Welcome to the huberman Lab podcast where we discuss science and science based tools for everyday life. I'm Andrew huberman, and I'm a professor of neurobiology and Ophthalmology at Stanford School of Medicine. My guest today is dr. Karen Parker. Dr. Karen Parker directs. The social Neuroscience has research program at the Stanford University School of Medicine. The goal of her Laboratories research is to understand the biological basis of social functioning at every
Each of the lifespan. So this includes the bonds that form between infant and parent or parents as well as the bonds that occur between children as they grow up which of course form the template for social functioning when we become adults. Dr. Parker's research is heavily focused on autism and indeed on all forms of autism spectrum disorders today, we discuss 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.
Solved 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 10 to 15 years. And today we discuss why it is in fact that the incidence not just the diagnosis but the incidence of autism has so dramatically increased and perhaps most excitingly. Dr. Parker shares with us brand new research findings 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 to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and 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 the sponsors of today's podcast. Our first sponsor is eight sleep eight sleep makes Smart mattress covers with cooling Heating and sleep tracking capacity spoken many times before in this podcast about the fact that sleep is the foundation of mental health physical health and performance.
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Element.com hubermann today's episode is also brought To Us by Aeropress Aeropress is similar to a French press for making coffee. But is in fact a much better way to make coffee. I first learned about Aeropress well over 10 years ago, and I've been using one ever since Aeropress was developed by Alan Adler who was an engineer at Stanford and I knew of Alan because he had also built the so-called Aerobie frisbee, which I believe at one time perhaps still now held the Guinness Book of World Records.
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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 we're heading to 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 or not the frequency of autism is indeed increasing or whether or not the field of medicine is getting
Getting better at detecting. What was always there over time? Do we have any clear answers to that? Well, I think it's a multifactorial answer. So we're getting better at detecting autism. Right? So in the past we were diagnosing kids at 9 or 10 years of age, right and now clinicians are able to reliably diagnose kids at two to three years of age. Right? So there's more people there are pediatricians have autism screeners and how so when you bring in your baby.
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 1 in 36 us children have a diagnosis of autism, which is over two years ago. It was one in forty four. So one in 36. Well, I feel like it was just yesterday when it was one in 80, but is one in 36 the average across boys and
Earl's does its cue differently if you look at just male births versus female births. Yeah, that's a great question. So autism is male biased and prevalence. So you have and again this studies very, I mean it's worth noting that autism is a highly clinically heterogeneous 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, you know different studies show that about for everyone girl
There's three to four boys that are 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 11 monitoring sites across the country. And so they they follow children and then that's where we that's where the prevalence rates come from and they release new prevalence rates every, you know few years. So if Physicians are able to detect
The autism early say in a two year old or a three-year-old to imagine that they're working off of tests that don't rely heavily on language because even though can get you know, some verbose two and three-year-olds 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 gaze among other things. We've already made clear that this is not
A discussion to allow people to diagnose themselves or others. But with that said what are some of the diagnostic tools that people use you know, is it language? Is it Vision or does it present as you know abnormal auditory processing maybe you could give us a sampling. So autism is a behavioral diagnosis, right? So unlike other areas of medicine where you might be able to take a blood test or there's other sort of tools. It's
Saul a behavioral diagnosis by an expert so usually a psychiatrist or a psychologist and they look for two core features. So the so this is based on the DSM 5 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 were a lot of people with sensory challenges. There are a lot of people with seizure disorders.
Sleep Disorders. So again, it's each person with autism has this sort of unique collection of traits 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 introduce nowadays. So if someone brings their child to the pediatrician and they take one of these tests and that child is deemed as having autism.
Will the will the one-year-old or the 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 variety of different ones that are used. There are some studies where because autism is highly heritable. You can have one child with autism and then you if you have subsequent children, you're at an increased risk of having subsequent children with autism and these are called Baby sibling studies. So what?
Doing is enriching the population of infants that you follow prospectively who are more likely to receive an Autism diagnosis. And there are studies where some of those children are enrolled in Behavioral Studies, even when their quote unquote at risk, I've heard before that, you know parents in which one or typically both parents are of the engineering mathy physics quote-unquote hard science type.
People are more likely to have autistic children. Is that true? I mean did that bear out in the data know if you look at profession or or undergraduate major does any of that correlate with the probability of having an autistic child? Yeah. Well what I can say is that there's been some studies. So what we know is that autistic traits are continuously distributed across the general population and there was a study and there's a couple different instruments that are used.
You be able to measure these autistic traits. So there's something called the social responsiveness scale. And then that's a US based instrument. And there's an Autism quotient. That's a similar measure that was designed in England. And what what we know from work with the a q is that individuals that are in intense stem Fields like engineering physics and math have a greater burden of autistic traits, even if they don't have an Autism diagnosis. Okay, so that leads me to wonder.
Whether or not this whole business of a spectrum is actually multiple Spectra spectrums. It spectrums are Spectra way. Someone will put it in the 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 spectrums, 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 undergrad
Graduate University UC Santa Barbara down the way from that school was the Devereaux school which was a school which has been there for a long time that parents would send their kids if they were quote unquote severely autistic. It was actually where Dustin Hoffman went to study for his role in Rain Man and the the kids who were really delightful they used to come into town every once in a while to the coffee shop where I'd study and they would also continue on from there to Kmart which is why the Dustin Hoffman care
Doctor would say gotta go to Kmart got to go to he would do that repetition. Right that Kmart was down the road from our you know, our College housing and the Devereaux 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 away to live there full-time. Of course, they get visits and they get visits home because they were I suppose we could say at the far end of
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 just simply thinking in terms of severity. I know people who have self-identified as autistic, that's how they 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 in healthy relationships and manage.
Life apparently, well, they have some traits that yes, I would agree or a little bit different right? So there's where we get into neuro Divergence, 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 kind of collections of different traits? Could there be a spectrum of severity also a spectrum of you know, more stereotyped behaviors another spectrum that intersects with that that has to do with you know,
Session with a particular topic, you know, you could imagine that there, you know 50 or 60 different Spectra or spectrums. I still don't know which one to say and that when we talk about the Spectrum. We're really talking about something that's in multiple dimensions and not just one line that goes from severe to mild. Yeah makes sense. Yeah. I mean, I think this is where understanding the biological basis of behavior would then allow us to be able to say you like here's these different dimensions, right? But not
ending the biology you're left with. Okay. Were are we lumpers or Splitters? Like how do we think about this because autism is highly heritable. So there's about 40 to 80 percent of autism is is genetic right? So these vary wildly right but that the common thinking is that the majority about 50% of autism is is associated with common genetic variants. And so the way that we've always thought about this is that there is
Is 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 underlie this spectrum, right? So if you have less of a dosing of some of these common variance, you might see somebody who's a lot more who's higher functioning like you said and if you end up with one of these single Gene highly penetrant,
Disorders you might see severe intellectual 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 know sort of an issue with autism 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, you know psychiatric and neurodevelopmental.
All disorders to date has there been any specific neural network that we can point to and say, oh, that's the neural network that seems to be different in people who are on the autism spectrum. I saw a study published recently that seemed to point to the idea that the genes that are altered in autism at least include a large number of genes that are altered or the proteins that are the consequence of those genes are altered and exist.
At the synapse at the connections between neurons and I'm asking it that way because you know some years ago. I was at a talk on autism at Stanford and someone raised their hand and says do we even know that autism is a brain issue right couldn't come to be an issue of the immune system or the cardiovascular system which at the time seemed like okay. Gosh, of course, it's but wait didn't you stop and you think that's a really good question. How do we know it's a challenge of the brain? Right? I think that's a great question. Right? And there may be people talk about autism.
Right. And so when you think about where the major player is, you know were 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 and 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 in understanding autism, right? And so the way I think about this is that let's just 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 cerebral spinal fluid, which is a fluid that bathes the brain brain tissue biopsies. It's very hard to get people especially children that are really impacted into a brain scanner, right because they can't sit still they may have sensory issues. They don't want to go into a scanner, right? So a lot of the tools that neuro scientists or psychiatrist have to
About looking at the brain are limited, right and then and then the other part is how do you model so the other way might we might think about getting access 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 features of control humans if you will, so we need to have complex cognitive abilities. We need to have complex social skills we need
Need to have an organism that has Vision as its primary sensory modality, right potentially sleep consolidating. So we need to think about all of those and and 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 I think that's you know, when we look at drug development pipeline.
About 50% of preclinical failures. So that would be something as tested in an animal that works and then fails in human clinical drug trial 50% of those failures can be attributed to poorly selected animal models. And so I think part of where 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 and people that's such a key point and for those
Said have not heard a preclinical models preclinical models are non-human model. So it 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 non-human primate preclinical models and the work that you've been doing and of course also the work that you've been doing in humans the other animal the other private the other primate it 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 and the environment interact right? It's never nature or nurture. It's always an interaction and that isn't just about the epigenome. It's also just about the fact that nature impacts the genome and our genome impacts the way that we interact with the environment Etc. So what is the role of the environment in autism both the frequency and the presentation of autism, so, I mean, there are again lots of different epidemiological studies. So Advanced parental age prematurely.
Charity severe prematurity is a risk factor for autism maternal illness during pregnancy. So there's 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. One of the things that I was really struck by in the early 2000s that least by my reading of the literature hasn't really gone anywhere was this idea that was proposed by posco Rakesh who used to run the neuro biology.
I meant at Yale expert in brain neuroanatomy and non-human primates and humans embryology really luminary of our field and a series of papers exploring how the migration of neurons during early development. You know, it's you and I both know but most people out there probably don't know because we haven't covered this in the podcast. It's not typical dinner table conversation, you know when you went an embryo when a human embryo is developing the neurons are born at one location and they migrated out some
distance to their final resting place where then they grow out their connections and connect with one another and that process of neural neuronal migration is 0 so critical for the eventual wiring in the brain and Rakesh had this idea that perhaps and I really want to emphasize perhaps that the more frequent incidence of autism might be correlated with the increase in early prenatal ultrasound and he had these papers published in a number of really high-profile journals and
Including protein is a National Academy and Science and elsewhere showing that in a mouse model. If you do Ultrasound with each successive ultrasound, you got more migration errors, right? So there's to me was a you know, an interesting example of the environment frequency of ultrasound in cell migration having some sort of interaction, but it seemed like it never went anywhere never got tacked to okay. You should keep in mind the number of ultrasounds that you're getting for your child. And of course ultrasounds are critical for for
Women to get because they can Stave off a number of developmental issues and they're super important. But you know, we've heard about ultrasound, you know it within the scientific literature and then occasionally will hear other theories about okay. It's having two parents who are both engineers and then we'll hear oh, you know, it's, you know toxicity in the food environment. We've heard, you know hypotheses about vaccines or the the adjuvants of the vaccines are contained in you know, in that large cloud of theories has anything really
Lee emerged from them. It's like okay there really seems to be at least one major risk factor environmental risk factor because I feel like all those theories that come up get some popular press bunch of papers are published. Sometimes those papers are retracted like in the case of the vaccines and then the theory kind of dies. Yeah. So is there any specific environmental influence on autism that we can say? Yes there really seems to be something there. Yeah.
I mean, 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 priori stratified trials where you could then, you know as a good scientist, you would only manipulate maybe 12 variables at a time. Right? But when you're doing these large epidemiological studies because you can't it's very difficult to do experimental studies, right, especially with developing children.
So I think that's an incredibly difficult study to do right. So there's been an interest in this field of there's these neuro genetic syndromes that have high penetrance for autism which basically means that you could have a disorder or you know, another genetic condition. Let's say it doesn't have to be a single Gene but that a lot of those kids tend to also get an Autism diagnosis. And so there has been work and like so for instance fragile X is a good example where because autism
Is so diverse in terms of clinical presentation that let's 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's 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 heterogeneous genetically heterogeneous study.
It's going to be very difficult to tease out these pieces because an environmental risk factor 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 subgroups of individuals and then be able to test the g b Gene by environment interactions or in this genetically defined group of individuals. Can we test this certain medication to see if it's beneficial for this subgroup of children got it, so you
In fragile X which we know presents with autism like symptoms and some cases and then I think of another disease like Timothy syndrome a mutation in an l-type calcium channel, which for those of you who don't know what these l-type calcium channels are there not just important for the function of neurons in the brain. They're really important for the function of neurons and other other tissues including the heart tissue, right so kids with Timothy Syndrome have cardiac issues and they have
Of autism. So, you know, I think it's important for us to kind of explore this a bit because in most people's minds, you know kids with autism have autism and occasionally, they'll have other issues gut issues or heart issues or musculoskeletal issues, but we often think that that's the consequence of the autism but oftentimes they have multiple things going on and the autism actually 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
No is you know, is it possible that what we call autism is actually like 50 different disorders or 50 different conditions. Depending on what one wants to call them. I mean, what is autism really? I mean, it's it's what does it really center around? What and 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 has autism if they also have a bunch of other things right that are challenging them? I mean, I think that that's the sixty-four thousand dollar.
