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 Accumbens

Deep Brain Stimulation for Loss of Control Eating.

The nucleus accumbens 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 that 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 it 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 of 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’s 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 like to thank the sponsors of today’s podcast.

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And now for my discussion with Dr. Casey Halpern.

Casey, I should say, Dr. Halpern, for those 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 bittersweet for me too.

Stanford’s loss is UPenn’s gain,

but let’s talk about your work.

So, you’ve been a neurosurgeon in the 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 could just educate us a bit.

What does a neurosurgeon do,

and what does the fact that you’re a neurosurgeon

do for your view of the brain?

How do you think about and conceptualize the brain?

Yeah, the scope of neurosurgery is quite broad.

When I was in medical school,

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 Baltuck,

who to date is one of my career mentors.

Deep brain stimulation is 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,

90% of what neurosurgeons do around the country,

taking care of herniated discs and lumbar fusions.

So the scope is the entire central nervous system,

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 mission in the field to subspecialize.

And so historically neurosurgeons

did everything in that domain,

but now we subspecialize

and I’m lucky to be at Penn Medicine

where we can focus on one of these areas.

So I’m Chief of Stereotactic and 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 tremor at the moment.

These two procedures are for me, my every day,

but still the minority of what neurosurgeons have to offer.

The majority of neurosurgery in my mind

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 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 very thin wire

that’s insulated deep into a part of the brain

that’s involved in Parkinson’s disease, for example.

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.

But that’s all done out of the operating room.

This stimulation wire is connected to 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 tool

to deliver you a medication,

but that medication is gonna be in the form of electricity

and it’s gonna 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 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 the kind of dark stuff,

you know, stimulate one brain area,

somebody goes into a rage, stimulate another brain area,

person starts laughing uncontrollably.

First of all, given that some of the information,

let’s hope not much,

but some of the information in textbooks is incorrect.

Are those sorts of statements true?

Can one observe those in the clinic?

And what are some of the more interesting

and I don’t necessarily mean entertaining,

but surprising things that you’ve seen

when you’ve poked around in the brain,

deliberately of course.

And what have you seen?

What have you heard?

I have to say, I am amazed by these effects every day.

Yeah, I’m very privileged to be able to interact

with the human brain in this way.

It’s always with the goal of trying to provide somebody

with a meaningful therapy.

But when we deliver electrical stimulation,

you know, 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,

a 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 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 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 tremoring 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

except help develop that type of therapeutic

for another kind of symptom.

I’m very interested in obesity and related eating disorders,

compulsive behavior, the urge to have something

that might be delicious, but dangerous,

or unhealthy, or a drug,

or a compulsion like we see in OCD

or obsessive compulsive disorder.

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 pick out one would be a challenge

because for me, this is my every day.

The speed of the relief that you described for tremor

is really incredible.

Just thinking about drug therapies,

and there too, there are side effects,

but there are still a lot of mysteries as to, for instance,

why SSRIs even work when they work.

The timing is always a challenge.

Timing, dosage, yes, absolutely.

I’d love to learn more from you about OCD.

I have several reasons for asking this.

First of all, I’m a somewhat obsessive person.

I tend to be 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 and thinking and work,

it’s very hard for me to exit that mode.

It’s like a deep trench.

Adaptive in some circumstances, less adaptive

in others, as you know.

The other is that when I was a kid,

I had a little bit of a grunting tick.

I used to, I had this intense, intense desire

to clear my throat to the point where my dad said,

look, you need to stop that.

And he used to squeeze my hand every time I’d do it.

And I used to hide in the backseat of the car

or in the closet to do it

because it provided so much relief.

And then it eventually passed.

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 kind of grunting.

And so it’s been sort of like a pet neurological symptom

for me that reminds me that these circuits exist

in all of us and that sometimes they go haywire

and sometimes they just have subtle 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.

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.

But my perspective on OCD may be a little bit different

than a psychiatrist who lives and breathes OCD

and sees patients every single day with OCD.

I probably take care of three to five patients a year

with deep brain stimulation

for obsessive compulsive disorder.

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 OCD.

So I do feel I have expertise and a perspective to share,

but just a brief disclosure.

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,

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.

For obsessive compulsive disorder,

the surgery risk is about the same.

However, the benefit is not quite as robust.

And so a lot of patients and their referring psychiatrists

are reluctant to refer these patients to us.

It’s completely understandable.

I’ve been leading an endeavor

with a number of collaborators around the country

to try to better understand these circuits in the brain,

study them in humans, both invasively and non-invasively.

That would be with an electrode-based surgery,

sort of like we do in epilepsy

to understand where seizures come from.

We wanna 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.

I consider OCD to be a spectrum disorder in a way.

And I apologize to those 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 you have.

As a neurosurgeon, I’m really obsessive about safety

and compulsive about my surgical procedures.

So I think that some aspect of OCD,

which we often joke about, but we should consider seriously

because people do suffer from this,

some aspect of it helps us.

There are famous CEOs that probably have some level of OCD,

surgeons and scientists alike.

So perhaps if it can be controlled, it’s an asset.

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 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 neurodrenergic 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 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 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 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,

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 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.

