Dr. Karen Parker: The Causes & Treatments for Autism

welcome to the huberman Lab podcast

where we discuss science and

science-based tools for everyday

[Music]

life I'm Andrew huberman and I'm a

professor of neurobiology and

Opthalmology at Stanford School of

Medicine my guest today is Dr Karen

Parker Dr Karen Parker directs the

social neurosciences research program at

the Stanford University School of

Medicine the goal of her laboratory's

research is to understand the biological

basis of social functioning at every St

age 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 D about the

causes of autism you may have heard that

the incidence 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

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discussion with Dr Karen Parker Dr Karen

Parker welcome thank you it's great to

be here this is going to be perhaps one

of the longer conversations that we've

been able to have over the years um in

part because whenever I see you on

campus we're headed in our respective

directions but I'm very excited because

the topic of autism is one that is on a

lot of people's minds and I think the

first question that always comes up it

seems is whether or not the frequency of

autism is indeed increasing or whether

or not the field of medicine is is

getting better at detecting what was

always there over time do we have any

clear answers to that well I think it's

a multifactorial answer so we're getting

better at detecting autism right so in

the past we were diagnosing kids at nine

or 10 years of age right and now

clinicians are able to reliably diagnose

kids um at two to three years of age

right so there's more people um there

are pediatricians have autism screeners

now so when you bring in your baby and

over the first couple years of life

you're filling out screeners that are

looking for autism symptoms right so so

there's just a lot more awareness around

autism but the rates have increased to

now 136 us children have a diagnosis of

autism which is over two years ago it

was 1 in 44 so 1 in

36 wow I feel like it was just yesterday

when it was 1 in 80 but is 1 in 36 um

the average across Bo and girls um does

it

skew 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 the studies veryy I mean it's

it's worth noting that autism is a

highly clinically heterogeneous disorder

which means that if you 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 every one girl there's three to four

boys that are impacted by autism so

there's you know 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 um

children and then that's where we um

that's where the prevalence rates come

from and they release new prevalence

rates every you know few years so if

Physicians are able ble to detect autism

early say in a 2-year-old or a

three-year-old have to imagine that

they're working off of tests that don't

rely heavily on language because even

though you can get you know some verbose

two and three year olds most two and

three-year-olds don't have a very

extensive vocabulary um and I'm guessing

that they're also relying on things like

visual gaze um among other things um

we've already made clear that this is um

not a discussion to allow people to

diagnose themselves or others but um

with that said what are some of the

diagnostic tools that people use you

know um is it language is it Vision or

does it present as um you know abnormal

auditory processing maybe you could give

us a sampling so autism is um 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 all a

behavioral diagnosis by um an expert so

usually um a psychiatrist or a

psychologist and they look for two core

features so the so this is based on the

DSM um five and there the two core

features are pervasive social

interaction challenges and the presence

of restricted repetitive Behavior but

there are a lot of people with Autism

who have anxiety there are a lot of

people with sensory challenges there are

a lot of people with seizure disorder

um 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

introduced nowadays so if someone brings

their child to the pediatrician and they

take one of these tests and that a child

is deemed as having autism um um will

the will the one-year-old or the you

know 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 a variety of different

ones um that are used there are some

studies where um 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

you're doing is enriching the population

of infants that you follow

prospectively um who are more likely to

receive an Autism diagnosis and there

are studies where some of those children

are enrolled in Behavioral Studies even

when they're quote unquote at

risk I've heard before that you know

parents in which one or typically both

parents are say of the engineering mathy

physics quote unquote hard science

science type are um more likely to have

autistic children is that true I mean

did that bear out in the data you know

if you look at profession or or um you

know undergraduate major uh 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 used

to 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 um designed in England

and what what we know from work with the

AQ is that individuals that are in

intense stem Fields like engineering

physics and 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 yeah is actually

multiple spectry spectrums is it

spectrums or spectry what 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 um you know

because when we hear the word spectrum

we think okay there's a spectrum of

severity right and in fact I have some

experience with um severe autism not in

my family but where I went to

undergraduate University uh UC Santa

Barbara down the way from that school

was the Deo school which was a school

which um has been there for a long time

that um parents would send their kids if

they were quote unquote severely

autistic it was actually where um Dustin

Hoffman went to um study for his role in

Rainman and the uh 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 character would

say gotta go to Kmart gotta go to he

would do that repetition right that

Kmart was down the road from our you

know our College housing and the Deo

School those kids were literally in a um

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'd get

visits and they'd get visits home um

because they were I suppose we could say

at the far end of some spectrum that

made it at 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 a autistic that's how

they've referred to it so I feel

comfortable um saying that they've said

I am autistic um and they seem pretty

high functioning meaning they have

driver's licenses drive cars are in

healthy relationships and manage life

apparently well um they have some traits

that yes I would agree are a little bit

different right so this is where we get

into neurode Divergence right um 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 um

kind of collections of different traits

could there be a spectrum of severity

also a spectrum of um you know more

stereotype behaviors um another spectrum

that intersects with that that has to do

with you know obsession with a

particular topic you know you could

imagine that there are 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 does

that make 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

understanding the biology you're left

with okay we're are we lumpers or

Splitters like how do we think about

this because autism is highly heritable

so there's about 40 to 80% of autism is

um is genetic right so these vary wildly

right but the but the common thinking is

that the majority about 50% of autism is

um is associated with common genetic

variants and so the way that we've

always thought about this is that there

is this you know autism is largely an

inherited polygenic condition and but

what I mean by that is that you have a

lot of common variants that are additive

and so if you think about this

collection of common genetic variant

that underly the Spectrum right so if

you have less of a dosing of some of

these common variants you might see

somebody who's a lot more who's higher

functioning like you said and if you end

up with one of these single Gene High

penetrant um 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 disorders to date

has there been any specific neural

network that we can point to and say Ah

that's the neural network that seems to

be different in people who are on the

autism spectrum um I saw a study

published recently that seemed to point

to the idea that the genes that are

altered in autism um at least include a

large number of genes that are altered

or the proteins that are the consequence

of those genes 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 um do we even know that autism

