing causing our stress problem, right? And what we want to do then is prevent it, right?

So, it’s a primary problem. And if it’s a primary problem, we want to get rid of it. The issue is, it may be compensatory, right? And what I mean by compensatory is if you run up a flight of stairs, your heart rate starts going faster, right?

What you don’t want to do is stop your heart rate from [laughs] going faster. Because what it’s trying to do is get more blood to your muscles, right? So, the heart rate increase is compensatory.

So, we need to know whether it’s primary compensatory because it determines whether we want to create the signature or get rid of the signature, right? So, the way we’re going to do this is we need to figure out some way to create cross frequency coupling in the brain.

You heard some talk — Antonio mentioned this. And Nicole mentioned this as well, about closed-loop modulation, right? So, we’re essentially going to use the same tools they talked about to create closed-loop modulation. And what we’re going to do in principle is we’re going to read electrical activity from infralimbic cortex.

So, the slow away from the infralimbic cortex. And then we’re going to stimulate the medial dorsal thalamus at the higher frequency, essentially coupling them across frequencies. And we somehow got to figure out how to read the information and put it back in the brain in about 30 milliseconds.

I had a really awesome undergrad in the lab who figured out how to do this. And so, we’re just going to extract information from the mouse’s brain, process it in a computer, and figure out what the wave is in infralimbic cortex.

And then stimulate a high frequency burst in thalamus that’s timed to it. And we’re going to use a tool called channelrhodopsin. The simple sort of take home of channelrhodopsin is blue light makes cells fire [laughs], and yellow light doesn’t, right?

So, blue light’s going to be our experimental group. Yellow light’s going to be our control. And we’re going to create this within the animal’s head and see what happens. When we did that, again, blue light’s our experimental group, yellow lights our negative control. I’m just showing you the amount of data mobility the animals show when we do this. When we basically play that signature, read from infralimbic [phonetic] cortex right into mediodorsal thalamus, it makes the mice less immobile.

In other words, it looks like we’re pushing some degree of resilience into the animal’s brain by doing this, right? And this argues that the signature isn’t actually primary. It is compensatory giving us a pathway to intervene now in specific animals. So, I’m just showing you what this looks like on the top here. In other words, when we time the signatures to the wave, the animals, green is good, right? It shows more behavior that looks like resilience.

But we did two important controls that really highlighted what we were running into. The first thing we did was we delivered the exact same number of light pulses into the brain, right? So, maybe this is just light going in the brain. This is just stimulation.

So, we delivered the exact same number of light pulses. We just delivered them in a fixed pattern where it wasn’t related to the oscillations. Now, it’s not timed and we were shocked. The animal’s behavior actually went in the exact opposite direction. In other words, they got worse. And so, this is — for an exam, this is like signal to noise for us. We’re just putting noise in the brain and canceling out how the circuit is normally computing.

And then we did one final control which is where we said maybe it’s the threes that are important and not, you know, the timing. So, we just had another experiment where we played threes, pattern of threes in the brain and the animal has no behavior change whatsoever. And the reason this is likely happening is some of the threes ended up at the bottom of the peak and some of the threes don’t. So, it all basically cancels itself out.

But what this really highlights is that if we’re going to intervene, it’s not that we just need to sort of find the area of the brain and stimulate it, we need to have approach where we can record or read and write in a closed-loop way that gets the timing right. The timing’s critical.

Okay. So, we’re really excited about this. This was somewhere around 2016. And we were like, “We solved all the world’s problems. We’re going to cure mental illness.” All we need to do is figure out how to create massive numbers of post-loop stimulation devices, deploy them across the world, make everybody resilient, and then we will retire and enjoy ourselves.

This is a picture of my family and the open chair is my uncle’s. And my family on the bottom row, four out of five of the siblings carries a major psychiatric diagnosis whether depression or bipolar disorder, schizoaffective disorder. And this is my grandmother’s funeral. The open chair is my uncle’s who’s — who has bipolar disorder and totally decompensated when his mom passed away.

And I used this picture because I had a conversation with him about a year and a half before as we come up with this beautiful closed-loop stimulation device. And my motivation for getting into science and getting into this area of work is entirely selfish. Like I want to help my loved ones. Everyone else will benefit as a process of this but I fear for my loved ones. And I just like to be upfront about that.

And I was talking to him and he was like, “This is wonderful. It’s amazing. The whole family is so proud of you. You’ve done it. Tell me more about how this is going to get to the third world because this isn’t God.” And I remember sitting there excited and then ashamed because there was no way it was going to get to the third world.

And in looking at those initial graphs that I put up, seeing the burden of illness worldwide with depression being a bit top of the list, it occurred to me that I was working on making interventions that was not going to move the needle on the burden of illness in the world at all because it just wasn’t going to get to enough people, right? It was going to take, you know, eight billion down to — let me not do the calculating, 7,999,999,999. In other words, it wasn’t going to move things enough. So, we needed to go back to the drawing board and think about how would one make a scalable intervention that could improve resilience.

All right. So, we started thinking — this is all conceptual, right? It’s a concept of a plan. And we started thinking about what is like a scalable intervention? So, it occurred to us like two things are for it to be scalable. Antibiotics and vaccines, and they could be deployed worldwide. My thoughts on vaccines changed a little bit after the pandemic but sure. Before then, I thought they can be deployed worldwide relatively quickly.

Now, antibiotics have an interesting thing. What they do is they target non-self, right, to make self, to protect self, right? So, that’s not what we’re trying to achieve with — in the case of mental illness. Vaccines on the other hand target self to make itself more resilient to the environment. So, in principle, the concept is what we will want to achieve is a vaccine, right? So, let’s see if we could turn this like brain stimulation device into a vaccine.

So, in 2018, I was on the BRAIN Initiative work group and I heard about like two exciting technologies being developed that made this concept a little more concrete. The first one was a human brain cell atlas that’s now underway. And the idea is we were going to sequence all of the cells in the human brain and find out the gene expression profiles, each individual cell type, and we’re going to do this across all ancestries so it’ll work for everybody. And what this would ultimately provide is a GPS system that you could use to express things in specific cell types. So, it’s a locator signal, right?

The second thing that was being created were delivery systems that would cross the blood brain barrier. There’s a colleague of mine at Caltech, Viviana, who’s working on AAVs that cross the blood brain barrier, right? If you could take these two technologies and combine them, you could create an AAV that you could deliver a package to specific brain cell types that you could package into a vaccine that could be scalable. And all you needed to do was take that closed-loop electrical stimulation system based in silicon and turn it into proteins. And so, the entire rest of this talk is going to be focused on our goal of turning our closed-loop device into proteins.

So, I’d spent time in medical school and as part of medical school, we rotate through a bunch of rotations. One of which is cardiology. And so, I’ve always been obsessed with the heart. And it turns out this heart has an interesting what we call [unintelligible] system that takes information. Ions from one cell and pass it directly to the next cell and it’s dumped through gap junctions which are called electrical synapses. You could use those terms interchangeably.

So, it passes ions from one cell to another, ions are electricity. So, it reads and writes from one cell to the next. That’s why your heart stays synchronized. These gap junctions are made of connexin proteins. They are expressed in most of the tissue throughout the body and 20 isoforms in humans. There are some challenges with them which is they’re bidirectional. You ever see a heart defibrillate, it’s like current moving in all kinds of directions. There are all kinds of things going on.

All right. What was interesting about gap junctions is about six or seven years earlier, somebody had taken these connexin proteins and put it in worms. They expressed them in neurons in worms. And what they showed you could do is just by expressing these proteins, you can create an electrical synapse or gap junction between them, synchronize these neurons, and it changes the behavior of the worm. So, you can essentially rewire or edit part of a circuit just by putting gap junctions in there.

Now, this is great in worms because worms have one cell of each cell type so your GPS system is like sort of really optimal. You can appreciate the challenges of trying to do this in a mammalian nervous system. Mostly because you have many cells of the same cell type. So, let’s suppose you wanted to have a closed-loop system that read from the presynaptic neuron on the left and wrote into the postsynaptic neuron on the right, you can insert gap junctions in between them that you see there in pink.

So, it’s sort of like an electrical synapsis that you put between them. But you would immediately have two problems. The first of which is you’d also express gap junctions on the other presynaptic neuron because it’s the same cell type. And what that would do, it would ultimately scramble the signal between the presynaptic neurons because current will be flowing in directions that it ultimately shouldn’t.

The second thing is because the gap junction is essentially poor, you’d have current moving in both directions. So, this is sort of like talking to somebody when they’re yelling at you. It’s not really useful.

And so, we had a concept of a plan and so we made a viral vector with gap junctions just to try this out to see what would happen. We put it in the ventral hippocampus in mice. I’m showing you two doses which we did this and we injected the mice. This is — my grad students said we really don’t have behavior. I said, this is the clearest behavior that I’ve ever seen. It was totally lethal. The animals had seizures and died. Because we were essentially hyperconnecting their hippocampus, exactly the picture that you would see on your left.

And so, we had a — what I call my dream team in science. It’s generally some really smart people. And here’s the idea that we came up with. Instead of having the gap junctions work like stickers, what if we made them work like magnets? Where there’s a positive end and a negative end. Excuse me for everyone — any one that’s color blind. The colors will have relevance later.

But the idea is the green, if it’s a positive event, it won’t interact with green. If red is negative, red won’t interact with red. But the green will interact with red. And just for kicks, let’s make it so current preferentially flows in one direction. So, this is conceptually what we’re trying to achieve.

