Our Episode

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
Consumer information about science and
science related tools to the general
public in keeping with that theme I'd
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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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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
ablation to the same area of the brain
that we've been delivering ablations to
for years for patients with OCD and it
helps a bit that's called a capsulotomy
um but really the outcome is probably
going to be about the same it's a nice
method because it's non-invasive but we
need to find a new Target for these for
these conditions and because of the
common denominator of the urge despite
the risk sort of that compulsion
um yeah perhaps it could be the same
Target I don't know
um but I would argue we need to do these
modulatory experiments either with a
device or with uh invasive recordings uh
to better understand where these
problems are coming from to Define where
we should do an ultrasound treatment so
um you're right historically
without much regulation we've we've
probed the brain
um
the problem we can't learn a lot from
those experiments now uh well in this
way at least we don't know exactly where
those electrodes were we didn't have MRI
scanning or high quality cat scanning to
to know where those electrodes were with
certainty
where and we know two or three
millimeters matters and we also didn't
have the tools to place electrodes in a
precise way back then so unfortunately
we can't learn a lot from those
experiments right now
so we're sort of redesigning them and
there is a way to do it now
um patients with epilepsy benefit from
this all the time there has been a
revolution in America it was in Europe
before it was in America where we would
do stereo encephalography which is
basically like doing an EEG of patients
with epilepsy but with invasive
electrodes and we would Place tiny
little wires less than a millimeter in
diameter all throughout the brain into
parts of the brain that we believe are
involved in seizures and we would admit
the patients to the hospital and figure
out where the seizures were starting and
propagating and then um you know we
could stimulate these electrodes to see
if there was a symptom that was
important and I try to identify a region
that we thought we could either remove
surgically ablate with a laser or put a
stimulator in it perhaps that's
commonplace now for epilepsy
um
and it works extremely well and it's
very safe of course it's still a brain
procedure but the uh the complication
rate is surprisingly low quite honestly
for the amount of electors that we place
um and it's extremely well tolerated
most these patients leave the hospital
and they don't even feel like they've
had surgery
so uh there's actually a lot of interest
in using that procedure to study mental
health disorders
we are trying to do it for patients with
obsessive compulsive disorder we're
awaiting an FDA decision on that uh but
actually I credit uh our colleagues at
Baylor and at UCSF for for studying this
uh already we have fabulous colleagues
at UCSF that have studied depression
using this type of approach a mutual
friend of ours uh you know Eddie Chang
who's a wonderful friend and colleague
somebody I've emulated for many years as
well uh and and the the Psychiatry team
at UCSF have worked together on this
sort of
bringing together the epilepsy technique
and the Psychiatry expertise to study
how we could better Target electrodes in
depression and I'll tell you if they
have a consistent Target
perhaps there becomes an ultrasound
Target
um but right now the approach is a bit
more reversible because you can always
shut that electrode off or even remove
the electrode if perhaps it's not in the
optimal location to treat the depression
uh but actually after a large volume of
cases perhaps they could pool that data
to develop a a new ultrasound Target for
depression I think that would be
fabulous and probably is their long-term
goal
um not to speak for them but that would
be something that I I'm sure is on their
radar and a Baylor is trying to do the
same thing for depression their
approaches are a little bit different
but a similar tool to try to understand
uh depression and you know we're working
with all these types of uh colleagues
some of these are our friends to try to
to bring this to OCD as well and you
know it makes sense to try to do this
for addiction and obesity and anorexia
you might ask well why aren't you doing
this for obesity right now in uh in our
in our study and the reason is that
um we've developed a target for obesity
uh and binge eating disorder uh
developed out of mice that we believe
um is relevant for the human State
because you can model this problem in a
mouse a bit better than you can model
depression or OCD so we feel like we can
rely on the pre-clinical studies more
whereas with these perhaps more I don't
want to say more complicated but more
human mental health conditions that are
hard to model in a mouse you really have
to study it in the human and you can
