Dr. Karen Parker: The Causes & Treatments for Autism
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I made a huberman and i'm a professor of neurobiology and opened ology at stanford school of medicine. My guess today is doctor Karen Parker.

Doctor Karen Parker directs the social neurosciences research program, the stanford university school of medicine. The goal of her laboratory research is to understand the biological basis of social functioning at every stage of the lifespan. So this includes the bonds that form between infant and parent or parents, as well as the bombs that occur between children as they grow up, which, of course, form the template for social functioning when we become adults.

Doctor partners research is heavily focused on autism, and indeed on all forms of autism spectrum disorders. Today we discussed autism. We talk about the prominent theories and current understanding of the biological basis for autism, as well as what still remains mysterious and unresolved about the causes of autism.

You may have heard that the incidents, or perhaps just the diagnosis of autism, has dramatically increased in the last ten to fifteen years. And today we discuss why IT is, in fact, that the incidents, not just the diagnosis, but the incidence of autism, has so dramatically increased. And perhaps most excitingly, doctor Parker shares with us brand new research foundation from her laboratory that point to a new understanding of what causes autism as well as a novel treatment for autism.

Before we begin, i'd like emphasize that this podcast is separate from my teaching and researchers at stanford. IT is, however, part of my desired effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, i'd like to thank sponsors of today's podcast.

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If you'd like to try the waking up, you can go to waking up dot com slash huberman and access a free thirty day trial. Again, that's waking up dot com slash huberman to access a free thirty day trial. And now for my discussion with doctor Karen Parker. Doctor current Parker, welcome.

Thank you. It's great to be here.

This is going to be perhaps one of the longer conversations that we've been able to have over the years, in part because whenever I see on campus were had in our respective directions. But i'm very excited because the topic of autism is one that is on a lot of people's minds. And I think the first question that always comes up, IT seems, is whether not the frequency of autism is indeed in increasing or whether not the field of medicine is getting Better at detecting what was always there over time. Do we have any clear answers to that?

Well, I think it's a multi fact toral answer.

So we are getting Better at detecting autism, right? So in the past, we were diagnosing kids at nine or ten years of age, right? And now clinic are able to reliably diagnosed kids at two to three years of age, right? So there's more people um there are pedestrians, have autism screeners and how so when you bring in your baby and over the first couple years of life, you're filling out screeners that are looking for autism symptoms, right?

So so there's just a lot more awareness around autism, but the rates have increased to now one in thirty six U. S. Children have a diagnosis of autism, which is over two years ago. I was one in forty four.

so one in thirty six. Well, I feel like I was just yesterday when I was one in eighty but is one in thirty six. Um the average across always and girls does IT kew differently if you look at just male birth versus female first. Yeah.

that's a great question. So out is missing biased prevalence. So you have and again, the study's vary. I mean, it's it's worth noting the autism is a highly clinically heartened ous disorder, which means that if you've met one kid with autism, you've met one kid with autism, right? So so we have to bear that in mind as we have this conversation.

But know different studies show that about for every one girl, there's three to four boys, they're impacted by autism. So there's differences in the prevalence rate and also there's different monitoring sites. So the way in the us. That these data are generated is the cdc has eleven monitoring sites across the country and so they they follow um children. And then that's where we um that's where the prevalence rates from and they released new prevalence rates every you know few years.

So if physicians are able to detect autism early, say in a two year old, there are a three year old to imagine that they're working off of tests that don't rely heavily on language because even though you can get some for most two and three years old, most two and three year olds don't have a very extensive vocabulary. And i'm guessing that they're also relying on things like visual gays, among other things.

We've always made clear that this is not a discussion to allow people to diagnose themselves or others. But um with that said, what are some of the diagnostic tools that people use know is that language as a vision or does IT present as you know, abNormal auditory processing? Maybe you could give us a thing.

So autism is a behavioral diagnosis, right? So like other areas of medicine where you might be able to take a blood test or there's other sort of tools, it's all a behavioral diagnosis by um an expert. So usually um a psychiatrist or psychologist.

And they look for two core features. So so this is based on the D S M um five. And there are the two core features are pervasive social interaction chAllenges and the presence of restricted repetitive behavior. But there are a lot of people with autism who have anxiety, there are a lot of people with sensory chAllenges, there are a lot of people with seizure disorders, um sleep disorder. So again, it's each person with autism has the sort of unique collection of trades and you know that's how they get diagnosed.

We're going to talk a lot today about interventions, but how early are some of the behavioral interventions, and I should just say, any interventions introduced nowadays. So if someone brings their child to the african and they take on these test and that a child is deemed as having autism, um well, the one year old or two year old immediately go into behavioral interventions.

Well, so usually you need to have the diagnosis of autism and then there are behavioral interventions or a variety of different ones um that are used. There are some studies where um because autism highly heritable, you can have one child with autism and then you if you have subsequent children, you are at an increased risk of having subsequent children with m and these are called baby sibling studies. So what you are doing is enriching the population of infants that you follow prospectively um who are more likely to receive an autism diagnosis. And there are studies where some of those children are enroll and behavioral studies even when they're couldn't quit at risk.

I've heard before that you know parents in which one or typically both parents or so of the engineering Matthew physics called on, quote, hard science type or more likely to have autistics children. Is that true? I did that bear out in the data. You know if you look at profession or or um you know undergraduate major, does any of that correctly with the probability of having an autistic child? Yeah well.

what I can say is that there is spend some studies. So what we know is that autistic traits are continuously distributed across the general population. And there is a study and there is a couple different instruments that are used to be able to measure these autistic traits.

So there's something called the social responsible scale and then that's A U S. Based instrument and there's an autism questioned that's a similar measure that was um designed in england. And what what we know from work with the aq is that individuals that are in intense stem fields like engineering, physics and mad have a greater burden of autistic trades, even if they don't have an autism diagnosis.

Okay, so that leads me to wonder whether not this whole business of a spectrum yeah is actually multiple spectrum spectrum, spectrum ums are speci with someone will put IT in in the comments on youtube. We know that for sure. Please let me know. I would like to know what is the plural of spectrum, spectrum.

Um you know because when we hear the word spectrum we think, okay, there's a spectrum of severity, right? And in fact, I have some experience with severe autism, not in my family but where I went to undergraduate university ucc of arba down the way from that school was the dever o school, which is a school which been there for a long time that parents would send their kids if they were severely autistic. IT was actually where dustin hofman went to study for his role in rain men here.

And the the kids who were were really delightful. They used to come in to town, everyone snowdown to the coffee shop study, and they would also continue on from there to came out, which is why the dust n hofman character would say, gotto go to cam mark got to. He would do that reputation that came mark was down the road from our in our college housing and the school.

Those kids were literally in a away from home facility full time. And I spoke to some of the parents at one point, and they were at that facility, meaning the parents had sent them their children a way, way to live there full time course. They get visits and they get visit home um because they were, I suppose we could say, at the foregone of some spectrum that made IT least to the parents idea impossible for them to be at home.

okay. Now at the other end of the spectrum, if one is you're simply think he in terms of severity, I know people who have self identified as autistic. That's how theyve referred to IT.

So I feel comfortable saying that they've said I am autistic and they seem pretty high functioning, meaning they have driver's licenses, drive cars, are healthy relationships and manage life apparently well. Um they have some trades that yes, I would agree or a little bit different, right? So where we get to the neurodiversity.

But I guess the point is, you know should we think about autism as on a spectrum or given the fact that there are these i'm kind of collections of different traits, could there be a spectrum of severity, also a spectrum of um you know more uh steroid c behaviors um another spectrum that intersects with that that has to do with you know obsession with a particular topic. You know you could imagine that there are fifty or sixty different spectrum, spectrum that I still don't know you want to say. And then when we talk about thus spectrum, we're really talking about something that in multiple dimensions and not just one line that goes from severe to mild.

Yeah yeah. I mean, I think this is where understanding the biological basis of would then allow us to be able to say you like, here's these different dimensions, right? But not understanding the biology you're left with.

Okay, where are we lump ers or splatters like how do we think about this? Because autism is highly heritable. Les, so there's about forty to eighty percent of autism is um is genetic right? So this very wildly right.

But the but the common thinking is that the majority, about fifty percent of autism is is associated with common genetic variants. And so if the way that we've always thought about this is that there is this, you know, autism is largely an inherited polygenic condition. And but what I mean by that is that you have a lot of common variants that are additive.

And so if you think about this collection of common genetic variants, that under why this spectrum, right? So if you have less of a dosing of somebody who's common variants, you might see somebody who's a lot more who's higher functioning, like you said. And if you end up with one of the single gene, highly penetrant resorters, you might see severe and electoral disability and sort of lower functioning on the other end of the spectrum.

But I think that there is a lot that we don't know. And what you're bringing up, I think, underlines you sort of an issue with a autism, which is common for many brain disorders, which is like if you don't understand the underlying biological basis, IT also gets very difficult to diagnose and treat, right. And that's where we are with a lot of different psychiatric developmental disorders to date.

Has there been any specific neural network that we can point to and say, oh, that's the neutral network that seems to be different in people who are on the autism spectrum.

Um I saw study published recently that seem to point to the idea that the genes that are altered in autism um at least include a large number of genes that are altered or the proteins that are the consequence of those genes that are altered and exist at the synapse that the connections between neurons, and i'm asking IT that way because you know some years ago was at a talk on autism at stanford and soon raised their hand and says, um do you even know that autism is a brain issue, right going to be an issue of the immune system or the cardiovascular system which at the time seem like OK cash? Of course it's. But wait, then you stop and you think and that's a really good question. How do we know it's it's a chAllenge of the brain.

right? I think that's a great question, right? And there maybe people talk about autism, right? And so when you think about where the major player is, you know, we're IT at the infancy of thinking about this, right? And so maybe for some people, it's more of a brain based disorder.

Maybe for some people it's, you know, the connection with the gut in the brain, right? I think what's also really tRicky, right? So one thing that you have to ask is what are the barriers to progress and understanding autism, right? And so the way I think about this is that let let us take for a moment that this is a brain disorder. How do you study IT in people, right? So you know it's very difficult to get access to either rebel spinal fluid which is a fluid debates, the brain um brain tissue biopsies.

It's very hard to get people, especially children that are really impacted into a brain scanner right? They can sit still, they may have sensory issues, they don't want to go into a scanner, right? So a lot of the pools that neuroscientist or psychiatrist sts have to think about looking at the brain are um limited, right? And then and then the other part is how do you models the other way we might think about getting access or or thinking about model systems? What we need to do is think about the control animals.

And we need to make sure that the species that were modeling them in has um features of control humans, if you will. So we need to have complex cognitive abilities. We need to have complex social skills. We need to have an organism that has vision as its primary sensory modality, right potentially sleep consolidating. So we need to think about at all of those and and the the tRicky part, I think, until fairly recently, was that we were doing all of this work in mouse models.

And you know the control mice just fundamentally lack many of the characteristics that are needed to model, you know, autism with fidelity, right? And and I think that when we look at drug development pipelines, about fifty percent of preclinical failures. So that would be something as tested in an animal that works and then fails in human clinical drug trial. Fifty percent of those failures can be attributed to poorly selected animal models. And so I think part of where we we will be getting traction is picking, you know, developing sophisticated models as a sort of point of entry into being able to understand some of these things that are really difficult to study on people.

Yeah such a key point. And for those that um not heard of preclinical models, preclinical models are non human models. So I could be mouse, could be non human primate, could be flies or worms for that matter.

But we're going to talk a lot about a non human primate preclinical models um in the work that you've been doing and of course also the worth you've been doing in humans. The other animal pride, the other primate, right? exactly.

I love to remind people that were primates, old world primates. So thank you for doing that. So you've been talking about the genetic influences on autism and of course genes in the environment interact.

It's never nature, or nature is always an interaction. And that isn't just about the fp genome. It's also just about the fact that nature impacts the genome and our genome acts the way that we interact with the environment. Is that a so what is the role of the environment in autism, both the frequency and the presentation of autism?

right? So I mean are again lots of different epidemiology, ical studies, so um advanced parental age, uh prematurity, severe prematurity as a risk Victor for autism, um maternal illness during pregNancy um so there's a bunch of different things that have been associated with an increased risk for autism in terms of environmental .

influences and how they can intersect with biology. Um one of the things that I was really struck by in the really two thousands, at least by my read of alerter, hasn't really gone anywhere, was this idea was proposed by possum used to run the new biotic department um at yell um expert in brain or o anatomy and on human prime and in humans and real logy um really illumination of our field and a series of papers expLoring how the migration of neurons during early development as you and I both know, but most people out there probably don't know because we haven't covered this in the podcast um is not typical dinner table conversation.

You know when when an embro when a human embro is developing that the neurons are born at one location and they migrate out some distance to their final um resting place, where then they grow out their connections and connecting with one another and that processes neutral migration is also critical for the eventual wiring in the brain. And rocky sha had this idea that perhaps, and I really want to emphasize perhaps, that the more frequent incidents of autism might be correlated with the increase in early pr nado ultrasound. And he had these papers published in a of really high profile journals, including national science.

And I were showing in a mouths model, if you do ultra sound with each successive ultrasound, you got more migration errors, right? So this, to me, was that, you know, an interesting example of of the environment, frequency of ultrasound. And so migration having some sort of interaction.

But I seem to like I never went anywhere, never got tacked to okay. You keep in mind the number of ultra sounds that you're getting for your child. And I of course, ultra sounds are critical for for pregnant women to get.

I'm because they can stave off a number of developmental issues and their super are important. But you know we've heard about ultra sound, you know IT within the scientific nature and then occasionally will hear other theories about, okay, it's having two parents who are both engineers and they will hear. Oh you know it's um you know toxic in the food environment.

We've heard you know hypotheses about vaccines or the the advance of the vaccines are contained in you know in that large cloud of theories. Has anything really um emerged from them? Is like, okay, there really seems to be at least one major risk factor, environmental risk factor, because I feel like all those theories and I come up, gets some popular press bunch of papers are published.

Sometimes those papers are retracted, like in the case of the accent es and then the theory kind of dies yeah. So is there any specific vironment tal influence on autism that we can say? Yes, there really seems to be something there.

I I mean, so it's a really spectacular good question.

I think the tRicky part about IT is that every single person that comes into a trial has a different genetic background, right? And so until we can have these a priories stratified trials, where you could then, as a good scientist, you will only manipulate maybe one, two variables at a time, right? But when you're doing these large epidemiology, ical studies, because you can't, it's very difficult to do experimental studies, right, especially with developing children.

