Dr. Casey Halpern: Biology & Treatments for Compulsive Eating & Behaviors | Huberman Lab Podcast #91

welcome to the huberman Lab podcast

where we discuss science and

science-based tools for everyday life

I'm Andrew huberman and I'm a professor

of neurobiology and Ophthalmology at

Stanford school of medicine today my

guest is Dr Casey Halpern Dr Halpern is

the chief of neurosurgery at the

University of Pennsylvania School of

Medicine his laboratory focuses on

bulimia binge eating disorder and other

forms of obsessive-compulsive behaviors

normally when we hear about eating

disorders or obsessive-compulsive

disorders of other kinds the

conversation quickly migrates to

pharmacologic interventions and

serotonin or dopamine or talk therapy

interventions many of which can be

effective

The Halpern laboratory however takes an

entirely different approach while they

Embrace pharmacologic and behavioral and

talk therapy interventions their main

focus is the development and application

of engineered devices to go directly

into the brain and stimulate the neurons

the nerve cells that generate

compulsions that cause people to want to

eat more even when their stomach is full

in other words they do brain surgery of

various kinds sometimes removing small

bits of brain sometimes stimulating

small bits of brain with electrical

current and even stimulating the brain

through the intact skull that is without

having to drill down beneath the skull

in order to alleviate and indeed

sometimes cure these conditions today's

discussion with Dr Halpern was an

absolutely fascinating one for me

because it represents the Leading Edge

of what's happening in modification of

brain circuits and the treatment of

neurologic and psychiatric disease for

instance they just recently published a

paper in nature medicine one of the

Premier journals out there

entitled pilot study of responsive

nucleus succumbings deep brain

stimulation for loss of control eating

the nucleus that Cummins is an area of

our brains that we all have in fact we

have two of them one on each side of the

brain that is intimately involved in the

release of dopamine for particular

motivated behaviors and while most often

we think about dopamine for the release

of behaviors that we want to engage in

in this context they are using

stimulation and control of neuronal

activity in nucleus accumbens to control

loss of control eating something that

when people suffer from it despite

knowing they shouldn't eat despite not

even wanting to eat they find themselves

eating so again this represents really

the Leading Edge of where Neuroscience

is going and certainly is going to be an

area of Neuroscience that's going to

expand in the years to come and Dr

Halpern and the members of his

laboratory are among a very small group

of scientists in the world that are

using the types approaches that I

described a minute ago and that you're

going to hear more about in today's

episode in order to resolve some of the

most difficult and debilitating human

conditions during today discussion you

will also learn about the use of deep

brain stimulation and other approaches

for the treatment of movement disorders

such as essential tremor Parkinson's

disease and various types of dystonias

which are challenges in generating

particular types of movement so whether

or not you or somebody that you know

suffers from an eating disorder from

obsessive-compulsive disorder or from a

movement disorder today's episode is

sure to teach you not only about what's

happening in those Arenas but also in

the Arenas of Neuroscience generally in

fact I would say today's episode is

especially important for anyone that

wants to understand how the brain works

and what the future of brain

modification really looks like for all

of us 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

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and now for my discussion with Dr Casey