perhaps start in an epileptic patient a
patient that has electrodes and try to
provoke a depressed state or study
epileptics like Dr Chang has done that
have comorbid depression for example and
that can really validate this approach
as well but in the end it's it's getting
into the human brain that we need to do
in the disease specifically that will
eventually lead to a non invasive
approach either a lesion or modulatory
approach modulatory would be like TMS or
lesion approach would be with ultrasound
couldn't agree more
meanwhile because there are many many
millions of people suffering from
depression Eating Disorders Parkinson's
and essential tremor
Etc
well first of all I should say based on
everything you've told me thus far it's
amazing to me that any pharmacologic
treatments work because of how systemic
they are and impacting serotonin
serotonergic neurons over here in
dopaminergic neurons over there and not
targeting any specific batch of cells it
makes perfect sense as to why all the
side effects exist
but earlier you said something that
really grabbed my attention I want to
come back to which is that
if people can be made to feel or make
themselves feel just a little bit better
a little less anxious just prior to a
craving episode or a binge episode
maybe even if people can become better
at detecting their own internal States
and when they're kind of veering toward
a binge or veering toward using a drug
or
maybe even veering towards suicidal
thinking
I based on what you said earlier that
those kind of um
pre-behavioral States
the kind of drift on the on the steering
um
those sound like powerful
levels of awareness at least for now
until we have specific sites in the
brain that we can Target non-invasive
methods that could be deployed to
millions and millions of people seems
like that awareness seems like maybe
among the best tools that people could
develop yes 100 agree with you you know
so for the person with OCD or uh who
suffers from anorexia or binge eating
disorder and to their clinicians you
know I I just want to highlight that you
said that I mean I'm not again I'm not a
clinician I always say this I don't
prescribe anything I profess things
um and uh but
awareness of one's thinking seems
immensely powerful in this context yeah
um and after all it is the clinical
probe that you use because the if let's
say the patient were to lie to you about
their experience of
what happens in their mind when you
stimulate you could basically the whole
thing the whole surgery the whole
procedure could go badly wrong so it's
it's up to the patient to be of course
honest with you in their their
incentivized to do that but to be honest
with themselves about ah you know I've
gone all day without a binge but you
know the the smell of a donut or the
thought of a donut is starting to have a
particular Allure that awareness seems
like an incredibly powerful thing to own
and to and to build and cultivate yes
I've always thought that if we could
improve awareness we can improve
outcomes I think that's probably true
for many of these patients the problem I
think comes down to the fact that some
of these patients are so resistant to
treatment
and the patients that we see as a
surgeon for example are the patients
that they've tried cognitive behavioral
therapy certainly have tried medications
they've tried Behavioral Management they
are aware of their problem and they've
shown that to us they can tell us when
they're craving
but despite the craving and despite
being involved in this invasive brain
surgical trial highly you know first in
human novel study which I think will
have a positive effect but it's still
experimental uh they still can't stop
themselves so there
sort of as made aware as could possibly
be did I use grammar there correctly I
think so
um they're as aware as they could
possibly be and they still lose control
we've had this studied in the lab so we
will bring patients to the laboratory
with this implanted device
to to try to provoke this electrographic
electrical signal that can be detected
by the actual device that will stimulate
them when they're at home
but before we actually initiate
stimulation we want us to see can this
device detect this craving cell signal
which is going to be different than what
we saw in the operating room because
that's a single cell but these devices
these electrodes are about a millimeter
in diameter instead of like a tenth of a
millimeter which is what we use in the
operating room
um so they're they're only hearing or or
detecting I should say thousands of
cells responses and
we actually have a way to provoke
binges it's called a mood provocation
it's very well well very well validated
it's a little bit like provoking
seizures in the epilepsy monitoring unit
but here in these sort of uh psychiatric
monitoring unit or the the food
monitoring unit uh we we actually have a
psychiatrist and eating disorder
Specialists come and
induce a mood that is related to
each patient's sort of self-described
binge episode so the psychiatrist comes
in and provokes yes a feeling that can
evoke the negative behavior that's
exactly right so that we can video and
synchronize the video to the brain