I think that's an incredibly difficult study to do, right? So there has been an interest in this field of there's these neurology etic syndromes that have high penetrant for autism, which basically means that you could have a disorder um or you know another genetic condition, let's say doesn't have to be a single gene, but that a lot of those kids tend to also get in autism diagnosis. And so there has been working extension since fragile x is a good example where because autism is so diverse in terms of clinical presentation that lets say you have a medication that could work for a handful of kids in the trial, you may not be statistically powered to see IT, right?

So so you know, the way I think about the autism world is there is so little we don't know. So think about being in a dark room, and you have a flashlight, and you only see where you shine the light, right? And so if you think about a very hard origin ous genetically had origen's study, it's gonna very difficult to tease out these pieces because an environmental risk factor um might be a driver for one kid but not another, right? And so I think what we need to do is to have these genetically defined sub groups of individuals and then be able to test the g by gene, by environment interactions, or in this genetically define group of individuals. Can we test this? Certain medication deceive its beneficial for this sub .

group of children got IT. So you mention fragile ax, which we know um presents with autism like symptoms in some cases. And then I think of another disease like Timothy sync me a mutation in an l type cost um channel which um for those who you don't know what these cell types telsey g channels are there they're not just important for the function of neurons and the brain.

They're really important for the function of neurons and other other tissues, including the heart tissue, right? So um kids with Timothy syn rome have cardiac shoes and they have autism. So you know I think it's important for us to going to explore this a bit, because in most people's minds, you know, kids with autism have autism and occasionally they will have other issues, you gut issues or heart issues or moscow skel till issues.

But we often think that that's the consequence of the artist. But often times that they have multiple things going on and the autism 是 could be secondary or independent of the other thing that's going on。 So this is what leads me back to this idea of a spectrum know is IT possible that what we call autism is actually like fifty different disorders or fifty different conditions coming on what wants to call them um I mean, what is autism really? I mean, what does that really center around? What did IT I I think here maybe it's useful to go like do we go to the diagnostic criteria? Like how do we decide if a child hazards sm, if they all save a bunch of other things that are chAllenging them?

I am I I think that that's the sixty four thousand dollar question, right? And again, in other areas of medicine. So if you think about, let's think about cancer biology, right? Like decades ago, somebody would come in with cancer and you would hit them with radiation chemotherapy, and that was the best that we could do, right?

But with the invention of a lot of molecular tools, you can remove a tumor and you can do molecular profiling and even, you know, have personalized medication made, right, to attack that tumor. And so you know what's really tRicky when you have a behavioral diagnosis that's not biologically defined, you you see a lot of horizons. So it's incredibly difficult, I think, to answer this question because we don't know how many kinds of autism there are, right? Like there will be people who say, if you have a disorder like fragile acts or potty Willy syndrome or timidly syndrome or or a variety of these other, there are people, people, people.

I've heard clinicians say, well, that's not really autism, right? That's a piece of fragile acts, right? But if it's a behavioral diagnosis and they meet behavioral criteria, IT becomes this weird circular argument, right? So like until we really understand what odd sm is, I think that it's going to be very tRicky to start you know sub defining different aspects of the condition.

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Let Greens dot com slash huberman to get the five free travel packs in the year supply of vitamin d three k two. Well, this is probably a good time for us to think about the work that you've done in terms of trying to tack the biology of social communication and behavior yeah with those things interact conscious language will also behavior to autism and humans using nonhuman primate models and then of course also discuss some of the words that you've been doing in humans. And we can't have that discussion without first having a discussion about two neuropathy des, that I think most people we've heard of at least one of them.

And I think there's a lot of misunderstanding about what you're going to clarify that for us, which are oxytocin and visio present. So before we dive into the uh the important worth that you've been doing on baza present in particular, but also oxytocin autism, what are oxytocin vaso present? really?

okay. So there are the small little peptide. There are nine amino acid blogs are very tiny. They only differ by two amino assets, and there are these ancient pep hides that are hundreds of millions of years old and in almost any species studied. Um whether it's the current version, you might have visit hotel or other mat hosen which are sort of precor forms in other species, but there are highly evolutionary conserved and they're involved in social behavior in pretty much any IT could be egging IT could be bit but reproduction and social behavior across the final genetic taxes.

So how cats make a pacer person in oxytocin, humans obviously make razor person and oxy, and pretty much every other species that has to interact with and connect with other members .

of its species, especially memory, right? So oxyde VISA person on our pervasive and mama species.

do the different species tend to make oxytocin in VISA present in similar brain areas and tissues?

Um yes but not completely overlapping. But I I think the thing that the the beautiful mystery about this and the infuriating piece of them is that because they're so structurally similar um they can have similar effects and they there are four receptor or that they bind to. So if you think about a hormone or a neurotransmitter, so oxytocin baza present, if you think about them like a key and a reception, like a walk, and you have to put them together to open a door, open behavior, they can bind to these four receptor, so IT can be very difficult to disentangle which one is acting and at which reception and where in .

the brain oh so ox via s chemically similar interesting. And where would you say is the greatest um output divergence which is just nerd speak for? Is there an example of something the oxytocin does that razor present? Doesn't vice vera?

Yeah okay. So what's really fascinating is these two other transmitters or hormones were discovered for their peripheral effects, which basically means not in their brain but somewhere in their body. And so oxytocin's involved in um uterine contractions and milk let down and so was a during lactation.

So people sort of always thought of IT as the female form and then VISA person has um at least and in the purfled system has been involved in urine regulate linate output regulation blood pressure um and so we only knew about their their physiological roles as that sort of classic hormones for decades and what was interesting is these um like naming conventions are fascinating medicine, right so you can a virus after where IT was first found right or IT could be named after somebody who discovered the disease's like alzheimer's. Ces is a good example. And what was interesting, oxytocin was only named once.

Vasa person was named twice. So it's either called arginine vasa person or ani diode tic cormon. And so I had two different names.

And so as you can imagine, sometimes genes or name twice. And so somebody cancer a studying one gene and somebody and autism is study another. They're not even communicating because they don't even realize that they've at least historically now we have all kinds of genetic sites.

So it's less likely to happen now. But but what was fascinating as they were, these hormones were named oxytocin is greek for quick birth. So for decades people only appreciated their physiological roles.

But but there are no oranmore ous saying, hey, so these are both made. There are made in a lot of different places. but. The actions sort of happens in the hype athalebs where they're made and there were anonymous. That said, weight, these are of project back into the brain. What are these doing in the brain? And one of my favorite historical stories was um I had a mentor um a colleague guy and you know who I didn't train with but he was a real source of wisdom to me for many years and his name is court Peterson and he told me this wonderful story about this duke zoloft named Peter cloth firm and Peter were studying ungulate so sheep and goats and he wrote a story of paper in one thousand nine hundred and seventy one called mother love what turns IT on and um you know one thing about science is I love going back and seeing where do the polls of wisdom come from and so he wrote this and said, you know, oxytocin is orchestrating all these events of motherhood.

And there are sheep and goats in particular that have offspring that are precocious, meaning they're basically born ready within an hour they can run with the heart, unlike our species, which is ulterior, meaning we are very helpless infants and mom needs to bond really quickly with that baby if it's going to be running around and you only from an evolution and perspective, you want to be investing in the baby that gears, not somebody else is right and um he hypothesized that IT was oxytocin that was being co released into the brain under milk let down. That was what turn mother love on and that was really the beginning of this whole field of thinking. And so that opened up thinking about oxytocin, road maternal care and a variety of other can I just briefly interpret because .

I find that so interesting and I know it's interesting to everyone listening as well because yes um and thank you for um making IT clear.

The oxidation has many different roles, but this role of mother love and bonding to infant um has been needing to ask whether or not the idea was that oxytocin is released in the mother when he interacts with her own baby um and that leads me to the question is oxytocin released in the baby um in reaction to to the mother and how long is that effect lasting because in order to have a pervasive bond with that baby and not just another baby and of course we still have visual cues and know we know our baby versus another baby most instances um the hair exceptions perhaps not aware exceptions but leaving those aside, you know the mechanism that would allow for mother infant bonding, an infant mother bonding by way of oxx y tos and presumably is something that is literally changing their brains saying is you are the are the center of my life and the baby of course as I will you are my life because you are the source of life right certainly for the early part um really part of life in the nowadays seems that that that can extend well into the the teens and eighties for some people but um how is oxytocin? King is working over the course of minutes, hours. Is there some specificity of this baby in this mom that links them in in some more pervasive way? I mean, how is oxy tom doing this magic of bonding?

Yeah I mean, it's it's very special specific, right? So I think that and you need to think about like the evolutionary history of the species, right? So if you think about sheep, goats, the early studies that we're done are you um the passage to the vagina inal canal with what you you had activated oxyde and receptors that way.

But if you give an oxytocin and tagging is meaning you would give into the brain something that blocked the oxytocin reception. So if the oxide toast and is being released into the blind brain, but you have a pharmacological agent blocking its ability to buy into its receptors, these shep goats wouldn't born to their baby. For instance.

I said, literally, the passage of the baby out of the vegan trigger the oxy tos pathway. The release .

of oxytocin.

Ata is so beautiful, because if you had to pick one event, yes, to trigger the release of oxytocin oxytocin's role is to create with offspring that will be the event because that's a tough one to mistake, right? right?

But what I will say, because I think you will know to avoid you getting attacked on .

twitter or where you might if if not for this discussion. And another one, but i'm tougher .

than one. So but it's really species specific, right? So if you think about our species in a water primate species, we live in these extended family groups and that's how we evolved. And so unlike a go to a sheep that might live in a heard where there's a lot of non relatives, we lived in a community of relatives, right? And so we and we do all kinds of care of extended relatives.

And so you wouldn't necessarily expect in a primate species where you have this long wearing history where helped from the family and and by bruno care, where where sort of everybody is sort of like IT takes a village to raise the baby we readily adopt in our in primate societies, right? And so um like I had A C I am not tell you something personal. I had A C section um and um had I had a lad of post part of complications and so lactation didn't work out that well for me.

One of my friends would say my massive dvds and plenary ebi. And so I almost died after my son was born the first time. And so I didn't have a vaginal delivery.

I could dv debo yeah and I .

was sort of like, welcome to motherhood and I was in the ICU and had to get a filter put in an inferior of in a cave of a filter to um stop me from dying as a scatter shot, clothes all over my lungs. And so I didn't really, I didn't I didn't do a vagina inal delivery. I had to see a section and I wasn't really able to lack ate and man, I love that baby, right?

So you know, I can give, you know, what I will say is it's really different in primates, and we don't really understand how bonding occurs. But what I will say is that bonding between a mother, you really to think about the evolutionary selected pressures. So I was an evolutionary biologist before I found nurse science, right? And so I really everything I do I think about from an evolutionary perspective um so but IT is um many people go into the oxytocin viasa present field because they have a lot of questions about social interactions, right?

Like I think if you think about this is being social is actually one of the what are the core characteristic tics of our species, right? So social interactions are rewarding from infancy. They keep us alive, as you mentioned, right? And so I think it's not an accident that the way we think about disorder in our species is many disorders are disorders because of lack of social connectiveness, right? So I could be something like autism where, you know, there's these pervasive social interaction and governments IT could be something like drug abuse where you know, you you a risk factor. Drug abuse is feeling you know socially disconnected and alone right um social um isolation or loss of a loved one is a very strong predictive of the onset of a stress related depressive anxiety .

disorder in terms of when and how oxytocin is released. You mentioned a mother infant bonding. Um I think you said yes that the infant is also releasing oxytocin, we think um so it's it's by directional we think .

I think most of the work has been done in mom would be and again, this has not been really done well in primates, right? We're extrapolating this information from species have different evolutionary histories than that, right? So it's goat, sheep, peri walls, my threads.

So what do we know about the role oxy token in humans, do you? I mean, we know it's there.

Yeah we presume based on the animal models that it's all in mother, infant bonding and presumably romantic partner bonding at least you hear that yeah what um IT was unfortunately nicknamed the love horn yes um and the reason it's unfortunate IT was is that well that might cure attention to oxytocin and you know big fan of people paying attention to biological phenomenon IT ah IT discards the other and many roles of of oxytocin but yeah what can we say about oxytocin in humans if anything? Like do we know that he does? I mean that we're just so we're assuming based on the animal moils that IT does something. I think this is very different than like dopamine where there is tons of animal model data, but we know but there are brain imaging where we know where double is expressed. And do we even know where oxytocin factors are expressed in the human brain presently, that information recently.

But again, there's a lot of specificity.

And I think if you're thinking about disorders, you would then have to study those specifics of populations, right? And and you need you know a lot of this work has been done, so you have to think how do we study IT, right? So the best way to study that would be to have radio tracers where you could then, which we do have for doping and and other compounds where you would then go and see where after some boy's performed a test do we see you know um activation rider uptake.

Um there are some imaging studies they're usually done giving intro oxy tos um and then you basically ask questions about, okay, we give you oxytocin entrance which presumably enters the brain this we can talk about reasons why we think that um and then we have you perform on some task, right? And so you know there's evidence if you give oxy hosts and IT diminishes the amiga ous response to fearful stimuli. Tes, so that I might have this sort of proof social effect and and IT was actually data like that that cause people to start thinking um initially about oxytocin and those were data .

in humans that's right. That reminds me that there was this brief moment where oxytocin wasn't just being discussed as the love hormone's IT was being discussed as the trust former right also far too simple heuristics. But but again, I think it's cool that the you, that the press picks up on these things and at least tells people about what's being discovered.

And we just always have to be careful, not, I have IT lead to the assumption that that's the only role of a given, of a given hormone, so I can reduce apparently IT can reduce the output of the amy galen some way, this brain area associated with threat detection um and so you could imagine how that would bias the person towards being more pro social. Have there been studies expLoring the role of oxytocin in making autistic children more pro social? And behind that question, I supposes the assumption you can verify or or not that autistic children are less pro social than other children.

Um is that true um or is IT that autistic kids are just. Maybe more pro social with the one friend they really, really like yeah happen to know some kids with autism or how do you want to phrase IT and they have close friends and they seem to really like those specific friends a lot like they seem very happy when they shop at the door and like all all the hallMarks of, you know, healthy social mind. But IT is true that they are uncomfortable in in groups and where there's a lot of noise of busy birthday party is overwhelming for them, but see them playing with one or two friends and like you could see all that and as soon, okay, it's just kind of an introverted kid actually reminds me, you know, I mean, I don't have a problem with crowds, but I I much prefer to be with a small group of friends .

or a one close friend yeah so I hear you.

I'm not wait to right so um you know how do you think about this?

Um okay well, I would say the social features of autism are interesting, right? And so you might have there were there was an attempt a long time ago, like one thousand nine hundred and seventy nine, there is a woman named lorna wing who tried to subtype the social features of autism, right? And so there could be people um that are socially avoided and really just don't wanna have social interactions. There could be kids that are um active but odd, which means that they have an interest in being social but maybe they don't read social cues right and they interact in ways that other kids don't understand or me could cause bully ying right.