So, I had a team of — I call this my dream team. They’re all — they were all undergrads at the time. Two of them have PhDs now. One’s a medical doctor. Just to show how long this has gone on. But I love using undergrads for projects because when you tell them stuff, they don’t know there’s no way it will work.

So, they searched through the literature. They searched through all kinds of connexins and all kinds of species. They searched for innexins which are invertebrates, pannexins, and came up with this pair that’s in goldfish and perch fish. And connexin 34.7 and 35, their names are based on how much they weigh in kilodaltons.

And what was really fascinating about this pair was this pair could come together, these two different proteins would come together to form a gap junction. They also conducted current at exactly the amount that we would want for the mammalian nervous system. And they had this cool property they tended to rectify. In other words, they sent current more in one direction than in the other. So, this is our baseline pair that we’re going to start with.

The issue with this pair is that while 34 and 35 will come together, 34 can also come together with itself and 35 can come together with itself. So, it does what we want but it also does things that we don’t want it to do. And so, at that time, I’ll be honest, I’m going to acknowledge this now, I barely passed biochemistry in medical school and cellular biology. But it was clear that we suddenly had to become biochemists and cellular biologists to figure out how to do protein engineering to make these cells, these proteins do what we wanted them to do.

So, it turns out that docking or the coming together between these connexin proteins, these halves, these hemichannels are controlled in part by extracellular loop 2. So, residues on extracellular loop 2. So, we just had the simple idea what if we could figure out which residues control the docking, mutate them, and then find a pair that does something that nature’s never created before. This was our idea that we put into our concept of a plan that we put into a BRAIN initiative grant. And believe it or not, they funded it.

So, here’s our strategy. A postdoc from my lab came up with this idea on how to achieve this. So, here’s a connexin life cycle that happens between two cells. So, you have two cells, cell on top, cell on bottom. The connexins are synthesized, trafficked to the circuit’s surface and then they combine to form a gap junction that you can see there on your right top left corner.

And when they do this, when you need to get rid of the gap junctions, you don’t actually rip it in half. One cell swallows the whole gap junction. And so, what you realize you could do was just tag the connexins with the green fluorescent protein or red fluorescent protein. So, one cell expresses red connexins and one cell expresses green connexins.

And then you know you formed the gap junction because you get green and red in the same cell when it swallows it. So, you’re simply asking question does a single cell have green and red in it. If it does, you form the connexin. So, I’m going to show you what this looks like. Pay attention to the upper left hand corner. I’m showing you a bunch of cells that we’re just doing live imaging. And you’ll see those sort of green and red little circles that show up. Really small green and red double layer circles that show up. That means that you formed a — you formed a gap junction.

So, here’s what we were able to do. We just take a connexin. We’ll take one of our mutant pairs that we’ve created. We created 70 of each one. We tagged one with green. We tagged one with red. We put them together. We let them hang out. And then we see if their cells with green and red in it using a technique called flow cytometry.

And all it’s going to do is tell me is whether individual cells have green and red in both of them. You see that on the bottom right hand corner. Pay attention to the plot all the way on the bottom right. One axis is how much green do you have. One axis is how much red do you have. Each dot is an individual cell. And you could see that there’s nothing really in the upper left hand — upper right hand corner. There’s only green on one axis and red on the other. So, those connexins proteins do not interact.

If you look at the other axis, the plot right on top of it, this is gap junctions are being formed. In other words, you have blue dots that are off the axis. They are all sort of filling out the center there. So, it’s a really simple quick assay that we could do when we have pairs to see if they form a gap junction. So, here’s what we’re going to do. We’re going to mutate a bunch of proteins. We’re going to test them against ourselves. And we’re looking for proteins that don’t interact with themselves. We don’t care why it doesn’t interact with itself. We don’t care if the protein never gets formed or it doesn’t corrupt. We just want to make sure it doesn’t interact with itself. So, that’s step one.

Then we’re going to take all the proteins that don’t interact with themselves and we’re going to see if it interacts with the other protein. If it does interact with the other protein, it means it’s getting formed correctly. And then because for kicks, we’re not interested in curing mouse depression. We’re going to test this against all of the other human connexin proteins just to make sure we have a translational path for it.

Okay. And you can see on the bottom right, basically 0.2 percent. So, none of the cells really have both. Here, 17 percent of the cells have both when it’s positive. So, we go through this process and again, here’s our three steps. We’re going to test them against themselves. We’re going to test them against the other one. And then we’re going to screen them against human connexin proteins particularly those in the brain but we ultimately did all of them to make sure it doesn’t do that.

When we do that, with 15 proteins make it past around when they’re screening. So, we started with 150. We ended up with 15. We screen them against each other. We’re really excited. We ended up with three pairs. These three pairs, the halves don’t dock with themselves but they dock with the other one so it’s a really cool property that hasn’t been seen before in nature.

And then we took the last step. Again, because selfishly, my goal is to help my loved ones so we want this to work with humans. And none of the pairs survived interacting with human connexin proteins. So, they all interacted with other human connexin proteins. So, we had what may have been a reasonable mouse tool but not a useful translational tool in the long run.

And so, we felt good but progress was sort of stifled. And then it got really bad. This was all in March of 2020. And the lab shut down. And at that point in time, we took — we all took totally new career directions. We were all sort of making bread and cookies, playing around with yeast. And I just had a new graduate student join my lab who’s — he finished up at Berkeley a little earlier and he’s back on his computer science. And he convinced us to get him a supercomputer that he would put in his house. And — because what else are we going to do when the world shuts down.

And he started doing protein modeling. And so, he took all of the protein sequences, all the means that we created. Stuck it in the computer. Figured out how to build them into an artificial membrane and then calculate how these connexin proteins were interacting with each other. Basically, running through all of these pairs and seeing what their patterns of interactions were and what controlled them.

And not to soon after that, he sort of found this interesting code and determined how connexin proteins interacted with each other and docked. They’re sort of four residues with a second one down interacted with the three residues on the other side. So, it’s sort of this mechanism where the whole thing locked together. And so, what we realized we could do from this computational model was mutate the residues at select sites and create versions of the protein that only docked with each other. Not with themselves and didn’t interact or dock with human connexin proteins.

And so, we created these in the computer. Eventually, the lab opened up again and then we made these proteins in the lab. So, some of them we had real proteins that did this. All right. We quickly tested them just to make sure that they were functional. So, we put them in oocytes. These are basically frog eggs that had been used, sort of things that had been used classically in neuroscience. We put them in the oocytes, one in each one and then you see if electricity moves back and forth between them.

On the top, I’m showing you the wild type pair. On the bottom, I’m showing you the mutant pair. The take home here is there is current moving thorough those connexin proteins. So, check one.

Okay. So, then we went back to the C. Elegans and we loved the C. Elegans. Reached out to my colleague, Daniel Colon-Ramos, who is at Yale. I see Yale represented here. And who had been doing really cool work in C. elegans. And the C. elegans is a really nice system for testing out these connexin proteins. I’ll sort of orient you as I go throughout. I never worked with C. elegans before, so all of this is like really new stuff trying to solve a problem for me.

But C. elegans is nice because when it’s clear, and you’ll see why it’s really useful, that it’s translucent. It has 302, exactly 302 neurons and neuroscientists have done an amazing job of mapping behavior onto those specific neurons. So, they know what those neurons do. And so, it’s a really nice system to test out if we could change how neurons are interacting with each other because C. elegans also don’t have connexin proteins. So, it’s a nice clean system to test our proteins out.

So, here’s our assay that I’ll orient you to. So, C. elegans, I say, are a lot like graduate students. Whatever you feed them, they will return. So, if you feed a C. elegans at cold temperatures, it migrates towards cold temperatures the next day. If you feed it warm temperatures, it migrates towards warm temperatures. And that behavior in part is controlled by the interaction between two neurons. One called AFD, which is a sensory neuron. It senses temperature. And then one called AIY, which is an interneuron.

When you feed the C. elegans at cold temperatures, you can sort of see the — see where it says calcium rises. Look under that. I don’t have a laser pointer. Do I have a laser pointer? All right. So, you could see as the temperature rises on the plot middle on the bottom, the activity goes up. This is different at 61 animals and that’s just showing you how much activity you have in each of the cells. In other words, the cells fire more as the temperature goes up because it’s a sensory neuron.

On the right, you see what happens with the postsynaptic neuron when the connection between them is weak. Temperature goes up, that the neuron doesn’t respond. That’s when you feed the animals cold. When you give them a chance to go to find food, they go towards the cold. Makes sense?

All right. If you feed the animals at warm, that connection between the two neurons becomes much stronger. All right. And now, you can see that when you rise the temperature, the second neuron also increases activity because the connection between them is strong. And then the animals migrate towards the warm when you give them a chance to eat food.

So, you can assay how strongly are those two neurons connected by — if the animal floor is warm and there’s a calcium rise in the second cell. So, what we’re going to do experimentally is we’re going to take our proteins and we’re going to put them in the two cells. In case number one, we’re going to take the lock and put it in both cells. In case number two, we’re going to put the key in both cells. In case number three, we’re going to put the lock in one and the key in the other.

So, here’s what it looks like when you have the lock and the lock. This is the calcium imaging. In other words, when you look on the right, the lock and the lock, 34.7M1 and the key and the key, 35, 35. There’s no postsynaptic calcium rise. In other words, the connection between those two cells is weak as temperature goes up. It’s exactly what you would expect. The lock and the lock and the key and the key aren’t doing anything.

But when you put the lock and the key in, suddenly, that neuron starts behaving really different. Now, with the lock and the key in it, it’s as if you’ve edited or changed the connection between those two cells and you have the postsynaptic calcium rise. So, you’ve change how that cell is functioning. But the question is what’s going on behaviorally.