Question, right and and 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 medications made right to attack that tumor and so, you know, what's really true.
When you have a behavioral diagnosis, that's not biologically defined you see a lot of heterogeneity. So it's incredibly difficult. I think to answer this question because we don't know how many kinds of autism's there are right, like there will be people who say if you have a disorder like fragile X or prader-willi syndrome or Timothy syndrome or or a variety of these other conditions, there will be people people I've heard clinician say Well, that's
That's not really autism right that's a piece of fragile X, 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 autism 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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To claim that special offer. 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, those things interact not just language but also Behavior to autism in humans using non-human primate models and then of course to also discuss some of the work that you've been doing in humans and we can't have that.
Action without first having a discussion about to neuropeptides that I think most people have heard of at least one of them and I think there's a lot of misunderstanding about but you're going to clarify that for us which are oxytocin and vasopressin. So before we dive into the the important work that you've been doing on vasopressin in particular, but also oxytocin and autism, what are oxytocin and vasopressin really? Okay. So there are these small
Little peptide their nine amino acids long. So very tiny. They only differ by two amino acids and their these ancient peptides that are hundreds of millions of years old and in almost any species studied whether it's the current version you might have Baeza tosin or other means a toast in which are sort of precursor forms and other species, but they're highly evolutionarily conserved and they're involved in social behavior in pretty much any it could be egg-laying it could be you know, but
Reproduction and social behavior across the phylogenetic taxes. So house cats make vasopressin and oxytocin humans obviously make vasopressin and oxytocin and pretty much every other species that has to interact with and connect with other members of its species, especially mammals, right? So oxytocin vasopressin are pervasive and mammalian species do the different species tend to make oxytocin and vasopressin in similar brain areas.
Has and tissues yes, but not completely overlapping but I think the thing that the beautiful mystery about these and the infuriating piece of them is that because they're so structurally similar. They can have similar effects and they there's four receptors that they bind to so if you think about a hormone or neurotransmitter, so oxytocin vasopressin, if you think about them like a key and a receptor like a lock and you have to put them together to open a door open Behavior, they
Bind to these four receptors so it can be very difficult to disentangle which one is acting and at which receptor and we're in the brain. Oh, so oxytocin vasopressin are chemically similar. Yes, interesting. Yes. And where would you say lies their greatest output Divergence, which is just nerd speak for is there an example of something that oxytocin does that vasopressin doesn't and vice versa? Yeah. Okay. So what's really fascinating is these two neurotransmitters?
As matters are hormones were discovered for their peripheral effects, which basically means not in their brain, but somewhere in their body and so oxytocin is involved in uterine contractions and milk letdown and so was during lactation. So people sort of always thought of it as the female hormone and then vasopressin has at least in the in the peripheral system has been involved in urine regularly like urinary output regulation blood pressure. And so
We only knew about their their physiological roles as they're sort of classic hormones for decades. And what was interesting is these like naming conventions are fascinating medicine, right? So you could name a virus after where it was first found right or it could be named after somebody who discovered the disease like Alzheimer's for instance is a good example. And what was interesting oxytocin was only named ones vasopressin was named twice. So it's either called Arginine vasopressin.
They're processing or antidiuretic hormone. And so it had two different names. And so as you can imagine sometimes genes are named twice. And so somebody in cancer is studying one Gene and somebody in autism is studying another and they're not even communicating because they don't even realize that they've at least historically now we have all kinds of Gene annotation site. So it's less likely to happen now, but but what was fascinating is they were these hormones were named oxytocin is Greek for quick birth. So for decades people only appreciated there are physiological role.
Al's but but there are neuroanatomists saying hey so these are both made they're made in a lot of different places but the the action sort of happens in the hypothalamus where they're made and there were not a miss that said wait these sort of project back into the brain. What are these doing in the brain? And one of my favorite historical stories was I had a mentor a colleague like a 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 that
Wonderful story about this Duke. So ologist named Peter klopfer and Peter was studying ungulates. So sheep and goats and he wrote a story of paper in 1971 called mother-love what turns it on and you know one thing about science is I love going back and seeing where do the Pearls 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 offs.
Spring that are precocious meaning they're basically born ready, you know within an hour they can run with the herd unlike our species which is altricial meaning we have very helpless infants and mom needs to bond really quickly with that baby. If it's going to be running around and you only you know from an evolutionary perspective you want to be investing in the baby that yours not somebody else's right and he hypothesized that it was oxytocin that was being KO released into the brain and during milk letdown. That was what
Grandmother loved on and that was really the beginning of this whole field of thinking and so that opened up thinking about oxytocin in rodent maternal care and a variety of other instances. Can I just briefly interrupt you because I find this so interesting and I know it's interesting to everyone listening as well because you know, yes and thank you for making it clear that oxytocin has many different roles, but this role of Mother Love and bonding to infant
Has me needing to ask whether or not the idea was that oxytocin is released in the mother when she interacts with her own baby and that leads me to the question is oxytocin also released in the baby in reaction to the mother. And how long is that affect lasting because in order to have a pervasive bond with that baby and not just some other baby and of course we still have visual cues and you know, we know our baby versus another baby most instances there are exceptions.
Our perhaps not so rare exceptions but leaving those aside, you know, the mechanism that would allow for mother-infant bonding and infant mother bonding by way of oxytocin presumably as something that is literally changing their brains saying it's you are the are that center of my life. Right? And the baby of course is going well. You are my life because you are the source of life, right Ed and the certainly for the early part really part of life and that nowadays. It seems that that that can extend.
And well into the the teens and 20s for some people but you know, how is oxytocin working? Is it working over the course of minutes hours? Is there some specificity of this baby and this mom that links them and some more pervasive way. I mean, how is oxytocin doing this magic of bonding? Yeah. I mean, it's very species-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 or goats
Early studies that were done. Are you The Passage through the vaginal Canal was what you know, so you would activated oxytocin receptors that way but if you gave an oxytocin antagonist meaning you would give into the brain something that blocked the oxytocin receptors. So if the oxytocin is being released into the blank brain, but you have a pharmacological agent blocking its ability to bind to its receptors these sheep and goats wouldn't bond to their baby for instance said literally the
passage of the baby out of the vaginal Canal triggers the oxytocin pathway. The release of oxytocin is in a lactation does nature is so beautiful because if you had to pick one event, yeah to trigger the release of oxytocin if oxytocin's role is to create bonding with offspring that would be the event because that's a tough one to mistake. Right? Right, but but what I will say because I think you will, you know to avoid you getting attacked on Twitter or wherever you might get into those fact. Anyway, if not before if not for this discussion then another one.
I'm tougher than I look so but it's really species-specific. Right? So if you think about our species and a lot of primate species we live in these extended family groups and that's how we evolved and so unlike a goat or a sheep that might live in a herd 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 rearing history where help from the family and by parental care. We're 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, you know, like I had a Seaside and I'll tell you something personal. I had a C-section and had I had a lot of postpartum complications and so lactation didn't work out that well for me one of my friends would say I'd massive.
TV's tease and pulmonary emboli and so I almost died after my son was born the first time and so I didn't have a vaginal delivery i couldn t be teased deep vein thrombosis. Yeah, and it was sort of like welcome to Motherhood and I was in the ICU and had to get a filter put in an inferior vena cava filter to stop me from dying because I had scattershot clots all over my lungs. And so I didn't really, you know, I didn't I didn't do a vaginal delivery. I had a C-section and I
I wasn't really able to lactate 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 need to think about the evolutionary selective pressure. So I was an evolutionary biologist before I found Neuroscience, right? And so I really everything I do I think about from an evolutionary perspective so but it is many
Go into the oxytocin vasopressin field because they have a lot of questions about social interactions. Right? Like I think if you think about us is being social is actually one of the one of the core characteristics 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 and our species is many disorders are
Orders because of lack of social connectedness, right? So it could be something like autism where you know, there's these pervasive social interaction impairments. It could be something like drug abuse where you know you risk factor for drug abuse is feeling you know, socially disconnected and alone, right social isolation or loss of a loved one is a very strong predictor of the onset of a stress-related depressive anxiety disorder.
Of when and how oxytocin is released a you mentioned mother-infant bonding? I think you said yes that the infant is also releasing oxytocin. We think so. It's bi-directional. We think I think most of the work has been done in mom would be and again this is not been really done well and primates, right? So we're extrapolating this information from species that have different evolutionary.
Therese than us. Right so it's go sheeps Prairie voles mice rats. So what do we know about the role of oxytocin and humans do I mean we know it's there. Yeah, we presume based on the animal models that it's involved in mother-infant bonding and presumably romantic partner bonding at least you hear that. Yeah a lot. It was unfortunately nicknamed The Love hormone. And the reason it's unfortunate it was is that while that might
You attention to oxytocin and I'm a big fan of people paying attention to biological phenomena it it discards the other and many roles of oxytocin. But what can we say about oxytocin in humans? If anything like do we know that it does? I mean we're just so we're assuming based on the animal models that it does something. I mean, this is very different than like dopamine where there's tons of animal model data, but we know but their brain Imaging where we know where dopamine is expressed and do we even know where oxytocin receptors are expressed?
Pressed in the human brain presumably that information is is out the 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 specific subpopulations, right? And you need you know, a lot of this work has been done. So you have to think about how do we study it? Right? So the best way to study it would be to have radiotracers where you could then which we do have for dopamine and other compounds where you would then go and see where after somebody's performed at asked do we see, you know?
Asian right or uptake there are some Imaging studies. They're usually done giving intranasal oxytocin and then you basically ask questions about okay, we give you oxytocin intranasally, which presumably enters the brain. There's we could talk about reasons why we think that and then we have you perform on some tasks, right? And so, you know, there's evidence if you give oxytocin it diminishes the amygdalas response to fearful stimuli, right so that it might have this sort of pro-social effect, and it was actually
A data like that that caused people to start thinking initially about oxytocin and those are data and humans. That's right. It reminds me that there was this brief moment where oxytocin wasn't just being discussed as the love hormone is it was being discussed as the trust hormone acts right also far too simple heuristic, but but again, I think it's cool that the you know 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 that not
Have it leads to the assumption that that's the only role of a given given hormone. So it can reduce apparently it can reduce the output of the amygdala in some way this brain area associated with threat detection. And so you can imagine how that would bias the person toward being more pro-social right have there been studies exploring the role of oxytocin in making autistic children more pro-social and behind that question.
And I suppose is the Assumption you can verify or or not that autistic children are less pro-social than other children. Is that true or is it that you know, it's a stick kids are just maybe more pro-social with the one friend. They really really like yeah, I happen to know some kids with autism or however 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 show up at the door and like
All the Hallmarks of a healthy social mind but it is true that they are uncomfortable in groups. And where there's a lot of noise a busy birthday party is overwhelming for them, but see them playing with one or two friends and like you could see all that and assume okay, it's just kind of an introverted kid actually kind of reminds me of me. You know, I mean, I don't have a problem with crowds, but I much prefer to be with a small group of friends or one close friend. Yeah, so I hear you. I'm that way too, right so, you know, how do we
About this. Okay. Well, I would say the social features of autism or interesting right? And so you might have there were there was an attempt a long time ago like 1979. There's a woman named Lorna Wing who tried to subtype the social features of autism, right? And so there could be people that are socially avoidant and really just don't want to have social interactions. There could be kids that are 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 make could cause bullying right and Junior High School. Yeah, exactly. And that's often why you know, some autistic kids do better with adults, right? Because adults know how to sort of Channel discussions with somebody who might be a little socially awkward right, but there's different phenotypes mean people having a disinterest in Social.
Actions could be that they're highly socially anxious right 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 overwhelming sensory abnormalities that make it very difficult to interact with other people, right and so like so let's just say again, that's another caveat there have been some studies administering oxytocin to individuals.