signal recordings
um the patients all wear an eye tracker
so we can see what they're eating at all
times and what they're looking at
specifically and that allows us to have
the best temporal resolution possible to
understand what is happening right
before the bite
and even under video surveillance
through a one day one-way mirror in a
laboratory setting when patients are
very well aware that their there to be
studied if they're going to binge
they still do and we believe they do
because they just can't control it as
aware as they are of it
and it's probably because they're the
most severe
so I think if we can improve awareness
not just the societal awareness that I
was talking about earlier but the
patient awareness around their problem I
think that could be a powerful way to
help so many of these patients and
that's sort of the role of cognitive
behavioral therapy
um the problem with cognitive behavioral
therapy or should say the limitation of
it I actually don't have any problem
with it I think it's a wonderful
treatment
um
is that if you stop it many of these
patients go back to their old behaviors
I don't say old habits but it might be a
habit but the old behaviors
and so um
that's the problem is it's not
necessarily lasting in the absence of
continued cognitive behavioral therapy
some people can benefit from it long
term but some can't uh
but I think in in in the less severe
patients improving awareness key but in
these really refractory patients this is
this is kind of like this is the disease
despite the awareness they can't control
themselves and that's what we're trying
to restore is that improved ability to
control their behavior
do you think there's a role for machines
and artificial intelligence here uh
there are a couple Laboratories up at
the University of Washington that are
using
particular signature patterns of within
voice to try and help
suicidal people who are suicidally
depressed
know when they're headed towards an
episode before they even can consciously
know so this gets right down issues of
Free Will and whether or not machines
can be smarter than we are but you know
one could argue that some of the search
algorithms on Google and other search
engines are actually more aware of our
preferences than we are
um
basically what these are these are
devices that are listening to people
talk all day they're also paying
attention to patterns of breathing and
how well people slept Etc integrating a
huge number of cues and then signaling
somebody with a you know a yellow light
like you know you're headed into a
depressive episode the person might say
I feel fine or I feel pretty good this
is kind of Baseline state for me and
they say ah this is where you were
preceding the last episode that took you
down a deep dark trench and it took
months to get out of
um I wonder whether or not some of these
devices could help with the sorts of
things that we're talking about today
yeah I think so
um I've always said we have to get in
the Brain before we get out of it and if
we get in the brain and understand what
these signals look like we'll know what
those non-invasive signals are I think
it's possible that we are
scientifically sophisticated enough to
use machine learning
um and sort of this kind of botan
technique to anticipate when somebody is
going to be highly impulsive you know
suicide it's the most dangerous impulse
it's something that is
immensely a focus of the lab is
impulsivity we've talked mostly about
compulsion compulsion being you know
going after a reward or the urge despite
the risk
um impulsivity is is similar but
different it's it's kind of going after
something
um a little bit if you if you model
impulsivity in a mouse it's you know
related to you know going after a food
reward without the sort of paired tone
that your the mouse is supposed to wait
for the mouse doesn't want to wait
anymore they just go after the food
um I've been that Mouse yeah we've all
been oh we could all relate with this uh
to a certain extent against the Spectrum
so
um
so in any case I uh non-sequitur but I I
I certainly think that there is a way to
use our own body's physiology
to anticipate
when these impulses are coming online
how best to do that I think we're just
scratching the surface but these are the
kinds of solutions we need these are
some of these problems are of epidemic
proportions the largest public health
problems in this country in this world
obesity opiate crisis depression
suicidality I mean that's like a third
of our country maybe more probably more
and think about it and a colleague of
ours at Stanford Psychiatry told me
something that still just blows my mind
which is that something like 75 percent
of the antidepressant and anti-anxiety
medication that exists in the world is
consumed in the United States it's
amazing which is I mean that's an
outrageous number yeah we do have an
obsession in this country for pharmacy
you know and the pharmaceutical industry
is very powerful here and probably
related some aspect of capitalism I'm
capitalistic and just like everybody
else but um I do worry about that a
little bit
um but you know we tend to over
prescribe and I think we as patients