All right. So, the wild type cases are normal C. elegans. They like the cold. All these are cold trained. We put the lock and the lock in. The animals go to the cold. The key and the key, the animals go to the cold. But when you put the lock and the key in, suddenly, the behavior of the animals changes and the animals immediately prefer the warm temperature.

So, you can change the physiology and behavior of the animal by inserting or editing the circuit between them. Okay. And we also tested this against the connexin proteins in the human brain. They do not interact with our proteins. So, again, we’re just — at every step, we’re trying to make sure that we have a translational pathway.

Okay. So, what kind of stuff can we do with this? All right. So, we got really excited and we’re like, “Well, let’s go back to the beginning and see what happens with these little puppies and mice.” So, back to the beginning. We have this two-day assay that we’re going to subject our animals to. And when we recorded the animals in this assay, we found two brain areas that were important and the interaction between them, infralimbic cortex and medial dorsal thalamus.

And so, we took our viruses and we basically put them in infralimbic cortex and medial dorsal thalamus. We put the lock in the infralimbic cortex. Sort of waited it for it to express along the axons going to the medial dorsal thalamus. We put the key into the medial dorsal thalamus. Again, you could see the red and the green. We could see that we could get sort of these colors coming together in the medial dorsal thalamus. We went through and did some physiological assessments of this circuit and we showed that we could strengthen the physiological interactions between these areas. And then we wanted to know what would happen to the behavior of this animal.

So, again, as I showed you, if you put an animal through the two-day task normally, the exposure to the stress causes their behavior to change and they are more sort of immobile on the second day as a result of the exposure to stress. So, this is what happens when we put the lock and the lock or the key and the key in. They are sort of — they have circles or X’s there. The populations basically overlap and are pooled together there. And animals show increased –f they show adaptation to the stress. So, they are changing in the way that unedited animals are.

But when we put the lock and the key in the circuit, suddenly, we saw that the population of animals weren’t changing. We repeated this a few times. We’ve actually looked across a bunch of different assays at this point in time. But we are changing the physiology and the behavior of this circuit. So, for us, we were really excited about this because we sort of started with our huge closed-loop pacemakers, left the country, went to Ghana, went through a pandemic, came back. All sort of trying to come up with something that would help us find a scalable approach to improving resilience to mental illness.

All right. So, I’m here with one of my favorite slides in the world. I saw this at BRAIN camp. Tom invited me at the time. I was — last year, I was a PhD student to meet a bunch of leading and eminent neuroscientists in [inaudible] put this up as a mouse researcher. So, I was hurt by this slide. I will say that people show their facial expressions in rodents are predictive since that beautiful paper a few years ago by Nadia.

But this is a real problem. Because as you think about the work we’re doing in mice, whether it’s guilt, or suicidality, or sadness, we don’t have great ways of measuring that in these preclinical model organisms. And, in fact, if any of us were to see a mouse or a rat run across the room, most of us will jump on our chair or run out the room. Because — we might even call an exterminator. Because we’re not entirely convinced deep down inside that mice have feelings. It’s unclear if they pass the Turing [phonetic] test. We surveyed the American population. It’s unclear if they were — believe that they passed the Turing test.

I’ll ask a question. Right hands up. How many of you have a dog? Okay. Left hand up if you believe your dog has feelings. Yeah. Right. I gave a talk at a vet school and I was immediately convinced. Frankly, I’ve never had a dog. But I was convinced that dogs passed the Turing test, right? So, if at its core, psychiatric illness is so sure of occupational dysfunction that could cause all the illnesses, it’s a common thing. It occurred to me that dogs are sort of the only species that live, and socialize, and work with us the way we live, and socialize, and work with each other.

So, they both pass the Turing test and they embedded themselves within the structure that is disrupted in psychiatric illness. And so, someone asked me and said, “Could you do this work in dogs? Wouldn’t that be cool?” I said, “Absolutely not. There’s no way I would go anywhere near that.” And the person said, “No, you don’t understand. You’re giving your mice fluoxetine. We give dogs fluoxetine.” I never knew the dogs got Prozac. Dogs get Prozac, believe it or not. Because they have behavioral disorders that look a lot like the behavioral disorders that we have in humans.

And anybody who bought a dog during the pandemic and then went back to work suddenly saw their dog had separation anxiety. Just like your kids when you’re leaving them at kindergarten the first day. They look exactly the same. And I came across this fact that really changed the way I thought about this. And I was talking to a bunch of vets and there are all these sort of mixed breed pit bulls in Raleigh.

And they get anxious and when they get anxious, they get aggressive. And when they get aggressive, they get euthanized. Because in dogs, it turns out, anxiety and aggression could be terminal. And so, the case that this person, this vet that I was talking to made was that if you could figure out how to do this, you’d actually be saving dog’s lives.

So, I got really motivated around this question. How could we use neuroscience and cutting-edge neuroscience, as I sort of think about the future and the opportunities to help dogs. Not simply because it’s like probably a really good translational approach to understand human neuropsychiatric illness and how encoding happens and get to an endpoint. But also, because it’s just really valuable and useful to help dogs.

And people in America care about dogs. So, it took about two or three years to build out my first team of collaborators to take on something like this. And I was able to ultimately bring in the humane society as collaborator to figure out how we can ask questions. Like if we can understand aggression in dogs, could we use neuroscience to minimize it so that they get adopted from shelters.

And how can we understand pain in dogs in a way that decrease osteoarthritis? How can we understand social behavior in a way that help dogs live in our homes better? And in doing so, could we understand neuroscience in a way that gets us closer to ultimately develop therapeutics and interventions that help people like my family members.

So, I’m extremely grateful to be here and with — I’ll take this last two-minute privilege just to say this. Because I think it’s a real statement about American science. So, I want to talk about the people who do this work.

Liz Ransey was a postdoc in the lab who tagged the connexin protein with the different colors. She’s a first — she was a first-generation college student and she’s now on faculty at Carnegie Mellon. Ryan was one of those really amazing Montessori kids from San Francisco. Came to my lab as an undergrad. He was on the dream team. Did the master’s at Carnegie Mellon.

Dalton Hughes was a Meyerhoff scholar in Baltimore, Maryland. I met him as an undergrad. He’s now finished his MD PhD. Elise Adamson was an undergrad in Biomedical Engineering, came to my lab later. Did her PhD in Biomedical Engineering and is now consulting. Daniel Colon-Ramos who grew up in Puerto Rico is on faculty at Yale, my collaborator on the work with C. elegans.

Tatiana Rodriguez, in the upper left-hand corner grew up in the Appalachian Mountains in Maryland, is now doing her PhD in Toxicology at NYU. Catherine, who’s right below her was — grew up in Iowa. Had two kids during the pandemic. I literally saw her in lab the morning before she gave birth. And a week and a half later, she’s zooming in the lab. And I was like, “Please don’t do that.” But it really highlighted for me the importance of taking care of young people and young families and giving them good supportive childhood care. Because they play an important role in the discoveries that we make.

Steve joined my lab after finishing up his PhD at University of Pennsylvania. It’s been fantastic with his expertise in addiction research. Eli who’s now an MD PhD student in Oregon. Hannah Schwennesen who’s on the undergrad dream team is now a medical doctor finishing up residency in internal medicine.

Gwenaelle Thomas who was an undergrad at UMBC as well joined my lab, who experienced countless members in inner city New York who were murdered while she was growing up. And really had deep insights about how that impacts a person going through science. She became the second black female to get a PhD in neuroscience from Duke. In the middle, Nenad Bursac, who migrated here from Serbia. Next to him, the whiz kid from Berkeley whose family migrated here from Russia.

And then finally, in the bottom right-hand corner is Rainbow who migrated to my lab from Iowa. And Rainbow’s story is one of the most unique ones. Some of you know her. In graduate school, she started suffering from debilitating migraines and couldn’t look at the computer.

She joined my lab as a postdoc because she wasn’t sure that there were places in science for people who had disabilities and challenges. She ultimately finished her PhD. She’s now on faculty at Iowa and she won the NIH New Innovator award to study the neural mechanisms underlying migraines.

So, I think it’s a real statement on American science in how we create spaces for everyone to bring their disabilities and perspectives in. We can bring things and ultimately have a potential for helping people throughout the world. So, thank you so much for having me here.

Almost all of this was supported by NIMH. So, I want to thank you all. I met Josh at Society for Neuroscience in 2007. We’re sort of the only two really talking about brain oscillations in mice and how you might be able to decode emotions and behavior from them. So, this is home for me. Thanks.

FEMALE SPEAKER: That was fantastic. I have many questions but I’m just going to ask one. Can you talk more — so, okay. I love the idea of hacking into the biology and figuring out ways that we can change electrical activity in the brain.

But I want to know how much you understand how that electrical activity is actually tied to the computations that lead to the behaviors. Because we have been talking all day about how complex behavior is, how complex mental disorders are. So, what are your thoughts on what we need to do to figure that out or should we or can we?

KAFUI DZIRASA: Yeah. I have a concept of a plan. I don’t know. We have to test these things out empirically. I’m not by any means arguing that human beings go playing around with their connexin proteins tomorrow. I honestly haven’t figured out what resilience is. It may be that these animals are resilient to some things and not resilient in others or vulnerable to some things and not vulnerable to others.

So, I think we do have to learn that as what making an animal sort of more resilient to one stressor, we’re sort of creating problems in another domain. So, we have to learn all of that. The idea of getting upstream is to figure out what is common or sort of one convergent place that we can target to ameliorate the likelihood that many different psychiatric disorders would emerge rather than thinking about how do we get rid of hallucinations, how do we get rid of sadness moving forward or upstream for that.