Autism and again, these are these single dose studies. So the first studies that were were done were looking at single dose oxytocin in males because some of the and we can talk a little bit about why oxytocin versus vasopressin which basil Preston actually would have been my choice based on the animal literature and we can talk about that but these oxytocin was given to males partly because it wouldn't the idea would be that the off Target is set of effects in the peripheral nervous system ie
Milk, like down uterine contractions are not going to happen in males. Right? And so that it was deemed that they might be safer subjects males are often also the go-to for research studies as you may have talked about on your podcast before it's something that fortunately is changing. Yes. Thanks to a mandate by the by the NIH I had to just kind of smiles / raise my eyebrows a little bit at the idea that you know the assumption that oxytocin administered to males. Yes one can see why it wouldn't cause milk letdown.
Or uterine contractions, but but of course there could be other peripheral effects of oxytocin to males, but they had to pick they had to pick one so they went with males. Okay, so and there is this higher incidence of autism in males. So it's not a terrible place to start you just would hope that they would also do the experiment on females, right? So they're doing this by nasal spray. So intranasal one dose, correct and for reasons that I don't understand it's 24 international units and I think maybe somebody did the first study using it and you know, this is how science
That's right, and it worked and so then everyone uses that protocol and so then there's been a lot of studies looking at, you know, there's one reading the mind in the eyes. So can you look at pictures of somebody's eyes and then ask what is the emotion that they're feeling right after receiving this in turn hasten or Placebo? Where is your eye gaze going in a picture? Right? So one of one of the theories is that people with Autism May 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 had high functioning autism. So they were verbal like you said, they could come in for studies and that it looked like it had some potential Effectiveness. And so there became a really strong interest in the field to think about oxytocin potentially as a therapy for autism and is oxytocin available over-the-counter. Does it require
Description. I mean you see sites that are selling it but that doesn't mean anything these days, right? Yeah, there's gray Market, there's all sorts of stuff going on, but I know people that used oxytocin. There's actually a market for and by the way folks. I'm not suggesting this but someone the other day told me that they've been regularly taking oxytocin ketamine nasal inhalations as part of their work with their licensed therapist on
Like PTSD type stuff relating to let's just call it relational trauma. Okay, so that's happening. But let's just think about oxytocin alone for the moment are parents of autistic kids able to like by oxytocin nasal spray now, so so it would need to be written like the prescription would be need to be written by a by a physician and it's not on the market, right? So there's one thing we should say is there's only two
Drugs that are approved by the FDA to treat autism and they're both antipsychotics, which they they treat Associated features like irritability and they have off-target effects like weight gain and and you know, so we don't have any medications that are currently approved in the US or anywhere else for that matter. It should treat the core features of autism interesting and unfortunate and hopefully that will change in the not-too-distant future do we know?
That children with autism people with Autism because I'm going to just sort of assumed that autism is stable over the lifespan like a child is diagnosed with autism. Are they going to be an adolescent and adult with autism? So I would say that in a lot of cases autism has lifelong impact, but there are people who outgrow their diagnosis, you know, there are people who respond well to behavioral therapy. I mean, obviously it's not the cure-all for everybody. There's lots of people go through intensive behavioral therapy and probably
I see minimal benefit, but I mean it's certainly something that occurs in childhood for the diagnosis occurs in childhood and it you know for most people will then be present across the lifespan so we could say people with Autism because each study sometimes will have adult sometimes you'll have teenagers. Sometimes you'll have kids.
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Dot-com hubermann, is it known whether or not people with Autism assuming they meet the criteria for being autistic of that at that moment have lower natural circulating or active levels of oxytocin because you know, it's one thing for a nasal spray to of oxytocin to improve social functioning. It's another to know that that the effect is addressing an underlying biological deficit.
Yeah, that's it's 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 mention oxytocin has all kinds of effects in the body as well as the brain and it's released into the blood but it's also released directly into the brain and there's variable evidence about if you measure it in blood, is it a readout 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 most studies.
So what I will say is there were there has been more a handful of small studies where there has been some, you know, there's been some benefit may be no benefit small effects. We did a study that was a small study at Stanford and it was based on Mouse genetic data and I'll sort of walk you through what we did. So there's multiple Mouse models of these neuro genetic syndromes where people have social impairment, right?
We can quibble about whether that's autism or not, but that they have social impairment. And so that there are this fragile X Mouse there's a prader-willi syndrome Mouse which is the module 2 Gene that I'm gets manipulated and then there's a catnap to Mouse and in all of those instances when you genetically modify those mice you see a reduction of oxytocin in the hypothalamus and what's interesting is that in those instances where you see this genetic modification you do see
Lower blood levels in these genetically defined models. What's really cool is you can give oxytocin across development in those models and at least in the catnap to Mouse, you can restore oxytocin neuron. Number two equivalent of control animals suggesting that oxytocin is doing something in these oxytocin deficient animals, right? So these are not an oxytocin Gene manipulation, but these are these syndromes where you see as a consequence of
relating genes for these syndromes that oxytocin gets knocked down, right and so are thinking when we went into our clinical trial was what if it's blood oxytocin levels that they're going to be a subset of individuals that just make less oxytocin humans humans and that maybe those are the individuals who could who stand to benefit the most from treatment and so we were the first group to ask, you know across this range of individuals who showed up and we
In all the trials that we'll talk about today. These are done with my colleague Antonio Harden at Stanford is a child psychiatrist. And we always have double-blind meaning that the investigative team is blind and that the or unaware I should say there are unaware of treatment and then the families and the children are underwear and then the randomize meeting there was an equal chance you could get either drug or Placebo and they're and they're controlled, right? Okay, so we asked if we know what your pretreatment
I meant blood oxytocin level is who's going to benefit from treatment and we thought a couple really interesting things one. Was that the lower your Baseline so your pretreatment blood oxytocin level you showed much greater benefit from the oxytocin intervention. These are children one intervention one nasals. This was four weeks. Sorry. I should have clarified. This is four weeks of treatment being administered oxytocin twice a day. Okay, and and and so we saw Effectiveness there man. Sorry to interrupt so much but just
Males male and female subjects did but again, you know because the autism is male bias in prevalence, even if you make this heroic effort to over recruit try to get more girls and in the study, we usually try to aim for the prevalence rate because it's difficult to get girls just because there's fewer of them got it. Okay, but boys and girls were included they're taking oxytocin over the period of several for weeks. And if they started off with lower Baseline levels of oxytocin, you observed a benefit of the oxytocin
Treatment in those individuals what about the individuals who had normal to high-level see much benefit, right? And so that was a queue to me to think that there may be a subset of individuals that you know, for whatever reason they have lower oxytocin 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 may be
These you know, 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 multi-site what's called a phase three oxytocin treatment trial that was done it I think five sites and they gave oxytocin for an extended period of time and they showed no benefit and and were they
Looking to see who started off with low levels of oxytocin that pretreatment. So what was interesting about that study and there were a lot of issues with it was that oxytocin is something where you have to if you look at it it degrades is like that's 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, right? So you go in and we have vacutainer tube stir cold and we put them on ice and then
Phlebotomist takes the blood from the child that we lot of technical by gnostics and then we make sure we spin it in a centrifuge cold and then we pipe it onto dry ice. 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, it can be very difficult to get an accurate read of oxytocin. And so I think for me it's still an open question. They didn't see the blood
Osen predicted response in that study the data weren't provided in the paper. It was just said that they didn't 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 where they'll say. No, no. No, we don't think that chronic oxytocin is a good idea that what you really should be doing is just giving it behaved before a behavioral therapy session, right? And so that
Maybe that is the way it is. If you give it a cutely like in those early studies we talked about that maybe oxytocin, you know diminishes sphere. We know that oxytocin decreases the stress axis the hypothalamic-pituitary-adrenal axis and then it 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 that once you have a negative trial it there isn't a lot of
stand funding 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 in until there's money to do that work. We may not never 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 whether or not there were any negative effects of oxytocin Administration in particular in the children that did not benefit from oxytocin treatment. The rationale is the following. Well, of course these things require a prescription if a parent has a child with autism, especially if they're young 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 presumably are willing to try almost anything provided it's safe. So let's assume and I'm making up these numbers now because I'm haven't seen this study. But according to what you told me that let's say a third of autistic boys and girls that come in have low Baseline levels of oxytocin. They're the ones that are going to benefit from this oxytocin intervention. The other two-thirds don't well given the difficulties of measuring based on levels of
He toasted most people don't have access to those kind of resources if it's safe to give oxytocin no matter what. Well then if I were that parent, I'd be knocking on my Physicians door saying hey, give me an oxytocin spray because my kid might fall into that one third 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 shotgun approach. Well, then I wouldn't do that. So is oxytocin spray safe, and if so, why doesn't
Every physician who has a patient with autism give them oxytocin nasal spray is a great question. And I know that you know, I'm a parent of three children and I know this sense of like you would do anything to help your child, right? And so I think the tricky part is that it was one thing I will say is that all of the studies and there's been many of them have shown that oxytocin is is relatively safe in a pediatric population, right? The tricky part is I don't know there was Physicians that you know, really pay attention.
The 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, you know, but I think the tricky part and what I will say is and we can maybe talk a bit about vasopressin which you know, my feeling is that if I was placing bats and having to choose between these
to my money would be on vasopressin. Well, we are definitely going to talk about vasopressin in detail. I mean, the reason I mentioned that hypothetical scenario is just the sense of urgency and in some cases desperation that parents feel and you know times ticking and if oxytocin safe then you know, I guess I'll put in my vote that you know parents should at least talk to their physician maybe even hand them the study to consider but I can also understand the perspective of a pediatrician who says we'll listen. It was a small number of kids that benefited.
You're welcome to try it but I don't you know doesn't seem like the results are that impressive but this gets to a bunch of larger issues about you know, Medical Care and randomized Control trials and the desperation of parents and kids to treat neuro developmental challenges. I just want to ask because it feels relevant in am in a real way, you know, if ultimately the goal of improving symptom profiles in autistic 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 ssris for the treatment of depression some cases. It works in some cases. It doesn't side effect profiles are a serious concern as I've discussed.
Podcast before but ultimately we know that depression is not a serotonin deficiency in most cases accessorize or atypical antidepressants like require on Wellbutrin and things of that sort when they work they probably work because of their ability to induce neural or assist neuroplasticity. Right? Right. Also, the trials on psilocybin are not really about psilocybin there about neuroplasticity at least the trials for depression right? There may be other uses of psilocybin that
Relate more directly to the effects of psilocybin But ultimately, you know, what we're talking about here is the attempt to rewire the brain in a specific way whether or not it assisted by oxytocin or some other mechanism. So the question is are there trials happening where people are exploring say psilocybin and MDMA which by the way, we know increases oxytocin. I was and serotonin dramatically as well as things like a typical antidepressants in
Kids that have autism not because we think that those autistic kids are deficient in any of the neurochemicals that these drugs would Target but that these drugs can help rewire the brain and ultimately that's what these kids need. Right? It's a really great point and I there might be subsets of kids right? There might be kids where there would be a medication that would Target other Pathways, but that potently releases oxytocin right that but there might be kids that have an oxytocin deficiency. Right? But I think that that circles back to your point.
At the beginning or our point is that autism is a very heterogeneous 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 going to move the needle right? Like it kind of requires a crystal ball. So there's a lot of guess work that goes into this but I would very much like to see I will say one other thing that they're I have a colleague named Adam goes Stella who's at the University of Sydney and
He published a paper a year or two ago. Now suggesting that oxytocin be may be most effective in kids at younger ages. And I don't quote me somewhere between two and two and five or three and six or find the paper and put it in the show. Ya show notes, but you know, so it could be to your point about neuroplasticity that oxytocin may be maximally beneficial in younger ages. Right? And if you're if these studies are these hodgepodge has across age
ages and across sort of different social phenotypes finding that signal is really important, right and and maybe age is a driver or maybe you know, low blood oxytocin regardless of what age you are or maybe an Adam's case if you recruit really young children, you're likely to see a benefit just because the blame the brain is wiring up and it's more plastic and you know younger ages. Yeah, that's also a vote in my opinion.
Were early examination of kids right? Like parents really need to get autism screening and perhaps maybe the most important thing is to make autism screening as available on 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, that's the clinic wait times are really long, right? So you have to have a specialist who's capable to diagnose autism and so you could have a clinic where you know your show
Sewing trouble some features and a parent wants to get their kid into a clinic and you could have a 12 month or more or 18 month wait time. Right? And so there were a lot of people that are thinking about are there are there laboratory-based tests that we can develop may be either for detection or clinical referral right? So can we come up with 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 rates.