tend to over want medication we like
quick Solutions and sometimes
medications provided sometimes not or
they're often just abandoned depends on
the problem of course
so
um but but I I agree that we need
scalable Solutions but you know I'm a
neurosurgeon I'm only going to be able
to treat the most severe of patients
with these problems you know you know
we've only done about 200 000 deep brain
stimulation surgeries ever
so I mean the problem we're talking
about here is
50 million Americans there's no
possibility that surgeons can address
that problem but we could help Inspire
an initiative to go after that kind of
problem or help make it more rigorous
because the last thing we need is a you
know some sort of wearable fancy tool
that you know
uh waste people's money and time you
know we need real therapies for these
things not that these devices that we're
discussing are not uh I think actually
there's lots of promise we use machine
learning in the lab all the time I'm not
a an electrical engineer or the
computational neuroscientist doing this
type of work I I just helped develop the
hypotheses around it but um and help
fundraise around it but I I definitely
think there's a future for it I just I I
suspect we're scratching the surface on
how best to do it
let's talk about your hands yeah sure
all the neurosurgeons I know are you
know very Faithfully protect their hands
because talking about insurance is too
expensive that's it right but I'm
guessing that you you all are not the
ones to reach into the garbage disposal
even if your eye is on the switch to
make sure that it isn't going to get
turned on they're just too precious they
are your livelihood yeah um and earlier
we talked about deadlifts uh there are
other forms of exercise
um they're things like tennis
um they're they're drawing and painting
a full range of things that one can do
with their hands use your imagination
sure
um is it true that neurosurgeons don't
do any uh really like heavy grip
activity because it can
refine the motor motor circuits in the
brain and elsewhere that can throw off
their neurosurgery game
I would say that
many neurosurgeons uh avoid activities
that put their hands at risk um another
one by the way you know there's a uh an
annual uh softball tournament uh that uh
neurosurgeons come to in New York City
in Central Park with a very softball no
I'm just kidding well actually it's
actually a very you know typical hard
softball I don't know why they call it
softball and uh actually a two close
colleagues of mine have gotten injured
at that tournament maybe this is a it's
also I must say and here I'm poking fun
but for those of you who are going in
the medical profession it's also one of
the more uh how should I say this well
I'm just going to say it there's a steep
hierarchy of training in neurosurgery
yes
um there's a certain harshness that's
been conveyed to me about the training
uh much like Astronaut training to be
totally fair and so maybe this is a
tactic to uh to weed out either the
younger or the older generation it says
Evolution right we uh have to evolve and
we need in medical the week I guess well
I I could say that one of the
individuals that got injured is one of
the more senior surgeons that I work
with now and is one of the best athletes
that I know and he's definitely not weak
but you can get injured playing these
Sports and uh that being said I can tell
you briefly is um I think that you know
it's funny my my mother came to me
recently she's she has osteopenia and
she told me her doctor told her she's
not allowed to do deadlifts and I was
like okay
um that's fine uh I'm not telling you
you should do deadlifts I just don't
exactly understand the relationship but
um
I can say that I do think
I'll give you a little story here the
reason why I'm being a little hesitant
to to confirm that I agree with you on
the deadlifts is I um
when I was operating this is when I was
at Stanford University operating and uh
we as I mentioned earlier we get an
interoperative CAT scan uh to confirm
accuracy of our lectures I do this for
all of my surgeries when I was reviewing
that CAT scan the x-ray technician
looked at me and said whispered into my
ear he's like your posture
really bad embarrassing your physical
posture while doing your surgeries yeah
and I looked at him and I kind of wanted
to say I won't curse but yeah exactly
I've been doing it intermittently during
our conversation because he made me
realize that I really did have bad
posture and
um we kind of had a little brief aside
and he I learned he was a personal
trainer and uh his name was Zach and he
uh you know he said to me you know your
posture is weak because or your posture
is poor because you're weak you need to
strengthen your body and strengthen your
core I was like how he's like power
lifting and I'm like I'm a little
hesitant to do this and I'll tell you I
started very slowly and I can't
prescribe power lifting to everybody for
the exact reason you said um and I've
gotten hurt doing it by the way but I do
think
I I wish I started a little younger
and I would argue that with close
supervision and very
well if you are if you have a very