But in the words of the great Desmond Tutu, don’t let him jump in the water.

FEMALE SPEAKER: And if I can just follow up that. In the way that you’re conceptualizing things and thinking about moving upstream, you really highlighted the importance of stress. And stress as being a driver, and trigger, and exacerbator of a number of different sorts. So, do you think you want to focus on understanding the mechanisms of — that explain how this neural activity leads to stress resilience or can we bypass that in a way and then still leverage these techniques?

KAFUI DZIRASA: It’s a great question. You’re sort of scratching on my multiple areas of training. So, I’m an engineer by origin. All right. So, my immediate gestalt is to say, “I just want to fix it. And if I can make it better and my family members aren’t suffering, I am okay and somebody else can figure it out,” right? So, it’s me gathering as much information as possible that’s necessary to solve the problem.

At the same time, I’m certainly a neuroscientist who’s curious and is taking a lot of tools and terms to understand things. But it’s understanding to a degree that I need to solve the problem and hopefully in the process, training some graduate students who will figure the rest out. If I could figure out how to modify neural circuits in a way they increase resilience and prevent the emergency psychiatric illness, I would be equally satisfied as the folks who created Prozac, and Haldol, and all of the other things that we still don’t understand exactly how they work.

FEMALE SPEAKER: Thank you.

FEMALE SPEAKER: Okay. We just have one comment from the participants online from Lauren Hill at NIMH. “That was awesome.”

KAFUI DZIRASA: Hello, Lauren. I actually thought it was a different Lauren Hill one. But we love you too, Lauren. [laughs]

FEMALE SPEAKER: Do we have more time?

KAFUI DZIRASA: Yeah.

FEMALE SPEAKER: Thank you for that fantastic talk. Such a fun one to end this long and interesting day. So, my question is coming from a clinical psychology background, interested in mechanisms, how specific or general do you think this mechanism is? I have two levels of that question so on the one hand, how important is it that your assay is the same day one and day two? And secondarily, what other kinds — you mentioned other assays. Like a swim test. I’m never good at — that’s my question. Thank you.

KAFUI DZIRASA: Yep. No, that’s exactly right. What our strategy has been is now, can we put animals through a bunch of different stress paradigms and with the same circuit beacon [inaudible]. Yeah. Let me just say this because I see Brianna sitting up there and I was super proud giving a talk. So, I met her when I went to the postdocs at Stanford and they invited me to give a talk. And I went out there.

And I’ll never forget her pulling me aside, “I’ve never met a Black faculty member.” So, for me, I have incredible sense of pride seeing her as a faculty member and all that she’s done to create space for other people. So, I wanted to just give her a special shout out. And I thank you all for having me here. It’s been a tremendous honor and a pleasure.

SHELLI AVENEVOLI: Wow. It’s been an incredible day on so many levels. I can honestly say I’ve learned something new from every talk I heard today. And I know it’s going to shape the way all of us in this room and those online think about the kind of science we’ve talked about.

So, first and foremost, thank you so much for being here. We know you’re incredibly busy people. But thanks for sharing the day with us. Traveling here, sharing the day, sharing your ideas, and letting us push you a little further. I acknowledge that the talks we asked you to give are much different than the talks that you would traditionally give. So, we appreciate that and acknowledge that.

It’s also my privilege to thank so many other people who were making — involved in making this day possible. I especially want to acknowledge Megan Kinnane sitting in the front row. Megan led the work group that really put together the agenda for today, the organization, and the implementation. And with her is Phyllis Ampofo up in the back. Syed Rizvi, Syed Rizvi and Nichole Cook are also in the back. And Elizabeth Sekine who is sitting up here next to Megan. Thank you all so much.

I also want to acknowledge that it takes a village to plan our 75th anniversary year celebration. And these are the people. We had three major symposium but we also had several different events throughout the year. We also have an amazing team that put together materials online. I do hope you check out our 75th anniversary website. It’s not going to stay there forever. But please check it out. We have videos. We have podcasts. We have feature stories. And I want to thank Natalie Zeigler, call her out especially for leading that aspect, creating the materials for us.

And lastly, I just want to thank members of the entire NIMH community which includes our investigators, our patients and families who contributed, our advocates and professional organizations that support everything we do. The celebration is really about all of us. So, we should give all ourselves a round of applause. And thank you for coming and enjoy the — I think we can stay here until 5:30 p.m. We have to be out by 5:30 p.m. So, enjoy yourselves and thank you again.

Transcript

FEMALE SPEAKER: Thank you for joining us for the National Institute of Mental Health’s third and final 75th anniversary celebration, our symposium, Inspiration and Aspiration: Future Perspectives in Mental Health Research, here at the National Archives Building.

Today’s seating is open, but we do ask if you could please fill the seats down front and in the center to make it easier for people who are arriving, possibly late. In case of emergency, please use the front. Please use the exits at the top of the stairs, near on either side of the theater, and proceed to the nearest marked building exit or follow NARA security and staff for further instruction.

Restrooms and a small cafe are located on this floor outside the theater and to your right. As a reminder, food and drinks are not permitted in the theater at any time. Once again, thank you for joining us today. Please take your seats. Our program will begin right now.

[start of video]

MALE SPEAKER: In the aftermath of World War II, America faced a great and compelling need to address the nation’s mental health. In response, President Harry Truman signed legislation leading to the 1949 creation of the National Institute of Mental Health.

It has been tolerated too long. It has troubled our national conscience, but only as a problem, unpleasant to mention, easy to postpone, and despairing of solution. The time has come for a great national effort.

The National Institute of Mental Health was at the heart of this effort.

For the first time, man now has the tools to explore the living brain.

Today, the National Institute of Mental Health is the lead federal agency for research on mental disorders, supporting discovery across the country and the world. We aim to transform the understanding and treatment of mental illnesses through basic and clinical research to envision a world in which mental illnesses are prevented and cured.

[end of video]

SHELLI AVENEVOLI: Good morning, everyone. Everyone hear me okay? So, I’m Shelli Avenevoli, the acting director — not the deputy — the acting director of the National Institute of Mental Health. I’d like to welcome you today to NIMH’s final symposium in celebration of our 75th anniversary.

Thank you so much for being here today, and it’s especially nice to see a pretty full room here in person and so many more of you joining us virtually online. I also want to recognize that we have two former NIMH directors with us today, Joshua Gordon and Richard Nakamura up hiding in the back.

As many of you know, NIMH is the lead U.S. federal agency for research on mental disorders and is one of the 27 institutes and centers that make up the National Institutes of Health, the nation’s medical research agency. Our mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure.

Mental illnesses are complex, and they can affect people of all ages, genders, races, and ethnicities. Mental illnesses are the fifth leading cause of disability in the United States, accounting for almost 7 percent of all disability adjusted life years. NIH is committed to overcoming these challenges by supporting high quality research and providing hope to individuals and families impacted by mental illnesses.

The celebration of NIMH is 75th anniversary allows the reflection of historical accomplishments. Over the past 75 years, NIMH has evolved to expand her urgent needs of the nation, while continuing to advance basic, translational, and clinical research to improve our understanding of treatment of mental illnesses. Our progress advances and successes are shared by the Greater research community and the individuals and families impacted by mental illnesses.

It’s really been a true pleasure to celebrate our 75th anniversary in several ways, including our three main symposia. The first one highlighted significant advances in mental research — mental health research over the past 75 years. The second one focused on inclusion and mental health research, disparities in health, and access to care and mental health workforce diversity and brought together people living with mental illness with clinicians and community leaders.

During today’s event, we focus on inspiration and aspiration, very appropriate. We will hear dynamic presentations by rising stars and trailblazers in the scientific community. Presenters will also share diverse perspectives and creative approaches to mental health challenges, including discussions about cutting edge advances that are shaping the future of mental health research.

Thank you especially to all of our speakers today for contributing to this final symposium, and for all attendees who are part of this historical event. So, before we begin our program today, we’d like to hear a few brief welcoming remarks from the NIH Director, Dr. Monica Bertagnolli.

MONICA BERTAGNOLLI: Hello, everyone. I’m Monica Bertagnolli. And I’m honored to serve as the director of the National Institutes of Health. Thank you for inviting me to provide introductory remarks at this important celebration. And I’m very sorry that I cannot be there to welcome you all in person. I’d like to thank Dr. Shelli Avenevoli for your introduction and for serving so capably as the acting director of the National Institute of Mental Health while a national search is underway for the next NIMH Director.

Thank you also to Dr. Joshua Gordon and all the former NIMH leaders who have helped the institute accomplish so much over the years in mental health research. Since I became NIH Director last fall, it has been inspiring to me to work with so many brilliant and deeply committed leaders across the NIH.

I’m incredibly grateful for the powerful team we have put together here throughout all of our institutes and centers to work toward our singular and noble purpose, to improve the health and wellbeing of all people.

Over the last 75 years, NIMH has supported basic and clinical research that has transformed our understanding and treatment of mental illnesses, paving the way for prevention, recovery, and cure.

NIMH research is more important now than ever, given the nation’s mental health crisis as we emerge from the COVID-19 pandemic. With its focused mission, NIMH is well prepared to respond to the growing attention to mental health research across the federal government, in Congress and from the public at large.

I know that NIMH is committed to supporting high quality research and making innovative tools available to help us better understand mental illnesses in all of their forms. And I am certain NIMH will continue to make enormous, if currently unknowable, strides in the next 75 years.

Today’s symposium entitled Inspiration And Aspiration: Future Perspectives in Mental Health Research will feature presenters with diverse perspectives and creative approaches to the mental health challenges that face us today. Research like this provides much needed hope for so many people.