And yeah exactly .

um and that's often why some artistic ds do Better with adults, right because adults know how sort of channel um discussions with somebody who might be a little socially awkward right but there's different finite types mean people having a disinterest in social interactions could be that they're highly socially anxious right um that making eye contact makes them anxious.

You could have somebody who has maybe is relatively, let's say socially intact if you will, but they have um overwhelming sensory abNormalities that make IT very difficult. Um turn iraq with other people right. And so like so let's just say again, that's another heavy. There have been some studies administering oxytocin to individuals with autism. And again, these are these single dose studies.

So the first studies that were we're done were looking at single those oxytocin in males because some of the and we can talk a little bit about y oxy tos verses viasa person, which VISA person actually would have been my choice based on the animal literature. We can talk about that. But these oxytocin was given to males um partly because IT wouldn't the idea would be that the off targeted set effects in the prefer nervous system I milk light down uterine contractions are not going to happen in males right? And so that was deemed that they might be safer subjects. Males are often also the that go to for research studies, as you may have talked about on your podcast before.

Yes, something that fortunately is changing, thanks to a anded by the by the nih. I I had to just kind of smiles slash raised my ebrow a little bit at the idea that know the assumption that oxytocin, minister to males. Yes, a one can see why I wouldn't cause milk back down or you during contraction.

But of course there could be other preferable facts of oxy thousand and males but they had big, they had to pick one so they went with males okay. So um and there is this higher incidents of autism in males. It's not a terrible place to start. You just would hope that they would also do the experiment on females. Um so they're doing this spite nasal .

spray so entrance one of correct. And for reasons that I don't understand, it's twenty four international units and I think maybe somebody did the first study using IT. And you know this is how science happens, right? And IT work.

So then everyone uses that protocol. And so then there's been a lot of studies looking at um you know there's one reading the mind in the eyes. So can you look at pictures of somebody y's eyes and then ask, what is the emotion that they're feeling?

right?

Oxy token or placebo? Um where's your eye gays going in a picture? right? So one one of the theories is that people with autism, me, at least a subset of them, lack social motivation.

So maybe they're not looking in the places like eyes where you receive a lot of social cues that are relevant to social communication. And so some of these early studies showed that a single dose of oxytocin in people that were um had high functioning autism. So they were very able, like you said, they could come in for studies and that IT look like IT had some potential effectiveness. And so they became a really strong interest in the field to think about oxytocin intially as a therapy for autism.

And is oxy tos available over the counter as IT require prescription? I I mean, you see sites that are selling, but that doesn't mean anything these days. There's great market. There's all sorts of that going on.

But I know people that have used oxytocin, um there's actually a market for and by the way, folks are not suggesting this, but so on the other day told me that theyve been regularly taking a oxytocin kadee nasal inhalation as part of their work with their licensed therapist on like ptsd types stuff relating to which is called relational trauma. Um so that's happening um just think about oxytocin alone for the moment. Um our parents of autistic is is able to like biaxial nassy no so .

so IT would need to be written like the prescription would be need to be written by a um by a physician and it's not on the market, right?

So there is one thing we should say, there is only two drugs that are approved by the fda to autism in their both in psychotics which they um they treat associated features like ritalin and they have off target effects like weight gain and and and you know so we don't have any medications that are currently approved in the U S. Or any else for that matter. I should treat the .

core features of autism and and unfortunate and hopefully that will change in the not too distant future um do we know that children with autism, people with autism, because I am, is just assume that autism is stable over the life spin like a child is diagnosed with autism, are they going to be an adolescent adult autism .

so I would say that in a lot of cases autism is life long impact. But there are people who outgrowth their diagnosis um you know there are people who respond well to behavior therapy. Um I mean, obviously, it's not the cure for everybody.

There's lots of people go through intensive behavior therapy and probably see minimal benefit. But I mean, it's certainly something that occurs in childhood for the diagnoses occurs in childhood, and, you know, for most people, will then be present across the lifespan. So we could say people with autism, because each studies, sometimes we will have adult, some times you will have teenagers. Some penny of kids is .

IT known whether or not people with autism is swimming. They meet the criteria for being able to seek that at that moment have lower natural circulating or active levels of oxytocin because you know one thing for an nasal spray to um a boxy OS to improve social functioning. It's another um to know that IT that the effect is addressing an underlying biological deficit.

Yeah that is such a great question. okay. So we should unpack that because there's been a lot of work in this area. So the first question is where are we measuring the oxytocin? right? So we mentioned oxytocin as all kinds of effects in the body as well as the brain, and it's released into the blood, but is also released directly into the brain.

And there's variable evidence about, if you measured in blood, is that a read out of the brain or not, right? Or should you be looking at something like spinal fluid that's maybe a Better biochemical proxy of the brain? Um most studies.

So what I will say is there were there has been more a handful of small studies where there has been some there's spend some benefit, maybe no benefit, small effects. We did a study that was a small study at stanford and IT was based on a mouse genetic data, and i'll all sort of walk you through what we did. Um so there's multiple mouse models of these neurogenetic syndromes where people have social impairment, right? We can quibble about whether that autism or not, but they have social impairment.

And so that there are this um fragile x mouse. There's a prodder Willy mouse with just the magic two gene that i'm gets manipulated and then there's a cat nap two mouth. And in all of those instances when you genetically modify those mies, you see a reduction of oxytocin, the hyper Thomas. And what's interesting is that um in those instances where you see this genetic modification, you do see lower blood levels in these genetically define models.

What's really cool as you can give oxide tosta across development in those models, and at least in the catnap two mouth, you can restore oxytocin, or a number two equivalent of control animals, suggesting that oxytocin is doing something in these oxytocin deficient animals, right? So these are not in an oxytocin gene manipulation, but these are these syndromes where you see as a consequence of manipulating genes for these syndromes that oxide tosa gets knocked down, right? And so are thinking when we went into our clinical trial was what if um its blood oxide toast in levels that they're going to be a subset of individuals that just make less oxytocin mans humans and that maybe those are the individuals who can who stand to benefit the most from trees.

And so we were the first group um to ask you know across this range of individuals who showed up and we did in in all the trials that will talk about today. These are done with my colleague tony hard in its stamford as a child psychiatry rist um and we always have double blind meaning that the investigative team is blind and that the um are unaware, I should say they are unaware of treatment and then the families and the children are unaware um and then the randomize meeting there is an equal chance you could get either drug or placebo um and then they are controlled right okay, so we asked if we know what you're pretreated pretreated blood oxy token level is, who's gone to benefit from treatment? And we've thought a couple really interesting things. One was that the lower your baseline, so your pretreatment blood oxy toast level, you showed much greater benefit from the oxytocin .

intervention. These are.

this was four years. Sorry, I should clarify. This is four weeks of treatment being administered to oxyde and twice a day. okay. and. We saw effectively there .

may sorry interrup so much, but male male and female object we did.

But again, you know because autism is male BIOS n prevalence, even if you make this heroic effort to over recruit, try to get more girls in um in in the study, we usually try to aim for the prevalence rate because it's difficult to get girls because there's fewer of them got IT.

okay? But boys and girls were included. They're taking oxytocin over the period of of several four weeks.

And if they started off with lower baseline levels of oxytocin, you observed a benefit of the oxytocin treatment. Yeah, those individuals. What about the individuals who had Normal to hire?

You didn't see much benefit, right? And so that was a acute me to think that there may be a subset of individuals that you know, for whatever reason, they have lower oxide toast and they may stand to benefit more from treatment. And none of the prior studies had looked at blood oxytocin levels. And so what we had thought was that, well, maybe if everybody had measured baseline blood oxytocin levels, maybe some of these maybe there would have been more positive outcomes. So but there's there's a lot of controversy in this field about whether oxytocin is a treatment for autism, right? So after we completed that trial there was a large multilight um which called a face three oxytocin treatment trial that was done IT I think five sites and they gave oxytocin for an extended period of time um and they showed no benefit um and and were they looking .

to see who started off for low levels of oxy toast and that pretreatment so what .

was interesting about that study and there were a lot of issues with IT that um oxy token is something where you have to if you look at IT degrades is like that kind of what I joke about, right? So you need to take IT. We take when we go in.

We have like these really intense protocols rights. You go in and we have vacuum iner tubes. There are cold and we put them on ice, and then the lobos .

takes the blood from the child.

and then we make sure we spin IT in a center, huge cold, and then we piped IT on to dry us. So like so we have very minimal loss of the signal. And so if you don't adhere to those rigid protocols, which is very difficult to do across multiple sites, um IT can be very difficult to get an accurate d of oxytocin. And so I think for me, it's still an open question.

They didn't see the blood oxytocin predicted response um in that study um the data weren't provided in the paper IT was just said that they didn't um but I still an open question to me like what if there was a group of children who had low oxytocin levels and they could benefit right? There is other people um where they'll say, no, no, no we don't think that chronic opposite descents. A good idea that what you really should be doing is just giving a behave before a behavioral therapy session, right? And so that, you know, maybe that is the way if you give IT acutely, like in there was early studies we talked about that maybe oxytocin diminishes sphere.

We know that oxytocin creases um distress access, the hythloday c petite I um jindo access and that I can diminish anxiety and animal models. So we that's well established. And in a former life I was a stress researcher. So i've spent a lot of time thinking about this.

But but it's sort of the sad thing is, is that once you have a negative trial, there isn't a lot of interest in funding at the work going forward, right? And so I think it's still really an open question about if there is a subset of individuals that could benefit from oxytocin replacement therapy, right? And it's until there's money to do that work, we may not ever know the answer.

Well, IT will be important for that work to be done eventually. Hopefully the fuel will return to IT despite whatever trends might be happening. Now I think it's important to know for the parents of autistic children um whether not there were any negative effects of oxytocin administration, in particular in the children that did not benefit from oxytocin treatment.

The rationales, the following well, of course these things require prescription um if a parent has a child with autism, especially if they're enough, that the behavioral interventions could possibly stand a good chance of inducing neuroplasticity rewiring of the neural circuits that underlie social connection. Well then there's this time limited window in which you know those parents presumedly are willing to try most anything provided is safe. So let's assume, and i'm making up these numbers now because I haven't seen this study, but according to what you told me that let's say, a third of the artistic boys and girls that come in have low baseline levels of oxytocin.

There are the ones are going to benefit from this oxyde an intervention. The other two thirds don't. Well, given the difficulties of measuring based on levels of oxy tos, most people don't have access to those kind of resources.

Um if it's safe to give oxytocin no matter what, well then if I were that parent, i'd be knocking on my physicians doors saying, hey, give me oxytocin spray because my kid might fall into that one through category if and only if IT turns out that oxytocin is safe to give. But if there's a risk profile that doesn't justify that kind of shock an approach, well then I wouldn't do that. yes. So um is oxy to spray safe? And if so, why doesn't every physician who has a patient with autism give the oxytocin nasal spread?

And a great question. And I I know that, you know, i'm a parent of three children and I know this sense of that you would do anything to help your child, right? And so I think the tRicky part is that there was a one thing I will say is that all of the studies and there's spend many of them have shown that oxytocin is is relatively safe in a pediatric population, right?

At the tRicky part, I don't know there's physicians that you know really pay attention in a clinical trials. And if they don't see a benefit, they may not be willing to write the prescription, right? So until we could identify a group of children that could benefit, you know, we need to create the opportunity for physicians to recognize that this could potentially still be a treatment, right? But that work. But I think the tRicky part in what I will say is, and we can maybe talk a bit about VISA person in which, you know, my feeling is that if I was placing bats and and having to choose between these two, my my money would be on VISA person.

We are definitely going talk about these oppressive in detail. I mean, the reason I mention that hypothetical scenario is just a sense of emergency, and in some case is desperation that parents feel and you know times taking and if tos and safe, I guess i'll put in my vote that you know should at least talk to their physician, maybe even hand them the study um to consider but I can also understand the perspective of pediatrician who says, well listening was a small number of kids that benefit um you're welcome to try IT, but I don't IT doesn't seem like the results are that impressive.

But ah this gets to a bunch of larger air shoes about you know medical care and renommist controlled trials and the desperation of parents and kids to treat new developmental chAllenges. Um I I just want to ask because IT feels relevant in a in a real way, you know if ultimately the goal of improving symptom profiles in artistic kids is about improving social cognition and social behavior and that process involves rewiring of brain circuits, neuroplasticity, is there any reason to think that other approaches to inducing neuroplasticity would be beneficial even if they're not in the biological pathways that are disrupted in autism? I think, for instance, about the now extensive use of assess for the dream of depression, some cases that works, in some cases IT doesn't.

Side effect profiles are a serious concern. yeah. As discuss on this podcast before, ultimately, we know that depression is not a serotonin efficiency. In most cases, accessorized are a typical into depression, like preparing you and things that sort when they work.

They probably work because of their ability to induce neu or assist neuroplasticity right um also the trials on Sullivan are not really about silicide and there are about neural plasticity. At least the trials for depression, right? There may be other uses of solicited and that relate more directly to the effects of slicer bm.

But ultimately, know what we're talking about here is the the attempt to rewire the brain in a specific way, whether assisted by oxytocin or some other mechanism. So the question is, are their trials happening where people are expLoring safe suicide? And M D M A, which by the way, we know i'm increases oxytocin, enter tone dramatically as well as things like a typical entire presence in kids that have autism. Not because we think that those uh autistics are deficient in any of the neurochemicals that these drugs will target, but that these drugs can help rewire the brain. And ultimately.

that's what these kids need, is a really great point. And there might be subsets of kids, right? There might be kids where there would be a medication that would target other pathways, but that potentially releases oxide toast and right, that.

And but there might be kids that have an oxytocin efficiency, right? But I think that that circles back to your point at the beginning. Or our point is that odysseus a very horigan, ous condition.

And being able to know before you begin a trial, right? Like who am I going to put into IT and what is my primary outcome? Like one measure that I think is gona move the needle right like a kind of requires a Crystal ball. So there's a lot of guest work that goes into this um but I would very much like to see I will see one other thing that um there have a colleague of animal good sTyler who is at the university of sydney and he published paper year two ago now suggesting that oxyde bit may be most effective in kids at Younger ages and I I don't call me somewhere between two and two.

five or three.