is a brain issue right could couldn't it

be an issue of you know the immune

system or the cardiovascular system

which at the time seemed like okay gosh

of course it's but wait then you stop

and you think that's a really good

question right how do we know it's a

it's a challenge of the brain right I

think that's a great question right and

there may be people talk about

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 um 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 neuroscientists or or

psychiatrist have to think about looking

at the brain are um limited right and

then and then the other part is how do

you model so the other way we might

think about getting access or or

thinking about model systems what we

need to do is think about the control

animals and we need to make sure that

the species that we're modeling them in

has um features of control humans if you

will so we need to have complex

cognitive abilities we need to have

complex social skills we need to have an

organism that has Vision as its primary

sensory modality right potentially sleep

consolidating so we need to think about

all of those and and the the tricky part

I think until fairly recently was that

we were doing all of this work in Mouse

models and you know the control mice

just fundamentally lack many of the

characteristics that are needed to model

you know autism with Fidelity right and

I think that's you know when we look at

drug development pipelines about 50% of

preclinical failures so that would be

something that's tested in an animal

that works and then fails in a human

clinical drug trial 50% of those

failures can be attributed to poorly

selected animal models and so I think

part of where we we will be getting

traction is picking you know developing

sophisticated models as a sort of point

of entry into being able to understand

some of these things that are really

difficult us studying people yeah such a

key point and um for those that um have

not heard of pre-clinical models

pre-clinical models are non-human models

so it could be Mouse could be nonhuman

primate could be flies or worms for that

matter but uh we're going to talk a lot

about non-human primate preclinical

models um and the work that you've been

doing and of course also the work that

you've been doing in humans um the other

animal um the other private the other

primate right exactly I love to remind

people that we're primates um Old World

primates um thank you for doing that so

you've been talking about the genetic

influences on autism and of course genes

in the environment interact right it's

never nature or nurture it's always an

interaction and that isn't just about

the epig genome 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 right so I mean

there are again lots of different

epidemiological studies so um Advanced

parental age uh prematurity severe

prematurity is a risk factor for autism

um maternal illness during pregnancy um

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 um one of the

things that I was really struck by in

the early 2000s that at least by my read

of the literature hasn't really gone

anywhere was this idea that was proposed

by pashco who used to run the

neurobiology department um at Yale um

expert in brain neuro anatomy in

non-human primates and in humans

embryology um really luminary of our

field and he had 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 um

it's not typical dinner table

conversation you know when you when an

embryo when a human embryo is developing

the the neurons are born at one location

and they migrate out some distance to

their final um resting place where then

they grow out their connections and

connect with one another and that

process of neuron neuronal migration is

oh so critical for the eventual wiring

of the brain and rakes had this idea

that perhaps and I really want to

emphasize perhaps that the more frequent

incidents of autism might be correlated

with the increase in early prenatal

ultrasound and he had these papers

published in number of really

high-profile journals including

proceedings of the 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 to me was a you know an

interesting example of of the

environment frequency of ultrasound and

cell migration having some sort of

interaction but it seemed like it never

went anywhere it 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 pregnant 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 we'll hear other theories

about okay it's having two parents who

are both engineers and then we'll hear

oh you know it's um you know toxicity in

the food environment we've heard you

know hypothesis about vaccines or the

the adant that the vaccines are

contained in you know in that large

cloud of the

has anything really um emerged from them

as like okay there really seems to be at

least one major risk factor

environmental risk factor because I feel

like all those theories I come up get

some popular press bunch of papers are

published sometimes those papers are

retracted like in the case of the

vaccines um and then the theory kind of

dies yeah so is there any specific

environmental influence on autism that

we can say yes they're really seems to

be something there yeah I I mean it's a

it's a really spectacularly 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 one two 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 um I think

that's an incredibly difficult study to

do right so there's been an interest in

this field of there's these neurogenetic

syndromes that have high penetrance for

autism which basically means that you

could have a disorder um 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's

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 genetic heterogeneous

study it's going to be very difficult to

tease out these pieces because an

environmental risk factor um might be a

driver for one kid but not another right

and so I think what we need to do is to

have these genetically defined subgroups

of individuals and then be able to test

the G by Gene by environment

interactions or in this genetically

defined group of individuals um can we

test this certain medication to see if

it's beneficial for this subgroup of

children got it so you you mentioned

fragile X which um we know um presents

with autism like symptoms in some cases

and then I think of another disease like

um Timothy syndrome a mutation in an L

Type calcium channel which um for those

of you that don't know what these cell

type calcium channels are they're

they're 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 heart tissue right so um kids

with Timothy Syndrome have cardiac

issues yeah and they have 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 you know gut

issues or heart issues or um muscular

skeletal issues but we often think that

that's the consequence of the autism but

often times that 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 you know 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 um I mean

what is autism really I mean is it it's

what does it really center around what

and I I think here maybe it's useful to

go like do we go to the diagnostic

criteria like how do we decide if a

child has autism if they also have a

bunch of other things that are

challenging them I I think that that's

The $64,000 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 a tumor

and you can do molecular profiling and

even you know have personalized

medications made right to attack that t

tumor and so you know know what's really

tricky when you have a behavioral

diagnosis that's not

biologically defined you 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

autismsocial people people I've heard

clinicians say well that's not really

autism right that's a piece of fragile X

right but if it's a behavioral diagnosis

and they meet be behavioral criteria it

becomes this weird circular argument

right so like until we really understand

what autism is I I I think that it's

going to be very tricky to start you

know

subing different aspects of the

condition as we all know quality

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well 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 right