experienced trainer which I would argue
if you're a neurosurgeon or an astronaut
uh or or have a highly specialized
profession where you need your your
limbs to to function dentists things
like that
um if you're going to take something on
like this it really needs to be
extremely carefully supervised and I can
tell you that you know my trainer had a
profound impact on my life and my
posture and my my physical health and so
uh we did deadlift I'll admit so when
you brought it up I kind of chuckled to
myself but uh yes I I have gotten mildly
hurt deadlifting but it was when I was
doing it by myself and I was kind of
cocky and I wasn't paying attention but
when I was with him and he was all over
my technique
it actually was the most efficient way
for me to feel stronger and it improved
my posture uh significantly and I I miss
him since I left California I I have a
new trainer in Philadelphia who's great
but uh uh and and I still deadlift
occasionally with him but I uh I I can
say I I am opposed to deadlifting
callously but if you're
extremely well monitored by it
experienced
um personal trainer or weight lifter uh
I think it could be a great exercise
great I love to be wrong in this case
um because I'm a huge proponent and on
the podcast I go on and on I mean
they're so there's so much data now
pointing the fact that 100 and 180 to
200 minutes of Zone 2 cardio kind of
jogging cycling swimming type behavior
is very healthy for everybody and we
should all be doing that at least that
yes I need to as well and that
resistance training on the order of you
know six hard sets per muscle group per
week are it's really important just to
offset deterioration of muscles and I'm
learning skeletal function and tendon
strength and that's just to maintain
we're not talking about all out sets to
Absolute failure but as you point out
with um with proper form so even the
neurosurgeons are doing this which I
think is is wonderful yes as a final
question
um but one that I think really or maybe
second to final question earlier I
commented on the remarkable calm at
least perceived calm of neurosurgeons it
could be caused or could be effective
the training but it's obvious to me why
one would want that trait in their
neurosurgeon
um I wouldn't want to hyperactive
certainly not an impulsive neurosurgeon
given that the margins of error are so
so tiny the spatial scale and probably
on the temporal scale too yes and you
don't want people doing things in time
that are or being spontaneous at all
do you think that this branch of
medicine that you're in selects for
people that at least can know how to
control any kind of fluctuations in
autonomic growl so they can calm
themselves in real time and here's a
specific question when I've never
operated on the human brain although
I've had the privilege of being in the
operating room and seeing this with some
of our experiments with people in VR
it's a remarkable thing I wish for
everybody that would get this experience
at some point not hopefully as a patient
unless they have a need but to observe
it but what was just striking to me is
the various uh stereotype behaviors of
the surgeon and when I did surgeries as
a graduate student as a postdoc in the
brains of other types of animals I would
find for instance that if I started to
tremble a little bit if I tapped my left
foot that my hand would stabilize a bit
that there's this kind of need to move
the body or one feels the impulse maybe
that's my my Tourette's like compulsions
again but but that one can kind of um
siphon off some of that energy into
another limb so that you could remain
precise so are these sorts of things
that I'm talking about are maybe it's
entirely my imagination but are these
the sorts of things that one learns as a
neurosurgeon how to still the body and
still the Mind do you have a meditative
practice when you go into the operating
room if you had a particularly
challenging morning or or a poor night's
sleep do you have tools that you use to
calibrate yourself and get yourself into
the Zone I think this would be very
interesting for people to get some
insight into even if they don't want to
be a neurosurgeon yeah I completely
agree and I I appreciate the earlier uh
reference to neurosurgeons as uh
astronauts because I've also heard you
know us compared to Cowboys before and
it's a little bit less flattering I uh
you know
some of what we do surgically really
does require a substantial amount of
confidence
um and that confidence hopefully comes
from years of training and experience
um
you always worry that the confidence is
sort of misplaced and that that is
problematic luckily I you so rarely see
that because our training is so rigorous
you know we have a board of uh American
Board of neurological surgeons that uh
sort of allows and and assesses surgeons
to continue practice and holds us to a
really high bar I do think it tends to
attract a certain personality uh in my
sub-specialty as a like a deep brain
stimulation surgeon we call it
stereotactic and functional neurosurgery
you know some people have likened us to
the neurologists with a scalpel
um we we tend to be a bit more
intellectual
um uh maybe maybe bedside manner is a