Halpern Casey I should say Dr Halpern

listening welcome thank you great to be

here yeah it's been a long time coming

we were colleagues at Stanford and then

recently you moved of course to

University of Pennsylvania also an

incredible institution we're sorry to

lose you so it was better sweet for me

too Stanford's loss is upenn's gain but

um let's talk about your work uh past

and present

as I've told the listeners already

you're a neurosurgeon which I consider

the astronauts of Neuroscience because

you're in somewhat Uncharted Territory

or very Uncharted Territory and yet

Precision is everything right the

margins of error are very very small so

for those that aren't familiar with the

differences between neurosurgery

neurology Psychiatry you just educate us

a bit what does a neurosurgeon do and

what does

fact that you're a nurse surgeon do for

your view of the brain how do you think

about and conceptualize the brain

yeah the scope of neurosurgery is quite

broad uh when I was in medical school I

I was drawn to neurosurgery because of a

procedure known as deep brain

stimulation when I was at Penn as a

college student I actually watched my

first deep brain stimulation surgery

performed by Gordon boltuck who to date

is one of my career mentors

deep brain stimulation is a one surgery

that neurosurgeons offer but it's

actually sort of

a very small minority of what

neurosurgery does

you know we take out brain tumors we

clip aneurysms in the brain

we take care of patients that have had

traumatic brain injury concussion spine

surgeries ninety percent of what

neurosurgeons do around the country uh

you know taking care of herniated discs

and lumbar fusions so you know the scope

is

the entire central nervous system

include including the peripheral nervous

system we take care of patients with

carpal tunnel syndrome and nerve

disorders

now over the course of the past two

decades or so there's been a a mission

in the field to to sub-specialize and so

historically neurosurgeons did

everything in that domain but now we

sub-specialize and I'm lucky to be at

Penn Medicine where we can focus on one

of these areas so I'm chief of

stereotactic functional Neurosurgery

all I do is deep brain stimulation

surgery and a compliment to that is

focus ultrasound or transcranial Focus

ultrasound which is a non-invasive way

to do an ablation in the brain recently

FDA approved and it's FDA approved for

Trevor at the moment uh these two

procedures are for me my every day but

uh still the minority of what

neurosurgeons have to offer the majority

of neurosurgery in my mind is is a bit

more structural than it is

physiology or

deeply rooted in how the brain functions

when we take out a brain tumor we have

to find a a safe trajectory to get to

the brain tumor and then we remove it

and we help the patient recover in the

ICU similar to a brain aneurysm often we

don't have to go into the brain to clip

a brain aneurysm but we go around the

brain or under the brain to get there

and in my mind those surgeries are a bit

more structural

deep brain stimulation the surgery that

I do routinely is a procedure where yes

there is structure involved of course we

have to place a a very thin wire that's

insulated deep into a part of the brain

that's involved in Parkinson's disease

for example uh

but that's actually not the therapy the

therapy is delivering electrical

stimulation through the tip of that wire

or one of the tips as there actually are

multiple contacts at the bottom of the

wire they're very small

uh

but that's all done out of the operating

room you know this stimulation wire is

connected to a a battery pack or a pulse

generator that's kind of like a

pacemaker and so we deliver this therapy

and I always tell patients it's a bit

more like I have to implant a uh a tool

to deliver you a medication but that

medication is going to be in the form of

electricity and it's going to be

delivered into a very small region of

the brain and it's that procedure that's

inspired me to not just become a

neurosurgeon but has really defined the

focus of my research laboratory as well

Maybe by way of antidote you could tell

us one of the more outrageous or

surprising or who knows um delightful

and thrilling things about the brain

that you've observed as a consequence of

stimulating different brain areas you

know in textbooks we always hear about

uh the kind of dark stuff you know

stimulate one brain area somebody goes

into a rage stimulate another brain area

a person starts laughing uncontrollably

first of all

um given that some of the information

let's hope not much but some of the

information in textbooks is incorrect is

are those sorts of statements true can

one observe those in the clinic and what

are some of the more interesting uh and

I don't necessarily mean entertaining

but

um surprising things that you've seen

when you've poked around in the brain

deliberately of course and uh

what have you seen what have you heard

I have to say I I am amazed by these

effects uh every day yeah I'm very

privileged to be able to interact with

the human brain in this way it's always

in them with the goal of trying to

provide somebody with a meaningful

therapy but when we deliver electrical

stimulation

you know the these electrodes while they

might be sitting in a very small region

of the brain there are regions

within a few millimeters of where these

electrodes are that if stimulated could

cause a temporary very brief side effect

a moment of laughter like you said or a

moment of panic and of course we can

just shut that electrode off but often

these side effects could be therapeutic

and actually that's how we have

discovered ways to use deep brain

stimulation not just for movement

disorders like Parkinson's disease but

for example patients with Parkinson's

disease that have a psychiatric uh uh

comorbidity like depression or

obsessive-compulsive disorder a lot of

these patients are highly compulsive and

impulsive

sometimes these problems actually melt

away and we're trying to help their

Tremor but the patients also tell us

that their gambling issue has gotten

better or their mood has improved and

why is that well you know there's

probably more than one reason you know

you can help somebody's Mood by making

their Tremor go away of course but we

see laughter in the clinic sometimes and

and why is that and that's because we're

stimulating parts of the brain that are

not just involved in these motor

circuits but they're also involved in

what we call a limbic circuit or part of

the brain involved in emotion and if we

learn how to modulate those areas

therapeutically step by step we can

actually develop these therapies for

other indications like depression I

would say the most impressive and

consistent effect we have when we have a

patient with Tremor who has been

tremming for the past 20 years if we can

deliver stimulation through that

electrode in the clinic we have

immediate relief of Tremor and that is

the effect that inspired me to be a

neurosurgeon when I was in college I've

never really wanted to do anything else

X accept help develop that type of

therapeutic for another another kind of

symptom I'm very interested in obesity

and related Eating Disorders compulsive

Behavior the urge to uh to to have

something that might be delicious but

dangerous or unhealthy or a drug or a

compulsion like we see in OCD or pests

of compulsive disorder uh interestingly

like we see Tremor melt away when we

deliver electricity to a certain part of

the brain we can see these psychiatric

more psychiatric problems they're not

all psychiatric disorders but let's say

disorders of the brain we can see

symptoms of those disorders also improve

and often immediately just like we do

with Tremor so I see it all the time to

to pick out one uh would be would be a

challenge because for me this is my my

everyday

the speed of the relief that you

described for Tremor is really

um incredible just thinking about drug

therapies and there too there are side

effects but they're still a lot of

mysteries as to for instance why ssris

even work when they work

and the timing is always

a challenge timing dosage yes absolutely

um I'd love to learn more from you about

OCD I I have several reasons for asking

this first of all I'm a somewhat

obsessive person I tend to be very very

narrowly focused although I confess it's

not a step function it takes me some

time to turn off the chatter but once

I'm into a thought train or a mode of

being uh and thinking and work it's very

hard for me to exit that that mode it's

like a deep Trench

adaptive in some circumstances less

adaptive than others as you know the

other is that when I was a kid uh I had

a little bit of a grunting tick I used

to I had a this intense intense desire

to clear my throat

um to the point where my my dad said

like you need to stop that he used to

squeeze my hand every time I do it and I

used to hide in the back seat of the car

in the closet to do it because it

provided so much relief and then it

eventually passed yes I wasn't medicated

they never did anything about it every

once in a while now if I'm very fatigued

if I've been working a lot I notice it

starts to come back I'll do this like

kind of grunting and so it's been sort

of like a pet neurological symptom for

me that reminds me that these these

circuits exist in all of us and that

sometimes they go haywire and sometimes

they just have subtle um you know over

excitation or something of that sort and

then the third reason is that I get

thousands of questions about OCD could

you perhaps just tell us what is OCD

sure um what are some brain areas

involved what are the current range of

treatments and

what's the difference between someone

who is obsessive and somebody who has

true OCD

so a brief disclosure as a neurosurgeon

I do take care of patients with severe

obsessive-compulsive disorder

um but my perspective on OCD may be a

little bit different than a psychiatrist

who who lives and breathes OCD and sees

patients every single day with OCD I'd

probably take care of a three to five

patients a year with deep brain

stimulation for obsessive-compulsive

disorders so I don't see these patients

as routinely but my laboratory is geared

as a researcher I'm very focused on

trying to improve outcomes of deep brain

stimulation for for OCD so I do feel I

have expertise and and a perspective to

share but just a brief disclosure I

I do feel that as a neurosurgeon I am

obligated to better understand where the

obsessions in the brain come from and

how we can interrupt them to stop the

compulsion that's associated with the

obsession

sort of the intrinsic

most feature of OCD uh better than we're

actually doing it for example if we were