I want to congratulate NIMH for the efforts you made this year to involve the nation in your yearlong anniversary celebration. With multiple public events and conferences and with resources such as podcasts and social media, you reminded all of us of your remarkable 75 years of discoveries and achievements. And you’re inspiring and bringing hope to all of those who work to bring health and wellbeing to all people.

Thank you to all the speakers who are here today to help us celebrate this important milestone and for providing your forward-looking vision of how research can advance to meet the needs of those affected by mental illness. I know that today will be filled with fascinating presentations, and I send you all my very best wishes for an inspiring and engaging day.

SHELLI AVENEVOLI: Great. Thank you. And now it’s my distinct pleasure to introduce our first keynote speaker, Dr. Chyrell Bellamy. Dr. Bellamy is a professor in the Department of Psychiatry Yale University School of Medicine, director of the Yale Program for Recovery and Community Health, and associate director of Diversity, Equity, Inclusion and Accessibility of the Yale Center for Clinical Investigation.

Her research and practice examine sociocultural experiences and pathways to wellness and recovery in the prevention and treatment of mental illness and addictions, peer support effectiveness, organization, and leadership transformation with a focus on anti-racism, cultural humility, and responsiveness, lived experience leadership and community-based participatory research and co-design methods.

Dr. Bellamy openly identifies as a person with lived, living experience of multiple marginalized and minoritized identities, including mental illness, trauma, and addictions. She uses this personal connection in her role as a service provider and academic researcher in the health and behavioral health fields. Please join me in welcoming Dr. Bellamy.

CHYRELL BELLAMY: Thank you so much for that lovely welcome. It truly is an honor to be here. And I also just want to thank my folks from Yale’s Program For Recovery And Community Health, who came down to visit us. And they’re right here in front. [unintelligible]

Thank you so much. Thank you. So, let’s get started. So, my talk today is called embracing lived experience as the future of research. I want to start with a land acknowledgement. All land in the United States was once on native territory. It is our duty to acknowledge that many of the institutions where we work or conduct research are indeed on native land. So, it’s important that we give thanks.

Land acknowledgements do not exist in the past tense or historical context. Colonialism is a current and ongoing process. We need to be mindful of our present participation.

The objectives of my talk today — I will be doing acknowledgements throughout my talk today. I think it’s so important that we recognize all that have gone before us, that have come before us. I know I’m going to forget people, but please know that I am acknowledging you now.

Also positioning, positioning is really important to me to really give a sense of where I come from and — about my journey. I was tasked to talk about my creative process, and so I’ll share a little bit about that. But because a big part of my creative process is the ability to use my — and embrace my own lived and living experiences, I will spend the majority of my talk today talking about that. And hopefully to provide some useful tips that could be really helpful to you.

So, let’s get grounded. There’s a poem that was written by my friend and colleague, Imani Harrington. Imani is a playwright and an activist in San Francisco. And she and I co-wrote a book, plays, monologs called Positive/Negative: Women of Color and HIV/AIDS. I was actually working on my dissertation at the time when I joined her as one of the co-editors.

The poem goes, “We need you, our brothers, our sisters, our people. Help us reaffirm ourselves and loving ourselves. Hold us, we can’t stand because souls of shoes have traveled on our backs for so long. We need you, our brothers, our sisters and our people.”

To me, this this poem grounds me. I say it at everything I do. I say it so much that my team at Yale Perch often say, “Oh no, here we go and again with the poem.” But the poem, to me, is really about, how can we make sure that we figure out how to help people reaffirm themselves and loving themselves.

And particularly for the people that we work with in is doing mental health research. But also, how can we help each other? Because we all need that affirmation.

So, acknowledgements. This woman right here as Dr. Carol Mowbray, who was my mentor at the University of Michigan. She was doing incredible work around mental health research and really looking at ways in which supported education could support people who had a sense of psychiatric illness as they transition back to post-secondary education.

And I actually went to the University of Michigan to do HIV research. But I needed a job, and someone said, you know, “Hey, Carol Mowbray is looking for someone that has experienced working in the inner city.” And I had come from New Jersey, and done a lot of work in Newark, New Jersey. And she needed someone that was ready and willing to go to Detroit, Michigan. And I was like, “I’m ready. I’m there.”

So, Carol Mowbray just really helped me affirm myself. And not only that, I was like, this program is about me. I was one of those students that struggle a lot, you know, when I was going through high school and post-secondary education. And so, for the first time, I felt this sense of being affirmed with research that I was taking part in. Carol Mowbray passed away when she was 57 years old, but she still has a place in my head, and I still go to her quite often.

The woman with the mole is my aunt, Halistine George. She was one of those people that was always reaffirming. Reaffirming about myself as a Black woman, reaffirming of myself as a Black queer woman. A woman that gave me the ability to stand tall, and no matter how I showed up. And Halestine also died at the age of 57.

I am 57 years old. And so, it means a lot for me to be able to stand here today and be alive and feel happy about being alive for the first time in many, many years. The woman down in the bottom, obviously, that’s her when she was cute and 18. That’s Dr. Alfrieda Daly. And Dr. Daly also passed away, but she died when she was 93. So, that gives me hope.

And Alfrieda was a person that I met at Rutgers when I was getting my masters in Social Work. And she overheard me advocating for myself. And she approached me, and she was like, “Hey, you did a good job advocating for yourself. Come work with me on this methadone HIV related project.”

And from that day, Alfrieda stayed in my life. She came down to South Carolina with me often to visit my family. She went to fish fries and all sorts of events that my family held over the years. But she also was a person that said, “You should go to graduate school, and you should go to the University of Michigan.”

And I was like, “University of Michigan, what is that?” And I thought they just did basketball. And, you know, never did I know that, you know, she was sending me to one of the number one universities in the world. And it was just really important for — to have Alfrieda in my life. So, thank you to all of them, and to all of the women people, non-binary people who have lifted me and continue to lift me. Ashay.

So, where I come from? I come from South Carolina. I’m from a little town called Brooksville, Little River. It’s all now known as North Myrtle Beach. And we are of the Gullah Geechee people. And this is our land. If you are familiar with the South Carolina, you’re used to seeing the mosque growing on the trees. And that’s the Gullah Geechee flag there.

And I mentioned that because that culture grounded me again in who I am as a Black woman. These are more pictures from the South Carolina area. Atlantic Beach is the beach in North Myrtle Beach that only Black people were allowed to be on that beach. Because Blacks were not allowed on the other beaches in Myrtle Beach to go to those beaches. So, still today, when I go home to visit my mom and my family in Myrtle Beach, I make sure that I touch the sand of Atlantic Beach. It’s called the Black Pearl.

And then we journey up north, like many of our folks did, from the Myrtle Beach area up to Trenton, New Jersey. And Trenton, New Jersey is where I grew up, where I attended public schools. And again, where I gained the sense of myself by growing up in a predominantly Black area, had predominantly Black teachers. And it helped me see that there were other people like me that are achieving and achieving successfully. But as they say, Trenton makes the world takes. I’m sure you’re used to seeing that on the train.

So, changing the discourse for many years, I was not out about my lived experience. But being a part of Carol Mowbray’s work really gave me a sense of it’s important that people step out and step into their own lived experience. That’s me when I was five years old. And that’s me with the hat on at the University of Michigan. That’s me and high school, that senior year picture.

And I want to talk a little about this article in The Michigan Record. When that article came out, it came out because the University of Michigan was doing a film called Depression on College Campuses. And they asked me to be a part of the film to talk about my lived experience. This film was shown at the university — at the Michigan theater in downtown Ann Arbor. And it was a wonderful success.

After the film, one of my colleagues came up to me and he said, “You know, I spoke to, you know, one of our professors. And he said, you know, our career is ruined.” And I just kind of looked at him. And at first I was like, taken aback, but then I was like, “No. Actually, it’s just starting.” It’s just starting, because I’ve received so many calls of people who are reaching out to talk about this. So many professors, so many students, so many community members who want to talk about their lived experience. So, to me, that is the start of my career.

I also realized that that person, the reason why he said that is because he also was a Black male. He came through academia at a time when we all were supposed to act a certain way in order to make it through the system. So, again, he was just giving me that sort of warning that I need to be able to learn how to walk light so that I don’t tread in ways that I shouldn’t.

But again, being myself, I stepped out and did what I was supposed to do in regards to lived experience. And the reason is based on this quote by Audre Lorde, which I’ll read to you. “Survival is not an academic skill. It is learning how to stand alone, unpopular, and sometimes revolve. And how to make common cause with those others identify as outside the structures in order to define and seek a world in which we can all flourish.

It is learning how to take our differences and make them strengths. For the Master’s tool will never dismantle the master’s house. They may allow us temporarily to beat him at his own game, but they will never enable us to bring about genuine change. And this fact is only threatening to those who still define the master’s house as their own source of support.”

And why is any of this important? I threw this slide in here because I think it’s important to acknowledge that so many Black and brown individuals are — continue to die because of suicide. We have a photo of Dr. Candia-Bailey, who was a professor and passed away due to suicide. We have Kryst, who was Miss USA, who also died as a result of suicide.

And then we have two of my colleagues, one is Elias from Brazil, who visited us as a visiting scholar. Amazing energy. He was there. And then November, just only three months after he visited us, we found out that he died as a result of suicide as well. He was a brilliant nurse in academia.

And then we have my colleague from Yale’s Program for Recovery and Community Health, Dr. Miraj Desai. Dr. Desai died last November 3rd, I believe. And he’s done some amazing work. He had a K Award. He had just submitted a DP1, I believe, the day before he passed away.