Our therapies for those patients right now,

I would say are worth pursuing, but not optimal.

And so it’s one of those things

that we have to balance as a researcher,

because when you see patients like this,

you wanna 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.

Others would say it’s safer to modulate.

I have seen patients do very well with these ablations.

And so, you asked me earlier

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 proceed,

especially when they know that their chance

of a transformative effect is quite low.

We can generally achieve a responder rate of about 50%.

And responders still have symptomatic OCD.

So, I’m really 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 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 I was an undergraduate still,

and work from Judith Rappaport

at the National Institutes of Mental Health,

this would be late 80s, early 90s,

had done some neuroimaging,

or maybe it was PET, or some other imaging technique,

and had identified portions of the basal ganglia,

caudate-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

that’s for this sort of work of ablations or stimulation,

where would you first start to probe in the brain?

Yeah, this is a disorder of both cortex

and the subcortex.

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 obrofrontal cortex

and the prefrontal cortex.

If you image these areas,

or study them even in 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 mouse or a rat,

but perhaps you can model compulsive behavior in a rat.

Sure.

Pulling out their hair.

Yeah, exactly.

You know, 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.

And most scientists do, I think.

And when we study OCD in models

or in humans with imaging,

and we’re trying to do it invasively with electrodes

like we do in epilepsy patients,

we find that areas in the cortex,

like the prefrontal and obronofrontal cortex,

are not functioning the way they would

in a non-OCD patient.

They’re often hyper-functioning,

such that while you might say,

well, they’re hyper-functioning,

so aren’t these patients functioning better?

Hyper-focused.

Yeah, hyper-focused, exactly.

No, I would say it’s not so much an up or a 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.

We tend to oversimplify brain function

by thinking about it with directionality too much.

Unfortunately, imaging studies

sometimes demonstrate activation or hypo-activation,

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 the frontal lobe is huge,

but areas of the frontal lobe that are a bit more basal,

like the OFC, or orbital frontal cortex,

the prefrontal cortex,

definitely consistently seem to be implicated

in patients with OCD.

And then there are projections to the subcortex.

This is the basal ganglia, like you were saying.

Caudate putamen are the dorsal stratum,

and these are interconnected with the ventral stratum.

This is an area of the brain

that I focus a lot of my energy in.

This is the ventral stratum,

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 gate compulsive behavior,

meaning a rat will pursue a reward despite punishment,

despite a foot shock, for example.

And that can be similar to an OCD patient.

They will 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 despite a foot shock,

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’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 if they feel contaminated,

they will 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

and brushing your teeth consistently.

Very, very common symptoms that we see

or signs that the patients report to us

or that we observe.

But, you know, patients with eating disorders,

they tend to, if they have binge eating disorder,

they’ll overeat.

If they have bulimia, they might purge

despite the risk of these things.

And so addiction is similar.

We tend to drug seek if we’re addicted.

We’ll pay off a dealer in order to get our fix

despite the risk.

And that type of urge despite the risk

is something that 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 today.

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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.

I’ll share a personal anecdote 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 were like pre-workout type things.

Not unlike energy drinks now, which I completely avoid.

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 came back

and I made one mistake.

I still think of this as one mistake,

which was I engaged 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 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 and 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 stop

because it did make me feel too alert,

I couldn’t sleep well, et cetera,

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.

It was really surprising to me how quickly this came on,

how quickly it engaged 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.

It’s not epinephrine, excuse me.

I misspoke, ephedrine.

Does what I described sound totally outside the bounds

of logic or am I imagining it all?

It did happen.

I’m certain it happened.

Yeah, no, I don’t think you’re imagining it at all.

The grunting that you mentioned to me,

first of all, I didn’t comment,

but that sort of, not to put a label on it,

but it sounds like a tick.

And ticks in young males, extremely common.

And they do tend to go away.

Blinking ticks.

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 blinking tick.

And when he gets fatigued, it comes back.

And he’s very high-functioning in his personal life

and his professional life.

But when you’re talking to him and he starts doing this,

you kind of start wondering like, what’s going on?

Yeah, and it’s unfortunate.

People with these problems,

especially as they get more severe,

then you get Tourette’s syndrome.

It’s hard to function in our society.

I have some friends that have Tourette,

and I’ll tell you, I’m just so inspired

because they’re so confident.

And people obviously notice these problems,

but they just live their life and they’re very successful.

And that’s not typical.

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 these problems cause people

to lose their confidence and not pursue their profession

as they may have done or things of that nature.

So I think it’s all related to the fact

that our brains are very vulnerable.

And to get back to your question about the stimulant,

I think your brain was very vulnerable to it.

You sort of may have had a predisposition to it.

You mentioned that you’re a little obsessive,

and with the tick there, maybe you have this kind of,

on the mild side of the spectrum, OCD.

And I probably do as well, by the way.

So I also have avoided drugs for that reason in my life.

I’ll drink a little bit of wine here and there,

but that’s about it.

And, but 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.

And that’s why I think we have these human conditions.

These are human conditions.

We try to model them in animals,

but most animals don’t have these kinds of problems.

I’ve heard that an animal, like 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.

And certainly it’s not as prevalent as depression

is in our human society.