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 discussion

without first having a discussion about

two 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 uh the important work that

you've been doing on vasopressin in

particular but also oxytocin and

autism what are oxytocin and vasopress

really okay so they're these small

little peptide they're nine amino acids

long are very tiny they only differ by

two amino acids and they're these

ancient peptides that are hundreds of

millions of years old and in almost any

species studied um whether it's the

current version you might have vasit

tocin or other Mosin which are um sort

of precursor forms in other species but

they're highly evolutionarily conserved

and they're involved in social behavior

um in pretty much any it could be egg

laying it could be you know but but

reproduction and social behavior across

the philogenetic tax 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 and vasor

pressin are pervasive and Maman species

do the different species tend to make

oxytocin and vasopressin in similar

brain areas and tissues um yes but not

completely overlapping but I I think the

thing that the the beautiful mystery

about these and the infuriating piece of

them is that because they're so

structurally similar um they can have

similar effects and they there's four

receptors that they bind to so if you

think about a hormone or a

neurotransmitter so oxytocin vasor

pressent 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 can bind to these

four receptors so it can be very

difficult to

disentangle which one is acting and at

which receptor and where in the brain oh

so oxytocin vasopressin are chemically

similar yes interesting yes and uh where

would you say lies their greatest um

output Divergence which is just nerd

speak for um 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 or hormones

were discovered for their peripheral

effects which basically means not in

their brain but somewhere in their body

and so oxytocin's involved in um uterine

contractions and milk let down and so

was during lactation so people sort of

always thought of it as the female

hormone and then vasopress has um at

least in the in the peripheral system

has been involved in um urine regul like

urinary output regulation blood pressure

um and so we only knew about their their

physiological roles as their sort of

classic hormones for decades and what

was interesting is these um 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

once vasor pressin was named twice so

it's either called Arginine vasor

pressin or anti-diuretic 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 and

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 sites 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 their physiological roles

but but there were neuron anatomist

saying hey so these are both made

they're made in a lot of different

places but the the the action sort of

happens in the hypothalamus where

they're made and there were anatomists

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 um I had a mentor

um uh a colleague like an you know who I

didn't train with but he was um a real

source of wisdom to me for many years

and his name is Court Peterson and he

told me this wonderful story about this

duuk oologist named Peter claer and um

Peter was studying ulet so sheep and

goats and he wrote a story of paper in

1971 called Mother Love what turns it on

and um you know one thing about science

is I love going back and seeing where do

the 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 offspring 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's yours not somebody

else's right and um he hypothesized that

it was oxytocin that was being

co-released into the brain and during

milk let down that was what turned

Mother Love 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 oxid doin has

many different roles um but this role of

Mother Love and bonding to infant um 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 um and that leads me to the

question is oxytocin also released in

the baby um in reaction to to the mother

and how long is that effect lasting

because in order to have a pervasive

bond with that baby and not just some

other baby and of course we still have

visual cues and you know we know our

baby versus another baby most instances

um there are rare exceptions or 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 is

something that is literally changing

their brains saying it's you are the are

the center of my life right and the baby

of course is saying well you are my life

because you are the source of life right

certainly for the early part um early

part of life and that nowadays it seems

that that that can extend well into the

uh the teens and 20s for some people but

um you how how is oxytocin working is it

is it working over the course of minutes

hours is there some specificity of this

baby and this mom that links them in in

some more pervasive way I mean how is

oxytocin doing this magic of bonding

yeah I mean it's 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 the early studies that were done

are you um The Passage through the

vaginal Canal was what you know so you

would activate 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 BL brain but you

have a pharmacological agent blocking

its ability to bind to its receptors

these sheep and goats wouldn't um bond

to their baby for instance so literally

the passage of the baby out of the

vaginal Canal triggers the oxytocin

pathway the release of oxytocin as in

lactation does too 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 I'm GNA get attacked

anyway if not if not for this discussion

then another one but I'm tougher than I

like so um 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 and biparental care where

where sort of everybody sort of like it

takes a village to raise the baby we

readily adopt in our in primate

societies right and so you know um like

I had a CE I mean I'll tell you

something personal I had a C-section um

and uh 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 um I massive um DVS

and Pulmonary emop 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

DVT thrombosis yeah and it was sort of

like welcome to Motherhood and I was in

the ICU and um had to get a filter put

in um an inferior vnea filter to um stop

me from dying because the I had

scattershot clots all over my lungs and

so I didn't really you know I didn't I I

didn't do a vaginal delivery I had a

C-section and 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 um 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 um so but it it

is um many people go into the oxytocin V

oppressing 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 in our species

is many disorders are disorders 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 you a risk factor for drug abuse is

feeling you know socially disconnected

and alone right um social um isolation

or loss of a loved one is a very strong

predictor of the onset of a stress

related depressive anxiety disorder in

terms of when and how oxytocin is

released you mentioned um mother infant

bonding um I think you said yes that the

infant is also releasing oxytocin we

think um so it's it's bidirectional um

we think I think most of the work has

been done in mom would be and and again

this has not been really done well in

primates right so we're extrapolating

this information from species that have

different evolutionary histories than us

right so it's go sheeps um Prairie vs

mice rats so what do we know about the

role of oxytocin in 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 um and presumably

romantic partner bonding at least you

hear that a lot um it was unfortunately

nicknamed The Love hormone yes um and

the reason it's unfortunate it was is

that while that might cue attention to

oxytocin and I'm you know a big fan of

people paying attention to biological

phenomena it uh it discards the other

and many roles of of oxytocin but yeah

what can we say about oxytocin in humans

if anything like do we know that 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 they

brain Imaging where we know where

dopamine is expressed and do we even

know where oxytocin receptors are

expressed in the human brain presumably

that information is is out there

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 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 radio tracers