Risk for developing autism. Can we make sure they're prioritize for getting a diagnosis? Right so we can get them in early intervention. But right now we don't we don't have that right? So having some sort of laboratory based test whether it could be biological or if we could do something with eye gaze and there's a lot of companies working on these things now to say this may not wrote you know there and also obviously again autism is always controversial right in this field, right? There's so many different styles.
Stakeholders a lot of clinicians will say well I don't I don't want a 30 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 that are in this line, you know, we could get diagnosed these faster. Well, you wouldn't want false positives but I would think that a 30 second video clip provided its of something useful. It's going to be more valuable than nothing. Yeah, given the time sensitivity. What are some of the barriers to getting this Behavioral?
Sting to be not just more prominent but pervasive like it seems to me that well, I recall in school. They gave us the hearing test. We all marched right bus we get the beat test and you know, you know for hearing challenges we have vision test you get the Babinski reflex test them not the moment you come out of the womb but pretty pretty soon after I mean, why isn't this stuff happening for autism for every kid? It's
Not scalable, right? So you these interviews with parents and the test that you do can take hours right and and any given clinician even if they're working really long hours there just aren't that many people that are have the extensive training needed to make these expert diagnosis. 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 people a week right and so have to be a physician. Sorry to interrupt does it or could it could you know could have well
In technician do this. Yeah. Well, I mean, I think technically it's a DSM diagnosis, right? So it's usually somebody was a clinical degree. So it would be a clinical psychologist. It could be a behavioral pediatrician. It could be, you know a child psychiatrist for child neurologist, but mean again that requires years and years of training and with if we look in areas where people have fewer accesses to access to Resource, I mean particularly in impoverished areas the mean age of an Autism
Gnosis 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 really Lobby 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, right? And so I think that you know, if there's some sort of 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 blood test or something like that, you know, it could be incredibly impactful. Are there human trials exploring MDMA methylenedioxypyrovalerone Peta mean also referred to as ecstasy and or psilocybin for treatment of autism, so I was aware that map's had an MDMA trial and autism.
I don't know what's happened with that. Yeah, perhaps it's still ongoing. I'll check the maps. I mean communication with them from time to time. I mean that the reason for asking and of course, you know, but maybe in case some of the listeners don't is that MDMA causes these massive increases in serotonin that seems to be the major source of the MDMA effect. So to speak based on the work of our colleague Rob milanka, and at least one human study comparing
Dma to very high dose oxytocin treatment ruled out the oxytocin Spike that's induced by MDMA as the as the source or the only source, but of course these chemicals can synergize. I mean it but based on its chemical profile oxytocin release massive serotonin release dopamine release and a propensity to enhance neuroplasticity. I mean, assuming all the safety protocols were were there. It seems like not the perfect drug, but not a bad choice. If 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's going to be a reluctance to potentially give them psychedelics. Right? 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 I guess to play Devil's Advocate not against you but
To State it very directly and then I'll take the heat as necessary. I mean I've done two episodes about the drugs that you know, Millions tens of millions, if not hundreds of millions of parents are already giving their kids for ADHD, which are include amphetamines including dioxane methamphetamine is actually a prescription drug for a very small subset of kids with ADHD. But he's like Adderall Vyvanse even methylphenidate Ritalin. I mean, these are amphetamines they induced dopamine release and Nora
A nephron release and again, I'm not suggesting people give their kids MDMA to try and ameliorate 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 how reach out to the maps group and see see what's happening. Let's talk about vasopressin. Yes, because there's a lot to discuss their so you told us this is a molecule that chemically is very similar to oxytocin. Is it manufactured in the human brain and body? Yes. Okay do
No subset of the sites that it's known to be produced and where some of its actions are you mentioned the kidney and the antidiuretic hormone roles, but within the brain like what brain areas have neurons that make vasopressin well, so we're half of the receptors for these receptors are all over our all over the brain. And again, it varies depending on the species and you know, the way the receptors are measured in or import post-mortem tissue, right which can be very difficult to get good.
Samples, right? And so we need to have that caveat going in. But yeah, I mean it's made in the hypothalamus and it's released all over the brain and there is vasopressin receptors all over the brain, right? And what's really interesting about vasopressin. I always sort of joke that oxytocin, you know always saw its day in the sun if you will and the vasopressin was sort of the stepchild that was like left, you know, sort of behind and the reason
I find this fascinating is again. Like I think back to my you know, my my roots as a you know, evolutionary biologist behavioural neuroscientist. And what was interesting is that there were studies in the early to mid-1990s showing that vasopressin was critical for male social behavior. And so there was work, you know, there was a variety of people and I think Rob malinka mentioned this on his on the podcast he did about you know, there was a group of people like Sue Carter Larry
young Tom Insel some of these early people and they gave vasopressin to male Prairie voles and very vasopressin was what induced pair bonding with a female mate and also paternal care. And as I recall those experiments were done in the context of looking at polygamy versus monogamy of these Prairie voles Prairie voles versus like a different species, so same genus
A different species so it might be a montaigne velour, you know highly related but these other species so Prairie voles are monogamous the males. Well, I mean that was 50% divorce rate. Yeah. That was not I don't think it's that bad. But I think we're better than we are. This is true. We should look to them for pointer and all the divorce folks are saying wait, why'd you say better have some divorce friends that have said divorce is like the greatest thing. So we always say like doing better doing worse, right? Anyway, that's a whole other podcast and certainly
Not the huberman loud podcast, but or maybe it is but or will we but yeah, my understanding is that you have certain voles that mate with almost exclusively with one other vole for their entire lifespan. And then you have other roles located elsewhere that in those colonies. They mate with lots of different goals for the males and females have lots of different partners raise young with lots of different partners mating with lots of different partners and that if you give
Vasopressin then you can make the was want to call them polyamorous. But I don't know if they love each other. I'm gonna anthropomorphize and assume they love each other the polygamist moles not polyamorous, but polygamous Smalls then become monogamous. Well, I yeah, I would say that is probably not the take-home message. So the take-home message would be they had let's say that there was like the good voles right which are the Prairie voles and they were the ones that form these monogamous pair bonds dad participates in paternal care with Mom. They Co raise babies.
Together and then Dad chases off Intruders, right? And then there's the more a social voles and so these are like the montaigne voles and it will stay it's a complicated story but there's these montane voles 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 paternal care at all. Mom races babies by herself, right? So that's these are really the two like 1950s versus 20.
Yes, yes should be it just too broadly stereotype to Bradley stereotype and if you give okay. So for Prairie voles, there are sort of primed to form bonds and to be the males to be good Daddy's if you will and all you have to do is give them a single injection of vasopressin and you know, or you can give an antagonist and usually the way they form the bond is through mating right? So they you put them with a female they made they cohabit for a bit. There's been all kinds of
Of parametric studies. I can't remember how many hours it takes to form a pair of bond, 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 hang out with a partner the montaigne bowls, you know, either after meeting with somebody May either be equal or maybe they'll even go spend time with the new individuals. The cleanest story was that Prairie voles are monogamous Monty moles are not monogamous but in the Prairie Village,
All's you could give vasopressin instead of made it to habitation 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 or you could induce paternal behavior. And I was working with a vole species and 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 lab is doing right eventually the members of your laboratory kick you out of the lab. They literally say like get out of here. You're leaving things on the wrong place. Whereas initially you're telling them. Hey that's in the wrong place it within a year or two. But for me, I think it took about 45 years by about your sex. Right? I was demoted to my office to just write grants and right, but I was told that one time I was back there and I tried to wait I was
So excited what they were working on and they basically just said go write grants bring in more money Riley that was kind of their attitude like we get to be the ones who get to do the cool stuff so back when I got to actually do the science. I remember I had this species where and I and again I told you I came at this from an evolutionary perspective. So these were called Meadow voles and I found them very interesting. So when I showed up in my thesis advisors lab, she's I said, I really want to study oxytocin and vasopressin and I really want to study voles and I know you have a v
PCS and she said why don't have prairie voles. I have these Meadow voles and I'm studying them because they're so sensitive to light and they change their behavior based on light. And as she said, well you can do what you want. But our grants basically have to have a circadian component. And so she said you got to work that in but then we kind of struck this deal. So I was hanging out in the animal rooms and I thought it was really fascinating. So she had animals that were either on low short day length store long day length. So the mimicking some some summer and winter and I was noticing that on win.
Day lengths the males were hanging out with the females and when the female had a litter he was like participating and I was like, whoa, 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 these are probably explain what those are putting a little transmitter Under the Skin it's painless for the animal but that allows the researcher to monitor the behavior of the animal interview remotely without having to you know, put them in cages.
Ages and stuff. So this is like under field conditions and voles are everybody's favorite snacks. So they have like a very limited life span in the wild. I mean like on the order of months and and so like if you have a short lifespan like you should just keep reproducing right? And so what was interesting is at the end of the summer days as you're going into winter territories claps and males are found with females and they Co raise babies. It makes sense. If it's you're going to have a litter and mom needs to get up to go eat. You need somebody to sit there and
Warm those babies are going to die because they're going to freeze to death, right? So I started saying like wow, I think these metals are good Dads like I'm noticing this and so I told my thesis advisor, I want to study how oxytocin and vasopressin can maybe this is involved in tracking these evolutionary mating strategies. And so again, like the coolest experience I ever had was on these males that were housed under short day length, so they were like winter males. I was able to put vasopressin
Likely into their brains and it 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 placebo into their brain, nothing happened and so to me, I always filed that away in you know in the back of my mind of like wow vasopressin. Is this really interesting hormone and maybe someday I will I did a postdoc and something else but it was always
You know back in the back of my mind of I really want to return to this. It's so incredible that a eight amino acid long peptide could basically turn these relatively negligent father's into very attentive father's. Yes. Yeah. It was fascinating. Right? I mean, it just speaks to the power of the peptide based on precedent also speaks to the power of brain circuitry. It also speaks to the idea that brain circuitry is often sitting Layton in the background, you know ready to be activated.
That it's not just about neuroplasticity and building up a new circuit that some forms of neuroplasticity are about unveiling. What's what's already there absolute and that peptides can act like switches which you know kind of makes sense on the one hand, but I've never heard of a result as dramatic as that, so
I'm presuming you're going to tell us that that then LED you to go back to vasopressin and explore its ability to induce good parenting and negligent fathers. So I think that you know, my mom always says Chance favors the prepared mind and so I was doing my postdoc at Stanford and I got recruited 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 Psychiatry department where I was surrounded by clinicians, and I realized that a lot of the stuff that I was doing had clinical relevance, right? And so sometimes you sort of meet the moment, right? And so right as I was transitioning to to have my own lab in my department there was 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 her.
Ethically underfunded really horrific lie Under Fire while I mean at rates of 1 in 36, not a time, right? So it was it was one in 150 or whatever. It was back then but there were all these parents and I mean again at their heroes in my eyes that they advocated so much for their loved ones. And so there was you know, they started forming parent Grassroots organizations that have culminated they all started joining together, which is now Autism Speaks and then there was a man named Jim Simons who runs one of the most successful hedge funds in the world.
Old and he decided wow, I'm in a you know, there's let's put money into autism. Right? And so there's you have a personal linked to autism you'd have to ask him because often times not always but often times when you hear about wealthy donors. Yeah, I'm devoting a lot of money to one area of science. There's a familial thing there, you know a member of their family or close friend has this Challenge and they really want to see that challenge. Absolutely. I mean a lot of money I've gotten for my lab from philanthropist and what I
Says the most impactful work I've ever done is through philanthropy right their crazy ideas that no funding agency ever touches, right? But yeah, so they put they both put a lot, you know, there was a lot of emphasis and so because the Simons Foundation started issuing request for applications. There was a group at Stanford that formed and it was a clinician with a basic scientist and my chair at the time said while you know, almost nothing is known about the biological basis of autism.