I think we haven’t evolved to manage the stresses

that are in this society that we currently have.

And stimulants is probably one of them.

And I suspect you are probably a little bit vulnerable.

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 superstition that you had.

So, no, I believe that entirely.

And I also think 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 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 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, and I think the nucleus accumbens

and the cortical areas that we’ve been discussing

that sort of send projections to these areas

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.

I always feel it close by, a long run helps.

So, you know, being a slightly fatigued,

not overly fatigued, but slightly fatigued

seems to move out the kind of physical compulsion,

but tried to channel it, never taken any medication for it.

Here I am still going.

I may call you for a referral at some point,

but at this point I’m feeling okay.

Let’s talk about nucleus accumbens and reward circuitry

and the relationship between OCD, reward, addiction,

and to just give you a sense of where I’m headed with this

is into the realm of food-related and eating-related

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,

one on each side of the brain.

What is it?

What roles does it play 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.

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,

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.

Fabulous scientist and mentor, taught me so much,

taught the world so much.

Incredible person, scientist and physician as well.

Yes, MD, PhD and brilliant in both ways

and very fatherly in a lot of way

in terms of teaching people how to do science

and be good citizens as well.

But the nucleus accumbens is an area

that is also very complicated

because it has a lot of functions.

It interconnects with many parts of the brain,

but there are some things about the nucleus accumbens

that are very consistent.

So when I started getting interested in reward

and 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’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.

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,

you know, perhaps better food choices

is an important way for you to be healthier

and not pursuing those better food choices,

that’s an urge that we probably need to treat.

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,

you know, 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.

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.

That’s an urge we gotta treat.

Eating disorders, the same.

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.

Not everybody with binge eating disorder has obesity,

but on average, most are overweight.

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 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 that body habitus.

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 and Eating Disorders.

And he said to me, Casey, be careful with obesity.

You’re interested in addiction,

and I understand you’re interested

in the addictive tendencies of certain patients with obesity

and their relationship with food,

but not everybody with obesity has that problem.

And in fact, it’s probably present

in about 20% of patients with obesity.

But now taking a step back,

20% of patients with obesity is still a massive problem

of epidemic proportions.

And perhaps some of these patients

have either some form of binge eating disorder,

or I should say some degree of binge eating disorder,

or at least loss of control eating,

which is common to both.

So that’s a feature that I think eating disorder experts,

obesity experts, neurosurgeons,

obesity medicine experts would agree is common

to eating disorders and obesity.

And I also believe it’s common to addicts.

And perhaps patients with OCD

is sort of a loss of control disorder.

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.

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 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.

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 a mouse.

And we’re trying to do that now in a human trial.

Fascinating.

Where is the stimulation provided?

Because I would imagine that 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 brief delivery of stimulation,

anywhere between five 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 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.

But for now, let’s forgive the oversimplification.

If we accept that depression is a state disorder,

or maybe Parkinson’s disease is a state disorder,

recognizing that they do fluctuate,

these types of problems most likely, but not definitely,

most likely need a continuous therapy of some form,

a therapy that’s consistent.

Perhaps a therapy that fluctuates with the condition,

but nevertheless still consistent.

Binge eating disorder, or OCD, or addiction,

and binge eating 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 function,

such that they have thoughts about food

or the drug of abuse that they’re really longing to have.

And so we wanna deliver a episodic therapy,

delivered at the right time, and only at the right time,

to try to interrupt the circuit aberration,

or the problem at hand,

that is gonna lead to that dangerous behavior,

and to kind of get the patient back on track

to what they’re doing.

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,

or at least this kind of recurring problem

that is happening.

People that have binge eating disorder,

at least at a severe level,

they tend to binge 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 binge eating disorder,

or is this a few too many buffets,

and I’m being entirely serious here,

you know, unlimited food,

and a circuit gets flipped,

or it kind of starts moving into the high RPMs,

so to speak.

So how does it come on?

And I’m actually surprised to hear that it’s once a day.

I would think, just hearing binge eating disorder,

I assume it’s like OCD,

which it probably fluctuates across the day as well.

But I would have thought,

anytime people are around food,

they just simply can’t control their intake of food.

Yes.

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 phenomenon?

That’s pretty interesting.

Yeah, so severe binge eating disorder,

these patients will binge about once a day.

It could be a couple of 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, and I agree with you,

but the reason for that

is actually just in the definitions of the word.

And as a neurosurgeon, in full disclosure, 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

in these problems that are highly innovative people.

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.

And so 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.

However, they can lose control quite often.

And in fact, perhaps even at every meal,

they might meet criteria for a bout of 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.

And that would be,

there’s no specific number to that, by the way.

It’s really just compared to their normal meal,

perhaps it’s 50% of their daily calories

in that one brief moment.

So that’s why I think it seems surprising

that binges 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.

And in fact, the patients that we’re studying,

we’ve seen patients that lose control 20, 30 times a week.

And that’s probably the term you have in mind

when 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.

So it’s hard to do that more than once a day.

I see.

You mentioned that some preexisting 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 girlfriend had a roommate who we were aware was bulimic

and would binge and then purge.

And often 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 sedative at 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 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 seesaw could go either way

and it can throw things off.