where you could then which we do have

for dopamine and and other compounds

where you would then go and see where

after somebody's performed a task do we

see you know um activation right or

uptake um there are some Imaging studies

they're usually done giving intranasal

oxytocin um and then you basically ask

questions about okay we give you

oxytocin and trenas which presumably

enters the brain there's we could talk

about reasons why we think that um and

then we have you perform on some task

right and so you know there's evidence

if you give oxytocin it diminishes the

amygdala's response um to fearful

stimuli right so that it might have this

sort of pro-social effect and and it was

actually data like that that caused

people to start thinking um initially

about oxytocin and those are data on

humans that's right it reminds me that

there was this brief moment where

oxytocin wasn't just being discussed as

the love hormone it it was being

discussed as the trust hormon right also

um far too simple heuristic but but

again I think it's cool that the you

know that the 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

um uh have it leads the assumption that

that's the only role of a given of a

given hormone so um it can reduce

apparently it can reduce the output of

the amydala in some way this brain area

associated with um threat detection um

and so you could imagine how that would

bias the person toward being more

pro-social right um have there been

studies exploring the role of oxytocin

in making autistic children more

pro-social and behind that question I

suppose is the assump you can verify or

or not that autistic children are less

pro-social than other children um is

that true um or is it that you know

autistic kids are just maybe more

pro-social with the one friend they

really really like um I happen to know

some kids uh with autism or however you

want to phrase it and um 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 all the Hallmarks of

you know healthy social mind but it is

true that they are uncomfortable in in

groups and where there's a lot of noise

a busy birthday party is overwhelming

for them but you 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 I

much prefer to be with a small group of

friends or one close friend so I hear

you I'm that way too right so um you

know how do we think about this um okay

well I would say the social features of

autism are interesting right and so you

might have there were there was an

attempt a long time ago like 1979

there's a woman named Lura Wing who

tried to subtype the social features of

autism right and so there could be

people um that are socially avoidant and

really just don't want to have social

interactions there could be kids that

are um active but odd which means that

they have an interest in being social

but maybe they don't read social cues

right and they interact in ways that

other kids don't understand or make

could cause bullying right and sounds

like Junior High School yeah exactly um

and and that's often why um you know

some autistic kids do better with adults

right because adults know how to sort of

Channel um discussions with somebody who

might be a little socially awkward right

but there's different phenotypes I mean

uh people having a disinterest in social

interactions could be that they're

highly socially anxious right um that

making eye contact makes them anxious

you again that's another caveat um there

have been some studies administering

oxytocin to individuals with autism and

again these are these single dose

studies so the first studies that were

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

vasopressin actually would have been my

choice um based on the animal literature

and we can talk about that but vas

oxytocin was given to males um partly

because it wouldn't the idea would be

that the of Target effects in the

peripheral nervous system I.E milk let

down uterine contraction 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 the

go-to for research studies as you may

have talked about on on your podcast

before too something that fortunately is

changing thanks to a mandate by the uh

by the NIH correct um I I had to just

kind of um smile slash um raise my

eyebrows a little bit at the idea that

you know the the assumption that

oxytocin administered to males yes one

can see why it wouldn't cause milk down

or uterine contract

but um but of there could be other

peripheral effects ofto and males but

they had to pick they had to pick one so

they went with males okay so um 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 the experiment on

females but um 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 happens right and it worked and

so then everyone uses that protocol and

so then there's been a lot of studies

looking at um you know there's one

reading the mind and 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 or Placebo um where's 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 rece receive a lot of social

cues that are relevant to social

communication and so some of these early

studies showed that a single dose of

oxytocin in people that were um had high

functioning autism so they were 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 is a therapy for autism and

is oxytocin available over the counter

does it require prescription I I mean

you see sites that are selling it but

that doesn't mean anything these days

right um there's gry Market there's all

sorts of stuff going on um but I know

people that have used oxytocin um

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 um uh

oxytocin ketamine nasal inhalations um

as part of their work with their

licensed therapist on um like PTSD type

stuff relating to let's just call it

relational trauma okay um so that's

happening um but let's just think about

oxytocin alone for the moment um are

parents of of autistic kids able to like

buy oxytocin nasal spray no so so it

would need to be written like the

prescription would be need to be written

by a um by a physician um 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 antis psychotics

which they um they treat Associated

features like irritability and they have

off Target effects like weight gain and

and and you know so we don't have any

medications that are currently approved

in the US or anywhere else for that

matter to treat the core features of

autism interesting and um unfortunate um

and hopefully that will change in the

not too distant future um do we know

that children autism people with Autism

because I'm going to just sort of assume

that um autism is stable over the

lifespan um like if 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 um you know

there are people who respond well to

behavioral therapy um I mean obviously

it's not the Cure All for everybody

there's lots of people who go through

intensive behavioral therapy and

probably see minimal benefits um 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

we'll have adults sometimes you'll have

teenagers sometimes you'll have

kids I'd like to take a quick break and

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huberman is it known whether or not

people with Autism assuming they meet

the criteria for being autistic at that

at that moment um have lower natural

circulating or active levels of oxytocin

because you know it's one thing for a

nasal spray to um of oxytocin to improve

social functioning it's another um to

know that it 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 mentioned oxytocin has all kinds of

effect 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 a better

biochemical proxy of the brain um most

studies so what I will say is there were

there's been m a handful of small

studies where there has been some you

know there's been some benefit Maybe no

benefit small effects we did a study

that was a small study at Stamford and

it was based on um Mouse genetic data

and I'll I'll sort of walk you through

what we did um so there's multiple Mouse

models of these neurogenetic syndromes

where um people have social impairment

right we can Qui quibble about whether

that's autism or not but that they have

social impairment and so that there are

this um fragile X Mouse there's a PR

willly syndrome Mouse which is the

magile 2 Gene that um gets manipulated

and then there's a catnap two 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 um 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 cat to