to offer a patient with Tremor deep

brain stimulation surgery of course

there's some risk to the procedure but

the outcome is so consistent and

positive that many patients are willing

to take on that risk

uh for obsessive compulsion compulsive

disorder the

surgery risk is about the same however

the benefit is not quite as robust

and so a lot of patients and they're

referring psychiatrists are reluctant to

refer these patients to us and it's

completely understandable uh I've been

leading an Endeavor with a number of

collaborators around the country to try

to

better understand these circuits in the

brain uh study them in humans both

invasively and non-invasively that would

be with an electrode-based surgery sort

of like we do at epilepsy to understand

where seizures come from we want to

understand better where obsessions come

from but we're also working with imaging

experts and geneticists to understand

OCD at a broader level as well

uh I I consider OCD to be a a spectrum

disorder in a way uh and I I apologize

to those who who might feel that I'm

using that term incorrectly I'm using it

in a way to describe

patients that have obsessions and even

some related compulsions might not meet

criteria for OCD it may be something

Andrew that that you have and as a

neurosurgeon I'm really obsessive about

safety and compulsive about my surgical

procedures so you know I I think that

some aspect of OCD which we often joke

about but we should you know consider

seriously because people do suffer from

this uh some aspect of it helps us there

are you know famous uh CEOs that

probably have some level of OCD uh

surgeons and scientists alike so perhaps

if it can be controlled it's an asset

and uh but if it goes awry and is

uncontrollable then it becomes

obsessive-compulsive disorder and I tend

to see the patients that are the most

severe so they have failed medication

and there are multiple medications that

are worth trying for OCD some can

actually be very helpful which

neurotransmitter systems do they tend to

poke at well ssris are sort of the the

first line for OCD but also tricyclics

can be helpful so this is still the

serotonin system but as we know the

serotonin system interacts with the you

know neurogenergic system and the

dopamine system so it's hard to

be specific to one of these things and I

think that's also why it's hard for us

to predict how these medications are

going to to work for these kinds of

patients but tricyclics and ssris can be

very helpful and are definitely first

line and there's others exposure

response prevention is uh probably the

most effective option which is kind of

like cognitive behavioral therapy but

these are different and offered by

psychologists and this is a whole field

and there's a a field or I should say a

whole clinic at my institution

focused it was started by Edna foa

at Penn who

this is what they do for these patients

uh is offer these types of cognitive

therapies exposure to the stressor and

to try to get patients to habituate to

whatever it is that stresses them and

causes these uh compulsions to help

these patients live in every day and

function these are all fabulously

helpful therapies for a variety of

patients but there's still about 30 of

patients that still suffer from OCD and

some of them have severe OCD sometimes

it's moderate to severe and those are

the patients that I'm really motivated

to try to help

um our therapies for those patients

right now I would say are are worth

pursuing but not optimal

um and so it's it's one of those things

that we have to balance as a researcher

because when you see patients like this

you want to do everything you can to

help them and I think it's important to

educate patients on the risks and

benefits of them this is deep brain

stimulation surgery but also capsulotomy

which is more of an ablation approach a

little bit like deep brain stimulation

but rather than delivering stimulation

through an electrode you can actually

heat the tissue and even destroy it some

would say this part of the brain is very

safe to destroy it's kind of like an

appendix

um others would say it's safer to

modulate I have seen patients do very

well with these ablations and so you

know you asked me earlier what what I

find so amazing about the brain these

effects that we can have sometimes the

lack of effect is what's so amazing you

can actually

Traverse parts of the brain without

having any adverse effects on patients

function at least that you can test but

you can also destroy small parts of the

brain we're talking three or four

millimeters in size these little

ablations can be really helpful for

patients but have no obvious side

effects that we can tell perhaps after a

short recovery from surgery but

nonetheless despite how safe they might

be these surgical procedures still are

surgical procedures and patients are

hesitant to perceived especially when

they know that their chance of a

transformative effect is quite low we

can generally

achieve a responder rate of about 50

percent and responders still have

symptomatic OCD so I'm really uh sort of

inspired to really find a way to deliver

these therapies in a more disease

specific or symptom-specific way but

we're years away probably from from that

therapy since it's all part of a

research study at the moment

what brain areas should I think about

when I think about OCD years ago I

remember opening a textbook I think it

was an undergraduate still and work from

Judith Rappaport at the National

Institutes of mental health this would

be late 80s early 90s was

um had done some neuroimaging or maybe

it was pet

or some other Imaging technique and had

identified portions of the basal ganglia

sure caudi putanum type structures in

OCD and maybe some differences in boys

versus girls so what brain areas are

there sex differences in terms of OCD

and were one to

come into your clinic this you know for

this sort of a work of ablations or

stimulation uh where would you first

start to probe in the brain yeah you

this is a uh

a disorder of both cortex and the Sub

sub cortex uh

the cortical control areas areas that

are involved in inhibitory control we

have found to not function properly in

patients with OCD so areas like the

orbital frontal cortex and the

prefrontal cortex if you image these

areas or study them even in a a rodent

model of OCD which quite honestly these

models they model aspects of OCD but OCD

is a human condition you can't really

model this whole condition in a in a

mouse or a wrap but perhaps you can

model compulsive behavior in a rat sure

and pulling out their hair yeah exactly

you know that's that's not necessarily

obsessive compulsive disorder but that

is compulsive behavior and perhaps if

you can ameliorate that in a rat that

might be helpful for a patient with OCD

but we have to approach animal modeling

of OCD thoughtfully uh and and most

scientists do I think uh when we study

OCD in in models or in in humans with

imaging and and we're trying to do it

invasively with with electrodes like we

do in epilepsy patients

we find that areas in the cortex like

the prefrontal and orbital frontal

cortex are are not functioning they will

the way they would in a non-oc patient

they are often hyper functioning uh such

that while you might say Well they're

hyper functioning so aren't these

patients you know functioning better

that hyper focused yeah hyper focused

exactly

um no I I would say it's it's not so

much an up or down it's more that

they're just dysfunctional and we need

to find a way to try to restore normal

function to these areas it's not so much

directional really

um we tend to oversimplify brain

function by thinking about it with

directionality too much

um unfortunately Imaging studies

sometimes demonstrate activation or

hypoactivation and that's where I think

these kinds of things can be

misconstrued but what I would call the

cortical areas of OCD is that they're

dysregulated and we need to find a way

to try to normalize their function so uh

the frontal lobe is is huge but areas of

the frontal lobe that are a bit more

basal like the ofc or orbital frontal

cortex and the prefrontal cortex

definitely consistently seem to be

implicated in patients with OCD and then

their projections to the subcortex this

is the basal ganglia like you were

saying caudi putamen or the dorsal

striatum and these are interconnected

with the ventral striatum this is an

area of the brain that I uh focus a lot

of my energy in um this is the

ventralstratum which is not limited to

but includes the nucleus accumbens this

is an area of the brain that we know to

be involved in gating reward seeking

behavior when it's perturbed it seems to

gait compulsive Behavior meaning a rat

will pursue a reward despite punishment

despite a foot shock for example and

that can be uh similar to an OCD patient

they will

um check their home for safety until 3

A.M in the morning and not sleep that

night in a way that is similar to a rat

seeking out a food reward uh despite a

foot shock

um doing something because of the urge

but despite the risk and perhaps there

is some normal

judgment there we all have to take risks

to function in everyday Society to be

successful we have to take a risk

to take care of patients with surgery

there's some risk there we make a

judgment call and that's not a condition

that that's just normal but when our

judgment is consistently sort of puts us

at risk that's where we have something

like OCD but OCD is also you know it's

one of many conditions that suffer from

these kinds of problems we tend to label

them because they tend to present in a

consistent way so we have patients with

OCD that have hyper checking Behavior or

contamination Behavior where they if

they feel contaminated they'll wash

their hands for hours repeatedly or if

they drop their toothbrush on the floor

this will lead to a compulsive behavior

of cleaning a toothbrush or brushing

your teeth consistently very very common

symptoms that we see or signs that the

patients report to us or or that we

observe

but you know patients with eating

disorders they tend to if if they have

binging disorder they'll overeat if they

have bulimia they might Purge despite

the risk of these things and so um

addiction is is similar we we tend to

drug seek if we're addicted

um uh we'll we'll pay off a dealer uh in

order to get our fix and despite the

risk and and that type of urge despite

the risk is something that I I've always

been really interested in and it's a

common denominator to all of these

problems and if you think about these

problems I mean these are some of the

most common conditions in our society

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to get the five free travel packs and