Why don't you go I mean introduce you to the 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 work or feature of autism. I thought wow, you know, these neuropeptides May really be, you know, a part of this puzzle. And so that's actually really how I got pulled into autism research was was through that and it was I was you know, everybody at the time was very
eight interested in oxytocin and you know, I remember thinking so we actually did probably the most definitive blood oxytocin study because there was this idea again like this marketing campaign of like the oxytocin deficit hypothesis of autism and you know, given how clinically heterogeneous autism was we got money actually from the Simons foundation and we did the first study with maybe 200 kids and what we were able to show was that blood oxytocin was not a marker of
of autism, right? So it wasn't like there was a bimodal distribution meaning to completely non-overlapping levels of oxytocin and people with Autism people without autism. So the lower your blood oxytocin levels actually regardless of who you were you could be a child with autism. You could be an unaffected siblings 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, you know, we're different
And 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 oxytocin level is not going to be this great differentiator between people with and without autism, 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 did it sets aside. We don't we don't want to say discards but it sets aside this thing that we call autism. Yeah, which is already
Eddie hard to Define and diagnose and there's all these different spectrums and you're trying to and just says okay children with autism have challenges in social cognition social behavior. Social bonding. Yeah, so do adults with autism for that matter. Let's just focus on that. Yeah and not worry so much about whether or not somebody is diagnosed as Autistic or not and just focus on what are some of the potential neuropeptide deficits or overexpression of neuropeptides that may in some ways.
82 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 like when we when we go after a disease like Alzheimer's we can often miss the possibility that Alzheimer's while it has, you know deficits in cognition and memory could also be a bunch of other things like a metabolic disorder of the body. And so maybe you go after a particular symptom ology. Yeah and trying to attack that and you might actually
potentially treat or cure multiple diseases. It's a very different approach and I hope people are catching on to the subtlety but also the potential impact of that 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 in and characterized her 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 it just sort of begs the question about you know, what is oxytocin has role in human sociality, right? I mean, I think there's just so much that we don't understand about both of these molecules in terms of their disease liability if they're low or their healing
Potential if we are, you know able to use them as modulator 's of other therapies. So how did you move from oxytocin to vasopressin? You mentioned that everyone was all excited about oxytocin still the one that we hear the most about although after this podcast episode and when I start blabbing about vasopressin to everybody, you know, maybe that'll change but it's I think it's gonna take a lot more than that, but maybe because the name
It isn't as though there's something about oxytocin that like kind of sounds like the love looks like the love hormone. But like vasopressin should be renamed right? Well, it should be called something else. I'm not antidiuretic hormone. Not vasopressin. I mean you're going to tell us how critically important it is. Perhaps even more important than oxytocin for autism and social functioning. So, I don't know by the end of this podcast will come up with a new name. It's needed right? Well, I'll put it off there. Okay. So, how did you
Get to vasopressin. Okay, so it was interesting with oxytocin because we didn't you know, and again I was skeptical that we would see these big group differences. But you know, it was a little bit of like, okay, you know what everyone's saying this is not going to be the big solution right? 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're you're a little bit of an outsider, right? Like I'm not a clinician. 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 was thinking about what are 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 and cerebral spinal fluid, right? So like the biological substrates or clues of markers of say various forms of Dementia or or Ms. Were for first found in spinal fluid, right? Because it's the it's the fluid that bathes the brain and the spinal column. And so if you're looking for the biochemistry of an illness, that's the closest fluid that you can get to the brain, right? So draw just won't do it maybe right so that was part of my thinking but then there was the issue.
Show 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 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 the spontaneously occur in children, and so it made me wonder could we identify
Defy monkeys in a large Colony that have social impairments in and after talking to two clinicians 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 or the California National Primate Research Center. And so what we did is
I think I mentioned earlier that there's these surveys that can be used to look at autistic 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's used for humans. And then what we did is modified it to be able to use this rating scale in rhesus macaques, which you're an old world monkey and I know you're familiar with them and 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 and as I mentioned previously these autistic traits are continuously distributed across the general human population and that this genetic say, let's call genetic liability, which is a fancy way of just saying that we think that there's a there's a genetic risk that underlies this Continuum of Behavioral traits, right? So if we think that that's true in humans and one of our
His 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's just assume that that's the premise that's what we went in with can we find rhesus macaques that are just living in a large outdoor colonies and identify animals that might be good models for autism and the answer is yes, we could do this all kinds of different ways one is we could just take people and score.
A monkey behavior is 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 responsiveness scale. So this is called the macaque social responsiveness scale revised. It's a mouthful but what it allows us to do is measure autistic-like traits in 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 monkey's you know, if they're making a film
- overtures do they do like, you know, you know overmix Global which is a positive response when they do that right? I'm going to apologize for interrupting again, but I just have to tell people this because I spend time of the UC Davis primates and he's a graduate student. And and by the way, what we're referring to here are non-invasive observational studies at least thus far so these are monkeys living in large exclosures not enclosures large x closures forming colonies and social relationships and
You know, I think anyone that sees monkeys at the zoo and we all learned that monkeys go eat and they don't eat if you want a monkey to like you you learn this working with macaques. First of all, they don't eat he the affiliate of call is a they do this really nice and the little ones you did very well spent a lot of time with these monkeys and the little ones they do this thing where they go I stood I stood nurse the little ones every once in a while they and there are just you know, I just like
Your heart may I think that there must have been an oxytocin dump at that moment? That's probably happening right now. But if you want the monkeys to like you you have to give an affiliate of facial gesture, which is not a smile that's actually an aggressive gesture. So as Karen, dr. Parker just showed you it's lip-smacking which has yeah. So if you see a monkey at the zoo and you want it to pay attention to you, you're gonna have to lip smack and if it doesn't either you're not doing it right or just doesn't like you exactly right great. All right. Thanks now. We'll go back to the study of
Of the establishment of this really key experiments, right? So then what we did is we identified these animals and we spent a lot of time. So one of the things that I do as one of my areas of expertise is validating animal models. So a lot of like I mentioned like a lot of reason why experiments fail is people will take an animal off the shelf and say, oh I'm going to do this right but if you're you know, if you're studying a disorder that's characterized by visual issues. Is it is it the
Thing to do in a nocturnal species that has olfaction as its primary sensory modality or is it random ice right or is it better? You know and again I will say all models have value. There's all either there's reasons you just have to you know, you basically have to stand by what your modeling and so I think one of my biggest issues I have with this sort of mouse phenotyping Mafia is that you know, there's this group of tests that they use and they use it in every single disorder, right and then if there's a positive hit it's like oh this is like, you know, this test is really four parts.
Kinnison's today, but it's for depression tomorrow. Right? And so so my goal was to devise 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 monkey's will come up and interact with them, but they don't engage in Social overtures them.
How much themselves they do less grooming less of affiliative behaviors. They in some of the work that we're doing. They don't lipsmack back and we can talk a little bit about that. We did a pharmacological probe and we can talk a bit about what vasopressin does to that which is kind of exciting and so we spent a lot of time validating this behavioral phenotype right to say that we really feel like there were our core aspects of it that are allowing us to model autism. Right and I have a paper which if you want
put it in it's all about creating this monkey model and and the power of doing it and where it took us. Clinically. We will provide a link to that in the show notes captions. I also just want to throw up my vote for the the fact that you did this work because again, I don't disparage Mouse model work, but we've just seen over and over again that the incredibly small fraction of mouse models that lead to valid Therapeutics and humans and there's just a lot of differences between primate brains and rodent brains and we have
very elaborate frontal cortex a bunch of other circuitry that mice if they have the that they probably use it for other things and it's just very hard to come to draw conclusions from those models and they're great for probing functions that are let's just call them or autonomic type functions and for doing some of the initial investigations, but you know, I think while I don't want to see every research lab switch over to primates, you know, I think one has to
be really thoughtful about the kinds of experiments one does with primates at all this sort of behavioral assessment and and the identification of a primate model for autism seems like a very good use of of Human Resources. Right? Well, and the other thing I will say is that there are medications that were only tested in rodents that when they were when they were tested in people had really negative consequences. I can give you two examples. So one is the lid amide, which was a more.
In sickness medication that was given to women that were pregnant and the safety testing and talks was toxicity testing was done only in mice and know that yes, and that's why it went on the market and went on the market in Europe and there were all these children born with profound lib at limb abnormalities when they went back and tested the drug in marmosets. Neither rhesus monkeys or Cinema Lagos monkeys and Old World monkey. They had the limb abnormalities and so they had to do
And again, I you know, I I as an animal lover treat the the you know, the life of a single monkey or or single Mouse for that matter an individual monkey scuse me or individual Mouse for that matter, as you know, as critical I am a species list. I do think there's a difference between their life and our lives when it comes to you know, what study one does but but just the idea that these severe developmental defects in humans could have been avoided by doing an experiment perhaps even on one right marmoset.
Wait, and again, I feel for the life of discomfort of that marmoset. But the idea that that could have saved so many human lives. It's just striking well in there was also that street drug mptp. That was a synthetic heroin, right that causes like overnight parkinsonian ISM, right when like, I think the dopamine cells were just a bladed right but when you went and looked in mice mptp didn't have those effects. It was only in primates and other humans and other primates, right so and I agree.
With you I am an animal lover. I think that we have to be very careful whenever we do any animal experiments, right? And so you really need to have a good justification. I think for any science that's done. I will say that upfront and you know, we have this, you know new generation of stem cell and organoid work, which I think is going to you know allow us to make all kinds of disease progress, right? So without having to study whole animal models or in complementary, right, but I mean, I think again, I think we need to
The model based on the question we're asking right and so if you want to have a medication that's safe and well tolerated, you know, when people were effective and you want to move the needle on complex social cognition. You want to be testing it in a species that also has complex social cognition with the Netflix show chimp Empire. Yeah. See if people haven't seen it. They should watch it when you watch it. You realize they're very much like us. Yeah and dare. I say we're very much like them. Oh, yeah, it's foreign.
Oi different than watching a bunch of mice. Yes, and I'm not being disparaging of mice. I'm assuming they have that mice also have complex social cognition roles also have complex social cognition, but it's of the mouse V hype and we don't know really even what to look for right? But with primates there's you know affiliate of gays, there's you know, affiliative grooming there's ostracization of individuals in a troop. I mean, there's a there's a, you know Banning it taking care of other babies. There's all sorts of interesting dynamics that map so
Leon the human behavior and vice versa. Yeah, so you establish this Colony up at Davis at the regional primate Center that where you identified some monkeys that we don't know if they have autism but you could see that they were less socially affiliative. Right and I would never say they have autism like I will say that up front, you know, they have features that resemble human autism and that allow us to model this right? So so we started studying those
Animals, and what we wanted to do was to do some biomarker Discovery. So what we wanted to ask was are there any molecules that allow us to differentiate these what we'll call them naturally low social or low social monkeys from socially competent high social monkeys. And so we measured a bunch of different readouts of neurotransmitter systems that were either involved in mammalian social behavior had been implicated in idiopathic meaning autism. That doesn't have a genetic cause or these
Road genetic syndromes that we've been talking about where there's Pathways that are really associated with them. And so if we measured a bunch of these systems with 93% 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 and was this by blood draw or cerebrospinal? This was spy. It was everything we did Blood we did CSF and we put all these measures into the hopper. We did a discriminant statistical analysis, which was like a machine learning algorithm where we just said, here's all this.
Action help me classify if this individual is higher low social for cerebrospinal fluid is collected by spinal tap, correct and my understanding I've never had one but that spinal tap is of course more invasive than a blood draw but it still is done as an outpatient thing in humans. Like you can go and get a needle inserted into the lower spine by an expert. Yeah. They're going to draw three row spinal fluid. I mean not that much more invasive and time-consuming than
Adding a needle into your vein for a blood draw, right? I mean, it's we think of it as it's technically a little bit more challenging. Yeah, but they're CSF drawers and humans all the time. Right? So in theory this could map to a human study and it did which we'll talk about very cool. So we went out and we did this. I have a spectacular statistician who's we spent a lot of time together. His name's Joe Garner and and he is a statistical genius and so he developed this.
And we do all of our work together or you know, I would say 95% of what we just love working together and he developed a statistical winnings winning strategy to identify. What were the key drivers and what was fascinating is in this first monkey cohort. It was the cerebral spinal fluid levels of vasopressin that were really what was driving this classification, right? So if we just knew your levels of your of vasopressin in spinal fluid, but not in blood interestingly. We could pretty closely perfect.
Perfect classify you as high or low social and so then we replicated that again in another monkey cohort because obviously as a scientist you always want to 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 monkeys and we saw that the vasopressin was consistent across measurement time. So there was a wide variety of vasopressin levels, but within an
Jill 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 vasopressin levels were closely linked to group spent grooming a Time spending grooming. And as we mentioned I think we mentioned earlier grooming is in many monkey species critical behavior that solidifies social bonds and maintains them and so the individuals with the lowest C sfa's or press and levels had spent the less time the least amount of time in grooming harming.