Mouse you can restore oxytocin neuron

number to 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 manipulating genes for

these syndromes that oxytocin gets

knocked down right and so our thinking

when we went into our clinical trial was

what if um its blood oxytocin levels

that there going to be a subset of

individuals that just make less oxytocin

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 um to

ask you know across this range of

individuals who showed up and we did in

all the trials that we'll talk about

today um these are done with my

colleague Antonio Harden at Stanford

who's a child psychiatrist um and we

always have double blind meaning that

the investigative team is blind and that

the um or unaware I should say they're

unaware of treatment and then the

families and the children are unaware um

and then they're randomized meaning

there's an equal chance you could get

either drug or Placebo um and they're

and they're controlled right okay so we

asked if we know what your pre

pre-treatment pre-treatment blood

oxytocin level is who's going to benefit

from treatment and we found a couple

really interesting things one was that

the lower your Baseline so your

pre-treatment blood oxytocin level you

showed much greater benefit from the

oxytocin intervention these are children

one one intervention one nasal spray

this was four weeks sorry I should have

clarified this is four weeks of

treatment being um administered oxytocin

twice a day okay and um and and so we

saw Effectiveness there may sorry to

interrupt so much but just uh males male

and female subjects we did but again you

know because the autism is male biased

and prevalence even if you make this

heroic effort to over recruit try to get

more girls in and um in 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 um boys and girls were

included they're taking oxytocin over

the period of several four 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 you

didn't see much benefit right and so

that was a a cue 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 maybe some of these you know

maybe there would have been more um

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 um what's called a phase

three oxytocin treatment trial that was

done at I think five sites and they gave

oxytocin for an extended period of time

um and they showed no benefit um and and

were they looking to see who started off

with low levels of oxytocin at

pre-treatment so what was interesting

about that study um and there were a lot

of issues with it

was that um oxytocin is something where

you have to if you look at it it

degrades it's 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 tubes that are

cold and we put them on ice and then the

FLOTUS takes the blood from the child a

lot of technical gymastics yeah and then

we make sure we spin it in a centrifuge

cold and then we pipe head it onto dry

eyes so like so we have very minimal

loss of the signal and so if you don't

adhere to those rigid protocols which is

very difficult to do across multiple

sites um it can be very difficult to get

an accurate read of oxytocin and so I

think for me it's still an open question

um they didn't see that blood oxytocin

predicted response um in that study um

the data weren't provided in the paper

it was just said that they didn't um but

it's still an open question

and so that you know maybe that is the

way if you give it acutely like in those

early studies we talked about that maybe

oxytocin you know diminishes Spar we

know that oxytocin decreases um the

stress axis the hypothalamic pituitary

um adrenal axis and then it can diminish

anxiety in animal models so we that's

well established um and in a former life

I was a stress researcher so I've spent

a lot of time thinking about this but

but it's sort of the sad thing is is

that once you have a negative trial it

um there isn't a lot of interest in

funding uh 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 and and until there's money to do

that work um we may not ever know the

answer well be it will be important for

that work to be done eventually

hopefully the field will return to it

despite whatever Trends might be

happening now I think it's important to

know for the parents of autistic

children um whether 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 um 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

underly social connection well then

there's this um Tim limited window um in

which you know those parents presumably

are willing to try most anything

provided it's safe right so let's assume

and I'm making up these numbers now

because I haven't seen this study but

according to what you told me that let's

say a third of the autistic boys and

girls that come in have um low Baseline

levels of oxytocin they're the ones that

are going to benefit from this oxytocin

intervention the other 23ds don't well

given the difficulties of measuring

Baseline levels of oxytocin most people

don't have access to those kind of

resources um if it's safe to give

oxytocin no matter what well then if I

were that parent I'd be knocking on my

Physician's door saying hey give me an

oxytocin spray because my kid might fall

into that onethird 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

yeah so um is oxytocin spray safe and if

so why doesn't every physician who has a

patient with autism give them oxytocin

nasal spray right it's a great question

and I 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 I think the

tricky part is that so one thing I will

say is that all of the studies and

there's been many of them have shown

that oxytocin is um is relatively safe

in a pediatric population right um the

tricky part is I don't know there's

Physicians that you know really pay

attention to 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 I think the

tricky part and what I will say is and

we can maybe talk a bit about vasor

press which you know my feeling is that

if I was placing bets and and having to

choose between these two my my money

would be on vasor press well we are

definitely going to yeah um talk about

Vaso pressent in detail I mean the

reason I I mentioned that hypothetical

scenario is just the sense of urgency

and in some cases desperation that

parents feel and you know time's ticking

and if oxytocin's safe then you know um

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 um to consider but I can also

understand the perspective of a

pediatrician who says well listen it was

a small number of kids that benefited um

you're welcome to try it but I don't you

know it doesn't seem like the results

are that impressive but um you 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 neurodevelopmental

challenges um I I just want to ask

because it feels relevant in a in a real

way um 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

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 um 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 yeah as I've

discussed on this podcast before but

ultimately we know that depression is

not a serotonin deficiency in most cases

ssris or atypical anti-depressants like

Ryon Wellbutrin and things of that sort

when they work they probably work

because of their ability to induce neuro

or assist neuroplasticity right right um

also the trials on psilocybin are not

really about psilocybin they're 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 re wire the

brain in a specific way whether or not

it's assisted by oxytocin or some other

mechanism so the question is are there

trials happening where people are

exploring say psilocybin MDMA which by

the way we know increases oxytocin and

serotonin dramatically as well as um

things like atypical anti-depressants in

kids that have autism not because we

think that those autistic kids are

deficient in any of the neurochemical

that these drugs would Target but that

these drugs can help rewire the brain

and ultimately that's what these kids

need right I 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 and 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 a

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 guesswork that goes into this um but

I would very much like to see I I will

say one other thing that um there I have

a colleague named Adam guella 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

I don't quote me somewhere between two

and or you know two and five or three

and six or something find the paper and

put it in the show 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 Haj podes across ages and across

sort of different social

phenotypes finding that signal is really

important right and and maybe age is a

driver or or maybe you know low blood

oxytocin regardless of what age you are

or maybe in Adam's case if you recruit

really young children you're likely to

see a benefit just because the BL the

brain is wiring up and it's more plastic

at you know younger ages yeah that's

also a vote um in my opinion um for

early examination of kids right like

parents really need to get autism screen

and perhaps maybe the most important

thing is to make autism screening as

available and as inexpensive as possible

for everyone because of the importance

of early intervention even if it's

purely behavioral intervention but

certainly if it's behavioral and Drug

intervention but 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 you're showing