And so IT could be to your point about neoplastic that oxytocin may be maximum beneficial in Younger ages, right? And if you if these studies are these huge podger across ages and across sort of different social finot pes, finding that signal is really important, right? And and maybe age is a driver, or or maybe you low blood oxytocin regardless of what age you are, or maybe an Adams case, if you recruit really Young children, you're likely to see a benefit just because the brain the brain is wire up and it's more plastic and you know Younger .

ages yeah it's also vote, in my opinion, for early examination of kids, right? Like parents really need to get autism screening and perhaps maybe the. The most important thing is to make autism screening as available and as inexpensive as possible for everyone because of the importance of early intervention, even if it's purely behavioral intervention, but certainly if it's .

behavioral and drug intervention, the clinic way times are really long, right? You have to have a specialist is capable to diagnose autism. And so you could have a clinic where you know you're showing trouble, some features and apparent wants to get their kid into a clinic, and you could have a twelve month or eighteen month wait time, right?

And so there are a lot of people that are thinking about other, other laboratory based test that we can develop, maybe either for detection or clinical referral, right? So could we come up with A A biomarker panel, for instance, where we might be able to say, wow, here's some here's a panel where we think this child is at reasonable risk for developing autism. Can we make sure their priorities for getting a diagnosis right so we can get them an an early intervention? But right now we we don't have that right.

So having some sort of laboratory based test, whether or can be biology um or if we could do something with ee gays. And there's a lot of companies working on these things now to say this may not work there. And also obviously, again, autism is always controversial in this field, right? There are so many different stakeholders.

OLED clinicians will say, I don't want a thirty second video clip replacing expert clinical opinion. There's good reasons for them to feel that way. But I think if there was a way to prioritize people, they're in this line, you know, we could get diagnoses faster. You wouldn't want false positives.

but I would think that a thirty second video clip provides of something useful. It's going to be more valuable than nothing yeah giving the time sensitivity. Um what are some of the barriers to am getting this behavioral testing to be not just more prominent but pervasive? Like seems to me that well I recall in school they gave us the hearing test.

We all much on the bus. We get the beat test. And um no for hearing um chAllenges um we get vision task. You get the babinski reflex test, not the moment you come out of the woman, but very pretty soon after. I think why isn't this stuff um happening for autism um for every kid?

Yeah it's not scalable right so you these interviews with parents in the test that you do can take hours right in any given clinical, even if they're working really long hours, they're just aren't that many people that are have the extensive training needed to make these expert diagnoses, right? And so I think that there's you know clinicians that are doing the absolute best they can, but they can only see a certain number of of people a week. great.

And does that have to be a physician start interact? Does or could you could you know could a well trained technician this yeah.

Well, I mean, I think technically is A D S M diagnosis, right? So it's usually somebody with a clinical degree. So IT would be a clinical psychologist. IT could be behavior pedi tion and IT could be you know what child's psychiatrist or child neurologist. But mean again, that requires years and years of training.

Um and with if we look in areas where people have fewer access to access to resource that I mean particularly in in poverty areas, the mean age of an autism diagnosis is years later than in wealthy areas where you know there's many different medical specialists with parents you know that aren't working three jobs and you know can sit waiting around you know and in really lobby and and really advocate for their kids, right? Because you know if they don't show up for work that day, they're not going to get fired from their job bread. And so I think that you know if there are some sort solution that allows there to be a more democratic approach to saying, we need a really quick way, like you said, to be able to identify at risk children, especially if it's A A blood test or something like that. You know IT could be incredibly .

impact for are there human trials for expLoring M D M A method xi meth eadem also refer to the x to c um and or sivan for um treatment of autism.

So I was aware that maps had an M D M A trial in autism. Um I don't know what's happened with that.

Yeah perhaps it's still ongoing. I'll check check them up site. I mean communication with them from time to time. I mean, the the the reason for asking, of course, you know but maybe in case let some of listeners don't. As m dma causes these massive increases in serotonin, that seems to be the major source of the m dma effect, so to speak. 嗯， based on the work of our colleague rob mulana, and at least one human study comparing m dma to very hypos oxytocin treatment can rule out the oxide tosa Spike that's induced by M D M A is that the source are the only source, but of course these chemicals considering ze I mean IT, but based on its chemical profile, oxytocin released massive surtout and release dopamine release and a propensity to enhance neuroplasticity. I mean, assuming all the safety protocols were were there um seems like not the perfect drug but not a bad choice um if of course, it's inducing the kind of plasticity that someone with autism would be seeking.

right? I mean, I think the tRicky part, especially in children, right, is there is going to be a reluctance to potentially give them psychodeviant s rate. And so you know is there a way to modify, you know, the chemical compound to, you know, be something that parents might be more willing to give to their children? right?

right. And I totally agree with that. Um I guess to play devils out but it's not against you. But um well, i'll just stated very directly and then i'll take the heat as necessary.

Um I mean, i've done two episodes about the the drugs that millions, tens of millions, if not hundreds of millions of parents are already giving their kids for A D H D which are um include m fetis including dioxins matt m fet ine is a prescription drug for a very small subset of kids with A H things like ador all vivants even metal fd date riddle in I mean these are in fact means they induced doping release and nand f release and again, i'm not suggested people give their kids M D M A um to trying to militate symptoms of autism but something chemically similar to IT ought to be developed or at least explored in a human trial in my in my opinion. Well, time will tell our reach out to the map group and see what's happening. Let's talk about VISA present.

Yes, because there's a lot to discuss there. So you tell us this is a molecule that chemically is a very similar toxic tosa um is IT manufactured in the human brain and body. Yes, okay, do we know subset of the sites that is known to be produced and where some of its actions are? And you mention the kidney and the anti diode corn rules, but within the brain, like what brain areas have, neurons that make this a present, the receptor.

or are all over, are all over the brain. IT varies depending on the species.

And you know the way that receptors are measured in postmortem tissue, right? Which can be very difficult to get good samples, right? And so we need to have that heavy at going in um but yeah I mean it's it's made in the hypothalamic s um and it's released all over the brain and there is vasa person receptors all over the brain right? And um what's really interesting about viasa person, I always sort of joke that you know always sides a day in the sun if you well and the VISA person was sort of this step child that was like left you know sort of behind and and the reason I find this fascinating is again, like I think back to my you know my roots as a you know evolution biologist, behavior neuroscientist. And what was interesting is that there were studies in the early to mid ninety ninety showing that vasa person was critical for male behavior. And so um there was work, you know, there was a variety of people and I I think rob mulan to mention this on his on the pike cast he did about, you know there's A A group of people like to Carter, their Young tom in souls, some of these early people and they give VISA present to male pary voles and VISA present was what induced um pair bonding um with A A female made and also Peterson .

al care as I recall, those experiments were done in the context of looking at polygamy versus monogamy of these y walls parry walls .

verses like a different species so same genus but a different species so that might be a mountainward or you know highly related but these other species, super vials, are monogamous. The male ah well, I mean.

that was the forty percent .

of yeah that was I don't think it's that bad.

but I Better than we should .

look to them for porters.

And all the divorce works are saying, why why do you say Better have some divorce friends that have said worse is like the greatest thing so we always say like doing Better, doing worse, right? Um anyway, that's the whole other podcast and certainly not the human podcast but or maybe IT is but or will be but yeah the body understand that you have certain votes that mate with almost exclusively with one other wall for their entire life span and then you have other voles located elsewhere and um that in those colonies they met with lots of different the males and females have lots of different partners. Um raise the Young with lots of different partners, made with lots of different partners and that if you give this a present then you can make the I just want to call them Polly cameras but I don't know they love each other i'm in the end for modifies and assume they love each other. The polygamous mls, not polymers, but polygamist smalls then become the arguments well.

I yeah I would say that is probably not the taken message. So the take home message would be, they had, let's see that there was like the good walls, right, wish of the pary walls. And they were the ones that form these monogamous carbines.

Dad participates in Peter nal care with mom. They could raise babies together. And then dad chases off in truder, right? And then there's the more a social walls and so these are like the mountains vols and um IT will see it's a complicated story, but there is this mountain walls where males and females live separately.

Females like maybe live on the male's territory. The male mates with a few different females absolutely doesn't provide any personal Carried. All mom raises babies by herself, right? So that these are really .

like one thousand, thousand and fifty versus twenty. Yes, to be IT just too broadly stereo pe.

broadly stereo pe. And if you give A A, A pery walls. There is sort of prime to form bonds and to be the males to be good dad is, if you will.

And all you have to do is give them a single injection of viasa present and you know, or you can give any tag ones. And usually the way they form the bond is through mating, right? So they you put them with a female.

They made a cohabit for a bit. There's spent all kinds of parametric studies. I can't remember how many hours IT takes a form, a parabolic.

But then you can do these things called partner preference test. And then you can say, here's the guy that you made IT with. Here's this guy you don't know.

And you can do IT for males. You can do IT for females. And they pick their partner. They choose to go hanging out with their partner, the mountain walls, you know, either after meeting with somebody may either be equal or maybe we'll even go spend time with the new individual. So the cleaner story was that pari VS, or monogamist mountain voles, or not monogamists, but in the paRowan, you could give VISA present instead of made a cohabitation and you could turn on like you know a bond with somebody after only living with them for a very short period of time right um or you could induce Peter behavior.

And I was working with the old species in grad school, I think the most interesting scientific experience that i've ever had, right? And you and I both know this, right, when you're Young, you're actually the person doing the work, right? As you become, you know, the head of your lab, you're mostly writing grants and giving talks, right? And then you get to hear about the super cool things that everybody in your life is doing right.

Eventually the members of your laboratory kick you out of the they literally say, like get out of here. You're leaving things in the wrong place where I initially you're telling me them, hey, that's in the wrong place within a year or two. For me, I think IT took about four, five years. About year six, I was dem to my office to just write grants.

And right, I was told that one time I was back there and I tried to wait, and I was like, so excited what they were working on. And they they only just said, go right, granting, bring in more money, right? That was kind of their attitude, like we get to be the ones you get to do the cool.

So back when I got to actually do the science, um I remember I had this species where and and again, I told I came at this from an evolutionary perspectives so these were called metal voles and I found them very interesting. So when I showed up in my this is advisors lab, SHE said, I said, I really want to study oxytocin in baza person, and I really want to study y walls. And I know you have a all species.

And SHE said, why don't have party walls? I had these metal walls and studying because they're so sensitive to light, and they change their behavior based on light. And as he said, well, you can do what you want, but our grants basically have to have a circadian component.

So SHE said, you got to work that end, but then we can struck this deal. So I was hanging out the animal rooms, and I thought I was really fascinating. So SHE had animals that were either unlike short, daily length or long daylings, so that mimic summer, winter.

And I was noticing that on winter daylings, the males were hanging out with the females. And when the female had a litter, he was like, participating. And I was like, wo these are not supposed to be monogamous animals? And so I went into the field research, and they were doing all these radio telemetry studies. And so like, if you.

I wish you truly explain with those, are putting a little transmitter under the skin is painless for the animal but that allows the researchers er to monitor the behavior of the animal remotely without having to you know and put them in cages and stuff.

And so this is like underfeeds conditions and walls are everybody's favorite snacks. So they have like a very limited lifespan in the wild, I mean, like on the order of a months. And and so like if you have a short life span, like you should just keep reproducing, right?

And so what was interesting is at the end of the summer days, as you are going into winter, territory collapse and males are found with females and they babies, that makes sense if it's you're gonna have a litter and mom needs to get up to go eat, you need somebody to sit there and warm those babies. They are going to die because they're going to freeze to death, right? So I started saying, like, wow, I think these metaphors are good dads.

Like, i'm noticing this. And so I told my, this is advisor. I want to study how oxytocin in VISA person can. Maybe this is involved in tracking these evolution are mating strategies. And so again, like the coolest experience I ever had was on these males that were housed under short daily lines. So they were like winter miles um I was able to put VISA present directly into their brains and and I was like turning on a light switch and they ran around the cage, picked up all these babies, put them in a nest and huddled over them. And if you put a placable o into the rain, nothing happened. And so to me, I always filed that away in in the back of my mind of like wow this a person is this really interesting hormone um and maybe someday I will I did a post stock and something else but I was always you know back in the back of my mind of I really want to return .

to this is so incredible that a eight amino acid long peptide could basically turn these relatively negligent fathers into very attentive fathers. Yes.

yeah, IT was fascinating.

right? I mean, I just speaks to the power of the peptide with the president, also speaks to the power brain circuitry, also speaks to the idea that brain circuitry is often sitting late in the background, you know ready to be activated. That is not just about neuroplasticity in building up a news circuit, that some forms of neuroplasticity about unveiling what yeah what's already they are and that peptides can act like switches ah um which you know kind of make sense on the one hand, but i've never heard of a result as dramatic. Is that so i'm presuming you're gona tell us that that then let you to go back to his oppression and explore its ability to induce good parenting and negligent fathers happens .

setting that yet? Um no well, so I think that, you know my mama always says chance favors the prepared mind. And so I was doing my post stock of stanford and I got recruit to stay on the faculty. And I you know had been doing work in stress vulnerability and stress resilience. And I really, and I love doing that work, but I still felt this tug of, you know, I had spent all this time in a psychiatric department where I was surrounded by clinicians.

And I realized that a lot of the stuff that I was doing, how clinical relevance, right? And so sometimes you sort of meet the moment, right? And so right, as I was transitioning to to hat my own lab in my department, there was, uh, a bunch of stuff going on. So there were a lot of very dedicated parents who were lobbying for funding for autism research because IT was horrifically underfunded, really horrifically.

I mean, at rates of one and thirty six.

not in the time, right? So I was one in one hundred and fifty year, whatever IT was back then. But they're all these parents and and I think again, their heroes in my eyes that they advocated so much for their loved ones and so there was you know they started forming parent grass roofs organizations that have culminated.

They all started joining together, which is now autism speaks um and then there was a man named jim m. Simons who runs um one of the most successful hedge funds in the world and he decided, wow, i'm in there. Let's put money into autism right and .

have a personal link to autism.

I have to ask because .

often times, not always, but often times when you hear about wealthy donors yeah devoting a lot of money to one area of science, there's a familiar thing there. Remember, their family or a close friend has this chAllenge, and they they really want to see that chAllenge.

absolutely. I know a lot of money i've gotten for my lab from philanthropy is in what I will say is the most importantly for work i've ever done. This is through right they're crazy ideas that no funding agency ever touches, right. Um but yes so they both put um a lot you know there there was a lot of emphasis and so because the Simons foundation started issuing requests for application, there was a group at stanford that formed and IT was um a clinic with a basic scientist and my chair at the time said, well you know almost nothing is known about the biological basis of autism.

Why not you go I mean, to introduce you to the head of child psychiatry, you should go talk to this group and so as I was preparing my slides and realizing that, you know social interaction impairments were core feature of autism, I thought, wow, you know these newer peptides may really be you know um a part of this puzzle. And so that's actually really how I got pulled into um autism research was was through that and I was I I you know everybody at the time was very interested in oxytocin. I remember thinking so we actually did probably the most definitive blood oxytocin study because there was this idea again, like this marketing campaign, like the oxytocin deficit hypothesis of autism.