little bit friendlier
um and then there's the vascular
neurosurgeon who doesn't sleep and so
they're not as friendly there's the
spine surgeons who operate the most and
so they're you know busy busy busy uh we
there are some of these kind of
reputations going around but I I agree
with you there's a sort of a common
feature of of a calmness across
neurosurgeons and you know there's some
of my obviously my favorite people my
closest friends
um and I I can relate with them probably
because of that
um sort of a big picture they don't get
sort of uh flustered uh they they tend
to
are they tend to be really good at
figuring out how to have quality time
because we work really hard our hours
are uh significant and so the time with
our families our friends is less than we
would like it to be
um that obviously that's true for people
who work hard across any profession but
definitely true for neurosurgeons and I
think that we're very good at figuring
out how to make that time high quality
um you know even just texting with some
of my friends
um in that are that are neurosurgeons a
great friend of mine just became
chairman at Duke and just connecting
with him by text which takes seconds you
know you feel we feel connected you know
and I I think that's a that's a trait
amongst neurosurgeons we sort of know
how to cut to the chase in a way
um and prioritize our time it's a skill
that we probably
have innately but is also part of the
training you know when we are interns
now there's a lot of work hour
regulations that is probably quite
appropriate by the way
um I I think our hours before were
bordering uh on on uh on not necessarily
let's just say they were not ideal for
mental health and sleep which we know
are very important components um
certainly we had no time for meditation
I definitely did not I wish I did
um now knowing what I know about
meditation my wife's a health coach I I
get it I see it I I practice it myself
with her
um I see the value I wish I had that
tool when I was in training because it's
stressful
um you know you even with workout
restrictions we still don't sleep very
much we're still at work a lot about 80
hours you know a week throughout the
entire career uh there are times when
it's more because after training there's
no work hour restrictions so sometimes I
feel like as faculty we get abused and
the trainees are a little bit more
protected now it definitely was the
reverse at one point and that's also a
huge problem probably more of a problem
um and I'm joking a little bit I don't
necessarily think we're abused but
certainly our hours are significant
um
but you know they come a bit more here
and there you know on my or days when
I'm operating those are long days but on
the days that I'm lucky enough to be a
researcher you know uh like you those
days tend to be a bit gentler unless I'm
great writing those days can be long as
you know
um so I so to answer your question I do
think we're we're sort of self-selected
for it but I also think it's part of the
training you know we because of the long
hours that we're in the hospital we're
taking care of sick patients and we have
sort of a type a mentor approach where
our mentors are hard on us
you know we learn to cope with our
stress and be efficient and prioritize
things despite the stress of it all and
I think you know we take from that this
sort of calm demeanor and you know
perhaps
um perhaps it's just amplifies what we
were probably drawn to because before we
come to neurosurgery we want rotated
neurosurgery we might spend a month you
know pretending to be a neurosurgeon
learning from residents and and faculty
that are practicing the specialty but
you know prior to actually starting your
training you you never experience
anything like being a resident in
neurosurgery uh the stress and the
volume of patients that you have to take
care of and the long nights it can be
quite Lonely by the way
um you develop friends in the hospital
but sometimes you're on your own when
you're on call and you have backup you
can call your chief resident or you're
attending but you really have to learn
how to take care of patients yourself
you obviously form teams with nurses and
staff and things like that and other
residents but it can be lonely it can be
really challenging and I think because
of those experiences that all
neurosurgeons go through uh
you know we tend to have this sort of
unflappable personality that perhaps we
started with a bit compared to the
average person but the training
definitely amplifies it and do you have
tools that you implement if you ever
feel that you're getting slightly
off-center
I do now
um
you know I
when I was in training I actually
remember in my
second year so most neurosurgery
programs when you're a junior resident
in some ways that's your toughest year
not in every way
um
it is your toughest year because you're
you're young and you're inexperienced
and you don't know what you don't know
and and that that's why it's such a
tough year because you have to learn a
lot very quickly for patient safety
reasons for self-survival you know you
just have to learn a lot
um and you're on call by yourself in the