Troublesome features and a parent wants

to get their kid into a clinic and you

could have a 12mth or or 18-month wait

time right and so there are a lot of

people that are thinking about are there

are there laboratory based tests that we

can develop maybe either for detection

or clinical referral right so could we

come up with a a biomarker panel for

instance where we might be able to say

wow here's some here's a panel where we

think this child is at reasonable risk

for developing autism can we make sure

they're prioritized for getting a

diagnosis right so we can get them an an

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 um or if we could do

something with ey gaze and there's a lot

of companies working on these things now

to say this may not you know and and

also obviously again autism is always

controversial in this field right

there's so many different 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 um you know we could get diagnoses

faster well you wouldn't want false

positives but I would think that a 30

second video clip provided itself

something useful is going to be more

valuable than nothing yeah given the

time sensitivity uh what are some of the

barriers to um getting this behavioral

testing 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 on the bus

we get the beep test and you know um you

know for hearing um challenges uh we get

Vision tests you get the babinsky reflex

test not the moment you come out of the

womb but pretty pretty soon after I mean

why isn't this stuff um happening uh for

autism um for every kid yeah it's not

scalable right so you these interviews

with parents and the tests 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

diagnoses right and so I think that

there's you know clinicians that are

doing the absolute best they can but

they can only see a certain number of of

people a week right and does it have to

be a physician sorry to interrupt does

it or could it could you know could a

well trained technician do this yeah

well I mean I I think technically it's a

DSM diagnos is right so it's usually

somebody who has a clinical degree so it

would be a clinical psychologist it

could be a behavioral pediatrician it

could be you know a child psychiatrist

or child neurologist but I mean again

that requires years and years of

training um and if we look in areas

where people have fewer accesses access

to Resource I mean particularly in

impoverished areas the mean age of an

Autism diagnosis is years later than in

wealthy areas where you know there's

many different medical specialist with

parents you know that aren't working

three jobs and you know can sit waiting

around you know and and really Lobby and

and really advocate for their kids right

because you know if they don't show up

for work that day they're not going to

get fired from their job 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 a blood test or

something like that you know it could be

incredibly

impactful are there human trials

exploring MDMA methylene dioxy

methamphetamine also referred to as

ecstasy um and oryan for um treatment of

autism so I was aware that Maps had an

MDMA trial in autism um I don't know

what's happened with that yeah perhaps

it's still ongoing I'll check the map

site in communication with them from

time to time I mean the the the reason

for asking it of course you know but

maybe in case um some of the listeners

um don't is the MDMA causes these

massive increases in serotonin that

seems to be the major source of the MDMA

effect so to speak um based on the work

of our colleague Rob malanka and um in

at least one human study comparing um

MDMA to very high does 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 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

um seems like not the perfect drug but

not a bad choice um if of course it's

inducing the kind of plasticity that

someone with autism would be seeking

right I mean I think 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 um you know the chemical compound

to you know be something that parents

might be more willing to give to their

children right right and I totally agree

with that um I guess to play Devil's

Advocate not against you but um uh well

I'll just state it very directly and

then I I'll take the heat as necessary

um I mean I've done two episodes about

the uh 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 um include

amphetamines including dioxine

methamphetamine is actually a

prescription drug for a very small

subset of kids with ADHD but things like

adderal viance even methylphenidate rlin

I mean these are amphetamines they

induce dopamine release and

norepinephrine release and uh again I'm

not suggesting people um give their kids

MDMA um to try and amarate 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 I'll reach

out to the maps group and see see what's

happening let's talk about vasopress yes

because there's a lot to discuss there

so you told us this is a molecule that

chemically is very similar to oxytocin

um is it manufactured in the human brain

and body yes okay do we know a subset of

the sites that it's known to be produced

and where it's of its actions are and

you mentioned the kidney and the

anti-diuretic hormone um roles but

within the brain like what brain areas

have neurons that make vasopressin well

or have the receptors for I mean The

receptors are all over are all over the

brain and again it varies depending on

the species and you know the way the

receptors are measured or in postmortem

tissue right which can be very difficult

to get good samples right and so we need

to have that caveat going in um but yeah

I mean it's it's made in the

hypothalamus um and it's released all

over the brain and there is vasor press

and receptors all over the brain right

and um what's really interesting about

vaser press and I always sort of joke

that oxytocin you know always saw its

day in the sun if you will and the

vasopress was sort of the stepchild that

was like left you know sort of behind

and and the reason why I find this

fascinating is again like I think back

to my you know my my roots as a you know

evolutionary biologist behavioral

neuroscientist and what was interesting

is that there were studies in the early

to mid 1990 showing that vasopressin was

critical for male social behavior and so

um there was work you know there was a

variety of people and I I think Rob

Minka mentioned this on his on on the

podcast he did about you know there's a

a group of people like Sue Carter Larry

young Tom inso some of these early

people and they gave Vasa pressen to

male Prairie voles and V

vasopressin was what induced um pair

bonding um with a a female mate and also

paternal care and and as I recall those

experiments were done in the context of

looking at um polygamy versus monogamy

of these Prairie VES um Prairie VES

versus like a different species so same

um genus but a different species so it

might be a Montaine V or you know highly

related but these other species so

Perales are monogamous the males uh well

I mean that was the 50% divorce right

yeah that was I don't think it's that

bad but I think they're doing better

than we are as a species that's true we

should look to them for pointers and all

the divorce folks are saying wait why'

you say better I have some divorce

friends that have said divorce is like

the greatest thing so we always say like

doing better doing worse right um anyway

that's a whole other podcast um and

certainly not the hubman Lab podcast but

or maybe it is but um or will be but

yeah my understanding is is that you

have certain vs that mate with almost

exclusively with one other V for their

entire lifespan and then you have other

vs located elsewhere um that in those

colonies they mate with lots of

different well so the males and females

have lots of different partners um rais

young with lots of different partners

mating with lots of different partners

and that if you give Vasa presson then

you can make the I was want to call them

polyamorous but I don't know if they

love each other I'm going to answer for

more and assume they love each other the

polygamous moles not polyamorous but

polygamous moles 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

vs right which are the Prairie VES and

they were the ones that formed these

monogamous parir bonds dad participates

in paternal care with Mom they co- ra

babies together and then Dad chases off

Intruders right and then there's the

more Ace social vs and so these are like

the Montaine VES um and um we'll we'll

see it's a complicated story but there's

these Montaine vs where um males and

females live separately females like

maybe live on the male's territory the

male mes with a few different females

absolutely doesn't provide any paternal

care at all mom raises babies by herself

right so that's these are really the

like 1950s versus 2020s yes yes to be to

to broadly stereotype to broadly

stereotype and if you give okay so for

Prairie voles they're sort of primed to

form bonds and to be the males to be

good daddies 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 mate they cohabit for a bit