It’s off balance in both cases.

Yes.

It’s, and that seems to be,

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 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 that binging goes away

or partial relief or complete relief,

but how do you know?

Are they in there with a donut and you’re tempting them?

So how do you actually know if ablating a brain area

is going to lead to relief or exacerbation

or no impact on this disorder?

Yeah, so there’s a lot to unpack there.

I’ll try to go one step at a time.

And if I miss something, please remind me.

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 neurosurgeons

because I have a couple of close friends

who are neurosurgeons and I consider Casey a friend.

I don’t know if he considers me a friend,

but I consider him 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 protection that you would guard,

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.

So if your neurosurgeon does heavy deadlifts,

you might want to consider getting a different neurosurgeon.

Hope I didn’t put anyone out of work there.

And then the other thing is that

you all tend to be very calm people,

at least on the exterior.

We’ll return to this later.

But I do throw three or four questions out at once.

So elevated autonomic arousal and alertness,

as well as decreased 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.

These are questions I think about all the time.

And I do want to come back to the deadlifting comment.

But regarding, and you referred to this earlier as well,

and I don’t know if I addressed it sufficiently either,

is sort of like what comes first here

or how does this develop?

I think, first of all,

I like to understand these kinds of problems

in sort of the construct of what I consider to be

a bit of a two-hit hypothesis.

So you sort of need, like in the concussion literature,

you need, the second hit can be devastating.

So if you have a concussion,

you know you want to only return to play

when your symptoms are gone and cleared by a physician.

So in the context of eating disorders,

or let’s say binge eating disorder,

first of all, I didn’t mention earlier,

but this is the most common eating disorder.

Affects anywhere between three and 5% of the population.

Wow.

And it’s probably underdiagnosed in obesity, by the way.

And if obesity affects 35% of our population,

most likely binge eating disorder affects

more than three to 5%.

But that’s the current literature estimate

on the prevalence.

So how do we develop binge eating disorder?

And is it related to this anxiety question?

You know, I think that there is a predisposition.

That’s the first hit.

I actually think all humans have this predisposition.

Just some have it more than others.

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 micronutrients.

It’s just the excess of it and how they’re refined

that I think is the problem.

You know, there’s high fructose corn syrup

in almost everything we eat.

It’s in bread.

I don’t even know why it’s in bread sometimes.

It’s just kind of crazy.

So I don’t think we’re evolved to live in a society

that has food that’s so readily available like that.

And cheap, by the way.

In fact, the cheaper the foods are,

sort of the more refined and palatable

and I would argue dangerous to eat.

I think they change our reward circuits for the worse

and put us at risk for wanting more.

I tend to get a headache when I eat food like that.

And perhaps that’s a evolutionary advantage

because I don’t want to eat those foods

because they actually do make me sick.

So in a lot of ways, I kind of wish that headache

on everybody because perhaps we wouldn’t have

all these problems or at least some of them would go away.

So I think that’s the first issue is a predisposition

to or a vulnerability to these types of foods,

which we undoubtedly all have to a certain extent,

but some more than others.

And 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.

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 had this question about how this develops.

And I’m not sure it’s actually well known.

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,

but also a stressor.

And that stressor is probably one that’s recurring.

And it’s obvious in our society,

these stressors are everywhere

and how we can manage them is often poor.

And I think we could 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.

Binging disorder patients, they do tend to be overweight.

That’s obviously a stigma.

Obesity is another stigma.

Then there’s the opposite.

In a way, it’s an opposite, by the way,

from a phenotype standpoint, that’s anorexia.

I mean, that’s another stigma.

And gosh, not to make this about one sex over another,

but when girls are told they’re pretty because they’re thin,

it just reinforces this problem.

And of course you want to compliment 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.

So 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 ill-meaning.

It’s all done by accident,

but that is the society that we live in.

So if we can try to improve that stigma

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 in the society that we live in.

So that’s kind of my brief sort of summary

of how I would answer your first question.

Then I think your second question,

I sort of take that as,

well, how do you study such a complicated problem

in the operating room and in the clinic?

Because I mentioned the operating room

because that’s sort of the first step here.

First, we have, just to clarify,

we have a NIH-funded trial approved by the FDA

for research to do this first-in-human study.

We’ve treated two patients.

We have four more to come at Penn.

And in this study,

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 involved

in this sort of reward-seeking behavior.

I would call it appetitive.

It’s kind of like appetite,

but the word appetitive is,

I think, a good word to use.

What part of the nucleus accumbens is appetitive?

Is the whole thing appetitive?

Probably not.

It’s huge.

In my world, it’s huge.

As a neurosurgeon,

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.

This sort of reminds me of discussions

around the amygdala.

Everyone thinks amygdala fear,

but amygdala’s got a lot of different sub-regions.

And stimulation of certain areas of the amygdala

makes people feel great.

And stimulation of other areas

makes them feel terribly afraid.

Exactly.

And that shouldn’t surprise us

because when we treat patients

with Parkinson’s disease for tremor,

if we’re in one part of the subthalamic nucleus,

we’ll 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.

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 reward seeking,

which is the overeating in this case.

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,

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 tremor cells.