hospital and it's uh it's a real
Challenge and I think that you know I
you know personally I I gained a lot of
weight during that year the only
exercise I did consciously was taking
the stairs I refused to take the
elevator and I was at uh Penn at HUB
where I currently practice now
and I remember I would see patients
anywhere from sort of the ground floor
where the Chama Bay was or the ER all
the way up to Founders 12th 12th floor
and I would never take an elevator that
was my rule for the year because I knew
I would not have time to exercise but I
would just take the stairs and in the
beginning of the year I would be a
little winded when I got to the 12th
floor but by the end of the year
actually it didn't really phase me it
became a great Habit to have
um the problem with that though is I
paired that unfortunately with you know
a lot of sleepless nights or not enough
sleep let's say
and I had this terrible habit of
drinking coffee late at night and I
would put a lot of sugar in it and it
was sort of the only way for me to get a
quick you know um a quick bout of energy
that for some reason I prioritized at
that time obviously knowing that I would
crash which I always did and I always
kind of regretted it but I still did it
anyway and I I attribute that to poor
decision making inexperience
um and perhaps being a little vulnerable
like I think we all are that's why I
relate with a lot of the research that I
do and I remember I got married in my
third year the year after my second year
and my wife and I or my fiance at the
time we started going to the gym
together in the morning and my hours
were a little better so I would actually
be able to exercise before I operated
that day and I operated almost every day
as a third year resident so I remember
I'd get to the gym really early in three
months I lost like 20 pounds and I
wasn't trying to lose weight I just was
sleeping better and taking care of
myself and I remember when we got
married I I you know I fit into a tuxedo
that I had in college or it would have
fit me in college it actually was a new
tuxedo admittedly but it was the same
size as my tuxedo from college so I I
think that um I've always related with
the problems that our our patients have
to a certain extent and you know I when
I've been most vulnerable which is what
I was working the hardest with the least
amount of sleep I I related with it the
most and
yes exercise for me has always been my
tool
um more recently exercise some some you
know strength training I think is
important compared with cardio
um I don't do enough of either
um but I definitely do some and that
helps meditation helps me a bit we I do
that every night before I go to sleep
um
you know I I use an app for it it's
probably not the best way to do
meditation but if it keeps you doing it
regularly that's the best way to do it
Andrew I couldn't agree with you more
you know it's one of those things where
I look forward to it every night and you
know sometimes my wife falls asleep and
I come to bed a little later and I
whisper I'm like are you okay if I turn
the app on so you know she does the same
to me because I think we both value it
and I think that's that that's been very
helpful I didn't have that tool probably
what I needed it most but I have it now
and it's very helpful
I really appreciate you sharing those
tools a number of people uh I'm guessing
out there might want to become
neurosurgeons I really believe that in
hearing today's conversation that you
will spark an interest in medicine and
or neurosurgery
um well certainly you need to be a a
physician before you can become a
neurosurgeon so end neurosurgery in some
cases and that would be beautiful and I
predict that will be happen that will
happen excuse me as a consequence of
um what you've shared today I really
appreciate your mentioning of the um
emphasis and appreciation on quality
time uh I very much see this as quality
time I know that our listeners were will
as well really want to thank you for
taking time out of your not just
immensely busy but very important
schedule because again the work that
you're doing is really out there on that
cutting I don't want to say bleeding
edge because in this context it's not
going to sound right but on that extreme
Cutting Edge of what we understand about
how the human brain works and how it can
be repaired
um they're doing marvelous work will
Point people to various places they can
find you online and should they need
your the help of your clinic to to your
clinic and your laboratory as well so on
behalf of everybody and and myself as
well thank you so so very much I'm
honored thank you so much for having me
thank you for joining me today for my
discussion with Dr Casey Halpern about
the use of deep brain stimulation and
novel Technologies for the treatment of
eating disorders and movement disorders
of various kinds for those of you that
are interested in learning more about Dr
halpern's research please see the links
in our show note captions that include
links to his laboratory website and to
his Clinic as well as various research
Publications that are available in
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