So, it is important that we nourish each other in academia. It’s important that we recognize and acknowledge that so many of us are going through things, and we may never talk about those things. But yet we continue to struggle and try to get that DP5 in and try to get that RO1 that check in on people, right? So, that’s my message for this.

So, my creative process. Someone asked me — you know about nerves? I tend to get nervous all the time when I’m giving these types of talks. 80 percent of time I vomit. I didn’t vomit today, though. [laughs] And so, I have this technique called palms down. And basically, that means panic at the last moment. You know, it was hard with this one, because as soon as Dr. Gordon sent me the message, and was like, “We want you to present.” I’m like, “Oh.” It started coming right away, right?

But it’s really important because if I don’t, then I spend so much time and energy focusing on the what, instead of really just embracing and sort of embracing that it’s okay for me to be proud. It’s okay for me to take this in. And don’t get so caught up in the words and the language of what it is that you’re trying to do.

Learning from and embracing community and lived experience, mine, and others. It’s those folks down here that I’ve worked with since I came to Yale’s Program for Recovery And Community Health, Kimberly guy and Richard Youins. I talk to them practically every day of the week. And they inspire me. We go to I go to them often with any idea. They either shoot it down or, you know, they give me advice on how to improve things.

And I just think it’s really important for me because that gives me a sense of purpose in this work. And that also goes with remembering my why. Why is it important that I do this work in the first place? That why might change depending on what it is that I’m doing that research. We’ll talk a little bit about that later.

Daring me to dream is critical. So, I remember early in my career, people would say, “Oh, you can’t study,” only Black people. Because people will not allow you to do that. You have to have a comparison group to other, you know, to whites. But I kept asking why, like, why is that the case?

And so, my thing with this is, don’t question the why — or question the why. But the question should be, what does it take to make it happen? What do I need to do to convince you that this is the research that I want to do? And seeing it all as a creative journey, as Dr. Shelley Best would call it, it’s a creative disruption, the work that we’re doing.

Revolutions begin when people who are defined as problems achieve the power to redefine the problem, John McKnight. We each have the power. This is one of those quotes at Yale’s Program for Recovery And Community Health that we use. I am privileged to now be the first director of Yale Perch, after my mentor, Larry Davidson, in 20 years.

I’m also proud to say that I am the second Black woman in the Department of Psychiatry in its history to receive full — to become full professor. And again, it is those experiences that I think it’s important that I say out loud, because there’s so few people who have been able to even get in the pipeline.

So, consumer involvement, user involvement, lived experience involvement, has been an increase in priority across our federal landscape, at least since 2002. We’ve added, you know, peer support. We’ve added, you know, the involvement of consumers — and that’s the word that we used to use, or service users in all, you know, aspects of work.

In terms of research, we do it, but we don’t do enough. Like there’s — while there’s a continuum of ways to involve people with lived experience. It’s usually just to help with recruitment, or just to have your, you know, quarterly advisory groups, because that’s what you told NIH that you were going to do.

Key to involvement is community based, participatory research, which I’m sure all of you know about. But I really want to focus on two aspects of this because it’s really about bringing the community together so that they are assisting throughout all aspects of the research. From conceptualization and that is generating the ideas to data collection, to design, to analysis.

And people often say, “Well, how can they do analysis? They don’t know statistics or they don’t know qualitative methods.” Then teach them, right? Teach people how to do those things. And there’s so many ways that we can involve people, particularly as well in terms of dissemination. Co-learning is very key to that process. And co-learning means a strengths-based approach that acknowledges privilege and power. And again, those are hallmarks of CBPR.

I’m now going to go through a few slides. And I’m going to go through them rather quickly, because I’m just pointing out, again, some of the history around the involvement of sort of patients, clients, state talk, stakeholders. Today, we’re using more of the terms lived and living experience experts and involvement and research. This goes back to the 1980s.

I actually was part of that process, as I mentioned, having done work in the area of HIV/AIDS. We were doing a lot of that work back then. I fear to say I was one of those gatekeepers when researchers would come to me, when I was the assistant director at the New Jersey Women and Aids Network to try to get research projects going. I would give them like a thousand questions of, why are you doing this? Why do you want to meet with our people?

So, we have Rose Kushner, who did some freelance writing and talked about breast cancer and surviving breast cancer. Lots of work around activism, again, AIDS and ACT UP, and groups like that. Maternal health, again, more work was done in that area. And the United Kingdom and Canada, I can say arguably, that they have one of the best systems of really engaging patient provider involvement throughout all aspects of their work. And it’s more of a mandate.

Over the years, PCORI has been instrumental in making sure that the target population is also key to that research and hired as partners in the research. And I’m thrilled, thrilled, thrilled, as a late to see that NIH across the board, I’ve seen RFAs that are asking for more lived and living experience involvement in projects.

So, why lived experience research? And I want to start with this first one. Rather than presume or guess, just ask the author. And actually, that’s a phrase that Kimberly Guy uses all the time, which is, if you want to know about the book, ask the author, you know. Don’t just — you know, go to the people that have the information. It gives us a connection with that human experience. And that’s so key when we’re talking about the future for research.

Because as we focus on future research, we’re bringing in all sorts of mechanisms like AI. So, we have to make sure that we continue to make that connection with the human experience. It also gives us rich stories that go well beyond the data, particularly if you’re coming at this from a quantitative perspective. And it reminds us that illnesses happen to people.

Another aspect of this is that it helps us in terms of bridging different communities. I love when I’m doing research projects, and I have the doctors in the room and the RAs in the room, and also, you know, people with lived experience. All coming from different walks of life to come together, to really figure out and solve a problem together and bring all of their resources and all their experiences. It just asks for a more rich learning environment.

It also allows us to address discrimination and other issues that sometimes are like, you know, we tend to hide in these situations. But working with people with lived experience, they have a way of bringing the issues right out and calling us on things that we need to be called out on.

Otherwise, include can we move away from just this illness model and really include, you know, things around the social determinants of health and other ways that people are, you know, living in these environments.

The other thing here I have is more honest responses from participants, and this is really key. I know that when we were doing a research project, we have all of our lived experience researchers examine our measures. And sometimes when they’re examining them, they’re like, “This doesn’t even make sense. Like, this question doesn’t make sense.” And I’m like, “Well, you’ve been to lots of studies. So, you’ve probably heard that study — I mean, that question a thousand times. And they’re like, “And I probably didn’t answer it right a thousand times.”

And I think that’s really important to know. It’s really important — I know that we have these standardized instruments, but we also need to make sure that they are standardized based on what human beings are telling us makes sense to them. Otherwise, we’re collecting data on questions that people may not even understand what you’re asking them.

And particularly, we tend to get these satisfaction surveys. I mean, I don’t know — and I can tell you, primarily in our state, in Connecticut, satisfaction surveys are like, really, really high. Most people are saying they’re, like, totally satisfied with everything. But then if you go talk to them, they always have some complaints about this, that and the other. So, how can we learn to collect richer data? More wise, better recruitment, getting the people that you need.

I have a project right now. It was originally funded through the NIH Common Fund, and it’s called the Imani Opioid Faith- based Breakthrough Project. And the thing I love about this project, in terms of recruitment, is that we have to go where people are. And when I say we have to go where people are, we do these deep dive recruitment efforts, where we’re going in alleys, where we’re going in places where no one else will go to have conversations with people about the projects that we’re working on.

And I think this is really essential that if we want to really reach the people, we can’t keep calling them the hard to reach population. Hard to reach to who? Only to us. The people in the community know how to reach these people. And here are just a few examples of those type of articles that we been able to publish as a result of some of this great work.

And as I mentioned, Kim is saying, if you want to know about the book, ask the author. We actually use that as our title for this for this paper. This paper was again led by Dr. Desai. Again, we miss you, Dr Desai. Another paper was led by another young researcher, Ana Florence, with a whole bunch of us.

Here’s the thing about lived experience research and doing sort of co-production and co-design work, it’s so important to also acknowledge all of the people who have been involved in those research projects. We acknowledge people with lived experience. We acknowledge Ras. Everyone needs to be acknowledged for all the work that they’re doing.

And so, a host of us are on this paper. During covid, we wrote this paper because many of the people talked about, you know, they were being approached because they have lived experience. Like, how — you know you’re surviving this better than most of us and can you tell us how you’re doing that. So, we had a series of conversations, and we wrote this when reality breaks from us, lived experience wisdom in the covid era.

Another one is by colleagues, Louise Byrne, Larry Davidson, and others. Louise is from Australia, to disclose or not to disclose. Again, talking about the central aspects of lived experience. Because disclosure, you know, I can stand here proudly and talk about my lived experience, but I will say that it’s a journey. It’s a constant journey of coming out about your various different lived experience, and it’s not easy. And this paper actually points to some of those factors. Again, all driven by lived experience and actually by lived experience researchers.

Another paper, which I just love the title That was a State of Depression by Itself Dealing With Society: Atmospheric Racism, Mental Health, and the Black And African American Faith Community. Dr. Desai and us, we worked with churches to get a sense of how do you even define those experiences that you have. They were not using the term depression, they were not using the term, you know, bipolar or schizophrenia. They were using other terms. So, how, if we’re trying to work with particularly the Black community, how can we define what it is that they’re calling those experiences.

And another paper that we work — we wrote, and I have Dr. Jonathan Edwards right here in the front, and this is a paper on surviving race with allies, disability, race, ethnicity, and human rights. And actually, this is for a chapter. We lost Celia Brown, who was an activist, just recently.