And they sound,

we convert their electrical signal

to an audible signal so we can actually hear it.

And it sounds kind of like the tremor looks,

like the frequency of the signal

is the same as the hand shaking.

So, shh, shh, shh, shh, shh, shh, shh, shh.

Exactly.

And so the patient with Parkinson’s is trembling.

Yep.

They’re awake,

and you’re poking around

in a dedicated, careful way, of course.

One poke at a time.

One poke at a time,

and with a very fine wire,

a set of wires,

listening to the electrical activity

until you encounter some cells

that are sending out electrical activity

at a similar frequency.

Exactly.

And then you can stimulate them or quiet them

and see if the tremor goes away.

So we are very confident

that when we stimulate that area of,

in this case, the subthalamic nucleus,

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 from a surgeon.

And tractable.

Yeah, exactly.

It makes us feel we understand the brain,

at least in that limited way.

So what is the 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’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,

if you ask them if they crave,

the answer will often be yes.

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.

But the word craving is relatable.

And so we set out to see

if we could identify craving cells.

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

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 human trials

where we’re trying to establish

where in the brain we need to be,

I think this type of approach is really critical.

And by the way, none of this has been published,

but I think it’s so important for people to know this.

So I am willing to share some aspects

of what we’re trying to do.

But that’s really the first goal of this trial

is to identify where in 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?

Well, there are some 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 depending on the patient,

it might be something that’s very salty,

it could be very sweet, like a donut.

Donuts are good.

I love donuts.

Donuts are great.

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 they change your brain.

It’s worth one bite.

Just try to stop yourself after that one bite.

So if I were one of these patients,

given the fact that the binges come on

pretty seldom once a day,

I imagine you have them come to the operating room fasted

or semi-fasted.

They’re fasted, yep.

Okay, they’re fasted,

which there are probably surgical reasons

for wanting that too.

Yes, they kind of have to be.

Right, and then you’ve done the craniotomy,

you’ve removed a patch of skull,

lowered the wire into the nucleus accumbens,

and then they are viewing pictures of food

that they crave and thinking about it.

Do they have olfactory cues,

smells of Cronuts and donuts?

Yeah, we’d love to do the olfactory cues.

We haven’t implemented that,

but that is a great thank you,

and I’ll give you full credit when we do.

Sure, I didn’t review the grant,

but it sounds,

I’m so glad this work is funded

because this time it’s not a joke.

When I referred to you all,

you neurosurgeons as the astronauts of the brain,

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-fat food.

Not that I’m not being disparaging of 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,

you know, I’ll cross the street, cross town,

be late for my meeting, eat three of these,

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.

These kinds of behaviors I’m projecting,

and I’m fortunate that I have cravings for things in life,

but donuts are not among the more extreme of them.

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 recording

from a small population of cells in the area?

Yeah, in fact, we do get multi-unit activity,

which is multiple cells,

but we really try to find one, a single unit to listen to.

One neuron.

Yeah, because it’s just much easier

to understand what that one neuron is doing

versus trying to listen to multiple,

and we also measure local field potential recordings,

but those are analyzed,

which is more of a population response,

thousands of cells.

Kind of chorus of cells.

Exactly, that we measure offline.

The device that we use to sort of treat these patients

or intervene 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.

I can explain that in a moment.

But yeah, so we try to identify these craving cells.

And because this is a feasibility study

and we can’t be in the operating room

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 developed with the NIH or the FDA

to make sure that what we’re doing

is feasible and safe as well.

So we will spend a limited time

trying to identify these craving cells.

But another sort of strategy

that we think is really important

is the effect of the stimulation.

So a lot of patients,

and this gets to sort of your question earlier

about what comes first.

A lot of people, when they binge

or they lose control over food,

or seek drugs,

that moment of vulnerability is preceded

by what we call 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 meets criteria for a binge.

So I try to specify that we are looking

at loss of control eating specifically

just because the criterion of a binge

is not as critical for us.

So what we want to be able to do

is trigger stimulation

when this craving is detected by the device.

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 10 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,

my depression came back or my OCD hasn’t gotten better

and my mood’s back to where it was.

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.

And I think there’s sort of a tolerance effect there

that is limiting the effect of continuous stimulation.

And actually in a mouse, if you do continuous stimulation,

the sort of blockade of binge eating goes away.

So actually in a mouse, we’ve actually demonstrated,

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,

that effect will be the most robust and durable.

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’s for these more episodic conditions.

Whereas these more quote-unquote state disorders,

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.

So in any case, the goal in the operating room

was to identify a craving cell,

deliver stimulation safely,

but also to capture a moment of elevated mood.

We were able to do that

as we are in our OCD patients as well.

And also to get an intraoperative 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.

You can see where the electrode is precisely.

Exactly, with 0.5 millimeters of error.

So super precise, or as precise as we think we need to be.

And we use connectomics.

So there’s a tool in brain imaging called tractography,

where we can actually measure circuit connections.

It’s an indirect assay, but we believe it’s powerful.

It has its assumptions, like anything in science.

But we can 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 structurally.

So those three goals of the surgery

we aim to set out to accomplish.

And we believed if we achieved two of those three,

that we would have a successful result in our early trial.