And you given how clinically had A A genius autism was. We got money actually from the Simons foundation, and we did the first study with maybe two hundred kids. And what we were able to show was that blood oxytocin was not a marker of autism, right? So IT wasn't like there was a bimodal distribution, meaning to completely non overlapping levels of oxytocin in people with autism, people without autism.

So the lower your blood oxy tos levels um actually regardless of who you are, you could be a child with autism, you could be an unaffected sibling with autism or you could be a unrelated control child. And IT was the lower your blood oxytocin levels, the greater your sort of social difficulties and the slopes. And we're different.

They started at different points because the behaviors were obviously different. But that's what got us thinking about our clinical trial, which is that blood oxy tostem level is not going to be this great differentiator between people within without artists and right. But we might be able to find a sub group who could benefit from treatment.

But what I like so much about your approach. The way you described IT is that IT IT sets aside, don't want to say discards, but IT sets aside this thing that we call autism, which is already hard to define and diagnose and there's all these different spectrum and try, okay? Children with autism have chAllenges in social cognition, an social behavior, social bonding 呀。 So do adults with auto m for that matter.

Let's just focus on that yeah and not worry so much about whether not somebody is diagnosis autistic or not and just focus on what are some of the potential european tide deficits or over expression of neopets tides that may in some way relate to those social chAllenges, right? And then one can circle back to the question about autism in collecting those data. But IT also points to this idea that we go after a disease like alzheimer's.

We can often missed the possibility that alzheimer, well, IT has, you know, deficits and cognition and memory could also be a bunch of other things, like a meta loc disorder of the body. And so maybe you go after a particular symptom. Ology, yes, and trying to attack that and you might actually potentially treat cure multiple diseases. It's a very different approach and I I hope um people are catching on to the the suddenly but also the the the potential impact of that um because if I heard correctly, you said there are people who are not autistic who have social functioning deficits and they too have less circulating oxytocin, right? So I would say we haven't studied .

people where we brought them and in characterised, right? So these are typically developing kids, but what we did is in the abilities that are typical of a control child, we still saw that gradient.

right? And so I think I just sort of begs the question about, you know what is oxyde tossings role in human service, right? I mean, I think there's just so much that we don't understand about both of these molecules um in terms of their disease liability, of their low or they're healing potential if we are you know able to use them as modulators .

um of other therapies. So how did you move from oxy to to VISA present? You mention that everyone was all excited about oxytocin, still the one that we hear the most about yeah although after this podcast episode and when I start blaming about VISA Price and everybody um you maybe that i'll change, but I think it's can take a lot more than that.

But maybe because the name is there's something about oxyde token that like kind of sounds like the love that looks like the love hormones like these are present should be renny. Ed, well, this should be called something else like not coro oppressing. I mean, you're going to tell us how critically important IT is, perhaps even more important than oxy tos for autism and social functioning. So I don't know by the end of this podcast come up with the .

new name is needed, right?

Well, i'll put IT out there. Uh, okay. So how did you get to visit groser? okay.

So IT was interesting with all axy tos because we didn't and again, I was skeptical, al, that we would see these big group differences. But you know I was a little bit of like, okay, know what everyone saying this is not going to be the big solution, right? Um and so I actually came at IT from the work that we did in monkeys.

And so I think I mentioned previously the beginning of the podcast that there were a lot of limitations that I saw. And then sometimes if you come into a field, you know when you you're a little bit of an outsider, right? Like i'm not a clinical and I don't see autism patients, but I also I have this really strong interest in social behavior and the biology of IT.

And so I I was thinking about what what are things that we need to do to Better address the chAllenges and autism. So one of them was why are we looking in blood, right? Like if you look at neurological conditions, there has been a lot of progress made by doing biomarker discovery insurable spinal fluid, right? So like the the biological substrates or or clues of markers of say um various forms of dementia h or um or M S or for first found in spinal fluid, right it's it's the fluid bave the brain and the spinal column. So if you're looking for the biochemistry of an illness that's the closest flew ID that you can get to the brain.

right?

So won't IT maybe, right? So that was part of my thinking. But then there was the issue of the animal models, right?

So there was drug after drug after drug that was tested in mice, and they failed in human clinical trials. And so IT made me start thinking, could we develop a primate model um of naturally occurring social impairments? right?

So can we because in autism these social impairments are, if you will, naturally occurring, right? And so you know this is this spontaneously occurred children um and so IT made me wonder, could we identify monkeys in a large colony that have social experiments in? And after talking to to clinton, who who treat these children, can I spend a lot of time validating a monkey model where there will be monkeys that have features that look like they have direct relevance to core autism symptoms.

And so what I did was there is a primate center, the california national primate research center. And so what we did is so I think I mentioned earlier that there's these surveys can be used to look at artistic traits in the general human population, right? And so we refined one of these, and we did what we call back translate. So basically it's an instrument that used for humans. And then what we did is modified IT to be able to to use this rating scale in race MC hacks.

S, which are an old world monkey and I know you're familiar with them and um and I was interested in looking at old world monkeys because there are some of the closest relatives to human that are used in biomedical research and um as I mentioned previously, these autistic traits are continuously distributed across the general human population and that this genetic a say, let's call genetic liability, which is a fancy way of just saying that we think that there is a there is a genetic risk that underlies this continuum, a behavioral traits, right? So if we think that that's true in humans and in one of our closest relatives, and we think that some of these genes create proteins, that then are what sets up the developing brain to develop in the way that autistic brains develop. So let just assume that that's the promise.

That's what we went in with. Can we find racist macos that are just living in at large outdoor colonies and identify animals that might be good models for artists? And the answer is yes.

We could do this all kinds of different ways. One is we could just take people and um score monkey behaviors outside their cages while they're interacting with their peers. We can use rating scales. And again, the rating scale we use is called the social responsibility scale. So this is called the Michael social responsibly scale. Revised its a mouthful, but what IT allows us to do is measure autistic like traits and monkeys, and we can also bring monkeys in for experimental test to see where their eyes look or how do they perform, how do they respond to videos of other monkeys. You know, if they're making a filename of overtures, do they do like you tax google, which is a positive response when they do that, right?

I'm going to apology for interpreting again. But I just have to tell people this because I spent time up of the U. C. Davis primate graduate student.

And by the way, what into here are non invasive of observational studies at least thus far sees are monkeys living in large a exclusion res, not enclosures, largest closures um forming colonies and social relationships and you know I think anyone that sees monkeys at the zoo and we all learn that monkeys go and they don't eat, eat if you want a monkey to like you, you learn this working with macaco. Um first of all, they don't in the affiliated call is a who they do this really not in the little ones. I got a lot of time with these monkeys in the little ones.

They do this thing where they go. I to nurse the little ones, everyone's a while. They and there just, you know, just like, makes your heart.

And I think there must x dump at that moment up right now. But if you want the monkeys to like you, you have to give him a fillip ative facial gesture, which is not a smile. That's actually an aggressive gesture.

So as Karen doctor Parker just showed you, its lip smacking, which is, yeah, so if you see a monkey zoo, you want me to pay attention to you, you're gonna have to lips, mac. And if IT doesn't, either you're not doing IT right or IT just doesn't like you. Exactly right, right, right. thanks. Now we'll go back to the a the study of, uh, where the establishment, this really key experiment.

right? So then what we did is we identify these, these animals, and we spend a lot of time.

So when one of the things that I do as one of my areas of expertise is validating animal model, so a lot of, like I mentioned, like a lot of reason why experiments fail as people will take an animal off the shelf and say, I am going to do this, right? But if you're you know, if you're staying a disorder that's characterized by visual issues, is that is that the best thing to do in an occurrence, al species that has all primary sensor removal? Or is IT or is IT Better? You know and again, I will say all models have value.

There's you know the reasons you just have to you know you basically have to stand by what you're modeling. And so I think one of my the biggest issues I have with the sort of mouse finit typing mafia is that, you know, there's this group of test that they use, and they use IT in every single disorder, right? And then if there is a positive hit is like, oh, this is like, you know, this test is really for parkinson's today, but it's for depression tomorrow, right? And so so my goal was to to devise a very specific test that would allow us to evaluate, you know, core features of autism in this model.

And the answers we found IT, right? So if you look at monkeys that spend a lot of time alone, they have a much greater burden of autistic like traits measuring on this rating scale. They have diminished social motivations.

So other monkeys will come up in in iraq with them. But they don't engage in um social overtures that much themselves. They do less gloomy ing less failure of behaviors.

Um they in some of the work that we're doing, they don't lip smack back. And we can talk a little bit about that. We did a pharmaceutical ical probe and we can talk a bit about what visor present does to that, which is kind of exciting. And so we spent a lot of time validating this behavioral pinot pe, right, to say that we really feel like there are our core aspects of IT that are allowing us to model autism, right? And I A paper which, if you want to put IT in, its all about creating this monkey model and and the power of of doing that and where IT IT took us clinically we will .

provide a link to that in the show captions. I also just wanted throw up my vote for the the fact that you did this work because again, I don't discourage mouse model work. But we've just seen over and over again that the incredibly small fraction of mouse models that lead to valid diapered tics in humans.

And there's just a lot of differences between primate brains and rodent brains. And we have a very elaborate from the cortex, a bunch of other circuitry that might if they have that, they probably use IT for other things. And it's just very hard to come to draw conclusions from those models. And and they're great for a pRobing um functions that are, let's just call them more atomic type functions um and for doing some of the initial investigations. But um you know I think well, I don't want to see every research labs which over the primates, you know I think one has been really thought ful about the kinds of experiments one does with primates at all um this sort of um behavioral h assessment and and the identification of a primate model for autism seems like A A very good use of of of human resources right?

Well in the other thing I will say is that there are medications that were only tested in roads that when they were when they were tested in people had really negative consequences.

I can give you two example so one is the little mind which was a morning sickness is medication that was given two women um that were pregnant um and the safety testing and talks with toxicity testing was done only in my yes and that's why I went on the market and won the market in europe. Um and there were all these children born with profound live at live at our alias when they went back and tested the drug in um marmy's. Neither racist monkeys or cinema st monkeys in old world monkeys, they had a lime Normalize .

and so they to do, and again, I has an animal ever treat, you know, the life of a single monkey or or a single mouths, for that matter, an individual monkey, excuse me, your individual mouse for that matter, as you know, as critical I am a specialist. I do think there's a difference between their life in our lives when IT comes to um you know what study one does but um but just the idea that these severe developmental defects in humans could have been avoided by doing an experiment, perhaps even on one a set again I feel for the life of discomfort marmoset. But the idea that that could have saved so many human lives is just striking what .

there was also that street drug, M P T P, that was a synthetic heroin that causes, like overnight parking unionism, right? When, like, I think, the dopamine cells were just da blade IT, right? But when you went and looked in mice, M P T P didn't have those effects.

That was only in primates and other humans and other primates, right? So, and I agree with you, I am in the animal lover. I I think that we have to be very careful when whether we do any animal experiments, right? And so you really need to have a good justification, I think, for any science that has done, I will say that of front. Um and now we have this a new generation of stem cell organ weight work, which I think is going to know allow us to make .

all kinds of disease progress.

right? So how to right? right. But I mean, think again, I think we need to pick the model based on the question we're asking, right? And so if you want to have a medication that safe and well tolerated, you know, in people are more effective and you want to move the middle on complex social cognition, you want to be testing IT in a species that also has complex social cognition.

Look, the netflix show chip empire, people have been seen that they should watch IT. When you watch IT, you realized there very much like us. yeah.

And there I say we're very much like them. It's far N N way different than watching a bunch of mice. Yes, and i'm not being disparage ging of mice and assuming they have that might also have complex social cognition.

Walls also have complex social cognition, but it's of the mouse vole type. And we don't know really even what to look for, right? But with primates, there's a fillet of gaze there, know, filet of grooming ing.

There's asturias ation of individuals in the trip. I mean, there is no band IT taking care of babies. There's all sorts of interesting dynamics that map so clearly on the human behavior and vice versa. Yeah so you establish this colony a bit, Davis um at the regional primate center that and where you identified some monkeys that we don't know if they have autism, but you could see that they were less socially affiliate .

and I would never say they have autism like I will say that of front you know they have features that resemble human autism and that allow us to model this, right? So so we started saying those animals, and what we wanted to do was do some biomarker discovery.

So what we wanted to ask was, are there any molecules that allow us to deferential these, what will call them naturally low social, low social monkeys from socially competent high social monkeys? And so we measured a bunch of different um redoute of neurotransmitter stems that were either involved in million social behavior had been implicated in idio pa thic, meaning autism that doesn't have a genetic cause or these neurogenetic synergy that we've been talking about, with the pathways that are really associated with them。 And so if we measured a bunch of these systems with ninety three percent accuracy without even knowing what the monkey, who the monkey was, if they were lower, high social, we could just put them in the low social or high social bucket or or so.

But I was everything. We did blood. We did csf, and we put all these measures into the hopper. We did a discriminate statistical analysis, which was like a machine learning algorithm, where we just said, here's all this information helped me classify, if this individual is a higher, low social.

cerebral spinal flood is collected by spinal tap, correct? In my understanding, i've never had one, but that spinal tap is of course more invasive than a blood draw but is still is done as an outpatient thing in humans like you can go in get a needle inserted into the lower spine.

An expert um they're going to draw respirable fluid I mean not that much more invasive in time consuming than getting A A needle intervene for a blood draw, right? I mean it's it's we think of IT is it's technical a little bit more, but there's csf draws in humans all the time, right? So in theory this could map to a human study.

and IT did, which will talk about. So we went out and we did this. I have a spectacular statistician whose we spend a lot of time together, the named joe garner, and and he is a statistical genius.

And so he developed this. And we do all of our work together, or what I was a ninety five percent of what we just love working together. And he developed his statistic windowing strategy to identify what were the key drivers.

And what was fascinating is in the first monkey cohorts, IT was the three responder fluid levels of VISA present that were really what was driving this classification, right? So if we just knew your levels of your of VISA present in spite but not in blood, interestingly um we could pretty closely perfect to perfect classify you as higher low social. And so then we reply that again in another monkey, cohorn, because obviously a scientist, you always wanted replicate your work.

And then if IT was really a biomarker, meaning it's a molecule in the body that gives us an indication of something, and in this case, it's an indication of your social functioning, we were able to look at um monkeys and we saw that the VISA person was consistent across measurement times. So there was a wide variety of VISA person levels. But within an individual monkey, IT was pretty much the same, right? So that's what you want to see with the biomarker.