So, I want to quickly walk you through an example of this process. Everything that we do, we do it from a place of starting with the why. I don’t know if you know Simon Sinek’s TED talk on starting with the why. But basically, Simon talks about it’s really important to focus on the why. Because when you focus on the why, then you focus on the passion. What draws people into this work in the in the first place?

And when you’re working with community and researchers and lived experience and RAs and, you know, a variety of different people, while people are excited to come together, they will also get very bogged down in the work. Particularly when there are conflicts. There might be conflicts coming from the lived experience side of things and say, “You know, I realize that you’ve been doing this for the last 20 years. But we’re telling you that you should probably think about doing it a little differently.”

And then, you know, so there are arguments on both sides. So, how can we do that and hold on to that why. By holding on to the why in your own passion, that’s how you’re able to hold on to the work.

And so, here’s a why that was central to a NIMH grant. We have an R34 which we called Harambe, which are folks down there name. And it means, let’s pull together in Swahili. And it was really a project that focused on, how can we, you know, really look at the fact that people with mental illness are dying 25 years earlier than the rest of the population.

Every time I say that, though it feels criminal to say it and not do anything about it, right? So, but how can we do something about it? And that is the thing that drove us that were in that particular study. That was our why. How can we make sure that this doesn’t happen? That was our collective why.

So, in order for that to happen. What do we need? So, the how engaging all of us is key. And when I say all of us, we all have stories or barriers and facilitators to healthcare. We were hearing from the doctors talking about their barriers and facilitators to healthcare when they go in as patients. It was awesome for the people with lived experience to hear them also talk about their experiences.

Because they thought for some reason that they had a gold card, that when they walked into the medical facilities, that for some reason they got treated differently. But it doesn’t work that way. We also got to hear from RAs right, research assistants. Oftentimes, research assistants are like at the bottom of the wrong and often are not counted on or talked to about their ideas. But in this project and this work, we want to make sure everyone was included and that their voices were being heard. And I think that’s central to making sure that you get great results.

Inclusion, partnership, and transparency. What’s really key for all the work that we do is entering and exiting communities respectfully. I don’t care whether that is the local mental health system. I don’t care if it’s someone’s home, someone’s neighborhood, that we are only there as visitors, and then we will be leaving.

So, that space doesn’t belong to us. And just like you know, I guess, because I’m a Southerner, and when you walk into any southerners — particularly a Black southerners house, the first thing that you do is acknowledge the elders in the house and make sure that you say hello, right? And I’ve been in so many of these centers where you can walk through them and you can walk out and never have had anyone not say hello to you at all. Right?

So, it’s really important that we acknowledge that people work in those communities, that that’s their lives, people work in those agencies. And key to that is relationship building. One way to start building relationship is to acknowledge the people who are there.

Transparency. Can we be — can we really be honest with each other, and are we willing to learn from each other? We know that that’s not going to happen in day one. I mean, trust is the automatic — you know, lack of trust is an automatic, you know, default for many of us. Particularly if you’ve had any, you know, experiences of trauma or you know, we know that it takes a long time to build up that sense of trust.

But ways that you can do that, one is again, talking about positionality. Talking about who are you and why are you here? Asking appreciative questions. Turning things around and asking questions of what works. Don’t get so bogged down in the problems. Because we get bogged down in the problems, we’re never going to solve anything.

And breaking it down, translating discussions on research and in a language that we can all understand. I tell my entire team that if Chyrell’s mother doesn’t understand, then forget about it, right? And I think it’s so key. And I say that because when I call my mother and I talk to her about research, and she’s not able to understand, I need to talk to her in a language that she’s able to understand what I’m trying to say.

And I don’t think — I think we all need to do that. What’s the purpose of writing these, you know, articles and, you know, doing this work, if your everyday person doesn’t have access to it and can’t understand the language that you’re trying to, you know, impart.

Fostering understanding and mutuality. It has to come with the willingness to keep the discussions going, even when they’re tough. And they will be tough, there will be times when they will be tough. I think about that even from the — I’ll talk about from my experience. You know, it’s humbling when a person with lived experience, or a person in community questions you and your direction.

It doesn’t mean that I, you know, don’t show up with all of the knowledge and all of the experience that I have as a person with a PhD and all of my research accolades. I show up with all of that. But I also have to be able to have those discussions with, you know, people from all different sides. So that we all can come to an understanding about what it is that we’re trying to talk about.

A willingness to listen, revise and adapt, right? So, often we get caught up and you know those check boxes? Oh, you know, you have your checklist. I did this today. I did that, I did this. But sometimes you go checking too fast, right? And one thing I will say about doing participatory work in any form is that it will take more time than anything else. And if you don’t make the time, then you’re not doing it properly. I already mentioned entering and exiting and the willingness to partner is just key, and validation of each other’s roles in this work is also key.

So, opportunities to take action. Here, I just have a few of — discovery, dreams, design, and destiny are terms from Cooperrider’s appreciative inquiry. And really those questions of, what gives life? You know, what is giving your — you life, but also, what is giving life to this research. What might be envisioning results? What should be the idea like, how can we co construct this together? And how to empower, learn, adjust, and improvise?

Again, constant throughout the process, right, being flexible. I know you wrote in there and your, you know, specific aims that you’re going to follow this, that, and in the other. But also, be flexible, so that you can learn and grow and revise and adapt along the way.

And then I just want to end with these questions. What are you currently doing in your community to enhance inclusion? What more might be done to build community? What might we do collectively to advance community? If we stay focused on the why, we all get something from the partnership. In that particular study around Harambe, we all learned about what was happening in terms of health choice and health outcomes for individuals with mental illness.

We improve health outcomes for those individuals. We improve services based on what it is that they’re asking for, rather than just going about in our own way. And we have informed research that is coming from person centered perspectives.

Participatory approaches and the need for leadership. Today, again, the language that we are using is called co-production and co-design, leadership and also knowledge equity. And this is so key to how we think about and do this work.

At the Yale Program for Recovery, we started a consumer research and evaluation network probably over 20 years ago. We called it CREN. And CREN was really about bringing people together so that when a researcher had questions, they could call up a CREN. And then a CREN would be able to provide them resources that they need, particularly lived experience Resources.

Today, I’m proud to say that we’re moving toward what we’re calling the lived experience experts as partners, LEAP initiative. And that, again, is bringing in more people who can focus on lived experience research. I also just want to acknowledge that I’m certainly not the only person that has done this work. We have lots of people who are doing great work in this area.

I have colleagues such as Nev Jones, Laysha Ostrow with Live & Learn. And I mentioned Peggy Swarbrick, all lived experience researchers like myself who make sure that this is key to the work that They’re practicing.

In closing, in embracing the future of research and involving lived experience — lived and living experience. And I keep saying lived and living experience, because right now, we are — it’s so key that we make sure that we’re talking not only about the people who have lived it, but the people who are currently living it.

Those people may not even use some of the language that we’re talking about around recovery, around harm reduction. They may still be struggling and in and out of hospital or in and out of using drugs or choosing to continue to live the lives that they live. We have to make sure that we hear from both people with lived and living experiences and invite them in the partnership. It can’t be just the people who we think are, well enough, you know, to be at the table.

In terms of research in this area, we do need more research in this area, there’s a lack of systematic evaluation regarding how lived experience expert partnerships translate into improved health outcomes and reduced disparities. So, we need more research in this area. Existing frameworks often fall short of providing clear operational guidance for involving LEEs in meaningful, non-tokenistic ways.

How can we make sure that they’re involved throughout in the variety of different roles? Key questions include, how does partnering with LEE happen so that people across all levels or skills or expertise feel valued. It’s that subjective feeling of feeling valued and being a part of the process.

How do invest investigators incorporate these values in their research? And how do we know the authentic engagement of LEE in research is happening across different contexts, different cultures and populations/ As we have learned over the 25 years of doing this type of work involving LEEs again.

I’ll just say it again involves commitment. It involves time, resources, humility, sensitivity, a genuine desire to learn from one another. And most important, the ability to develop authentic relationships that build on mutual trust and respect. If we all had that, I think we could all go home at the end of the day and really feel like you could take a good nap, right?

And actually, I will say that actually — when they were asking me again, like, what is your creative process? That is my creative process. Because it starts off in the morning, talking to people that I love, that I love working with about research, about what’s up for today. And then ending it and knowing that we’ve done our best for the day.

Those relationships are not just part of the process. They are the process, right? They are the process. It’s so important that we make it a part of the process. And of course, make sure people get paid too, right? And in closing, the future, research needs to develop rigorous, psychometrically valid measures that can capture the multi-dimensional nature of lived experience, expert partnerships. And again, that’s cross diverse populations, diverse research contexts, and ensure that it’s authentic and inclusive.

And I just want to end here so I can open up questions. But these are two of our projects and two of our amazing research teams. First is the Imani U01 that I have with Dr. Ayanna Jordan out of MIU. And these are folks here in Connecticut, and they’re just beautiful faces. And the folks here, I actually have a Brazil Peer Implementation R34 grant where we are trying to implement peer support in the city of Campinas.

And these amazing folks have been meeting for the last year to learn about research, to learn all about peer support. They’ve adapted a peer support intervention and made it their own. They showed up. You know, obviously there were language challenges. I got a chance to visit them in May with Dr. Mark Costa over there. And it was just a tremendous experience to also just hear from them about how much they felt valued as being a part of the research team with Dr. Rosano Maco Campos [phonetic] over there. So, again, you can see this big smile on my face, because, you know, they just bring so much joy to my life.

And in closing, you belong. For belonging to be real, people need the recognition of others. A message given in word, deeds and attitudes that says you do belong. You are a valuable member of this community, and we need you. Thank you.