the year supply of vitamin D3 K2 I

really appreciate that you're building

this bridge from OCD to nucleus

accumbens which is of course associated

with reward in various forms and we'll

get to that

um I'll share a personal anecdote as a

as a form of question when I was in

college and studying a lot I relied on

caffeine as a stimulant I've never

really been into drugs or alcohol I've

been Lucky in that sense I don't drink

and I care less if alcohol disappeared

never really liked recreational drugs so

I was never drawn to them

however when I was in college at the

time there were these little epinephrine

pills that were common in a lot of

sports supplements these are like

pre-workout type things yes not unlike

energy drinks now which I completely

avoid

um and I had this experience of taking

one of these and drinking some coffee

and of course it gave me a lift in

energy these are very similar to

amphetamine they were legal over the

counter at the time they're now either

banned or illegal I do not recommend

them and I had a lot of energy but what

I noticed is that my grunting tick came

back and I had I made one mistake I

still think of this as one mistake which

was

um I engage in a superstitious Behavior

I knocked on wood and then somehow it

felt very rewarding like it gave me some

totally irrational but internally

rational sense of of security around I

forget what I was knocking on wood about

and I found that I couldn't break that

knock on wood compulsion I felt I needed

to knock on wood and so then I started

sneaking knock on Woods like in mid-exam

and studying and pretty soon I was

knocking on wood often I developed a

superstition

and so I'm curious about the role of

superstition and compulsion in the

crossover there it makes sense logically

to me but I was equally shocked to learn

that when I stopped taking this

stimulant which I was quite happy to to

stop because it did make me feel too

alert couldn't sleep well Etc

that the Superstition went away as well

and I'm guessing this has something to

do with some of the reward circuitry as

it's called related to stimulants

again

I am not encouraging anyone to take

stimulants although healthy use of

caffeine or safe use of caffeine might

be the one universally accepted

stimulant

um it was really surprising to me how

quickly this came on how quickly it

engaged my my thinking and my behavior

the obsessions and the compulsions and

how quickly it turned off when I stopped

taking this Sports stimulant or whatever

it was I don't even remember I think it

was some form of epinephrine ephedrine

sure some saw epinephrine excuse me I

misspoke ephedrine

um

is what I described sound totally

outside the bounds of of uh logic or or

am I imagining at all um no it did

happen I'm certain it happened yeah no I

don't think you're imagining it at all I

you know this the grunting that you you

mentioned to me you know first of all I

didn't uh comment but you know that that

sort of not to put a label on it but it

sounds like a tick and you know ticks in

in young males extremely common and they

do tend to go away linking to like since

I have a good friend who actually a

famous neuroscientist I won't mention

who it is who's worked very hard to

suppress his his blinking tits and when

he gets fatigued it comes back and and

um he's very high functioning yes in his

personal life and his professional life

but but when you're talking to him and

he starts doing this so you kind of

start wondering like what's going on

yeah yeah and it's unfortunate you know

people with these problems especially as

they get more severe then you get

Tourette Syndrome you know it's hard to

function in our society I have some

friends that have Tourette I'll tell you

I I'm just so inspired because there

there so

um they're so confident and you know

people obviously notice these problems

but they they just live their life and

they're very successful and that's not

typical

um I have I have friends that I went to

Penn with undergrad that had these kinds

of problems and I was always just so

happy and inspired by them but what's

more typical is uh you know these

problems cause people to

lose their confidence and and not you

know uh pursue you know their profession

as they may have done or

um things of that nature so I I think

it's all related to the fact that we our

brains are very vulnerable and to get

back to your question about the

stimulant you know I think I think your

brain was very vulnerable to it you know

you you sort of may have had a

predisposition to it

um you mentioned that you have you're a

little obsessive and with the tick there

maybe you have this kind of you know on

the on the mild side of the spectrum OCD

um and I I probably do as well by the

way so I also also have avoided drugs

for that reason uh in my life I'll drink

a little bit of wine here and there but

that's about it

um and uh but I I think most people

don't avoid these things and we see

these problems in relation to not just

taking a stimulant but any kind of

environmental exposure our own Society

causes so much stress

um and that's why I think we have these

human conditions these are human

conditions we try to model them in in

animals but most animals don't have

these kinds of problems you know I've

heard that you can a an animal like a a

monkey in the wild can have depression a

monkey's version of depression but I

don't think it's really typical or human

depression you know and certainly it's

not as prevalent as depression is in our

human society I think you know we

haven't evolved to manage the stresses

that are in this society that we

currently have and stimulants is

probably one of them you know and I I

suspect you are probably a little bit

vulnerable

um it's possible the stimulant led to an

overdrive of your prefrontal and orbital

frontal cortex and even brought out a

little OCD Behavior related to this

super uh this Superstition that you had

so um no I believe that entirely and I

also think you know that's why things

like OCD and other kinds of psychiatric

disorders tend to present themselves in

college when people leave their home and

they're in school and they're stressed

and they're getting exposed to things

that they haven't been exposed to before

outside of the home and and you know

their brains aren't evolved and

sophisticated enough yet to help them

cope with these kinds of stresses and

how it manifests is in these kinds of

conditions and it's I don't want to put

a label on those conditions but

certainly could be a psychiatric

disorder but could also just be lots of

anxiety it could also be the kind of

problems that you had as well so um and

I think the nucleus accumbens and the

cortical areas that we've been

discussing that that sort of send

projections to these areas are are

probably at least one of the main

circuits involved in these kinds of

things

I'm relieved it's no longer present but

I confess it oh I always feel it close

by a long run helps so move you know

being a slightly fatigued not overly

fatigued but slightly fatigued seems to

move out the the kind of physical

compulsion but try to channel it um

never taken any medication for it then

here I am so I'm still still going I may

call you for a referral at some point

but sure at this point I'm uh I'm

feeling okay

um let's talk about nucleus accumbens

and reward circuitry and the

relationship between OCD reward

addiction uh and to just give you a

sense of where I'm headed with this is

into the realm of a food related and

eating related uh

behaviors and disorders because I know

you're doing some very important work

there what is nucleus accumbens I know

we all have one or two

um one on each side of the brain what is

it what roles does it play

um in healthy brain behavior and in

pathology

yeah the nucleus accumbens is a part of

the brain part of our reward circuits

The Hub of the reward circuits that I've

always been most fascinated in

um

there are scientists around the world

some of the leading arguably some of the

leading scientists in the world the

father of addiction Neuroscience I call

him

um although he tells me I'm nuts Rob

malenka who has studied the nucleus

accumbens since the beginning of his

career and who I worked with when I was

at Stanford

um fabulous scientist and Mentor taught

me so much

um taught the world so much incredible

person scientist and phys and Physicians

yes MD PhD and uh brilliant in both ways

and um very

fatherly in a lot of way in terms of

teaching people how to how to do science

and and be good citizens as well

um

but uh

the nucleus accumbens is an area that is

also very complicated because it has a

lot of functions uh

it it interconnects with many parts of

the brain

um

but there are some things about the

nucleus accumbens that are very

consistent uh

so when I started getting interested in

reward and what a what I could do as a

surgeon to try to improve how we manage

Rewards and what I mean by that

specifically is if you have an urge for

a reward

that that's a normal phenomenon that's

not something we're trying to stop the

issue is if you have an urge for a

reward that either puts you or somebody

else at risk it's probably a reward we

shouldn't have I suppose you could say

well it depends on the size of the

reward and the size of the risk and how

that fits into your societal Norms

um but for example if you're obese and

you have a doctor who is advising that

you lose weight and try to control your

eating habits uh you know perhaps better

food choices is an important way for you

to be healthier and and not pursuing

those better food choices that's an urge

that we probably need to treat

uh if you're a drug addict and you use

heroin or opiate considering the opiate

crisis right now or cocaine

which is untreatable at the moment uh

you know that that cocaine might make

you feel

like you have some more energy that day

to deal with your work or that opiate

might make you feel better because life

is stressful but the risk of doing those

things is really high in fact

potentially lethal uh so that's an urge

that's treatable if you have OCD and you

can't sleep at night because you're so

nervous that you didn't lock the door

and you've checked 30 times

that's a reality for some people with

severe OCD

um that's an urge we got to treat

eating disorder is the same eating

eating disorders and obesity are

obviously linked because of the

relationship of a patient with food but

they're also quite distinct not

everybody with obesity has an eating

disorder and obviously not everybody

with an eating disorder has obesity I'm

particularly interested in patients that

have binge eating disorder as well as

obesity because they're so heavily

linked

but not everybody with binging disorder

has obesity but on average most are

overweight

um we are doing a deep brain stimulation

trial at Penn where we're trying to

modulate the nucleus accumbens and

understand it better in patients that

have failed gastric bypass surgery the

most aggressive form of treatment for

obesity and we and we believe they

failed gastric bypass surgery because of

binge eating disorder meaning they just

can't control how much they eat so their

obesity is either related or even due to

overeating not some predisposition to

um that body habitus you know obesity is

a phenotype something that we can see

not everybody is obese because of the

same thing so it's very important I was

taught this by a close mentor and friend

Tom wadden when he was the director of

the Obesity Center at Penn or the center

for weight eating disorders

and and he said to me you know Casey uh

you know be careful with obesity you're

interested in addiction and I understand

you're interested in the addictive

Tendencies of certain patients with

obesity uh

uh and and their relationship with food

but not everybody with obesity has that

problem and and in fact it's it's

probably present about 20 of patients

with obesity

but now taking a step back twenty

percent of patients with obesity is

still a massive problem of epidemic

proportions and perhaps some of these

patients have either some form of

binging disorder or or I should say some

degree of bingeing disorder uh or at

least loss of control eating which is

common to both

um so that's a feature that I think