And then we showed that the VISA person levels were closely a link to a group spent grooming, a time spending grooming. And as we mentioned, I think we mentioned earlier, glooming is in many monkey species a critical behavior that sillier fy social bonds and maintains them. And so the individuals with the lowest cfs or present levels had spent the last time, the least amount of time in grooming .

grooming other other month yeah this static grooming is a very interesting behavior. And from watching chip empire, I can tell you that new relationships are established in many ways by um monkeys, these champs chimpanzee of offering their back for grooming and another um chance to yes groom that chimp.

Then IT establishes a some form of trust and and and and all seems have to do with proxim ity like how closer you gna let me get to you voice first. Humans that you know we tell about personal space and there's a whole set of things related to consent in this whole empathic grooming thing. And then if they um you know if a chm misbehaves on on a noting, then they aren't grown by others and they can actually get parasitic infections and that can be very costly. Very interesting you know uh to just think of alphabetic grooming as a as not a kind of a primitive of language but a whole language into itself absolutely .

yeah and also just critical for the species. So that was really interesting to me that we were seeing these hints that VISA present could be, you know, really important. But of course, you know, somebody will say, and I will say up front, monkeys don't have artists.

And right? So then the question becomes, does this have what's called translational value? So, you know, can I see this observation in an animal model and will IT provide fundamental insights into humans rate? And so I wanted to get repeal spinal fluid from people to test this hypothesis, because we had, in parallel, done a study looking at blood vasa president levels in people with without autism.

And we didn't see a group difference there, unlike this really profound difference that we saw when we looked at spinal fluid in the monkeys. And again, I think I mentioned the blood visor present levels or in distinguish, if you were higher, low social monkeys. So there were something about looking more proxim ate to the brain that was giving us more information than, say, the blood alone.

And so I said I wanted to get final fluid. And like you said, people do this all the time. How would we um but where you know, it's not going to be a first passes, especially when we don't really have any evidence in people to go in for what we would call a research lumbar r punctual right? And so I had to get really creative about how do I get spinal fluid from children.

And what we did was we key back onto a clinical indication for um a spinal fluid draw. So and and we did this, so I tried to get funding for this. This is like, you know, again, I mean, I think this is important for people to know how science is done, right? And so I wrote all these grand applications.

Nobody would find that. They said that this is really interesting. It's too high risk. You won't be able to pull IT off.

And you know, I don't usually back down from a chAllenge like if I think something is a good idea and I want to do and I need to find a way to do IT as IT. If it's impossible, that's one thing. But if it's hard to do IT doesn't mean you shouldn't do IT. You just have to figure out to do IT.

And so I always try to see bridges where other people see barriers, right? And so it's like, well, how can I access spinal fluid? And so I went around talking to all my friends who were on ancient forts. Really wonderful because it's such a small school, right? And so you're on all these different committees .

with all these different people.

And so ee talk is you're on them with people .

from all different yeah I know people in departments that I wouldn't otherwise know yeah um and you get very um you get to know these people well in these many committees .

and where we live in a small community.

right so were the experiment here. Maybe there's I we always wonder where they're not. There's a larger experiment like not on monkeys, not on the the patients that they close up, like maybe worthy experiment, right, right? And they're looking at how we interact on committees. Anyway, please continue.

So I started going up to people that I knew and said, hey, if you're taking final fluid, can I get a little bit of extra right? Of course, we got I R be approval, meaning we had ethical approval in all this. And or you could get the remnant sample and obviously get get consent from the families.

So we could either get a little bit extra when I was being drawn for a research indication. So so they we're getting a final tap no matter what. And then we were either we're getting a little bit extra or we were going to getting the remnant that they were going to throw out, right?

So you are usually take more than you need because you don't want to have to do another spinal tap, right? And so we were able to go around, and I hustled around and got all these people involved to help me. We put hot pink stickers on the lumbar punctures trays so that in the emergency room so somebody was doing a spinal tap they would call us.

So we knew about IT and we could get you know samples um again under people's consent. Um so we had all these people involved and we finally got samples from children with autism and children without autism. And then we also made sure that whatever they were being worked up for with negative, right? So we got the the sort of healthier people we could, given that everybody was coming in for a medical reason to have a lumber puncture. And in this in this first study, we had seven children with autism, seven children without autism and we could nearly perfectly classify thirteen out of fourteen individuals by just knowing their C S A vasser person level a lot um which is pretty remarkable given that there isn't a biological indicator that we a robust .

ological indicator that know. So basically in this relatively small having low with oppressive about mark of otis .

and and again and what I will say is in our monkey studies and in our human studies, csf oxytocin level became our control right? So in our monkeys there were no difference in csf oxytocin by group um and then in this first study um there were no differences in csf oxy toxin levels. Uh a sample size of fourteen is intriguing but given autism so clinically had to regeneration, we want to replicate IT.

And so I knew that there was a professor at the n age named amu swede who was collecting a three bro spinal fluid in as part of a research study because he was interested in immune parameters and volte efficiency. So he had children that were medical healthy, and they were getting, you know, just like IT and age of these huge workshops, right? So they were very well characterised participants.

So we were able to look at. And again, we also, this is the first time we were able to look at girls. So we had a small sample of girls, and we had boys.

And we basically just ask the question, can we replicate this? And I was very interested in will will oxides and be what's different in the girls, right? So maybe there will be some suspect ity here and it'll see low CS or and in the males and low CS of oxyde and girls, that was not the case. What we found was that if in the individuals with autism, regardless of their biological sacks um that they all had lower C S face or person levels than the individuals without autism, and because they were so well characterised, we were also able to show on a gold standard research died the assessment of autism.

So it's a an assessment that used um um to be in a research situation, alia autism diagnosis by an expert clinical opinion that the lower your VISA person levels in spinal fluid, the greater your social symptom severity um your clinical symptoms parity and then we ask, it's like well viasa presence involved in social behavior, but it's not really that involved in restricted repetitive behaviors and that was actually the case. So IT was the csf VISA present track the social severity, not the repetitive symptoms severity. Suggestion that there might be other biological measures that could be included as a way to you know have a more powerful way to differentiate people within without autism.

Um and so then I was really so so that was really exciting to reapplication that um and then I had a colleague named john const. Tino who is now at emory but he used to be a washing and I knew that john, I been at a meeting and I think he was twenty ten, and I found out that he had what I all called liquid goals. So he had this, a minus eighty sea freier that was a, had a bunch of neon nadal infant csf samples that he had him from human infants, and he had collected them.

And again, this was under at the cold approvals. And IT was basically that these infants came in for something that needed to be worked up, that was very rare. But if they had a, they would you, they could die.

So they needed to get a medical treatment for IT. But the the vast majority of these children ended up being healthy. So IT was a pretty healthy sample, if you were right. And so I knew he had all these samples, and I said to him, won't be really interesting if we teamed up and we look at this, uh C S face or present finding in children before the period when behavior symptoms s first manifest .

and so so sorry again to so I said every time. No, no, I just I bet I think it's important because this there was a question that I was seeing about earlier and I imagine many other people were two you you find these monkeys that have social uh interaction deficits, you find um kids that have social interaction deficits. And you see that there is no ways oppression in both groups.

This extends to male and female children. But then of course, the question becomes, well, maybe they have love is oppression because of so many years or even months of social interaction deficit, right, that the direction of casuality isn't clear. And so when you said liquid gold, you know referring to the um csf from these infants um taken prior to any opportunity for a social interaction beyond you know whatever interaction they had with their their mother up until the point the C S draw a was taken. Um this really gets to the issue of cassity.

right? So it's a quasi perspective because IT was baked and then a lot of time went by, right? And so what we realized we could do was, and this was a heroic undertaking on johns parts.

So these were um this was the samples were collected back on paper medical records. So he had to trace two thousand paper that what yeah exactly? So we add to trace two thousand, I think, paper medical records to an electronic medical record. And then what we did is we, he looked to see who went on to develop autism and who didn't write.

So then what we had with spinal flu examples that have sort of been waiting in the freezer, if you well, and then we could ask, you know, do individuals who later receive an autism diagnosis many months or even years later already have low as a person levels as infant? And the reason why this was a compelling question to ask is there is evidence to suggest the behavior therapies are more effective the Younger the child is, right? And if you think about IT, if if behavioral al characteristic of autism emerge across development, you know what if? And this was my, this is what of my.

We haven't. We haven't substantiated this yet. But this is like sort of my big question.

What if all these autism acceptability genes some and interact and converged upon a few common pathways in the brain? right? And so for years, people have talked about this exciting tory and habitat baLance theory of autism.

But what if this is a present is one of those pathways because it's so critically involved in social functioning. And so what I was interested in, and so let let's just say for a moment, you know, your genes are set at birth. What if the VISA person is already low in the brains of these infants? And so IT puts them on this very different trajectory where you have this cumulative effective.

There may be a little bit less socially interested, and maybe they are not making the eye hand act. And if there was a way to intervene really early, even potentially with a VISA present replacement therapy, that you might be able to put them on a different developmental trajectory. So that was my big what if question.

And what was really remarkable was so I had been asking, john, hey, can I have your spinal food and sam males and and he finally agreed after, saw a couple of those papers, understandably wanted to make sure that we already had shown something in people and animals that were sort of, if you will, symptomatic with social experiment. And what we found was, yes, this was the case. So what was a small sample? IT needs to be replicated, but individual is so influence that went on to have an autism diagnosis later in life, already had low csf visor present levels.

Oxytocin levels did not differ between infants. They received a subsequent autism diagnosis and those that didn't. So suggesting that we have a biomarker that you know might really be a good read out for you know clinical referral, risk management monitoring.

incredible. So you're telling us that levels of VISA person corporate with social cognition deficits alright I think that warns a brief discussion about three bal spinal fluid. I teach her anatomy of medical students so um forgive me for for having access but you know I think of three will spinal fluid as the stuff that exist in the ventral and down the central canal of the spinal cord and provides essential nutrient and for neurons and other cell types in the brain but it's also a reservoir for chemicals coming from the brain which is why the final type is useful um but in the context of a three bro spinal tap and you're measuring C S F in okay, lower levels of VS oppression in these individuals, with these chAllenges, with social deficits. Does that mean that they are making less face? Oppression does IT mean, I mean, I could not go on the other way too, like they're dumping too much ways of pressing into the csf and it's not able to function in the brain like, you know, what do we know about csf and what does that mean.

right? Well, I mean, it's a great question. So I I think this is just the tip of the iceberg, right? So I think of the csf is as sort of like the kitchen sink of the brain, right? And what we need is real specificity. And so I mean, my working hypotheses, and we'll talk a little bit about ARM maco logy, is that there is a deficiency in in VISA product VISA present product in individuals with autism. But there's a lot of elegant experiments that need to be done to be able to answer this question.

So we have funding currently to look in a post modern human brain tissue um to look at um in both blood C S F and hope islamic tissue where VISA person is made to look at inner relationships, right which is very difficult to do but also to see if there is a few a number of VISA person producing cells and a VISA present gene expression is dimension strike because that would help us begin to answer, is this a production issue right right? If you think back to the party walls, there's sort of prime to be parental right um or in in my case the metal walls right. But you can do this in any val species at well, at least the two that I am thinking. And you put VISA present into the brain and then all of us sended IT unlocks this behavior, right? So is that possible that children with autism, or at least a subset of them, um all you have to do is replace face a present and that there might be a subset of these kids minimally that could benefit from baza person replacement, if you will.

Is there any evidence for excessive urination in kids with autism which if anyone's going, what was asking that if you recall, the suppression is also anti diode cormon. Um I suppose that other question is, could you has anyone looked at levels of viasa present in the urine of autistic kids versus on autistic kids because it's acting preferred and um you said blood draws don't reveal any differences and in circulating blood we know that you're in his filter blood faring off but um seems at least worth OK.

So I had this awesome medical student in my lab nimbler in Clark and we with three different physicians from different background. So um wrote a perspective piece that's currently under review and IT actually asked this questions. So you know given all these weird medical naming conventions is possible that this information is existing in information silos in different disciplines, right? So IT raises this idea of if you have low VISA person, so there's if you really don't have you're not making VISA person.

You have a disorder called central diabetes incipit tis right which is characterised by excessive thirst um lots of your nation um and and you know bad wedding potentially um and so what we wanted to do was ask, has this been missed? right? So shouldn't there be a subset of kids with auto where we might be able to look at these other physiological features and say, yeah, this is the subset we want to be giving VISA present to? And so he wrote this perspective where we did a little bit of a review and the answers there are some intriguing um studies that we reviewed in this paper where IT looks like and what's funny is when you read the discussion section, i'll be like, wow, there is all these kids with autism that are in lots of water and we don't know why or well, there's a lot of bad wedding, but it's not tight analytical disability where you might see a lot of bad wedding or something. So all of these studies is kind of raise this point of like, well, this is really interesting um and there's been no big epidemiologic study done on this and certainly not any study where people who come at IT from brain science and then the practitioners who are like an ideologist for instance, which is ware of some of these people could show up um are are really connecting the dots so I think that remains to be determined, but we are actually about to watch a study to investigate this right? I was meeting with Lauran yesterday about IT so is a really good question and I hope to have information on IT in the not too distant future.

As I recall, alcohol is an tagged ist of VISA present, so there's a .

lot of different drugs that can interact with VISA person.

And so one thing i'm interested in is, are there any rugs that release face or person as a side effect? And could some of them be mobilized to treat autism? We also know that like a acute g sure can release space, a person there spend some studies done in rats on that um and so one question would just be there, there are any alternative therapies where we can be released in bassa person naturally or do we need to you do a replacement study where we give you know, intractable vasa presented children with autism, right? And of course I am not. I want to say i'm not advocating that people go out and do this on their own right like I I am a big proponent of randomized clinical trials where you access safety.

right? And yes, right. But I appreciate you saying that yet. Um some years ago, so this would be mid nineties. There was a small but very active subculture that I was not a part of O I swear um that were combining G H B gma draxy beauty ate um and VISA present as a combination called sex drugs yes yeah um and I don't know what the rationale for including basic present was in any case whether not that's by way of enhancing social bonding or a direct effect on sexual roles itself still unclear but in an event since we're talking about bazoo reson, maybe you should tell us about the actual science of these Operations sorry. Maybe I should allow you to tell us about the actual scientific study of VISA impression um in other words, what happens if you give people with a present in a controlled environment, not ort of environment? I M in the thing.

I think I have people contact us all the time saying, where can I get VISA person? And what I would say is VISA person means you're having effects on blood pressure. You're having .

effects .

and really important, right? And and the dosing has to be appropriate. You don't want people just going in trying this because there could be really severe adverse ve facts, right?

So that's why we've been studying this in a in a control clinical trial, right? So um I teamed up with the antonio harden who's the child syc atrix that i've been working with for years and we did the first sort of first in class VISA present treatment trial and children with autism. So again, this was everyone was unaware of who was on bed a present, whether IT was the family or the clinton who was doing the evaluation.