Amazing.

Given that, at least to me, the non-clinician,

that anorexia is the mirror image of binge eating disorder,

and at least from what I learned,

one of the more deadly psychiatric conditions,

but also quite common.

Yes.

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?

Yeah.

And I ask this for two reasons.

One, because I’m genuinely curious about anorexia.

I’ve observed anorexia in a number of people 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 an 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 see you have an appreciation for the oboes.

Those usually get left out.

What’s that, the oboes?

Yeah, they usually get ignored.

My partner plays the oboes.

Oh, wow.

Yeah, so.

I think it’s a great analogy, by the way.

You know, I make this statement.

It’s a little controversial,

but I actually think people would understand

where I’m coming from

across all of these sort of subspecialties of medicine.

But I actually think, especially with obesity,

remember, it’s a phenotype that’s reflective

often, but not always, of a behavior.

But if you consider patients that have obesity

and they exhibit some sort of compulsion towards food,

so they overeat despite the risk of it,

I think those kinds of patients

are more similar to anorexics than they are different.

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 undereat

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 patient’s predisposition

or perhaps preference.

That’s hard to know.

Like you, I have a personal connection

to these eating disorders, anorexia included,

and yeah, I think it’s very scary.

And it’s a condition that often instills fear

in psychiatrists because I think,

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 scary

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.

So it is a scary condition.

I relate with that.

I am trying, over time,

to bridge what I’m doing in obesity

and binging disorder to anorexia for two reasons.

One, because I think these problems

are more similar than they are different,

and two, because of the need.

And I think we’re well-positioned

to sort of tackle anorexia using similar approaches,

not identical, but similar approaches.

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 when I was at Stanford

as a neurosurgeon in China before he came to me,

actually was involved in a trial of anorexia

that had some benefits.

And there’s studies in Europe

and elsewhere that have examined preliminarily

the effects of deep brain stimulation

targeting the nucleus accumbens for anorexia.

Colleagues of mine in Canada,

Andres Lozada, who’s a wonderful neurosurgeon scientist,

has been studying the effects of going after area 25,

which is directly connected to the nucleus accumbens by,

you know, it’s a monosynaptic connection.

So in a lot of ways, you know,

perhaps delivering stimulation there

could be very similar to delivering stimulation

to the nucleus accumbens.

It’s all part of one critical inhibitory control circuit.

He’s seen benefits as well.

So I definitely think there’s some evidence

that this is an area that we need to be studying.

I think our more episodic approach

with responsive 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

in our study.

It’s right now just being conceived though.

These studies, they move so slowly

because you have to get a grant

and 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, my obesity study took two years to get funded.

And I worry about that timeframe

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, but 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 more to come on that.

And we’re not the only lab that’s trying to go after

because of 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.

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 drum beat.

And then all of a sudden, because of the stimulation,

it was impossible for me to keep time with the drum beat.

That’s cool.

It’s a pretty wild experience to not have motor control

and then to have motor control returned

at the flip of a switch

when someone else is controlling the switch.

It makes it especially eerie.

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 drilling through the skull.

Surgeons don’t like that.

Surgeons love to cut and drill with purpose, but they do.

With purpose, yes.

But my understanding is that

the spatial precision isn’t that great.

Yes.

Ultrasound is something I hear a lot about these days.

And my understanding is that ultrasound can allow researchers

and clinicians to stimulate specific brain areas,

perhaps with more precision.

Maybe you could just give us a brief coverage

of what those are being used for.

What are your thoughts on these forms of non-invasive,

meaning no flipping open of a piece of the skull,

type brain stimulation and blockade of brain activity?

Sure.

Yeah, and I wanted to clarify also,

these surgeries generally don’t, 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 to clarify.

Painless too, right?

Usually without pain.

Yeah, a little bit of scalp numbing.

We give a scalp block

and the patients are getting IV sedation.

So they, in general, don’t feel anything.

And if they do, they tell me

and we give them more local anesthetic,

but they’re usually asleep during that part.

So it’s minimally invasive, but in a lot of ways,

there’s no such thing as a minimally invasive procedure

in the brain.

It’s kind of a misnomer.

I’m so glad to hear you say that.

Oh, no, I am not one of those neurosurgeons

that you’ve probably encountered

and we have mutual friends that,

and these mutual friends

are some of my favorite people in neurosurgery

and they probably actually think more like me 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 closer to the ground truth.

And I get that,

probing with purpose.

I actually really like that.

I’m gonna use that if you don’t mind.

It’s just describing what you do.

But I actually have always said this,

I’ve said it publicly, I’ve said it to my boss,

I’ve said this to my team.

We need to embrace non-invasive approaches.

Some of them are a little fluffy,

fluffy in that we don’t understand how they work.

We don’t necessarily understand

how deep brain stimulation works, by the way.

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.

At Stanford, we have great collaborators

that I think are doing this,

people like Nolan Williams and Connor Liston

at Cornell and others.

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 things,

or more or less?

Yeah, so they put it over,

well, it’s always on the scalp and 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.

But what the FDA has approved for depression,

I believe is similar to what’s been approved for OCD.