eating disorder experts obesity experts

neurosurgeons

obesity

obesity medicine experts would agree is

common to eating disorders and obesity

and I also believe would is common to

addicts and perhaps patients with OCD is

sort of a loss of control disorder

um it's actually not a disorder known by

like the DSM-5 some diagnostic manual

but a feature I should say of these

conditions that's common and that common

denominator I believe can be

restored or at least this problem can be

ameliorated or improved upon by a better

understanding and a tailored treatment

to the nucleus accumbens specifically

we've learned in mice that if you expose

a mouse now this is just a model if you

expose a mouse to high fat food not food

that they would normally eat food that

is like 60 fat high fat it's like butter

um

we've learned that if you expose them to

food like that within two weeks their

nucleus accumbens is not functioning

like a mouse that was never exposed to

that high fat food there's aspects of it

that are hyperactive I could say and

there's aspects of it that are

hypoactive or decreased activity but

either way it's it's not functioning

properly and most likely that function

is predisposing continued behavior and

then probably eventually leads to things

like a habit that gets developed and

that's a whole nother area of these

kinds of problems that is very

complicated and poorly understood but in

any case if we just focus on the

behavior at hand

it seems that repeated exposure to

something like high fat food

a drug of abuse or any type of reward

that is a really strong reward in a way

it can hijack normal functioning of the

nucleus accumbens so the goal of our

invasive trial is to try to restore

normal functioning to that nucleus

accumbens uh in mice there seems to be a

signal that predicts when they're going

to lose control and we can use that

signal to deliver a sort of a real-time

therapy in the form of deep brain

stimulation just a brief amount of

stimulation and that actually blocks the

behavior

and what's interesting is over time that

signal actually decreases in frequency

which suggests some level of restoring

normal function to that circuit in the

mouse and we're trying to do that now in

a human trial

fascinating where is the stimulation

provided because I would imagine if one

were to stimulate nucleus accumbens you

would see a reinforcement

of whatever Behavior coincided or

preceded the stimulation so the

stimulation it's a a brief delivery of

stimulation anywhere between 5 and 10

seconds

that is intended to just disrupt the

perturbed signaling that's happening in

the nucleus accumbens

there are disorders like

depression let's say that I I would

describe as a bit more of a state

disorder and this is obviously

oversimplified because we know that

there's fluctuations in mood and

depression as well so don't let me

oversimplify it too much

um but

um but but for now let's forgive the

oversimplification if we if we accept

that depression is a state disorder or

maybe Parkinson's disease is a state

disorder recognizing that they do

fluctuate

uh these types of problems most likely

not but not definitely most likely need

a continuous therapy of some form a

therapy that's consistent uh perhaps a

therapy that fluctuates with the

condition but nevertheless still

consistent

um

binge eating disorder or OCD or

addiction

um and binging disorder in the context

of obesity a lot of these patients are

functioning quite normally every single

day it's just that intermittently

throughout the day there's brief

interruptions in their normal functions

such that they have thoughts about food

or the drug of abuse that they're really

longing to have

and so we want to deliver a episodic

therapy delivered

at the right time and only at the right

time

to try to interrupt the

circuit aberration or the the problem at

hand that is going to lead to that

dangerous behavior and to kind of get

the patient back on track to what

they're doing

um

I don't necessarily think that it leads

to a reinforcement it's possible we have

to study that more but rather the goal

is to just disrupt perhaps what is kind

of Habitual

um or or at least this kind of recurring

problem that is happening you know

people that have bingeing disorder at

least at a severe level they tend to

about once a day

but they don't binge all day long of

course they have a moment perhaps when

they get home from work and they're

stressed where they might

have a bout of binge what constitutes a

binge and I also want to know does binge

eating disorder come on suddenly meaning

as an entire disorder one day

people wake up Suddenly they have

binging disorder or is this you know a

few too many buffets and I'm being

entirely serious here you know kind of

unlimited food and a circuit gets

flipped or kind of starts moving into

the high RPMs so to speak

um so how does it come on and um I mean

I'm actually surprised to hear that it's

once a day I would think just hearing

binging disorder I assume it's like OCD

which it probably fluctuates across the

day as well but I would have thought

anytime people around food they just

simply can't control their intake of

food yes so so what does this look like

in terms of the onset of the disorder

and then what do you think underlies

this once a day type of phenomena that's

pretty interesting yeah so severe

binging disorder these patients will

binge about once a day it could be a

couple times a day but in general it's

not more than that moderate is about

three to four times a week for example

the reason I think that that seems

surprising to you

and

if you think about it it is surprising

but but

um and I agree with you but the reason

for that is is actually just in the

definitions of the word

and as a neurosurgeon in full disclosure

as I as I mentioned you know I don't see

these patients clinically I see them for

research trial purposes and I try to

understand the literature around eating

disorders and I obviously collaborate

with fabulous Eating Disorders uh uh in

in these problems that are that are

highly Innovative people

uh but the word binge is a definition

there's a definition to that word and

you can't necessarily binge all day

because our stomachs are not big enough

um and so uh there's a limit to how much

one can eat and to meet criteria for a

binge you have to have a sense of loss

of control

you have to eat an enormous amount of

food in a brief period of time

and yes generally that doesn't happen

more than about once a day in a patient

with severe binge eating disorder uh

however they can lose control quite

often and in fact perhaps even at every

meal they might meet criteria for about

a loss of control where they yes they

may have lost control but they might not

have eaten enough

to constitute what we would Define as a

binge

um and that would be a there's no

specific number to that by the way it's

it's really just compared to their

normal meal you know perhaps it's uh 50

of their daily calories in that one

brief moment

um so uh that's that's why I think it

seems surprising that binders aren't

happening more often than that what I

would say is if we replace the term

binge with loss of control eating loss

of control eating Could Happen dozens of

times a week

um and in fact you know the patients

that we're studying you know we've we've

seen patients that lose control 20 30

times a week and that's probably the the

term you have in mind when you're saying

you're surprised that it's just one time

a day and it's specifically related to

the fact that these patients have to eat

such a large amount of food in such a

brief period of time

um so it's hard to do that more than

once a day I see

um you mentioned that some pre-existing

anxiety might bias somebody to have a

binge

I'm also fascinated by something I've

observed before which was when I was in

college my my girlfriend had a roommate

who we were aware was bulimic and would

binge and then Purge and often uh when

she ingested alcohol that would lead to

a binge sure which is kind of the

opposite of anxiety when I think about

alcohol as something that slightly

reduces prefrontal activity somewhat of

a sedative or certainly a set of higher

dosages

so this brings to something that you

said I'm just gonna I won't say it as

eloquently as you did that it seems like

it's not neither the case that anxiety

leads to binging nor that hypo reduced

activation of the forebrain and lower

anxiety leads to binging it's this

dysregulation of circuitry that the the

Seesaw could go either way and it can

throw things off it's off balance in

both cases yes uh it's uh and that seems

to be a that seems to pose a problem it

seems like it's a particularly tricky

problem and kind of explains to me in my

non-clinical awareness why medication

might be really hard to use as a way to

treat this but that being able to poke

around in the brain and assay in real

time you know how do you feel do you

feel like binging now or do you feel

um further from the binge impulse

is that what you do with these patients

are they awake while you're stimulating

the brain because it's one thing to say

I stimulate a brain area and the binging

goes away or partial relief or complete

relief but how do you know are they in

there with a donut

um and you're tempting them so how do

you actually know if it's ablating a

brain area is going to lead to uh relief

or exacerbation or no impact on on this

disorder

yeah so uh there's a lot to unpack there

um I'll try to go one step at a time and

if I miss something please remember no

and I tend to ask these three-part

questions specifically of neurosurgeons

because I like to challenge you guys

because again you are the astronauts of

Neuroscience also I'm just going to take

a moment to poke at neurosurgery because

I have a couple close friends

um who are neurosurgeons and I consider

Casey Randy I don't know if he considers

me a friend but of course I am a friend

I'm teasing there too which is first of

all they all have incredible hands right

they have I'm not they all guard their

hands with the kind of

um uh protection that you would guard

the the tools of the most important

tools of your trade so they're very

careful with their hands you're not

going to see them doing heavy deadlifts

you're not because of the way that

impacts the motor neurons it's all about

fine control yes um so if your

neurosurgeon does heavy deadlifts you

might want to consider getting a

different neurosurgery I hope I didn't

put anyone out of work there and then

the other the other thing is that

um

you all are tend to be very calm people

at least on the exterior we'll return to

this later okay

um but I do throw three or four

questions out at once so so elevated

autonomic arousal and alertness as well

as decrease autonomic arousal and

alertness both seem to be able to lead

to binging and then there's this

question of how do you know whether or

not to stimulate or to ablate or whether

or not to leave a structure alone in

other words what does one of these

experiments look like in the laboratory

yeah sort of a clinic excuse me yeah of

course yeah these are questions I think

about all the time

um and um

I do want to come back to the

deadlifting comment but I

um

regarding and you and you referred to

this earlier as well and I don't know if

I've addressed it sufficiently either is

is sort of like what what comes first

here or how does this develop

um

I I think first of all I

I like to understand these kinds of

problems in in sort of the the construct

of what I I consider to be a bit of a

two-hit hypothesis

um so you sort of need like in the

concussion literature you need the

second hit is can be devastating so if

you have a concussion you know you want

to only return to play when your

symptoms are gone uh and cleared by a

physician

um

so uh in the context of Eating Disorders

or let's say binge eating disorder first

of all I I didn't mention earlier but

this is the most common eating disorder

affects anywhere between three and five

percent of the population wow

um and it's probably

under-diagnosed in obesity by the way

and if obesity affects 35 of our

population most likely binging disorder

affects more than three to five percent

but that's that's the current uh

literature uh estimate on on the