Other monkey's yeah this all that Pathak grooming is a very interesting behavior and from watching chimp Empire. I can tell you that new relationships are established many ways by monkeys these chimps chimpanzees sort of offering their back for grooming and if another chimp elects to yes groom that chimp then it establishes a some form of trust and it all seems to have to do with proximity. Like how close are you going to let me get to you vice versa humans, you know we talk about
Signal space and is there's a whole set of things related to consent in this whole telepathic grooming thing. And then if they you know, if um, if a chimp misbehaves on an outing then they aren't groomed by others and they can actually get parasitic infections and am be very costly. It's very interesting, you know to just think of allopathic 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.
It was really interesting to me that we were seeing these hints that vasopressin could be, you know, really important. But of course, you know, somebody will say and I will say upfront monkeys don't have autism, right? So then the question becomes does this have what's called translational value? So, you know, can I see this observation in animal model and will it provide fundamental insights into humans? Right? And so I wanted to get cerebral spinal fluid from people to test this hypothesis because
we had in parallel done a study looking at blood vasopressin levels and people within 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 vasopressin levels were indistinguishable if you were high or low social monkee, so there was something about looking more proximate to the brain that was giving us more information than say the blood alone. And so I said I wanted to get spinal fluid and like you said people do this all the time. How would we
But were you know, it's not going to be a first pass especially when we don't really have any evidence in people to go in for what we would call a research lumbar puncture. Right? And so I had to get really creative about how do I get spinal fluid from children? And what we did was we piggybacked onto a clinical indication for spinal fluid drawers. So and we did this so I try to get funding for this. This is like, you know again, I mean, I think this is important for people to know how
How science is done, right? And so I wrote all these Grant applications. Nobody would find it. They said 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 it. I'm going to find a way to do it if somebody 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 how 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?
My friends who were on in Stanford's 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 a lot of committees w i can attest lot of commands that is really cool because you're on them with people from all different people and departments that I wouldn't otherwise know. Yeah and you get very you get to know these people well in these many committees and where we live it's a small community, right? So like they were the experiment Karen. Maybe there's a I always wonder whether or not there's a larger experiment.
Right, not on monkeys not on the patient. So they cloned rubber like we're maybe were the experiment. Yeah, 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 spinal fluid, can I get a little bit of extra? Right? And of course, we got, you know, IRB approval meeting we had an Ethics approval and all this and or you could get the remnant sample and obviously again get consent from the families so we could either get a little bit extra when it was being drawn for a research indication. So,
They were getting a spinal tap no matter what and then we were just 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 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 puncture 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, Sam.
Apples again under people's consent. So we got 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 was - right. So we got the the sort of healthiest people we could given that everybody was coming in for a medical reason to have a lumbar puncture. And in this in this first study, we had seven children with autism seven children without autism and we could new
Early perfectly classify 13 out of 14 individuals by just knowing their CSF vasopressin level alone, which is pretty remarkable given that there isn't a biological indicator that we robust biological indicator that we know. So basically in this relatively small cohort. Yeah having low vasopressin correct biomarker of ought is correct 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
He's there were no difference in CSF oxytocin by group. And then in this first study, there were no differences in CSF oxytocin levels a sample size of 14 is intriguing but given autism so clinically heterogeneous. We want to replicate it. And so I knew that there was a professor at the NIH named sus we do who was collecting cerebral spinal fluid in as part of a research study because she was interested in
Immune parameters and folate deficiency, so she had children that were medically healthy and they were getting you know, just like at NIH get these huge workups, right? So they were very well characterized 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 oxytocin be what's different in the girls, right? So maybe there will be some sex specificity.
Be here and it will see low C sfa's or pressin in the males and low CSF oxytocin girls. That was not the case what we found was that if in the individuals with autism regardless of their biological sex that they all had lower see sfa's or press and levels then the individuals without autism and because they were so well characterized we were also able to show on a gold standard research diagnostic assessment of autism. So it's a an assessment that's used.
Used to in a research situation to validate an Autism diagnosis by an expert clinical opinion that the lower your vasopressin levels in spinal fluid the greater your social symptom severity your clinical symptom severity and then we asked it's like well vasopressin is 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 vasopressin track the social symptom severity not the repetitive.
Miss Verity suggesting 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 with and without autism and so then I was really so that was really exciting to replicate that and then I had a colleague named John Constantino who is now at Emory, but he used to be at washu. And I knew that John I had been at a meeting and I think it was 2010 and I found out that he had what I will call Liquid Gold so he
This - 80c freezer that was had a bunch of neonatal infant CSF samples that he had human from Human infants and he had collected them. And again, this was under ethical approvals and it was basically they these infants came in for something that needed to be worked up that was very rare. But if they had it they would you know, they could die. So they needed to get him medical treatment for it. But the vast majority of these children ended up being
Unhealthy so it was a pretty healthy sample if you will, right? And so I knew he had all these samples and I said to him wouldn't it be really interesting if we teamed up and we look at this see sfa's or Preston finding in children before the period when behavioral symptoms first manifest, right? And so sorry again to sorry, but I think it's important cause this was a question that I was seeing about earlier and I imagine many other people were to you find these monkeys that
Of social interaction deficits you find kids that have social interaction deficits and you see that there's low vasopressin in both groups. This extends to male and female children, but then of course the question becomes will maybe they have low vasopressin because of so many years or even months of social interaction deficits right that the direction of causality isn't clear. And so yeah when you said Liquid Gold, you know referring to the CSF from these infants taken prior.
ER to any opportunity for social interaction Beyond just you know, whatever interaction they had with their mother up until the point. The CSF draw was taken this really gets at the issue of causality. Right? So it's a quasi perspective, you know, because it was banked 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 John's parts. So these were this was the samples were collected back on paper medical records. So he had to trace 2000 paper metal. What's that? Yeah, exactly.
We had to trace 2000 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 fluid samples that have sort of been waiting in the freezer if you will and then we could ask, you know, do individuals who later receive an Autism diagnosis many months or even years later already have low vasopressin levels as infants and the reason why this was a compelling question,
Question to ask is there is evidence to suggest that behavioral therapies are more effective. The younger the child is right and if you think about it, if behavioral characteristics of autism emerge across development, you know, what if and this was my this is sort 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 susceptibility genes some and interact and converging upon a few common Pathways in the brain, right? And so for years people have talked about
This excitatory inhibitory balance theory of autism, but what if vasopressin is one of those Pathways because it's so critically involved in Social functioning. And so what I was interested in and so let's just say for a moment, you know, your genes are set at Birth. What if the vasopressin 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're not making the eye contact.
And if there was a way to intervene really early even potentially with a vasopressin 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 fluid samples? And and he finally agreed after he saw a couple of those papers understandably you wanted to make sure that we already had shown something and people and animals that were sort of if you will symptomatic with social impairment and what we found was yes.
Was the case so it was a small sample it needs to be replicated. But individual is so infants that went on to have an Autism diagnosis later in life already had low CSF vasopressin levels of oxytocin levels did not differ between infants that 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 or risk management monitoring incredible.
So you're telling us that levels of vasopressin correlate with social cognition deficits that right? I think that warrants a brief discussion about cerebral spinal fluid. I teach neuroanatomy to medical students. So forgive me for having to ask this but you know, I think of cerebrospinal fluid as the stuff that exists in the ventricles and down the central Canal of the spinal cord and provides essential nutrients and for neurons,
Other cell types in the brain, but it's also a reservoir for chemicals coming from the brain which is why the spinal tap is useful but in the context of a cerebral spinal tap and you're measuring CSF and you're seeing okay lower levels of vasopressin in these individuals with these challenges with social deficits. Does that mean that they're making less vasopressin does it mean
I mean, it could have gone the other way to like they're dumping too much vasopressin and of the CSF and it's not able to function in the brain. Like you know, what do we know about CSF? And what does it mean? Right? Well, I mean, it's a great question. So 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 hypothesis and we'll talk a little bit about pharmacology is that there is a deficiency
See in invasive productive vasopressin production and 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 postmortem human brain tissue to look at in both blood CSF and hypothalamic tissue or vasopressin is made to look at interrelationships, right which is very difficult to do but also to see if
There's a fewer number of vasopressin producing cells and vasopressin gene expression is diminished right because that would help us begin to answer is this a production issue? Right. So if you think back to the Prairie voles, they're sort of primed to be parental right or in my case. The meadow vole is right, but you can do this in any evil species or at least the two that I'm thinking of and you put vasopressin into the brain and then all of a sudden it unlocks this Behavior, right? So is it possible that children with autism or at?
Just a subset of them. All you have to do is replace vasopressin and that there might be a subset of these kids minimally that could benefit from vasopressin replacement. If you will, is there any evidence for excessive urination and kids with autism which if anyone's going what what why is he asking that if you recall vasopressin is also antidiuretic hormone. I suppose the other question is could you has anyone looked at levels of
Vasopressin in the urine of autistic kids versus non autistic kids because it's acting peripherally and you said blood draws don't reveal any differences and in circulating blood we know that you're in is filtered blood burn off but seems at least worth worth the look see okay. So I have this awesome medical student in my lab named Lauren Clark and we with three different Physicians from different backgrounds. So wrote a perspective piece that's currently under review and it actually asks,
Question so, you know given all these weird medical naming conventions. It's possible that this information is existing and information silos in different disciplines, right? So it raises this idea of if you have low vasopressin, so there's a if you really don't have you're not making vasopressin you have a disorder called Central diabetes insipidus, right which is characterized by excessive thirst. Lots of urination.
And and bedwetting potentially and so what we wanted to do was ask has this been missed right? So shouldn't there be a subset of kids with autism where we might be able to look at these other physiological features and say yeah, this is the subset we want to be giving vasopressin to and so she wrote this perspective where we did a little bit of a review and the answer is there's some intriguing studies that we reviewed in this paper where it looks like and what's funny is when you read the discussion
And section will be like, wow, there's all these kids with autism that are drinking lots of water and we don't know why or wow, there's a lot of bed wedding, but it's not tied to intellectual disability where you might see a lot of bedwetting or something. So all of these studies kind of raise this point of like wow, this is really interesting and there's been no big epidemiological study done on this and certainly not any study where people who come at it from brain science and then the the practitioners who are like an endocrinologist.
Instance was which is where some of these people could show up are really connecting the dots. So I think that remains to be determined, but we are actually about to launch a study to investigate this right. I was meeting with Lauren yesterday about it. So it's a really good question and I hope to have information on it in the not too distant future as I recall alcohol is an antagonist of vasopressin so out. There's a lot of different drugs that could interact with vasopressin. And so one thing I'm interested in
Is are there any drugs that release vasopressin as a side effect and could some of them be mobilized to treat autism? We also know that like acupuncture can release vasopressin. There's been some studies done in Rats on that. And so one question would just be are there any alternative therapies where we can be releasing vasopressin naturally or do we need to you know, do a replacement study where we give you know intranasal vasopressin to children with autism, right? And of course I am
I'm not I want to say I'm not advocating that people go out and do this on their own right? Like I'm I'm a big proponent of randomized clinical trials where you assess safety, right? And advocacy. Yes. I answer science and medicine right but I appreciate you saying that yet some years ago. So this would be mid 90s. There was a small but very active subculture that I was not a part of I swear that were combining GHB.
Gamma hydroxybutyrate and vasopressin as combination quote-unquote sex drugs really? Yes. Yeah, and I don't know what the rationale for including basil Preston was in any case whether or not that's by way of enhancing social bonding or a direct effect on sexual arousal itself is still unclear. But in any event since we're talking about vasopressin, maybe you should tell us about the actual science of vasopressin. Sorry. Maybe I should allow you to tell us
About the actual scientific study of vasopressin. In other words what happens if you give people vasopressin in a controlled environment, not the sort of environment. I'm talking about what a control and the one thing I will say because I had people contact us all the time saying where can I get vasopressin and what I would say is vasopressin means, you know, you're having effects on blood pressure you're having effects and really important they sewed right and people church and they dosing has to be appropriate, you know, you don't
People just going and trying this because there could be really severe adverse effects, right? So that's why we've been studying this in a controlled clinical trial, right? So I teamed up with Antonio Harden who's a child psychiatrist that I've been working with for years and we did the first sort of first in class vasopressin treatment trial and children with autism. So again, this was everyone was unaware of who was on vasopressin whether it was the family or the clinician who was doing the evaluation and
It was randomized placebo-controlled and then we basically gave vasopressin again twice a day for four weeks to children. They're about to 6 to 12 years of age. And then we had a primary outcome measure which was the social responsiveness scale. We could get into discussions about what a primary outcome measures should be, you know, wouldn't it be great if there was a biological measure but this is sort of what had been used in the past and something that the FDA approved us using I was partly
Using the SRS because we had used it in monkeys, right and we had shown at least in monkeys. We've never looked at this and people because of you know the lack of available samples, but in monkeys in this general population that we've looked at there's a continuous distribution of these SRS scores that relate to the CSF phaser, press and levels. And so what was I wanted to know if we use the SRS has an outcome measure and we're administering vasopressin. Can we change?