And then IT was randomized, placebo controlled um and then we basically gave vasa person again twice a day for four weeks to children. They're about six to twelve years of age. And then we had a primary outcome measure, which was the social responsible, the scale.

We could get into discussions about what a primary outcome measure should be, you know when to be great if there was a biological measure. But this is one of what had been used in the past and something that the fda proved us using. I was partly interested using the aura because we had used in monkeys, right? And we had shown, at least in monkeys.

We have never looked at this and people, because of, you know, the lack of available samples, but that in monkeys in this general population that we've looked dead, there is a continuous distribution of these assar scores that relate to the C. S. A. Aser percent levels. And so what was I wanted to know if we use the arrests and outcome measure and word ministry in visor person, can we change, you know, this scoring on this instrument based on .

our animal data? So a social responsibility. E um without going into a lot of detail because we can always refer people, the paper. And I think most people just want to understand the top control the S R S personally has to do with um how often the kid interacts with another kid, how often they initiate that interaction versus s on the receiving and things like a filler of play, how often they look at one another verses, averting gaze.

these kinds of things yeah. And then there's also a little bit about restructured repetitive behaviors. So even though is called the social response of the scale, there is also an assessment of other features of autism in IT. But you can sort of think about IT as a quantity way to assess features of interest in autism. And this was related to our biology in the monkeys.

And so then we use this as this outcome measure um in our trial and and you know as as an experimental alist I have this sort of trust but verify right so you you want to see the same thing over over and over again. Rightly scientists like repetition. And so we had parents fell out of their impressions of what the child's behavior was before and after being on the medication. We also had a clinton making evaluation, but we also had the kid's perform laboratory based test, where they would see, like I mentioned, that the reading the mind in the eyes test, or we would show them a picture of face and say, what emotion.

This and so we were able to have what's called convergent validity, right? right? So it's a fancy scientific term to say, do all these measures that we think should be related? Are they related and are we seeing the same thing? And um the answer was yes so that when we gave children with autism baza person versus kids with autism plica o, the kids who were treated with VISA person showed increases in social abilities on parent report, clinical evaluation and child performance on laboratory based test was .

that was that immediate like they did the nail spray and they immediately started receiving an an initiating more social engagement. Where was this to build up over time? And what i'm getting at here is where they are not. This is the reflection of a short or a longer term neoplastic like where the structural changes in the brain, or or or this is something that was more acute.

We don't know the answer to that.

So we basically looked at dosing with the idea that we and again, I think we've mentioned this about limitations on, like there are so many things that a scientist would would like to do, but you were always limited by a budget, right? And so when we started this work again, IT was like, filthy pic shoe string budgets s right? And so you had to really be laser focused on what are the things that we can do on the budget at hand.

So unfortunately, we didn't do like eeg or brain imaging or other things that would be, I think, potentially very interesting to do because you might be able to see an early signature of response, right? So maybe after the first dose, let's say, wow, like there are some interesting changes that are predictive of somebody who would be a responded to the medication. And we don't know that yet, but we do know after this before we period that we we saw you know these changes and and then in a subset of kids we actually saw diminished aniele and also diminish restricted repetitive behaviors um so suggesting that the VISA person effect may not only be on um social behavior.

Have you ever just wanted to try or try VISA present in in a psychic .

department after all?

And i'm not suggesting that members of psychiatry department are constantly testing the drugs that they use on their patients. And so but but i've had several members of this department, of which I am a courtesy member membered by courtesy and event, and we'll see if i'm still am after what i'm about to say. Uh doctor called that who is a clinical a first a guest on the hudco also a phenomenal neurobiology searcher David speel romela um and others um that I ve spoken to you know I think all of whom said you know that they felt as clinicians robs not clinton but anymore right but as a clinical that they felt almost a responsibility to understand the effects and science fc profiles of the drugs that they were giving their patients to which I saw not as renegade experimental but rather is a very compassionate like seeking empathy um so i'm curious, have you ever just snuck the world?

No, no, I never have. But there is a long history in medicine of people trying out. They believe so much in their solution that they go in vaccinate their family with the new vaccine that they've created or they try the medication themselves, right?

So m. Dma was developed by social kogan and laboratory in the east bay, first by farm circle company. In the early one thousand nine hundred per ten disappeared.

IT did disappear, and then IT was resurrected IT independently in the in the nineteen, I think, seventies and eighties. And then now it's one of the so hot topic items for the treatment of P T, S D. Still in late face colonic trial, still illegal, but self experimenting is is one of the central themes of psychiatry, Frankly. Yeah.

I mean, I guess, you know, I have I gotten trouble in class for being too social, right? So so I guess i've never might send .

you over the other.

Yeah, yeah. exactly. Who knows? But no, I never know. And the thing is, is that these oxyde viasa person, and again, these are done, and this is this is something that I think we've hit on over and over again.

In the pod cases, you need to know whose you're studying, right? What's the species, who's the individual? You know, most of these have been done in know neuro.

I mean, a lot of the oxytocin, a little bit of the vasa person work, the single dose work was mostly done in what will call neurotypical people, right? Just asking, can we move around social behavior by just giving the single drug administration? Most people that are neurotypical didn't say that they could tell if they are run the drug or the policy boat, right? So so I think the question really becomes, you know drugs have different know they work differently based on the individual who's taking them.

So if you have a neurotypical individual and you give them based a person, you maybe they'll self report that they don't see a difference. But if you had somebody who isn't producing enough is a present, maybe you know they would self reported after a period of time, or maybe even after the first dose. Wow, I really see something different, right?

Did any of the kids report how they felt? I just said, like, wow, I like playing with other kids, Moore, where they self aware in that way. And also feel free to mention if IT feels right to you any, uh, let's consider two outlier cases.

One spectacular result of that you know a kid that went from very socially isolated, you know maybe very gregarious. And yeah but let's also baLance that with another outline that the kid with low via press and who took VISA present who for whom there was no significant shift. I'm presuming that within the data that you probably observe something like each of those.

Yeah so I mean, what else say is that um so yeah, I mean, there were definitely kids who didn't respond the medication. I mean, one thing I think it's important to saying again, this was a small pilots. Al, right, we're in the process of replicating this in a much larger sample.

So you know, as a scientist, again, you want to say, okay, this is really intrigued and interesting. And i've invested a lot and you know this monkey model and then doing all the CS of work in patients to suggest that there may be there there, here but I wanted see IT replicate. Um we did have an article um that stanford medicine I can send you the link.

They were able to, I think, and review a family that had been in the trial. And so obviously, there is patient privacy. And you know you have they have to say it's okay to talk about that, but this is a family that was contacted. I think they were anonymous, but this is in this report and they basically said the dad said that his son was walking around the he was on VISA person and his son was walking around a grocery store and he like was looking for him and he turned around and he said he was gob smacked because his child was, you know, just talking to making chit chat with somebody like in an I O and he said he had never seen that happened before um and so you know, we do have anecdotal reports like that.

And I think, you know, the tRicky part is, are we we didn't stratify anyone going into this trial, right? And so the concern always is, did we get really lucky in the first trial and we somehow got the the quote, quote right, people that entered the trial that we're going to be the ones who would respond to the medication? Or is this a medication that has sort of broad use in this population? And we you know the second trial will be um positive.

You used nasal spray to deliver the vase oppression and prison ably that gets into the blood circulation of the brain um and supplies neurons with these are present but it's very non specific and i'm not criticizing. But if you think about you just putting a bunch of viasa present into the brain, and if people onder why this is, that is because basically you have neurons of your central neurotic system, are part of your own factory system and believe in not right behind your where your nose meets your forehead. Um the brain is right there, there's a little bit of bone and then the brain is is right there.

So um one of the reasons you can get in there um and is easier than an ocular injection or something that wouldn't a good approach and and is easier than a preferred that injection in the vein. But at the same time I have to resume that this am imagine this wage of present just kind of like premium through the brain binding to whatever recept tors happen to be there. You said the receptor ors are everywhere and then this significant improvement in social cognition, right? So that raises all sorts of interesting questions about like what what relevant circuits are impacted? Or is IT some global in could IT be some global increase in kind of awareness of surroundings um although some want to, the kids are overwhelmed by their awareness of surrounding so um yeah what are some thoughts about how vizor present might be working to exit this really impressive and Frankly important effect, right?

So that mean could IT increase social motivation? Does IT so let's talk about like how sort of complexity of social century processing is IT that were directing attention to social cues where the wind of necessarily been as much a tenniel ess, right? Um are we increasing social motivation which would suggest from some of the animal studies may actually be happening, right? Um we don't know. And I think that's currently when you have other models or if you're able, you know to do imaging studies.

I mean, one thing that spent out a little bit of a holy grail in this field is that if we could get um tracers that are um basically like you know a molecule that would allow us to inject IT into somebody and then visualize the brain like i'm thinking about a pet trace or a radio like and where you can then ask questions about, you know what's happening in the brain. Can we can we give VISA present in the context of a functional brain imaging scan? And asked, like, where is the visitor present? Finding what kinds circuits are involved? Like that needs to be the next step of the work to know like where where our targets are.

And you can do something like functional proteomics, right? Where, if you know where these a present receptors are, you can overlay that with studies of functional brain imaging, right? And that would allow you to say these areas are dancing phase or present receptors.

And do we see similar responses in what we call bolt signal on on a on brain scans? So let let's be more cloquet about this. Like do certain areas the brain light up, if you will, where we know these are present recept tors are are densely distributed. Um in ways that we know are tied to social motivation or social silence or other things that we think could be moving the middle here um in the trial.

How is this happening? And and I think you know one thing, the reason why we did this work is, and I think that speaks to what you said earlier, there is an urgency on the part of parents to say, you know, my child's brain is developing, right? And and there is a sense that, you know, the sort of western model has failed a lot of people.

You know, they looked to doctors and say, what what are the solutions? And doctors will say, what? We have a limited number of tools in the tool. Get here.

We just don't know, right? And so you know, one of the reasons why they did that big oxytocin study was that people were trying to get the oxytocin anyway. So IT was like, let's just make sure that this is safe. Let's see if it's effective.

And so some of our thinking was, you know, as soon as some of this work hits, you know, like I get in, some of the work has been covered by the media and so know our feeling was we can give this intractable um and we can do IT under safe monitoring ways um and so people are going to think about doing these things anyway. So let's just make sure that this is safe and let's test this in a rigorous way. So we don't know the mode of action. But then our feeling is, is that you know at at least from the initial safety data, IT looks pretty safe um and you know and so the idea would be and there's a long tradition and psychiatry of we don't know the the mechanism of action, but if we have a medication that can be impact for and improve the lives of people with autism and we can diminish suffering and people can more readily reach their full potential, you know, to me that actually seems unethical not to move forward in a way that scientifically sound.

Amen to that. This seems like a good time to raise the topic of the microbiome and not as an unrelated topic. And and here's why i've seen a fair number of studies in mouse models arguing that in a mouths model of autism, which now live, have to have to wonder about the the power of that model.

But anyway, that models are out there in the field. One can take the microbial basically once, be direct fecal transport from a, and here are using air quote to non autistic mouse, or a mouse that doesn't have social interaction deficits, and put that fecal transplant into a host that does have social deficits and rescue some degree of social deficits. I don't know if this has actually been done in humans as well and for those either cringing, yes, they do equal transplants in humans for treat of obesity and a bunch of other things.

Um this isn't because scientists are obsessed with final matter. It's because um fecal matter contains a lot of the microbial elements. Um so the micro bacteria of the of the gut um and the reason i'm raising this now is you know one possibility and it's not mutually exclusive with a brain mechanism, is that the administration of viasa present somehow rescued a viasa present deficiency in the gut so the questions as follows, is there any evidence that VISA oppression is manufactured in or impacted by the gut microbiome of humans? We'll just start with humans and I think most and um because that would that ouldn't be a smoking gun, but it'd be an interesting detective story.

Well, okay, so the one piece of evidence that I will say that I find provocative and fascinating, and one thing I want to say is I I think there's a really great work done. Mice, I don't want to be a mouse special. So I wanna just like where to go on the record that i'm not bashing other models um if it's a conserves, I think about everything from that. Like an evolutionary perspective, if a mouse res a brain structure with a human and is highly conserved, you know mouse work can be incredibly important and very importantly.

ful right? My lab did years of mouse work, some primate work. We're necessary, and now I only work on humans. But IT absolutely has its uses. But clearly, the primate model for social deficits as a relates to autism, you at least have me convince ed that that one has a lot of power. We just say that.

okay. But I mean, I now say there is a really cool mouse study that was done that I found, and there's been know lots of different study. So there has been mice. So there's these, like I said, these genetically modified mice that have genetic syndromes that are what the individuals have, social impairments and some of these individuals and again, here's here's a problem with a field.

Often they will measure oxytocin but not VISA person, right? So like they're not often both measured together, which I always do now um but there's been some really of interesting evidence that in these mouse models that and and again multiple studies, but like certainly low blood oxytocin levels in these mouse models with the sense that maybe they have some sort of abNormal got microbiome and then what they've done is theyve given a probiotic to these mice, Normalize their social functioning um and that in there is an increase in oxytocin and in a recent study also raza person at the level of the hypothalamic by giving a probiotic. I believe the oxytocin levels were increased in the blood you saw more species typical social behavior and this was all driven by this up regulation of oxytocin e expression and also says a present in this very recent study. And what's interesting is there is this nerve called the vegas nerve, which is um is I think IT IT .

means the wondering yeah exactly .

right and even it's in the gut, but IT actually has a direct projection to the nuclear iron hypothesis where oxytocin in VISA present are made. yes. And so when you server the vegas, you then in this one study is a neon paper.

Um it's like twenty twenty. It's a super cool paper. And then what you do is you decrease the gene expression and you don't see the rescue of the oxytocin levels or the social behavior in this model. So so in other words.

if I interpret ate and i'll go to cut the paper and provide a link to IT um there there by increasing the diversity of got microbiota because that's really what a probiotic is sort of across the board increases the diversity of got microbiota. No one specific elas I always the end multiple here we go um you up regulate gene expression and thereby action of oxytocin and v oppression in the hypothalamus. But that's a neural mediated thing.

It's not as if the microbiota travel to the brain. Something changes in the gut which activates the vial pathway from god to the specific nucleus in the brain. And um we know that the vehicle pathway is involved because IT seems at least partially necessary.

If you server that you give a vega y then ah the uh this effect is is blunted or eliminated that's very interesting in and ties the microbes O M to oxytocin VISA press production in a neural and somewhat cares away um and makes the data on fecal transplants make a lot of more sense because I always wondered, okay, you taking the microbiology, one animal put him in to another animal you're creating. You're transfer the middle of the gut but he doesn't say anything about mechanism. So this this is a really cool paper.