prevalence

so um how do we develop a gene disorder

and is it related to this anxiety

question

um

you know I think that there is a

predisposition that's the first hit

um

I actually think all humans have this

predisposition just some have it more

than others

um I don't think that we've evolved to

live in a society where

foods are so readily available and

enormously delicious and have so much

sugar and fat in them not that there's

any particular problem with either of

these macronutrients it's just the

excess of it and how they're refined uh

that I think is the problem

um

you know those high fructose corn syrup

in almost everything we eat we it's in

bread I don't even know why it's in

bread sometimes it's just kind of crazy

so so I don't I don't think we're

evolved to live in a society

um

that that has food that's so readily

available like that

um and cheap by the way in fact the

cheaper the foods are sort of the the

more refined and palatable and I would

argue dangerous to eat I think they

change our reward circuits for the worse

um and put us at risk for wanting more

um

I tend to get a headache when I eat food

like that and and perhaps that's uh

evolutionary Advantage because I don't

want to eat those Foods because they

actually do make me sick

um

so um in a lot of ways I kind of wish

that headache on everybody because

perhaps we wouldn't have all these

problems uh or at least some of them

would go away

so I think that's the first issue is a

predisposition to

uh or a vulnerability to these types of

foods

um which we undoubtedly all have to a

certain extent but some more than others

and then and then and that's so that's

the first hit

is this predisposition in the context of

this sort of food focused Society

and then the second hit is

probably a stressful event or a

stressful life

um and probably a recurring stressful

event I'm not sure this is published

I've never sat down with like a eating

disorder expert and and had this

question about how this develops and I'm

not sure it's actually well well known

um

but in a lot of ways I think that that

answer anybody would agree with that we

need sort of a predisposition in the

exposure the environmental exposure and

the genetic predisposition

um

but also a stressor and that stressor is

probably one that's recurring and you

know it's obvious in our society these

stressors are everywhere and how we can

manage them is is often poor and you

know I think we can all relate with that

and then there's something else in the

background that I think is really

important to mention is that patients

with these kinds of problems are

embarrassed because our society doesn't

think fondly of these kinds of patients

you know binging disorder patients they

do tend to be overweight that's

obviously a stigma obese obesity is

another stigma then there's the opposite

in a way it's an opposite by the way for

a phenotype standpoint is that anorexia

I mean that's another stigma and you

know gosh you know

not to make this about one sex over

another but when when girls are told

they're pretty because they're thin it

just reinforces this problem and of

course you want to complement people and

make them feel good about themselves but

the problem is that in this vulnerable

society that that can lead to problems

because people start thinking oh I

should be thin or thinner

um so I

I think that it's a little bit of a

societal understanding that our brains

are very vulnerable and I think that

will really help changing Society is

hard and most of society is not you know

ill meaning uh it's all done by accident

um but that is the society that we live

in so if we can try to improve that

stigma uh and and be kinder to people in

that way I think a lot of these problems

would get better people that are obese

that feel embarrassed by their obesity

it doesn't help it only makes it worse

because they give up

same thing might be true for anorexics

so I really think it's important to

consider all of these things and that's

why it's so complicated and it would be

so hard to do a well-controlled study to

understand it better because there's so

many of these variables to control for

that you really can't control for you

might be able to control for them in a

mouse's home cage but not not in the

society that we live in so

so that that's kind of my brief uh sort

of summary of how I would answer your

first question then I think you know

your second question I I sort of take

that as well how do you

study such a complicated problem in the

operating room and and in the clinic

because I mentioned the operating room

because that's sort of the first step

here first we want to we have uh just to

clarify we have a nih-funded uh trial

approved by the FDA for for research to

do this first in human study

um we've treated two patients we have

four more to come at Penn in um

and in this study uh it's something I've

been working towards my entire career

what we don't know is

where in the nucleus accumbens

will we identify

cells or

regions that seem to be uh

involved in this sort of reward seeking

Behavior I would call it a peditive it's

kind of like appetite but the word

repetitive is I think a a good word to

use what part of the nucleus Cummins is

repetitive is the whole thing repetitive

probably not it's huge in my world it's

huge as a neurosurgeon you know I Target

parts of the brain that are three or

four millimeters in size the nucleus

accumbens is almost a centimeter in size

wow I didn't realize it was that large

yeah it sort of like reminds me of

discussions around the amygdala everyone

thinks amygdala fear but Miguel has got

a lot of different sub-regions and

stimulation of certain areas of the

megdala makes people feel great that's

right another stimulation of other

errors makes them feel terribly afraid

exactly and that shouldn't surprise us

because you know when we treat patients

with Parkinson's disease for Tremor you

know if we're in one part of the

subthalamic nucleus will help their

Tremor if we're in another part of the

subthalamic nucleus the neurologist is

looking at me like why isn't this

working and that shouldn't surprise us

we already know that you know two or

three millimeters deviation or two or

three millimeters away from where we

want to be and you might not have the

result you want and that's probably also

true for these more limbic structures

like the amygdala and the nucleus

accumbens uh so you know regarding the

nucleus accumbens we Traverse some of

the nucleus accumbens not all of it in

order to place the electrode that we

want to use to

detect when Cravings are happening for

example and to try to block the Cravings

from leading to the behavior related to

the the reward seeking which is the

overeating in this case

uh

so what we decided to do in the

operating room was

to actually try to leverage a tool that

we use all the time when we take care of

patients with Parkinson's so with

Parkinson's these a lot of these

patients not all have Tremor and so when

we place an electrode into this motor

structure

to try to improve their movement

disorder we often can hear Trevor cells

and they sound we convert their

electrical signal to an audible signal

so we can actually hear it

um and it sounds kind of like the Tremor

looks like the frequency of the signal

is the same as the handshaking

exactly and so the the patient with

Parkinson's is is Trump trembling Yep

they're awake and you're poking around

in a in a dedicated careful way of

course one poke at a time one poke at a

time with a very fine wire a set of

wires listening to the electrical

activity until you

you encounter some cells that are

sending out electrical activity that's

right at a similar frequency exactly and

then you can stimulate them or quiet

them and see if the Tremor goes away so

we we are very confident that when we

stimulate that area of in this case the

subcollamic nucleus uh

we will make that Tremor we will disrupt

that Tremor circuit and that Tremor will

dissolve and it does that's why

Parkinson's is so beautiful and

inspiring and uh from us retractable

yeah exactly but what is the it makes us

feel we understand the brain right at

least in that limited way so what is the

um analog to Tremor in terms of appetite

and desire to binge craving

so craving is a term that you know

there's probably other terms we could

use by the way but that that's the term

we've chosen to use for a number of

reasons one because people relate with

that term people that have binge eating

disorder or obesity they if you ask them

if they crave the answer will often be

yes

um if you ask them if they lose control

or binge they might not know what you

mean or they might not actually feel out

of control even when they are

um so uh but the word craving is

relatable and so we set out to see if we

could identify craving cells

um in a patient with OCD which is

related in fact we target a very similar

part of the brain

we tried to identify

cells related to obsessions and we

believe we did do that it was a single

case study uh where we tried to optimize

where our electrode was placed so we had

some proof of concept that we would be

able to elicit a sort of

disease-specific symptom in the

operating room assuming the patient

could tolerate being awake not everybody

needs to be awake for this procedure but

at least for these first and human

trials where

um we're trying we're trying to

establish where in the brain we need to

be uh I think this type of approach is

really critical and you know

by the way none of this has been

published uh but I think it's so

important for people to know this so I I

am willing to share some aspects of what

we're trying to do

um but uh but that's that's really the

first goal of this trial is to identify

where the nucleus accumbens we can

detect these craving cells so we have to

provoke food craving in the operating

room that's the first thing how do you

do that ah well um there are some uh

somewhat validated ways to do that so

for example we asked patients to provide

pictures of food that they rate very

highly as something that they would

typically crave and you know depending

on the patient it might be something

that's very salty it could be very sweet

like a donut

um oh that's very good I love donuts

right Donuts are great you should you

should try the Cronut when you're here

in New York City I just might I try not

to eat that sort of thing for all the

reasons

just try to stop yourself after that one

so if I were one of these patients given

the fact that uh the binges come on

pretty seldom once a day do you you I

imagine you have them come to the the

operating room fasted or semi-fasted

they're faster okay they're fasted which

probably they're probably surgical

reasons for wanting that too they kind

of have to be right and then you they've

you've done the craniotomy removed a

patch of skull yes you've lowered the

wire into the nucleus accumbens and then

they are viewing pictures of food that

they crave and thinking of about it do

they have olfactory cues smells of

cronuts yeah I would love to do the

olfactory because we haven't implemented

that but that is a great uh thank you

for and I'll give you full credit when

we do review the grant but it sounds I'm

so glad this work is funded because I

mean this is what I I'll make this time

it's not a joke when I refer to you all

uh you neurosurgeons uh as the

astronauts of the brain you know this is

out on the

extreme edge of what we don't know about

how the brain functions and this is so

far and away different than giving a

mouse access to a high high fat food not

that I'm not being disparaging in the

mouse work but so the person says

well I'm the patient in this case so I

might say you know I'm hungry a donut

sounds really good right now but craving

to me is like I you know I'll cross the

street cross town be late for my meeting

eat three of these yes maybe even hide

that from somebody that cares about me

that doesn't want me doing this this

kind of thing hide it from myself yes

these kinds of behaviors I'm projecting

and I'm fortunate that

um I I have cravings for things in life

but uh Donuts are not among the more

extreme of them so

um so this is all happening in real time

and you're listening to the cells the