Ange, you know the scoring on this instrument based on our animal data. So SRS is social social responsiveness scale 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 Contour on the SRS presumably has to do with how often the kid interacts with another kid how often they initiate that interaction versus on the receiving end things like affiliative play. How often they look at one another versus averting.
Is these kinds of things? Yep, and then there's also a little bit about restrictive repetitive behaviors. So even though it's called the social responsiveness scale. There is also an assessment of other features of autism in it, but you can sort of think about it as a quantitative 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 in our trial and and you know as a as an experimental
A list I have this sort of trust but verify, right so you want to you want to see the same thing over and over and over again, right like scientists like repetition. And so we had Parents fill out their impressions of what the child's Behavior was, you know before and after being on the medication. We also had a clinician make an evaluation but we also had the kids perform laboratory based test where they would see like I mentioned that the reading the mind
Eyes test or we would show them a picture of a face and say what emotion is this and so we were able to have what's called convergent validity, right? So it's a fancy scientific term to say to all these measures that we think should be related are they related in are we seeing the same thing and the answer was yes so that when we gave children with autism base depressin versus kids with autism a placebo the kids who were treated with vasopressin showed increases in Social abilities.
He's on parent report clinician evaluation and child performance on laboratory-based test is that it was that immediate like they did the nasal spray and they immediately started receiving and initiating more social engagement or was this a build up over time? And what I'm getting at here is whether or not this is the reflection of short or longer term neuroplasticity like where their structural changes in the brain or or is this something that was more acute? We don't know the
For that so we basically looked at dosing with the idea that we would you know in and again, I think we've mentioned this about limitations on like there's so many things that a scientist would like to do, but you were always limited by a budget right? And so when we started this work again, it was like philanthropic shoestring budgets, 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
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's 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 four-week period that we saw, you know these changes and in then in a subset of kids, we actually saw diminished anxiety and also diminish restricted repetitive behaviors. So suggesting that the vasopressin effect may not
Lie, Beyond social behavior. Have you ever just wanted to try or tribe is oppressing, you know, I haven't but Irina Psychiatry Department after all and I'm not suggesting that members of the Psychiatry Department are constantly testing the drugs that they use on their patients with themselves. But but I've had several members of this department of which I'm a courtesy member member by courtesy any event and we'll see if I'm still am after what I'm about to say. Dr. Karl deisseroth. He was a clinician
first guest on the human Lab podcast also have a phenomenal neurobiology researcher David Spiegel Rob milenka and others that I've spoken to, you know, I think all of whom said, you know that they felt as clinicians Rob's not a clinician but a anymore right but as a clinician that they felt almost a responsibility to understand the effects and side effect profiles of the drugs that they were giving their patients who which I saw not as Renegade or
Until but rather is a very compassionate like seeking empathy. So I'm curious. Have you ever just snuck a little roll Mouse? 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 and vaccinate their family with the new vaccine that they've created or they try the medication themselves, right? So I don't dma was developed by Sasha Colgan in a laboratory in the East Bay first by pharmaceutical company in the early 1900's, but then
you can't disappear disappear and then it was resurrected and independently in the in the 1990s 70s and 80s. And then now it's one of the sort of Hot Topic items for the treatment of PTSD still in late phase clinical trials still illegal, but self-experimentation is is one of the central themes of Psychiatry correctly. Yeah. I mean, I guess I you know, it's I probably I got in trouble in class for being too social right? So so I guess I've never might send you over the other.
Yeah, exactly. Who knows but no I never know and the thing is is that these oxytocin vasopressin and again, these are done and this is this is something that I think we've hit on over and over again in the podcast is you need to know who's you're studying right? What's this species whose the individual? You know, most of these have been done in you know neuro you mean a lot of the oxytocin and a little bit of the vasopressin work the single dose work was mostly done in what we'll call neurotypical people right? Just asking can we move around?
And social behavior by just giving the single Drug Administration. Most people that are neurotypical didn't say that they could tell if they were on the drug or the placebo, right? So Christmas, so I think the question really becomes, you know, drugs have different, you know, they work differently based on the individual who's taking them. So if you have a neurotypical individual and you give them vasopressin, you know, maybe they'll self-report that they don't see a difference. But if you had somebody who isn't producing enough face
A person may be you know, they would self-report 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 I like playing with other kids more where they self aware in that way and also feel free to mention if it feels right to you. Any let's consider two outlier cases one spectacular result if that, you know a kid that went from very socially
Waited to you know, maybe very gregarious. And yeah, but let's also balance that with another outlier that kid with low vasopressin who took vasopressin who for whom there was no significant shift. I'm presuming that within the data set. You probably observed something like each of those. Yeah. So I mean what I'll say is that so yeah, I mean there were definitely kids who didn't respond to the medication. I mean one thing I think it's important to say and again, this was a small pilot trial right? We're in the process of replicating this in a much.
Your sample so, you know as a scientist again you want to say okay. This is really intriguing and interesting and I've invested a lot and you know this monkey model and then doing all the CSF work and patience to suggest that there may be a there they're here, but I want to see it replicate we did have an article that Stanford medicine I can send you the link they were able to I think interview a family that had been in the trial and so obviously there's patient privacy and you know, you have to they have to say
It's okay to talk about it. But this is a family that was contacted. I think they were Anonymous but this is in this report and they basically said the the dad said that his son was walking around the he was on vasopressin and his son was walking around a grocery store and he liked was looking for him and he turned around and he said he was gobsmacked because his child was, you know, just talking to making chitchat with somebody like in an aisle and he said he had never seen that happen before and so you
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 quote unquote 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 positive.
If you use nasal spray to deliver the vasopressin and presumably that gets into the blood circulation of the brain and supplies neurons with vasopressin, but it's very nonspecific and I'm not criticizing but if you think about you're just putting a bunch of vasopressin into the brain and if people wonder why this is that it's because basically you have neurons of your central nervous system are part of your olfactory system and believe or not right behind your where your nose meets your forehead.
His right there is a little bit of bone and then the brain is is right there. So one of the reasons you can get in there and it's easier than an ocular injection or something that wouldn't be a good approach and it's easier than peripheral infection injection in the vein. But at the same time I have to presume that this I'm imagining this vasopressin just kind of like / me through the brain binding to whatever receptors happen to be there. You said The receptors are everywhere and then this significant Improvement in social cognition, so
That raises all sorts of interesting questions about like what are what relevant circuits are impacted or is it some Global in could it be some global increase in kind of awareness of surroundings? Although some autistic kids are overwhelmed by their awareness of surroundings. So what are some thoughts about how vasopressin might be working to exert this this really impressive and frankly important effect, right? So, I mean could it increase social motivation does it in you know like so let's talk about like how
Sort of complexity of social sensory processing is it that were directing attention to social cues where there wouldn't have necessarily been as much a tentativeness. Right? Are we increasing social motivation which would suggest from some of the animal studies may actually be happening, right? We don't know and I think that's partly when you have other models or if you're able, you know to do imaging studies. I mean one thing that's been a little bit of a Holy Grail in this field is that
That if we could get tracers that are 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 Tracer a radioligand where you could then ask questions about, you know, what's happening in the brain. Can we can we give vasopressin in the context of a you know, functional brain Imaging scan and ask like, where is the vasopressin binding? What kind of circuits are involved like that needs to be the
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 vasopressin receptors are you can overlay that with studies of functional brain Imaging right? And that would allow you to say these areas are dense and vasopressin receptors and do we see similar responses in what we call bold signal on it on a brain scan. So let's let's be more colloquial about this like do certain areas of the brain light up if
You will where we know vasopressin receptors are densely distributed in ways that we know are tied to social motivation or social salience or other things that we think could be moving the needle here in the trial. How is this happening? And I think you know one thing the reason why we did this work as and I think it speaks to what you said earlier is there is an urgency on the part of parents to say, you know, my child's brain is
Being right and and there is a sense of them, you know by the sort of Western model has failed a lot of people, you know, they look to doctors and say what are what are the solutions and doctors will say well we have a limited number of tools in the toolkit 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 it get in some of the work has been covered by the media. And so, you know our feeling was we can give this intranasally and we can do it under safe monitoring ways. 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 that, you know, at least from the initial safety data. It looks
Save and you know and so the idea would be and there's a long tradition in Psychiatry of we don't know the mechanism of action. But if we have a medication that can be impactful 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 it actually seems unethical not to move forward in a way that's scientifically sound Amen to that the seems like
like a good time to raise the topic of the microbiome and not as an unrelated topic and here's why I've seen a fair number of studies in Mouse models arguing that in a mouse model of autism, which now frankly I have to wonder about the the power of that model. But anyway, the models are out there in the field one can take the microbiome, basically.
Let's be direct fecal transplants from a and here I'm using air quotes 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 is actually been done in humans as well. And for those of you that are cringing. Yes, they do fecal transplants in humans for treatment of obesity and a bunch of other things. This isn't because
Scientists are obsessed with fecal matter. It's because fecal matter contains a lot of the microbiome elements. So the micro bacteria of the of the gut 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 vasopressin somehow rescued of a suppression deficiency in the gut. So the questions are as follows. Is there any evidence that
Is a precious and is manufactured in or impacted by the gut microbiome of humans will just start with humans as I think most end because that would that would 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 think there's really great work done in mice. I don't want to be a mouse Basher. So I want to just like sort of go on the record that I'm not bashing other models if it's a conserves, I think about everything from it like an evolutionary perspective if a mouse shares a brain structure with a human and it's highly conserved, you know, Mouse work can be incredibly important and very impactful right my mouth. My lab did years of mouse were some primate work where necessary now I only work on humans, but
Absolutely, it has its uses but clearly the primate model for social deficits as it relates to autism you at least have me convinced that that one has a lot of power. Let's just say that exactly okay, but I mean I now say there is a really cool Mouse study that was done that I found and there's been you know, lots of different studies. So there has been my so there's these. Like I said these genetically modified mice that have genetic syndromes that are you know, what
The individuals have social impairments and some of these individuals and again, here's a here's a problem with a field often. They will measure oxytocin but not vasopressin, right? So like they're not often both measured together, which I always do now, but there's been some really interesting evidence that in these Mouse models that and again multiple studies but like it's certainly low blood oxytocin levels in these Mouse models what and with the sense that maybe they have some sort.
Sort of abnormal gut microbiome. And then what they've done is they've given a probiotic to these mice normalize their social functioning and that in there is an increase in oxytocin and in a recent study also vasopressin at the level of the hypothalamus. So by giving a probiotic you I believe the oxytocin levels were increased in the blood you saw more species typical social behavior, and this was all
Of in by this upregulation of oxytocin gene expression and also vasopressin in this very recent study. And what's interesting is there's this nerve called the vagus nerve which is its. I think it means the wandering nerve a good mom. It's for Vagabond. Yeah, exactly, right and even it's in the gut but it actually has a direct projection to the nuclei in the hypothalamus were oxytocin and vasopressin or made interesting. Yes, and
So when you sever the Vegas you then in this one study, it's a neuron paper. It's like 2020. 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 it's so in other words if I interpret this correctly and I'll go look up the paper and provide a link to it there there by increasing the diversity of gut
Because that's really what a probiotic does serve across-the-board increases the diversity of gut microbiota. No one specific illus says I always say because they all seem to end an illness. You know. Multiple Alyssa's Zilla see Stella see here we go again you up regulate gene expression and thereby action of oxytocin and vasopressin 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 visual
pathway from gut to the specific nucleus in the brain and we know that the vagal pathway is involved because it seems at least partially necessary. If you sever that you give a vagotomy then the this effect is is blunted or eliminated that's very interesting and ties the microbiome to oxytocin vasopressin production in a neural and somewhat causal way and makes the data on fecal transplants make a lot of
More sense because I always wondered okay, so you take a you know, taking the microbiota from one animal put him into another animal you're creating you're transferring the milieu of the gut but it doesn't say anything about mechanism, right? So this this is a really cool paper writing and there's also a study of always wanted to do is you can get a vagal nerve stimulator. They used to do them as implants. Right? But you can also get one that you sort of clip onto the ear and I've always wanted to ask if we use this in
Autistic individuals and you know, could we increase like can 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 doing that experiment? No, but I've always I've always said we gotta get we have to get you the funding to do that experiment and and I know a few times you raised the issue of funding. It's not something we spent a lot of time on this discussing on this podcast, but I think what should be abundantly clear to the listeners throughout the course of this episode.