And there's also what a study of I always wanted to do is you can get a vegal nerve stimulator. They used to do them as implants, right? But you can also get one that you sort of clip onto the air. And I ve always wanted to ask if we we use this in autistic individuals, and you know, could we increase, like we alter social behavior, right? And would that be something that we could actually measure in the blood, especially for seeing this this change in these blood levels.

right? That experiment? no.

But i've always, always we have to .

get you the funding to do that experiment. And and I know a few times you've raised issue of funding is not something we spend a lot of time on discussing on this podcast. But I think what should be abundantly clear to the listeners throughout the course of this episode is humanity.

You're very determined to get worked on. You will figure out away. But the way I describe finances and research is that it's absolutely necessary, but it's not sufficient. You, of course, I ve had the right people in the right, a lab head directing the work, but no money, no no project. And IT and IT is disappointing to see that despite the federal budget for research being still reasonable, it's not what we would like IT to be.

Um it's still very hard for amazing world class labs like here is to say here you know listen, there's this vehicle thing and clearly there's a rationally it's not like you're pulling us out of of nowhere and um you want to go to this study but we're really talking about is three to five years of grant writing before you could even initiate that study. Meanwhile, autistic kids are going from age two to five to six. These are critical windows. So if ever there was a um there was a rationally for um you know moving a lot of funding to uh no I don't even called high risk but you know logically sound hypothesis testing for the treat of autism. It's it's now so i'm i'm going to get an active on on this front so I won't get into how but you know when I get something in my in my neural circuits for for talking, they tend to not shut down for a while.

There will be a community that is going to be immensely grateful.

Well, IT seems like the parents of these kids and the kids themselves could greatly benefit. So you mentioned that the first study on um these Operations and administration that saw these improvements in social functioning, you said a small cohort, how many how many kids was IT ultimately that you .

could use data from? okay. So we had mean you screen a lot. So I because we had very rigid criteria, so we ended up with seven kids that were on active drug and thirteen that were on policy .

o and not a tiny study.

no. And the placebo should we always have, like a humAnitarian open label extension, ARM, which allows for anybody who is implicit bo, can get access to the drug. So both antony and I fl very strongly about making sure that if we're doing a medication trial.

everybody can benefit from right OK. I was the a gw. I really want a chance thing. Yes, again. But then you also get more data.

We get right. So I think when the families are now aware that their child is on baza person and the clinic are aware, you really want there is a huge placebo response rate, right? And so I mean, it's not a plica response rate here, but.

But we really would want to make sure that our evaluation of the social behavior is done unaware to the medication. But you can get good safety data, right? So so you can have those you know thirteen children who are on placebo. We can then also make sure that their blood chemistry labs look good, that their electoral diagrams look good, right? And so that also allows us to safety parameters and a greater .

number of children. In a fairly broad literature search, I was able to find, okay, microbes and was a fecal transplant is something that people .

are excited about this. And there are trials .

in people with autism ongoing OK oxo san nas spray presumed ly still being investigated by some groups or it's been abandoned. Well.

I think it's mostly been abandoned because there's no funding priorities for IT, right? So so I know that maybe in australia, because of Adams's positive findings that I don't know what his plans are, but maybe he's doing work there. Um there might be a little bit of work with behavioral therapy and oxytocin, but this is the problem when there is one big trial that fails, the funding just completely drives up. So even if there is promise, I don't know a single funding agency that's .

gonna touch IT got IT and then there's the VISA present administration work that you're doing. I think it's worth contrasting that work with the fairly large trial that was done by a major pharmacy ticals company expLoring the role of the oppression for the treatment of autism. You could tell us what they did because it's basically the opposite of what you did. And you can tell the outcome because I think that, if anything, that study inadvertantly provide support for the results that you observed, which is that administering, say, increasing base Operation and levels in the brain seems to imperial some of the social .

deficits to sm. So rose had a compound called ballot open, which was a VISA present v one, a recept and tag ones which basically means, as I think I mentioned, there's these four neuro petite receptors and oxytocin vasa present bind to each other other's receptors.

But the v one a receptor is the one that is um most implicated social behavior um and so they had, this is the tRicky part about when medications are developed in farm of versus and academics right in academics there is definitely to transparency. We write grants, the abstraction are publicly available. We register trials.

They do to but a what is the shall we say, early development is all put out in publications, right? And then it's also peer reviewed. And there's you know an open trail of why we're doing what we're doing. But in a pharmacy, al company know they have the ability because also they have all the funding to be able to do all kinds of development that may never see the light of day because of the proprietary basis of IT, right? And so you know when you go back to so it's not still is not clear to me why they took the approach of using an antagonistic, the main VISA person recept in the brain.

Um what's interesting as if you go back and you look at the animal literature, there are hamsters that if you give them VISA person, they become aggressive, right? And if you give male puri walls days are present, they can become aggressive. But let's think about the context that they're doing this in. These hamsters that show aggression are a social, they live by themselves if you give them VISA person.

And the only social rapid war they have is to have sex with a female or to fight a mal that they see, they have a very limited social rapid air, right? And when the pario male is being given vasa present, it's often in the context of permit, like protecting his mate and his offspring. And so then it's actually species appropriate for him to attack a morado ing male on his territory.

Who's going to, you know, kill us babies, right? And so so my thinking in reading the preclinical literature, the animal literature, was that alright? That makes a lot of sense in the on text to those species.

But we've never seen any evidence in our trial. Aggression didn't change. We also have an aggression measure in this current in the current trial as well. But you know for me, the vast majority of evidence from the animal literature suggested that VISA person was prosocial.

Um and then you know especially given our R C S F findings like over and over across species, across studies, across ages that we we should be giving VISA person, especially given the correlations between VISA person in csf and symptoms, severity and autistic traits know the former and people in the latter in the monkeys um and so they had some preliminary studies that I believe were maybe single dose one that they published um but then they had a trial where the primary outcome measure, the social responsive ni SQL was negative. And then they had um some secondary measures that maybe showed some promise and then they were conducting another trial um and then they did a utility analysis. And I know they stopped the trial and I don't think IT was for safety reasons.

But again, you know a lot of this isn't made public right, because it's a pharmaceutical. So you know we we will see because we are going to be completing our larger trial, you know this year. And you know as they say, the proof is in the puddings.

So we will see if you know, we can reapply. Hate our initial pilot findings. Well.

sounds like they got IT backwards. That blocking based Price pathways would just make things worse and that augmenting this a present makes things Better. Um although that last statement um needs to be supported by this more extensive.

I think there has been a lot of speculation and maybe there are people closer to the trial than me who might be able to speak to making them but you know, I would meet the rose people at conferences and they were coming to my talks and I would always ask him like, what's the mechanism of action? Why are you tagging zing the system when we're giving know is a person agonis if you well and you know some people had said, well, maybe by blocking the VISA person receptor, you know, there's a way to have oxytocin. Me be more .

bioavailable.

I tally. And so i've never had a i've never received a compelling response from anybody about why they did their trial. And then you know the differences.

I mean, when this was ongoing and you know there was potentially room for both, right? You know, maybe I thought that maybe there's some some optimal and a vasa present signalling in the brain, right? And so maybe there's some people where they have too much baser person and some who have too little, right. And so this was a lot of maybe, but IT doesn't to seem like that the case, especially of our current trial, has a positive read out.

I D be remiss if I didn't ask for your stance and read of the landscape on the data about vaccines and autism are not time about COVID vaccines here might be really clear about that but there was a theory running about um not just in the press but in um the scientific literature for a while that uh vaccines could cause autism yeah that was proposed um my understanding is that was debunked.

That idea still lives on the internet but what is the evidence or let's say, let's go through the sequences what was the idea? What was the evidence for that idea? And then what caused the demise of the, at least the scientific support for that idea leaving open? Of course, that new data may come right, but let's talk about what is known IT now, right?

And I think what I will say being evidence space is sort of like something that all scientists should strive right and so so the back story on this is there was a good named Andrew wakefield who publish to pay um and he basically said the pressure atis and vaccines are causing autism so .

not the specific vaccines, but the edge event, the stuff that's preserving, the stuff that's keeping the the vaccines um bioEthanol tive .

right at least that was my interesting .

yeah that's .

mine as well and so and then IT.

I want to be clear because the internet is is a cruel and my stance is that that was the hypotheses. I don't agree with that stance.

right, right. And so or if we wanted just back up a little bit broader, there was this idea that something about vaccines were autism, but the study was designed, he lost his medical license and the paper was retracted, right?

He was his medical license on the basis of the fact that the study was wrong or was their the data there. That's why I we're calls well that there is evidence of him literally making up the data. So IT wasn't a case of like sloppy technique. IT was a case of of intentional fraud.

right?

That's my stand. What was does anyone ever like look into what his motivation for what what IT was like why someone would I mean throw away his whole career right?

Yeah I don't I don't know um but but I think the hard part about that is understandably, people got very frightened, right, that we're doing something to our children that could have and anticipate the consequences. And you know when something like that happens, then we dump we spend a lot of money investigating that.

And the good news is at this point, there have been multiple, multiple studies that haven't shown a correlation between you know, vaccines and autism. I do believe the preserve tips have been changed. There was a result so that something we should check, you know, that might be something where know there's been a public health change on preservation ves that .

are in vaccines interest in right I want to alarm but that's that's interesting you know that that in this data fraud d case IT might have ued people to the idea that certain things might have been needing change even though IT wasn't a specific issue that this ah this fragile lent researcher was focused on.

The change was made to make sure people would vaccinate their children, rightly so.

This is something that I think we should have lots of caveats here like you know post post the studies like make sure that what we're saying is accurate, right? But but I think that my concern is that we've spent you the good news is that you know them, like every single study that i'm aware of, does not show a relationship between vaccination and autism, right? And so I think that most scientists and medical doctors that I know that are part of like the you know standard biomedical research community, do not believe the vaccines cause autism theyve vaccinate their own children. You know they recommend vaccinations to other people's children um and and so I think that's where we are um question .

um uh and I feel more than obligated to do this because I think I don't you know I think I have a pretty good finger on the pulse of the listenership at this podcast. I think there's a range of of stances on this um where some people have a lot of trust in the standard medical establishment and others have less trust in the standard medical establishment.

And I wouldn't be doing my job if I didn't try to um all those sides um and you know one thing that i've heard IT is that over the last twenty or thirty years, there's been a dramatic increase in the number of vaccinations that kids get. And I don't know that's true, but when we save vaccinations, we could be talking about, you know, muscles mms rebell's polio um we could also be talking about muslim month review polio flu shots every year, rabies vaccine tnz vacine know H P V right? With one that was even available when I was in college. You know everyone in college, which is that was well, well, are there wasn't h vaccine um didn't change people to behavior a whole lot. But um you know.

There's there's a vaccine, there's multiple vaccines and then there's you know all the vaccines, right? And I think that one of the concerns that I hear about um is the idea that okay, there are some critical vaccines but then which ones are perhaps less critical, if any um and these are the kinds of discussions that are starting to surface um and that you know have parents and potential parents you know write fully thinking about this stuffin and no one really knows where to get the information like I tried and I can't find a pediatrician that says he listen these but not those or you can certainly find board thirty five physical that say many and certainly d thirty five physicians that say no. You actually can find those the non category tend to hide themselves a little bit more than others for obvious ous reasons.

But it's hard to get a sense of like which which vaccines are critical in which ones aren't. If you're a parenting, you're not worse in this site. And so you could imagine that like people are, the kids are taking many more vaccine. Only some of those are critical or maybe all of them are critical.

I think guess we I would maybe turn IT on its head. Is that, you know, because of this this study that did in some way so much harm, right? right.

We spent. I I don't even want to hazards a guess about how much money worldwide went into studying though. You know, vaccines and artists based on a fragile in data, right like that, to me, a real tragedy.

But they didn't. We went after thinking was.

So I think I think the consequence of all this that I think is also extremely sad, is that everybody, because everyone got so riled up and so fearful that his ban, historically, until recently, many researchers who are like, old man, I don't want to touch immunology and autism with a ten foot pole, right? And a.

you know, I wouldn't concern myself fearless but like my lab never had any reason to work on those yeah on those important problems but i'll tell you like yet seems like not a kettle of fish. It's it's a about barb wire with a bunch you know name pom burning around IT know mean you say one thing, your career ending. You say the opposite thing, your career also ending. You know it's it's a it's a mess.

But but I think this highlights that there are so many parents, you know again, and I think we need to listen to parents stakeholders, right? Like there's there needs to be a dialogue whenever anybody sending any illness to to talk to the people who are involved, right? And and I think that there are parents who will report, well, like there are there is immune system direct lation in my child and but because of this historical issue with vaccines, it's only been very recently that I think people, scientists, medical doctors have said OK we're hearing a lot about this from parents and are there a group of individuals who have you know um immune issues that could be driving their autism, right we don't know when everything should be evident space but I think that like you said, with this cancel culture and all this fear, scientists sometimes will pick topics very judiciously based on, you know, like, hey, I just want to be left in peace and i'm trying to help this community. And if there is areas of the enterprise that you think you're going to cause all kinds of grief, then people are going to be less reluctant study them even if it's critically needed.

Well, that's a perfect place to say thank you. I realize you're not addressing the vaccine autism issue directly, but you're so clearly going after the target trying to figure out what are the biological mechanisms that disrupted in autism and by extension, other deficits of social function in kids and adults. You identify this incredible relationship between base of present, which should have more prominence in my opinion than oxytocin lesser cousin just kidding oxy to lovers um but also have shown you know yes, in a small study, but you're now extending this to a larger cohort. As you mentioned, a causal relationship when VISA present is administered to these low VISA present slash low social functioning kids, their symptoms improve.

So I know I speak for many people when I say that um I truly appreciate your dog dss and in going after this problem, especially on the complicated landscape of lack of funding for doing novel and truly high risk work, um especially on the backdrop of the socio political landscape or on autism, it's complicated thing even to discuss you know as I mentioned the introduction you we had have some fluency around autism. So we sometimes said autistic, sometimes we said people with autism. And it's a it's a tough one.

But in order to make progress, real progress in this area, we need people like you. We need you and you're doing that to get in there and just go, okay, you know, let's get at the biological functions. Let's get at the novel treatments and you're making amazing progress. So am so grateful that you're doing IT and that you will continue to do IT and that you came here today um to teach us what you've been up to. Um i'm also grateful and I just want to say thank you for that and that we absolutely have to get you back here to give us an update on your progress really soon and and again and again and again.

thank you so much. I love being here.

Well, i've loved this conversation and um i'll sign off by saying, folks, this is how diseases are cured. Thank you for joining me for today's discussion with doctor current Parker about the biological basis of social functioning and autism. To learn more about doctor Parkers research, please see the links in our shown ote captions.

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