I’m not sure if we have time for questions, but I wanted to make sure that when we did end, because I know we’re doing a lot of transition, and that presentations are back to back. That people had time to talk, but questions?

MALE SPEAKER: Yes, hi. So, thank you very much. That was really fantastic and inspiring. I wanted to really make just two comments. I think a lot of attendees are probably not aware. So, I’m in the peer review branch at NIMH. So, we review a lot of the applications that come in that are sort of a specialized initiatives, and RFAs and whatnot.

And I think the point I wanted to make, which I think really follows up on what you’re saying, is that, first of all, we’ve seen a very large increase in the number of applications that include community based, participatory research. And so, I think that’s inspiring, and it certainly is consistent with the level of importance it takes.

The other point I thought would be worth making is that, you know, our study sections, which include — they focus on effectiveness of mental health interventions and also mental health services research. Again, something many of you may not know is they have built into them what are called public reviewers. And these are individuals with their people with lived experiences. They often have worked or do still work in community health clinics, at foundations, at advocacy groups.

And they are — like we have standing members of these panels that are such individuals. And it’s very clear that they bring a profoundly valuable real world perspective. That I think the scientists understand a lot of these issues, but they sometimes get a little bit bogged down in the design of the studies and whatnot and lose track of the practical realities.

And so, I guess my point is, NIMH, I think is definitely making efforts both that are inspiring applications, and then also in how we evaluate them. Thanks.

CHYRELL BELLAMY: For sure, for sure. And I haven’t served on the standing review for NIMH serve for two years. Shout out to Eileen Schultz [phonetics], who was just an amazing person. I just want to say that, you know, I love it when those folks are in the room. Because they always offer, you know, just get right down to the, you know, the plainness of it all and just pose these like, great questions that we all can think about. So, yeah, I love that you do that. Keep doing that. That’s awesome. Yes?

FEMALE SPEAKER: It’s very inspiring. I’m a researcher from [inaudible] program. [inaudible] I’ve been trying to involve lived in and folks with living experience, but it’s been difficult. One, because, you know, you have to know how to include them and build capacity before you get [inaudible]. Otherwise, that’s the [inaudible]negative consequences.

Plus, also this kind of approach that they don’t know something. Whereas I’ve tried to build capacity within our team, to engage them in appropriate ways first, and build capacity and try to get them to the people. Any suggestions for building capacity [inaudible].

CHYRELL BELLAMY: First of all, give us a call. [laughs] And you can talk to some of our folks down here. I think that — I don’t think we should over sort of inflate what capacity means, and just really think about inviting people to the table, right, first. To have conversations about the research itself, about what it is that you’re doing. And maybe focus on — even if you have to do that several times, like three or four times, until everyone has a good sense of what it is that you’re trying to study here.

And I will say that that’s not just important for people with lived experience, though. That’s important for the RAs on the team. That’s important for other people on the team too. Because, you know, the PIs, you know, you write the grants and you have, you know, you know it in and out. But most people at the table actually don’t know it in and out.

So, I think we all need to slow down and break it down so that we can explain it to everyone. Now, in terms of building capacity, there are so many things that you can do like for us, like take qualitative interviews. Like, if we wanted folks involved in qualitative interviews, we first might start off by shadowing right? So, having them shadow me while I’m doing a qualitative interview, have them in a room where we’re doing like qualitative analysis.

But again, giving them some of that same training that you would give any new researcher, you know, postgraduate student who’s coming to work with you and having and taking the time to do that. Because one of the things you mentioned about like that, you don’t want to further like sort of increase, you know, disparities, right? Or make people feel sort of, sort of less than because they don’t know certain information.

Larry Davidson used to have his daughter when she was young. She’s now that — she now done the intern with me over the last two summers. But when she was, like 10 years old, she made signs for us. And basically, it was like stop signs that said, break it down. So, in our staff meeting, if someone said something, you can hold up the sign to say, “We don’t understand what you’re saying.”

And I think again, that was important, because in our staff meetings, we have people come from all over the world. And they have — they’re talking about a variety of different science related topics. And I study social science, so I may not know exactly what they’re saying, sort of in the neuroscience area. But often, we just sit there and we’re like staring, and we don’t even know what the heck people are saying, right?

So, again, breaking it down allows everyone to say, “Let’s step back a bit so that we all can make sense of this material together.” And I think that that is heartwarming for other people, that it’s not just the people with lived experience that need this information and need to have it broken down, but it’s all of us, in some ways.

MALE SPEAKER: A great presentation. Congratulations. I’ve had this burning questions that I’ve been at Perch. And I’m glad I’m in the house so that I really present it and say it. And try to get some really solid understanding of exactly what’s going on here. I mean, research, I think, is needed. It is designed to make our lives better.

But what I’m considering, I’ve always thought about is sustainability. So, you know, we have gotten people to participate in the research. We’ve gotten people that we’ve seen their lives really blooming and get better. And so, knowing that this is funding by, you know, you guys here. And I don’t see why other government agencies that you’re not coinciding that with the research and research information to sustain it within communities, if it’s really, truly working.

I mean, what good is research? What good is discovering it’s something that [unintelligible] somebody life if it’s only for two years or four years? I mean, I’m not the sharpest knife in the drawer, but damn. [laughter]

So, that’s always been my issue with a lot of grants that we’ve done. And I’ve witnessed this. I’ve seen people get clean. I’ve seen people lives change and get their kids and they’re growing and their kids are in school. And I’ve seen folks really get it back together, you know, and get on their medications, and come back out in the community.

And at Perch, we got so many things going. We got a bigger group. We got, I mean, there’s so many things that people connect with and feel up into being a part of, you know. So, it’s — but it’s two years, and after two or four years, or three years it’s done. And it’s like, you know what it reminds me of? And my surgeon, this guy who did my hand, told me, he said my hand is so bad. It’s like a house that’s burned down.

But after you come in our community, you do your research, you get our information, and then we you give us a little, small stipend, and then you leave, and it’s like a burnt house with the train still up.

CHYRELL BELLAMY: Thank you. Yes, sustainability is key. I’m not sure. Maybe someone from NIMH can speak to whether or not you — you’re now putting in a sustainability statement. I know that when I was talking recently, actually last week, to a PO from NIDA [phonetic], she mentioned the acronym SPECS. And one of the S’s stands for sustainability.

And so, now you have to complete a form stating how you actually will sustain this work that you are proposing. And so, I — that was new for me, hearing about this particular form. I think that’s a wonderful idea. I think it’s a wonderful idea because, you know, I get the pleasure of working with this young man, Richard. And, you know, and if it wasn’t — if I didn’t have him in my ear of how can this be sustained, I probably would just say, “Okay. Here’s my — I did my analysis. I published my paper. Now it’s time for me to write the next research grant, right?”

But instead, you know, Richard and the other people on the team will say to me, “Nope. Let’s figure out how to then take this information and take it to the community. So, after you know Harambe, we then approach the city, — the state of Connecticut. And we were able to do three Harambe groups at local mental health in Bridgeport and Middletown, as well as in New Haven. So, they were able to see what does this look like with just people doing it in the community. And that was a great opportunity.

Again, it’s important that we continue to try to focus on how can we sustain this work? Because if we don’t, then we run — we are truly doing the disservice for our community. And we might, in a sense, be further increasing some of those disparities. Because people get to a point where they get start trusting in you. They see some improvements in their health. And then you kind of pull away, because the research is over, right?

So, we got to make sure that once we get this research done, that you know, we’re doing some translational activities. And then making sure that, you know, our agencies, our mental health agencies, our substance use agencies, our communities are really embracing the work. And then, you know, using our findings to do these programs. So, thank you, and thank you very much. One more question. Sorry.

FEMALE SPEAKER: Morning. Thank you for your talk. Cognizant of the time, this actually relates to what the gentleman before me said. So, we have some research that is traditional and it takes from the community. We have some that’s transactional. If you give to me, I’ll give you something I determine. Yours is more participatory, is more collaborative and relational, which I appreciate. But I’m curious, what did the individuals that you’re with, that you’re co-producing with, ask of you when you came to them?

CHYRELL BELLAMY: Wow. For me, individuals are asking for the honesty and transparency from the beginning, right? So, they want to know exactly how this works. And I say that because recently I was involved — I do this in various different projects. And several of us are in another project that I’m not the PI on.

And I noticed that, you know, we were in a separate meeting than the research team. And I said, “Why are we separated?” And they said, “Oh, it just makes it easier, because we don’t want to bore you.” I said, “Who says they’re going to be bored?” Like you just made an assumption that other people are going to be — because they have lived experience, that they’re going to be bored. I said, “Actually, I bet the people that you’re talking to, are probably bored. You know.”

But I mean, I say that because I think it’s important that they’re included in all aspects of the research, right? So, that they understand it, that they trust, that I’m not just using them. One of the things that they often want to make sure is, what do they get from it, you know? And often, that involves for them, they want to make sure that they got trained.

They loved all of the training from human subjects to HIPAA to learning about the different measures, to qualitative analysis, quantitative, you know, all of the different aspects. And also learning about health disparities in our communities, right? So, this is something that we all study. We know what the health disparities are in Black and brown communities. But when you are a person that has lived experience and you’re just you might be just hearing it for the first time, it’s also giving up my time to be able to talk to someone, even after the meetings, to say, “Chyrell, you mentioned this. Is that for real? Black people really are dealing with that?”

And just being really able to have those conversations that they may not be able to do in the room from the beginning, right? You know that also takes time, right? So, yeah, thank you. That’s a great question. I really appreciate that. And thank you all so much.