But for addiction, I believe it is a different target,

but we’d have to ask our TMS experts on that.

Can they direct the transcranial magnetic stimulation

deep below the cortex?

They try.

And we’re actually studying this in OCD patients now.

As a part of our invasive trial,

we are trying to pull patients from a TMS trial

that’s in parallel to what we’re doing,

all funded by the Foundation for OCD Research,

where we believe we can use TMS 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 just can’t imagine how that is gonna be as effective

as probing with purpose,

but you can do that non-invasively as well.

And I think we need to do better in that way.

I do believe that’s possible,

and I think people are actively trying to do it.

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, 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’re even doing less with the brain stimulation.

So we have so much work to do there.

Eating disorders and TMS have been so,

sort of scarcely studied,

or there’ve been such little research done in that space.

And so it is an area that we need to work on.

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 worry that we’re a long way away

from a non-invasive approach that really works consistently.

Sorry to interrupt, but I want to make sure

we touch on ultrasound.

Yes, sure.

Historically, it seemed that there was a bit more permission

for people to probe around in the human brain.

I sometimes refer the podcast to some of these papers

that were done allowing patients

to self-stimulate in the brain.

These are work done in the 60s,

and now his name escapes me, Robert.

Anyway, there’s a couple of papers published in Science

allowing patients to stimulate

a couple of different brain areas,

asking which ones they preferred.

And I was always shocked and slightly intrigued

by the fact that 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.

Regulatory was not the same as it is now.

Things have changed, fortunately.

But all three of them seem to like

some midline thalamic structure,

which for those listening is just an area

kind of in the dead center of the brain, 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, these 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 kind of people repeatedly engaging in battles

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-

It’s a deep one.

It’s a deep one and kind of gets to our nature as humans

and what we find interesting or rewarding.

But 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, would offer the opportunity

to really come to an understanding

about how the human brain works

without all these issues

of how to translate for mouse studies.

And again, there’s huge value to animal studies,

as we both agree,

but so many of the things that we want to know

about the human brain involve asking the person,

hey, what do you feel when that set of neurons is stimulated

and what don’t you feel?

And a mouse, we can ask and ask,

but they’re not going to tell us,

and they do tell us, they’re not going to tell us in English.

So how do we overcome this challenge?

But first, ultrasound, or if you prefer after ultrasound,

is ultrasound going to be really useful

toward solving these clinical issues and these basic issues?

Yeah, so I think, let’s start with ultrasound

and then we’ll come back to it.

So ultrasound right now, transcranial magnetic guide,

magnetic resonance guided focus ultrasound.

So 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.

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,

perhaps for a brain tumor or something like that.

So it’s a very exciting field

and it is FDA approved for tremor right now.

And so I actually do it routinely

for patients with tremor with Parkinson’s

or essential tremor.

And so I love doing it.

It’s 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,

obviously they should talk to a neurologist,

but a neurosurgeon,

but this non-invasive approach could be incredible for them

as opposed to just only taking drugs

to increase dopamine levels.

Yeah, so 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 essential tremor.

Essential tremor is 10 times as common as Parkinson’s.

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 tremor

feel they have their forgotten disease

because there’s no Michael J. Fox for essential tremor.

I sent a letter to Bill-

Sorry, is it essential tremor or-

Essential tremor, yep, E-S-S-E-N-T-I-A-L.

I actually sent a letter to Bill Clinton.

I’ve observed tremor in him,

and I think he’s actually disclosed that he has it,

and I hoped he’d become a champion

for patients with essential tremor.

Sandra Day O’Connor does as well.

She’s also public about it,

but 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.

But unfortunately, it’s a bit of a forgotten disease.

Nevertheless, because of the FDA approval

of focus ultrasound for tremor,

they’re trying to get some attention for sure.

And it’s fabulously effective for these patients.

It treats patients on one side,

usually their dominant hand or their worst hand.

And it really speaks to the fact that,

wow, you can deliver noninvasively 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?

Well, perhaps.

Actually, that would be the ideal.

The problem is we don’t know where to do the ablation.

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.

But really the outcome is probably gonna be about the same.

It’s a nice method because it’s noninvasive,

but we need to find a new target for these conditions.

And because of the common denominator

of the urge despite the risk, sort of that compulsion,

perhaps it could be the same target.

I don’t know.

But I would argue we need to do these

modulatory experiments,

either with a device or with invasive recordings

to better understand where these problems are coming from

to define where we should do an ultrasound treatment.

So you’re right.

Historically, without much regulation,

we’ve probed the brain.

The problem, we can’t learn a lot

from those experiments now.

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 know where those electrodes were with certainty.

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.

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 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.

And it works extremely well, and it’s very safe.

Of course, it’s still a brain procedure,

but the complication rate is surprisingly low,

quite honestly, for the amount of electrodes that we place.

And it’s extremely well tolerated.

Most of these patients leave the hospital

and they don’t even feel like they’ve had surgery.

So 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.

But actually, I credit our colleagues at Baylor

and at UCSF for studying this already.

We have fabulous colleagues at UCSF

that have studied depression using this type of approach.

A mutual friend of ours, Eddie Chang,

who’s a wonderful friend and colleague,

somebody I’ve emulated for many years as well,

and 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 it becomes an ultrasound target.