Is it as you mentioned earlier you're very determined to get work done. You'll figure out a way but the way I describe finances in research is that it's absolutely necessary, but it's not sufficient you of course have to have the right people in the right 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.
It's still very hard for amazing world-class Labs like yours to say Hey, you know, listen there's this vagal thing and clearly there's a rationale. It's not like you're pulling this out of out of nowhere and 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 there was a rationale for you know moving
Of funding to you know, I don't even call it high risk, but you know logically sound hypothesis testing for the treatment of autism. It's now so I'm going to get active on this front so I won't get into hell but you know when I get something in my in my neural circuits for we're talking they tend to not shut down for a while was there will be a community that is going to be immensely grateful. Well, it seems like the parents of these kids in the kids themselves could greatly benefit. So you mentioned that the
study on these are precious in the administration that saw these improvements and 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 I mean you screen a lot. So I think our because we had very rigid criteria. So we ended up with 17 kids that were on active drug and 13 that were on Placebo and they're not a tiny study. No and the placebo showed that we always have like a humanitarian open-label extension arm, which allows for
Anybody who is in Placebo can get access to the drug. So both Antonio and I feel very strongly about making sure that if we're doing a medication trial everybody can benefit from it, right so afterwards if they say, okay, I was in the placebo group and I really want the chance to try this thing. Yes, it can't but then you also get more data we get right. So I think when the families are now aware that their child is on vasopressin and the clinicians are aware, you know, you really want there's a huge Placebo response rate, right? And so, I mean, it's not a place to see Beau response right 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, 13 children who were on Placebo we can then also make sure that there are blood chemistry Labs look good that they're electrocardiogram look good. Right? And so that also allows us to assess safety parameters in a greater number of children.
In a fairly broad literature search I was able to find okay microbiome. So fecal transplant is something that people are excited about as we're in there are trials in people with Autism ongoing if using fecal transplants, okay, oxytocin nasal spray, presumably 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 Adam's positive 5
Endings that I don't know what his plans are, but maybe he's doing work there. There might be a little bit of work with behavioral therapy and oxytocin. But this is the problem when there's one big trial that fails the funding just completely dries up. So even if there's promise I don't know a single funding agency that's going to touch it got it and then there's the vasopressin Administration work that you're doing right? I think it's worth contrasting that work with the
Fairly large trial that was done by a major pharmaceutical company exploring the role of vasopressin 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 us the outcome because I think that if anything that study inadvertently provides support for the results that you observed which is administering. Let's say increasing basil press and levels in the brain seems to ameliorate some of the social deficits of autism, right? So Roche had a compound called Battle of Apt in which was a vasopressin V1 a receptor antagonist, which basically means there's a
I mentioned there's these four neuropeptide receptors and oxytocin vasopressin bind to each other's receptors. But the V1 a receptor is the one that is most implicated in the social behavior. And so they had the and this is the tricky part about when medications are developed in Pharma versus in academics right in academics. There's definitely this transparency. We write grants. The abstracts are publicly available. We register our trials they do too but a lot of the
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 pharmaceutical company, you 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 it still is not clear to me why they took the approach of you.
Being an antagonist to the main vasopressin receptor in the brain. What's interesting is if you go back and you look at the animal literature, there are hamsters that if you give them vasopressin they become aggressive right? And if you give male Prairie voles vasopressin, 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 vasopressin and the only
A social repertoire they have is to you know have sex with a female or to fight a male that they see they have a very limited social repertoire. Right? And when the Prairie vole mail is being is being given vasopressin. It's often in the context of permeate like protecting his mate and his offspring and so then is actually species appropriate for him to attack a Marauder email on his territory who's going to you know, kill his babies, right? And so so my thinking and reading the preclinical literature they are
Literature was that alright that makes a lot of sense in the context of 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 vasopressin was pro-social and that, you know, especially given our CSF findings like over and over across species across studies across
stages that we should be giving vasopressin, especially given the correlations between vasopressin in CSF and symptom severity and autistic traits, you know, the former and people and the latter and the monkeys and so they had some preliminary studies that I believe were maybe single-dose one that they published but then they had a trial where the primary outcome measure the social responsiveness scale was - and then they had
As some secondary measures that maybe showed some promise and then they were conducting another trial and then they did a futility 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 company. So, you know, 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 pudding so we will see if you know, we can replicate our initial.
Pilot findings sounds like they got it backwards that blocking vasopressin Pathways would just make things worse and that augmenting vasopressin makes things better. Although that last statement needs to be supported by this more extensive writing pop. Well, I think you know, there's been a lot of speculation and maybe there are people closer to the trial than me who might be able to speak to mechanism. But you know, I would meet the Roche people at conferences and they would come to my talks and I would always ask him like, what's the mechanism of action? Why are you in
Agonizing the system when we're giving you know, uh vasopressin Agonist if you will and you know, some people had said well maybe by blocking the vasopressin receptor, you know, there's a way to have oxytocin me be more bioavailable sounds like some gymnastics. Yeah. I totally agree. 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 band of vasopressin signaling in the brain, right? And so maybe there's some people where they have too much vasopressin and some who have too little right and so this was a lot of maybes but it doesn't to me seem like that's the case especially if our current trial has a positive read out. I'd be remiss if I didn't ask for your stance and read of the
Upon the data about vaccines and autism. I'm not talking about covid vaccines here to be really clear about that. But there was a theory running about not just in the Press but in the scientific literature for a while that vaccines could cause autism. Yeah that was proposed. 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 sequentially. What was the idea? What was the evidence for that idea? And then what caused the demise of the 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 and now right and I think what I will say is being evidence-based is is sort of like
Something that all scientists should strive for right and so so the back story on this is there was a guy named Andrew Wakefield who published a paper and he basically said the preservatives and vaccines are causing autism. So not the specific vaccine, but the adjuvant the stuff that's been preserving me. It was the stuff that's been keeping the the vaccines bio effective right? At least. That was my understanding. Yeah, that's - well and so and then it what I want to be clear because the internet is
Is a is a cruel and diabolical place. My stance is that that was the hypothesis. I don't agree with that stance, right? Okay, right. And so or if we want to just back up a little bit broader there was this idea that something about vaccines were causing act on to autism but the study was debunked he lost his medical license and the paper was retracted. Right? Well, he lost his medical license on the basis of the fact that the study was wrong or was there ever keep this big data?
That's why we're calls while that there was evidence of him literally making up the data. Right? Right, so it wasn't a case of like sloppy technique. It was a case of of intentional fraud, right? That's my understanding. What was it? Does anyone ever like look into what his motivation for what it was like why someone would I mean threw away his whole career, right? Yeah. I don't I don't know 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 you know, unanticipated consequences and you know, when something like that happens then we dump, you know, we spend a lot of money investigating it and so the good news is that this point there have been multiple multiple studies that haven't shown a correlation between you know, vaccines and autism. I do believe the preservatives have been changed as a result. So that's something we should check that the you know, that might be something where you know, there's been a public
All change on preservatives that are in vaccines that's interesting in its own right? I mean that we don't want to cause alarm if but that's that's interesting. You know that that in this data fraud case, it might have queued people to the idea that certain things might have been needing change even though it wasn't the specific issue that this this fraudulent research was focused on the change was made to make sure people would vaccinate their children right like so this is something that I think we should have lots of caveats here like, you know post the post.
Studies like make sure that what we're saying is accurate, right? But I think that my concern is that we've spent news the good news is that you know, the mid like every single study that I'm aware of does not show a relationship between vaccinations 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 they vaccinate their own.
And you know, they recommend vaccinations to other people's children. And so I think that's where we are. You know, could I just ask a question and I feel more than obligated to do this because I don't you know, I think I have a pretty good finger on the pulse of the listenership or this podcast, but I think there's a range of stances on this where some people have a lot of trust in the standard medical establishment others have less trust in the standard medical establishment and I
be doing my job if I didn't try and represent all those sides and you know, one thing that I've heard is that over the last 20 or 30 years. There's been a dramatic increase in the number of vaccinations that kids get and I don't know if that's true. But when we say vaccinations we could be talking about, you know, measles mumps. Rubella polio. We could also be talking about measles mumps. Rubella polio flu shots every year rabies vaccine 10
Vaccine, you know EV HP HP V right with one that wasn't even available when I was in college, you know as everyone in college who was it was well aware. There wasn't an HPV vaccine didn't change people's behavior a whole lot, but 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 is that the idea that okay, there's some critical vaccines, but then which ones are perhaps less critical if any and these are the kinds of discussions that are starting to surface and that, you know have parents and potential parents, you know, rightfully thinking about this stuff and no one really knows where to get the information. I like I'm
I tried and I can't find a pediatrician that says Hey listen these but not those or you can certainly find board-certified Physicians that same any and certain board-certified Physicians. That's a nun. You actually can find those the nun category tend to hide themselves a little bit more than others for obvious 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 parent and you're not versed in this site and so you could imagine that like people are
Kids are taking many more vaccines and only some of those are critical or maybe all of them are critical. I think I guess the way I would maybe turn it on its head is that you know because of this this study that did in some ways so much harm, right like we spent we spent I don't even want to Hazard a guess about how much money worldwide went into studying, you know, the the, you know vaccines and autism based on fraudulent data, right like that's too
Real tragedy but at the time they didn't know it was fraudulent. Yeah, right exactly. So they went after this thinking it was true. Okay, but I think I think the thing the consequence of all this that I think is also extremely sad, is that everybody because everyone got so riled up and so fearful there has been historically until recently many researchers who are like, oh man. I don't want to touch immunology and autism with a 10-foot Pole, right? And yeah,
yeah, you know and I wouldn't consider 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 yeah, it seems like it's not a kettle of fish. It's a ball of barbed wire with a bunch of you know, Napalm burning around it. And you know, you mean you say one thing your career is ending you say the opposite thing your careers also ending, you know, it's it's 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
Listen to parents stakeholders, right like, you know, there is there needs to be a dialogue whenever anybody studying any illness to talk to the people who are involved. Right? And and I think that there are parents who will report. Wow, like there are there is immune system dysregulation 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, okay.
Okay, we're hearing a lot about this from parents. And our there were a group of individuals who have you know immune issues that could be driving their autism, right? We don't know and everything should be evidence-based 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 are going to
Has all kinds of grief then people are going to be less reluctant to study them. Even if it's critically needed. 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 are disrupted in autism and by extension other deficits of social function in kids and adults you've identified.
I had this incredible relationship between vasopressin which should have more prominence in my opinion than oxytocin. Its lesser cousin just kidding oxytocin lovers, but also have shown, you know, yes in a small study, but you're now extending this to larger cohort as you mentioned a causal relationship when these are pressing is administered to these low vasopressin / low social functioning kids.
Symptoms improve so I know I speak for many people when I say that I truly appreciate your doggedness and in going after this problem, especially on the complicated landscape of lack of funding for doing novel and truly high-risk work, especially on the backdrop of the socio political landscape around autism. It's a complicated thing even to discuss, you know, as I mentioned in the introduction, you know, we had to have some fluency around autism. So we sometimes said autistic
like sometimes we said people with Autism, you know, I mean, 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 it to get in there and just go. Okay, you know, let's get it to biological functions. Let's get it the novel treatments and you're making amazing progress. So I'm so grateful that you're doing it and that you'll continue to do it and that you came here today to teach us what you've been up to. I'm also grateful and I just want to say, thank you.
That in 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. All right. Well, I've Loved this conversation and I'll sign off by saying folks. This is how diseases are cured. Thank you for joining me for today's discussion with dr. Karen Parker about the biological basis of social functioning and autism to learn more about. Dr. Parker's research. Please see the links in our show no captions if you're learning from
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