there's been all kinds of parametric

studies I I can't remember how many

hours it takes to form a parabond um but

then you can do these things called

partner preference tests 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 their

partner the Montaine BS you know either

after meting with somebody May either be

equal or maybe they'll even go spend

time with the new individual so the

cleanest story was that Prairie voles

are monogamous Mont voles are not

monogamous but in the prairie vs you

could give vasor pressen instead of

mated cohabitation and you could turn on

a like you know a bond with somebody

after only living with them for a very

short period of time right um or you

could induce paternal behavior and I was

working with a V species in grad school

I think the most interesting scientific

experience that I've ever had right and

you and I both know this right when

you're young you're actually the person

doing the work right as you become you

know the head of your lab you're mostly

writing grants and giving talks right

and then you get to hear about the super

cool things that every in your lab is

doing right eventually the the members

of your laboratory kick you out of the

lab they literally say like get out of

here you're leaving things in the wrong

place whereas initially you're telling

them hey that's in the wrong place

within a year or two for me I think it

took about four or five years but by

about year six right I was um demoted to

my office to just write grants and write

Pap I was told that one time I was back

there and I tried to waigh and I was

like so excited what they were working

on and they basically just said go write

grants and bring in more money right

like 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 um 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 meadowes and I found them very

interesting so when I showed up in my

thesis advisor lab she I said I really

want to study oxytocin and vasopressin

and I really want to study VES and I

know you have a v species and she said

why I don't have prairie vs I have these

meow voles and I'm studying them because

they're so sensitive to light and they

changed their behavior based on light

and I 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 short

day lengths or long day lengths so the

mimicking some um summer and winter and

I was noticing that on winter day

lengths the 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 I we should probably explain

what those are putting a little

transmitter um under the skin it's

painless for the animal but that allows

the researcher to um monitor the

behavior of the animal remotely without

having to you know put them in cages and

stuff so and so this is like under field

conditions and vs are everybody's

favorite snack so they have like a very

limited lifespan 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 collapse and males

are found with females and they co- ra

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 or

they're going to die because they're

going to freeze to death right so I

started saying like wow I think these

metales are good dats like I'm noticing

this and so I told my thesis adviser I

want to study how oxytocin invasor press

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 um I was able to

put Vaso pressent directly into their

brains and 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 Vasa pressin is

this really interesting hormone um and

maybe someday I will I did a postto on

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 um

relatively negligent fathers into very

attentive fathers yes yeah it was

fascinating right that I mean it just

speaks to the power of the peptide baso

pressent also speaks to the power of

brain circuitry it also speaks to the

idea that brain circuitry is often

sitting latent 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 and that

peptides can act like switches um which

you know kind of makes sense on the one

hand but um I've never heard of a result

as dramatic as that so

um I'm presuming you're going to tell us

that that then LED you to go back to

vasopress and explore its ability to

induce good parenting and negligent

fathers I haven't studied that yet um no

well so I think that you know my mom

always says Chance favors the prepared

mind and so I was doing my postto 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 uh a bunch of

stuff going on so there were a lot of

very dedicated parents who were lobbying

for funding for autism research because

it was horrifically underfunded really

horrifically underfunded wow I mean at

rates of one in 36 well not at the time

right so it was it was 1 in 150 or

whatever it was back then but there were

all these parents and and I I mean again

they're heroes in my eyes that they ad

ated 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 um

and then there was a man named Jim

Simons who runs um one of the most

successful hedge funds in the world and

he decided wow I'm gonna you know

there's let's put money into autism

right and so does he have a personal

link to autism I you'd have to ask him

because often times not always but often

times when you hear about um wealthy

donors um devoting a lot of money to one

area of science there's there's a

familial thing there you know a member

of their family or a close friend has

this Challenge and they 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 will say

is the most impactful work I've ever

done is through philanthropy right there

are crazy ideas that no funding agency

ever touches right um but yeah so they

put they both put um a lot you know

there there was a lot of emphasis and so

because the s's Foundation started

issuing requests for applications there

was a group at Stanford that formed and

it was um um a clinician with a basic

scientist and my chair at the time said

well you know almost nothing is known

about the biological basis of autism why

don't you go I'm going to introduce you

to the 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 were a core

feature of autism I thought wow you know

these neuropeptides May really be you

know um a part of this puzzle and so

that's actually really how I got pulled

into um autism research was was through

that and it was I I was you know

everybody at the time was very

interested in oxytocin and you know I

remember thinking so we actually did

probably the most definitive blood

oxytocin um 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 um and what we were

able to show was that blood oxytocin was

not a marker of autism right so it

wasn't like there was a bimodal

distribution meaning two completely

nonoverlapping levels of oxytocin in

people with Autism people without autism

so the lower your blood oxytocin levels

um actually regardless of who you were

you could be a child with autism you

could be an unaffected sibling with

autism or you could be a unrelated

control child and it was the lower your

blood oxytocin levels the greater your

sort of social difficulties and the

slopes you know were different they

started at different points because the

behaviors were obviously different but

that's what got us thinking about our

clinical trial which is that blood

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 subgroup who could

benefit from treatment but what I like

so much about your approach the way you

described it is that it it sets aside we

don't we don't want to say discards but

it sets aside this thing that we call

autism yeah which is already hard to

Define and diagnose and there's all

these different spectrums and you're

trying to F 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 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 way relate to those Social