same way you would listen to it and

search for Tremor cells exactly same

exact tools and you're doing that by

um recording from a small population of

cells in the area yeah in fact we do get

multi-unit activity which is multiple

cells uh but we really try to find one a

single unit to listen to one neuron yeah

because it's just um much easier to

understand what that one neuron is doing

versus trying to listen to and we also

measure local field potential recordings

but those are analyzed which is more of

a population response thousands of cells

kind of a porous of cells exactly

um that we measure offline

um the device that we use to

um

sort of treat these patients or

intervene uh that we're studying it

can't do single unit recordings it's

only doing these more population

responses so we correlate what we see in

the operating room at the single unit

level to the population response but we

do that all offline

um I can explain that in a moment uh

but yes so we we try to identify these

craving cells and uh because this is a

feasibility study

um and we can't

you know be in the operating I'm

searching for hours and hours and hours

we do have some sort of we have

guidelines that we've set for ourselves

that we've uh developed with the NIH or

the FDA to make sure that what we're

doing is feasible and safe as well

um so we we will spend a limited time

trying to identify these uh craving

cells but another

uh sort of um strategy that we think is

really important is

um the effect of the stimulation so a

lot of patients and this gets to sort of

your question earlier about what kind of

what comes first

um you know a lot of people when they

when they binge or they lose control

over food

um or seek drugs that moment of

vulnerability is preceded by

what we call a a moment of sort of

pre-meal negative effect which basically

means right before they binge they're

feeling down or they feel stressed or

anxious

and they compensate for that momentary

symptom by binging or losing control

over food not everybody needs criteria

for a binge so I try to specify that we

are we are looking at loss of control

eating specifically just because the

Criterion of a binge is not as critical

for us

um

so um so what we want to be able to do

is trigger stimulation when this craving

is detected by the device uh

but we trigger it only when the craving

is there and we believe that if we can

sort of

temporarily Elevate their mood ever so

briefly again this is about five to ten

seconds of stimulation only that perhaps

that elevation in mood could actually

sort of

disrupt the

craving to binge cycle

maybe that's a habit maybe it's not but

if you crave and then you binge if we

can interrupt that with this moment of

feeling good

that might be a really good therapy for

a patient and in fact

when we do deep brain stimulation for

obsessive-compulsive disorder we can

fairly reliably induce a positive affect

the problem is that it's not sustained

and the reason it's likely not sustained

is because with obsessive-compulsive

disorder we treat that condition with

continuous stimulation

and it's not surprising that over time

the effect kind of goes away so when

they're in the clinic and we turn the

device on our patients feel great and we

feel like we've solved the problem

but they call us the next day and

they're like you know my my depression

came back or my OCD hasn't gotten better

and my moods back to where it was can

you can you get it back to where it was

yesterday because that felt great the

brain loves homeostatic regulation it

does and it does not like to shift

patterns regression to the norm right

um and I think there's sort of a

tolerance effect there

um that uh is is limiting the effect of

continuous stimulation and actually in a

mouse if you do continuous stimulation

um the the sort of blockade of binge

eating goes away so actually in a mouse

we've actually demonstrated

um we published this not too long ago in

pnas that if you deliver stimulation

intermittently and only when sort of a

craving signal is detected so to speak

um

that that X that effect will be the most

robust and durable

um but if you deliver it continuously

actually the benefit goes away over time

so I've always encouraged my colleagues

to consider more of an episodic

stimulation approach rather than

continuous deep brain stimulation but of

course that that's for these more

episodic conditions whereas these more

quote unquote State disorders uh as I

oversimplified earlier they might need

more of a continuous therapy so that's

definitely subject for a lot of research

in the future

um so in any case um the goal in the

operating room was to identify a craving

cell

um deliver stimulation safely but also

to capture a moment of elevated mood we

were able uh to do that as we we are in

our OCD patients as well

and also to get an interoperative CAT

scan we have devices now in the

operating room that allow us to get

Imaging in real time they're fabulous

tools that we didn't have 10 years ago

so we can confirm accuracy

um you know where the you can see where

the electrode is exactly precisely

exactly

um you know with 0.5 millimeters of air

so super precise uh or as precise as we

think we need to be

um and we use connectomics so there's a

tool in brain Imaging called

tractography where we can actually

measure circuit connections it's it's an

indirect assay but we believe it's

powerful it has its uh assumptions but

um like anything in in science but we

could actually

map out where the nucleus accumbens

connects to the prefrontal cortex sort

of the cortical control inhibitory

control pathway and where that pathway

intersects with the nucleus accumbens

and we can Target that area

um structurally so those three goals of

the surgery we we aim to set up to

accomplish and we believed if we

achieved two of those three that we

would have a successful result in our in

our early trial

amazing

given that at least to me the

non-clination that anorexia is the

mirror image of binge eating disorder

and at least from what I learned one of

the more deadly psychiatric conditions

yeah um but also quite common yes

um

is it possible that nucleus accumbens

this

so-called reward circuit is also

involved in anorexia but somehow it is

the resistance to eating the craving of

the fasted state or something like that

that's being reinforced and and I asked

this for two reasons one because I'm

genuinely curious about anorexia of

observed anorexia in a number of people

that I know and it's a striking thing to

see somebody just resist food despite

all

better knowledge of the fact that

they're getting quite ill maybe even at

risk of death but the other reason is

that

if in fact nucleus accumbens is the site

which can Harbor cells to promote

craving and craving of fasted States so

to speak then that I think might tell us

something fundamental about how the

brain works which is that structures

don't control functions per se

structures control dynamics of

interactions sort of like a

Orchestra conductor has a certain number

of operations that they perform but

really their main function is to

coordinate the actions of a lot of

things not to make sure that the violins

always play in a certain way alongside

the oboes you can tell I'm not a

musician here

I actually have an appreciation for the

openings yes those usually get left out

what's that the obos yeah they usually

get ignored my partner plays the elbows

oh yeah so yeah I think it's a great

analogy by the way

um

you know I I make this statement it's a

little controversial but I actually

think people would understand where it's

where I'm coming from

um across all of these sort of

sub-specialties of medicine uh but I

actually think especially with obesity

remember it's a phenotype that's

reflective uh often but not always of a

behavior

um but if you consider patients that

have obesity and they they exhibit some

sort of compulsion towards food so they

they overeat despite the risk of it I

think those kinds of patients are more

similar to anorexics than they are

different

um anorexia and obesity are both

phenotypes that are at least in this

specific case of obesity and in anorexia

a result of a compulsion to either over

or under eat despite the risk these

types of compulsions are driven by

societal pressures

brain vulnerabilities that are probably

more similar than they are different

they just happen to manifest differently

why they manifest differently is

probably related to each predisposition

or perhaps preference that's hard to

know like you I have a personal

connection to these Eating Disorders

anorexia included and uh yeah I think

it's um

it's very scary and it's a condition

that

often instills fear in psychiatrists

because I think you know not not

everybody by the way I mean I have some

phenomenal psychiatrists that I work

with both at Stanford and at Penn

they're also involved in my obesity

study that take care of these patients I

mean these are heroes but there's a lot

of psychiatrists that are not in this

domain that find anorexia scared for the

reason you said it has the highest

mortality of all psychiatric conditions

that includes depression because not

only can these patients die of suicide

but they die of metabolic complications

of being underweight

um so it's a uh it is it is a scary

condition I I relate with that I am

trying over time to bridge what I'm

doing in obesity and binging disorder to

atorexia for two reasons one because I

think these problems are more similar

than they are different and two because

of the need

um and I think we're well positioned to

sort of tackle anorexia

um using similar approaches not

identical but but similar approaches um

the nucleus accumbens has been studied

in patients with anorexia in China

actually my postdoc my first postdoc who

I had the honor to train uh when I was

at Stanford as a neurosurgeon in China

when before he came to me actually was

involved in a trial of anorexia that had

some benefits

um and uh there's studies in Europe

um and elsewhere that have examined

preliminarily uh the effects of deep

brain stimulation targeting the nucleus

accumbens uh for anorexia colleagues of

mine in Canada Andres lozado is a

wonderful neurosurgeon scientist has

been studying the effects of going after

Area 25 which is directly connected to

the nucleus accumbens by

um you know it's a monosynaptic

connection so in a lot of ways you know

perhaps delivering stimulation there

could could be very similar to

delivering stimulation with nucleus

accumbens it's all part of one critical

inhibitory control circuit he's seen

benefits as well

um

so I I definitely think there's some

evidence that this is an area that we

need to be studying

um I think our more episodic approach

with response to stimulation going after

sort of a signal in the nucleus

accumbens that seems to be related to

the compulsion to withhold from eating I

think is what we will be trying to

accomplish uh in our study it's a

right now just being conceived though uh

yeah these studies they move so slowly

because you have to get a grant that

Grant gets reviewed by the NIH six

months after you submit it often gets

rejected because it's too Innovative and

too high risk so then you have to edit

it and decrease the risk so it takes by

obesity so it took two years to get

funded

and I worry about that time frame

because that's a lot of time for

patients with anorexia to suffer that I

might be able to help at least in a

small sample of patients so

um but that that is the nature of how

these things go you also have to get FDA

approval to do these kinds of things we

try to do all of this in parallel it's

an enormous undertaking and in a lot of

ways we're starting from scratch but in

some ways we have some preliminary data

to go after this so my hope is in about

a year we'll have a similar trial for

anorexia at Penn so so more to come on

that

um and and we're not the only lab that's

trying to go after because of the the

clear need so what is the status of

non-invasive brain stimulation ablation

and blocking activity in the brain I get

a lot of questions about transcranial

magnetic stimulation yeah I've actually

had that done as a research subject sure

when I was at Berkeley Rich Ivory's lab

put a coil on my head I was tapping my