Challenges right and then one can Circle

back to the question about autism in

collecting those data but it also points

to this idea that like when we when we

go after a disease like Alzheimer 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

symptomology yeah and try and attack

that and you might actually potentially

treat or cure multiple diseases it's a

very different approach and I I hope um

people are catching on to the the

subtlety but also the the the potential

impact of that um because if I heard

correctly you said there are people who

are not autistic who have social

functioning deficits and they too have

less circulating oxytocin right so I

would say we haven't studied people

where we brought them in and

characterized it right so these are

typically developing kids but what we

did is in the abilities that are typical

of a controlled child we still saw that

gradient right and so I think it just

sort of begs the question about you know

what is oxytocin's role in human

sociality right I mean I think there's

just so much that we don't understand

about both of these molecules um in

terms of their disease liability if

they're low or their healing potential

if we are you know able to use them as

modulators um of other

therapies so how did you move from

oxytocin to vasopressin um you mentioned

that everyone was was all excited about

oxytocin still the one that we hear the

most about yeah although after this

podcast episode and when I start

blabbing about vas oppress to everybody

um you know maybe that'll change but

it's I think it's going to take a lot

more than that but um maybe it's because

the name isn't as 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 like not anti-erotic

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 we'll we'll come

up with a new name I it's needed right

well I'll put it out there um uh okay so

how did you get to vas oppressor 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 um and so I

actually came at it from the work that

we did in monkeys and so I think I

mentioned previously at 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 I was thinking

about what are what are things that we

need to do to better address the

challenges in autism so one of them was

why are we looking in blood right like

if you look at neurological conditions

there's been a lot of progress made by

doing biomarker Discovery in cerebral

spinal fluid right so like the the

biological substrates or or clues of

markers of say um various forms of

Dementia or um or MS were for first

found in spinal fluid right because it's

the it's the fluid that bathes the brain

in the spinal column and so if you're

looking for the bio chemistry of an

illness that's the closest fluid that

you can get to the brain right so blood

draw just won't do it maybe right so

that was part of my thinking but then

there was the issue of the animal models

right so there was drug after drug after

drug that was tested in mice and they

failed in human clinical trials and so

it made me start thinking could we

develop a primate model um of naturally

occurring social impairments right so

can we because in autism these social

impairments are if you will naturally

occurring right and so you know this is

these spontaneously occur in children um

and so it made me wonder could we

identify monkeys in a large Colony that

have social

impairments in and after talking to to

clinicians who who treat these children

can I spend a lot of time validating a

monkey model where there will be monkeys

that have features that look like they

have direct relevance to core autism

symptoms um and so what I did was

there's a um primate Center the

California National Primate Research

Center and so what we did is so I think

I mentioned earlier that there's these

surveys 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 to use this rating scale in

reesus Max which are an old world monkey

and I know you're familiar with them and

um and I was interested in looking at

Old World monkeys because they're some

of the closest relatives to human that

are used in biomedical research and and

um as I mentioned previously these

autistic traits are continuously

distributed across the general human

population and that this

genetic uh say let's call it 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 in one of our closest

relatives and we think that some of

these genes create proteins that then

are what sets up the developing brain to

develop in the way that autistic brains

develop so let's just assume that that's

the premise that's what we went with can

we find reesus maacs that are just

living in large outdoor colonies and

identify animals that might be good um

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 um score monkey behaviors outside

their cages while they're interacting

with their peers we can use rating

scales and again the rating scale we Ed

it's called the social responsiveness

scale so this is called the MAAC social

responsiveness scale revised it's a

mouthful um 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 monkeys

you know if they're making affiliate of

overtures do they um do like you know

you know ma goo which is a a positive

response well they do that right I I um

I'm going to apologize for interrupting

you again but I just have to tell people

this because I spent time up at the UC

Davis primate Center as 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 uh

exclosures not enclosures large

exclosures um forming colonies and

social relationships and um you know I

think anyone that sees monkeys at the

zoo and we all learn that monkeys go and

they don't if you want a monkey to like

you you learn this working with macx um

first of all they don't the affiliative

call is

a they do this really nice and the

little ones the babies I spend a lot of

time with these monkeys and the little

ones they do this thing where they go I

used to I used to nurse the little ones

every once in a while they and they're

just you know just like makes your heart

melt I think 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 affiliative 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

is so if you see a monkey at the zoo and

you want it to pay attention to you

you're going to have to lip smack and if

it doesn't either you're not doing it

right or it just doesn't like you

exactly right great all right thanks now

we'll go back to the uh the study of uh

or the establishment of this really key

experiment right so then what we did is

we identified these these animals and we

spent a lot of time so one one of the

things that I do as one of my areas of

expertise is validating animal model so

a lot of like I mentioned like a lot of

reason why experiments fail 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 best thing to do

in a nocturnal species that has old

faction as its primary sensory modality

or you're referring to mice right or is

it better you know and again I will say

all models have value there's all you

know there's reasons you just have to

you know you basically have to stand by

what you're modeling and so I think one

of my the biggest issues I have with a

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 for

Parkinson's today but it's for

depression tomorrow right and so so my

goal was to to devise very specific

tests that would allow us to evaluate

you know core features of autism in this

model and the answer is we found it

right so if you you look at monkeys that

spend a lot of time alone they have a

much greater burden of autistic like

traits measuring on this rating scale

they have diminished social motivations

so other monkeys will come up and

interact with them but they don't engage

in um social overtures them that much

themselves they do less grooming less uh

affiliative um behaviors um they in some

of the work that we're doing they don't

lip smack back and we can talk a little

bit about that we did a pharmacological

probe and we can talk a bit about what

vasor press does to that which is kind

of exciting um and so we spent a lot of

time validating this behavioral

phenotype right to say that we really

feel like there are are core aspects of

it that are allowing us to model autism

right um and I have a paper which if you

want to put it in it's all about

creating this monkey model and and and

the power of of doing it and where it it

took us clinically we will provide a

link to that in the show note captions I

also just want to um throw up my vote

for the the fact that you did this work