finger in concert to a uh a drum beat

and then all of a sudden uh because of

the stimulation it was impossible for me

to keep time yes with the drum beat

that's cool cool it's a pretty wild

experience to not have motor control and

uh than to have motor control returned

at the flip of a switch when someone

else is controlling the switch it makes

it especially Eerie

um so my understanding is that

transcranial magnetic stimulation is

being used to treat depression and a

number of other brain syndromes

non-invasively so no no drilling through

the skull the surgeons don't like that

surgeons love to cut and drill with

purpose but they do

um but uh my understanding is that the

spatial Precision isn't that great

um ultrasound is something I hear a lot

about these days

um and my understanding is that

ultrasound can allow researchers and

clinicians to stimulate specific brain

areas perhaps with more Precision

um maybe you could just give us a

coverage of what those are being used

for what are your thoughts on on um uh

these forms of non-invasive meaning no

no flipping open of a piece of the skull

type brain stimulation and blockade of

brain activity sure yeah I wanted to

clarify also these these surgeries

generally don't

um by the way require a full craniotomy

it's usually just a small opening about

the size of a dime in the bone so just

just to clarify but that's painless too

right uh well usually without pain yeah

there's a little bit of scalp numbing we

give a scalp block and the patients are

getting IV sedations so they in general

don't feel anything and if they do they

tell me and we give them more local

anesthetic but that's they're usually

asleep during that part so it's

minimally invasive but you know in a lot

of ways there's no such thing as a

minimally invasive procedure in the

brain you know it's a it's kind of so

glad to hear you say that oh no I you

know I'm I'm not one of those

neurosurgeons that you've probably

encountered and we have mutual friends

that uh and you know these mutual

friends are some of my favorite people

in neurosurgery and they probably

actually think more like me than than

not but there are neurosurgeons that

you're absolutely right and this is true

for all surgeries they really

in a lot of ways they think what they do

is sort of the ground truth or is it

closer to the ground truth and I I get

that

um uh you know probing with purpose I I

actually really like that I'm going to

use that if you don't mind

um just it's just describing what you do

so yeah but I I actually have I've

always said this I've said it publicly

I've said it to my boss I've said this

to my team

um we need to embrace non-invasive

approaches

um

some of them are a little fluffy

um fluffy in that we don't understand

how they work

we don't necessarily understand how deep

brains too much works by the way so

um but because we don't know exactly how

they work

they're not as precise as we would like

them to be so we have work to do there

and I actually think that work is doable

and actually underway

um you know at Stanford we have great

collaborators that that I think are

doing this people like Nolan Williams

and Connor Liston at Cornell and others

um so we uh I think that

TMS transcranial magnetic stimulation it

is FDA approved for depression by the

way it's also FDA approved for OCD and

for nicotine addiction where do they put

the coil for those three or more or less

yeah so they put it over was always on

the scalp and uh over the frontal lobe

and there's different parts of the

frontal lobe that have been demonstrated

to be a little better or a little bit

worse

um but what the FDA has approved for

depression I believe is uh similar to

what's been approved for uh OCD but for

addiction I believe it is a different

Target but we'd have to ask our our TMS

experts on that can they direct the

transcranial magnetic stimulation deep

below the cortex they try uh and we're

we're actually studying this in OCD

patients now

um I as a part of our invasive trial uh

where we are trying to pull patients

from a TMS trial that's in parallel to

what we're doing

um all funded by the foundation for OCD

research

where we believe we can use TMs to to

define a circuit that if modulated

improves OCD albeit temporarily and in

those patients if it's temporary they

would be appropriate for an invasive

study so something we're actively

working on I've always believed that

neurosurgeons need to be part of the

discussion with these non-invasive

approaches we don't need to do them but

I think we can help make them more

precise and to probe non-invasively with

purpose

rather than this more kind of

I don't know a non-invasive blast effect

kind of you know

I I just can't imagine how that is going

to be as effective as probing with

purpose but you can do that not

invasively as well and I think we need

to do better uh in that way I do believe

that's possible and I think people are

actively trying to do it

um getting deep in the brain with TMS I

think will always be hard but you can

get there indirectly by using

connectivity assays and targeting

superficial structures that have

High connectivity to deep structures so

for example

um perhaps one day there will be a TMS

Target for anorexia and obesity

if we are scratching the surface with

invasive approaches to these problems

we we're even doing less with the brain

stimulation

um so we have so much work to do there

eating disorders and TMS have been so

um sort of scarcely studied or or there

have been so such little research done

in that in that space and so it is an

area that we need to to work on

um for the obvious reason for example in

a patient with anorexia just thinking

practically you know placing a device in

a patient who is significantly

underweight might not be the best

approach you know wound erosion and

issues like that could come up so

developing a non-invasive approach I

think is critical the problem is where

do we target

and so the only way to answer that I

think reliably is to accept that we have

to get into the Brain before we're out

of the brain and with these kinds of

conditions we're only just starting to

get into the brain you know so I I worry

that we're a long way away from a

non-invasive approach that really works

consistently

um sorry to interrupt um I want to make

sure we touch on ultrasound because yes

um but um his

historically it seemed that there was a

bit more permission for people to probe

around in the human brain I I've um

sometimes refer the podcast to some of

these papers that were done uh allowing

patients to self-stimulate in the brain

these are work done in the in the 60s

and now his name Escapes Me Robert

um anyway there's a couple papers

published in science allowing patients

to stimulate a couple different brain

areas asking which ones they preferred

and I was always shocked and slightly

intrigued by the fact that the the brain

area that all three of these patients

who I don't think had any syndromes I

think they volunteered for these

experiments I don't think you could do

this anymore yes um regulatory yeah yeah

I think uh was not the same as it is now

things have changed

um fortunately but they

um all three of them seem to like some

midline thalamic structure which for

those listening it's just area kind of

in the in the dead center of the brain

um more or less that evoked a sense of

kind of frustration and anger which

surprised me because I would have

thought oh it's Robert Heath his

experiments rather than patients

preferring to stimulate areas that evoke

laughter or Joy or a feeling of

drunkenness or Delight it also explains

a lot of what I observe in social media

this sort of um kind of people

repeatedly engaging in battles

um that are kind of trivial it seems

like frustration and anger might have

its own reward circuitry anyway I don't

want to go too far down that rabbit hole

but it

um it's a deep one it's a deep one and

and kind of gets to our nature yeah you

know as humans and what we find

interesting or rewarding but you know

the ability the inability to probe

around the brain in a safe way without

the need for somebody to be very sick

would be I think would be enormously

powerful and at least in my mind if I

were in charge which I'm not

um would offer the opportunity to really

come to an understanding about how the

human brain works without all these

issues of how to translate from Mouse

studies and again there's huge value to

animal studies as we both agree but

um so many of the things that we want to

know about the human brain involve

asking the person hey do you what do you

feel when that set of neurons is

stimulated and what don't you feel uh

and a mouse we can ask and ask but

they're not going to tell us something

they do tell us they're not going to

tell us in English so

um how do we overcome this challenge but

first

ultrasound or if you prefer after

ultrasound what is ultrasound going to

be really useful towards solving these

clinical issues and these basic issues

yeah so I think

um

let's start with ultrasound then we'll

come back to it um so ultrasound right

now

transcranial magnetic

magnetic resonance guided Focus

ultrasound so

um uh this this is an FDA approved

method

to

deliver an ablation to the brain

non-invasively

there are researchers myself included

that are trying to use transcranial

magnetic guided magnetic resonance

guided Focus ultrasound or MRI guided

Focus ultrasound

to use it in a modulatory way not just

as an ablation but to drive neuronal

activity or inhibit it perhaps we're

still learning how to do that

um there are trials that are trying to

understand if you can use ultrasound to

open the blood-brain barrier so you can

deliver a medication to that specific

area uh perhaps for a brain tumor or

something like that

so um it's a very exciting field

um and it is FDA approved for Tremor

right now and so I actually do it

routinely

um

for patients with Tremor with

Parkinson's or a central Tremor and so

um I I love doing it it's uh often just

kind of a miracle because there's no

incision I don't have to place an

electrode into the brain to achieve a

similar result how early into the

pathology of Parkinson's can someone

think about approaching this so for

instance if somebody has a parent or a

sibling and they're developing some

resting Tremor yeah obviously they

should talk to a neurologist but a

neurosurgeon but this non-invasive

approach could be incredible for them as

opposed to just take only taking drugs

to increase dopamine levels yeah so um

depending on the reason you have Tremor

would dictate the kind of medication you

would use it could be Parkinson's but if

it's not it might be a central Trevor by

the way essential tremors 10 times as

common as Parkinson's really essential

tremor is the most common neurologic

condition in patients over the age of

70. we often aren't aware of that people

with essential Trevor feel they have

their forgotten disease because there's

no Michael J fox for a central Tremor I

sent a letter sorry is it essential

tremor or or essential

um

I actually sent a letter to Bill Clinton

I I've observed uh Tremor in him and I

think he's actually disclosed that he

has it and I hoped he'd become a

champion for for patients with a central

Tremor um Sandra Day O'Connor does as

well she's also public about it but I I

was not able to get them eager to become

the champion for this condition but like

Michael J fox these patients need a

champion like that

um but unfortunately it's a bit of a

forgotten disease nevertheless because

of the FDA approval of focus ultrasound

for Tremor

um another's trying to get some

attention for sure and uh it's

fabulously effective for these patients

it treats patients on one side usually

their dominant hand or their worst hand

and it um it really speaks to the fact

that wow you can deliver non-invasively

an ablation to the brain in a

hypothesized zone that we think is

related to the problem at hand and at

least with Tremor it works really well

could this be effective for psychiatric

disease obesity Eating Disorders uh well

um perhaps uh actually that would be the

ideal the problem is we don't know where

to do the ablation

um there is a trial that we would like

to do for OCD where we would deliver an