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.

But actually, after a large volume of cases,

perhaps they could pool that data

to develop a new ultrasound target for depression.

I think that would be fabulous

and probably is their long-term goal,

not to speak for them,

but that would be something that I’m sure is on their radar.

And Baylor’s trying to do the same thing for depression.

Their approaches are a little bit different,

but a similar tool to try to understand depression.

And we’re working with all of these types of colleagues,

some of these are our friends,

to try to bring this to OCD as well.

And 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 our study?

And the reason is that we’ve developed a target for obesity

and binge eating disorder developed out of mice

that we believe 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 preclinical studies more,

whereas with these perhaps more,

I don’t wanna 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 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 a modulatory approach.

Modulatory would be like TMS

or lesion approach would be with ultrasound.

I couldn’t agree more.

Meanwhile, because there are many, many millions

of people suffering from depression, eating disorders,

Parkinson’s and essential tremor, et cetera.

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 serotonergic neurons over here

and 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.

Based on what you said earlier,

that those kind of pre-behavioral states

on the kind of drift on the steering,

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.

It seems like that awareness seems like

maybe among the best tools that people could develop.

Yes, I 100% agree with you.

So for the person with OCD

or who suffers from anorexia or binge eating disorder

and to their clinicians,

I just want to highlight that you said that.

I mean, again, I’m not a clinician.

I always say this, I don’t prescribe anything,

I profess things.

But awareness of one’s thinking

seems immensely powerful in this context.

And after all, it is the clinical probe that you use.

Because 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 up to the patient to be, of course, honest with you

and they’re incentivized to do that.

But to be honest with themselves about,

ah, I’ve gone all day without a binge,

but 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 build and cultivate.

Yes, I’ve always thought that if we can 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 first in human novel study,

which I think will have a positive effect,

but it’s still experimental.

They still can’t stop themselves.

So they’re sort of as made aware as could possibly be.

Did I use grammar there correctly?

I think so.

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 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 to see can this device

detect this craving cell signal,

which is gonna 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 10th of a millimeter,

which is what we use in the operating room.

So they’re only hearing 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 validated.

It’s a little bit like provoking seizures

in the epilepsy monitoring unit,

but here in the sort of psychiatric monitoring unit

or the food monitoring unit,

we actually have a psychiatrist

and eating disorder specialist 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 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.

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-way mirror in a laboratory setting,

when patients are very well aware

that they’re 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.

The problem with cognitive behavioral therapy,

or I should say the limitation of it,

I actually don’t have any problem with it,

I think it’s a wonderful treatment,

is that if you stop it,

many of these patients go back to their old behaviors.

I don’t want to say old habits,

but it might be a habit, but the old behaviors.

And so 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.

But I think in the less severe patients,

improving awareness, key.

But in these really refractory patients,

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?

There are a couple of laboratories up

at the University of Washington

that are using particular signature patterns within voice

to try and help people who are suicidally depressed

know when they’re headed towards an episode

before they even can consciously know.

So this gets right down to issues of free will

and whether or not machines can be smarter than we are.

But 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.

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, et cetera,

integrating a huge number of cues

and then signaling somebody with a yellow light,

like you’re headed into a depressive episode.

The person might say, oh, 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.

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.

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

and sort of this kind of bot technique

to anticipate when somebody is going to be highly impulsive.

You know, suicide is the most dangerous impulse.

It’s something that is

immensely a focus of the lab is impulsivity.

We’ve talked mostly about compulsion,

being going after a reward or the urge despite the risk.

Impulsivity is similar, but different.

It’s kind of going after something a little bit,

if you model impulsivity in a mouse,

it’s related to going after a food reward

without the sort of paired tone

that the mouse is supposed to wait for.

The mouse doesn’t want to wait anymore.

They just go after the food.

I’ve been that mouse.

Yeah, we all have been.

We could all relate with this to a certain extent.

Again, it’s the spectrum.

So in any case, non sequitur,

but 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.

Some of these problems are of epidemic proportions,

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, if you 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%

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.

And the pharmaceutical industry is very powerful here

and probably related to some aspect of capitalism.

I’m capitalistic and just like everybody else,

but I do worry about that a little bit.

But we tend to over-prescribe,

and I think we, as patients, tend to over-want medication.

We like quick solutions,

and sometimes medications provide it, sometimes not,

or they’re often just a Band-Aid.

Depends on the problem, of course.

But I agree that we need scalable solutions.

But I’m a neurosurgeon.

I’m only gonna be able to treat the most severe of patients

with these problems.

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 some sort of wearable,

fancy tool that wastes people’s money and time.

We need real therapies for these things.

Not that these devices that we’re discussing are not.

I think, actually, there’s lots of promise.

We use machine learning in the lab all the time.

I’m not an electrical engineer

or the computational neuroscientist doing this type of work.

I just help develop the hypotheses around it

and help fundraise around it.

But I definitely think there’s a future for it.

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 very faithfully protect their hands.

And let’s talk about-

It’s because hand insurance is too expensive.

That’s right.

But I’m guessing that you all are not the ones

to reach into the garbage disposal,

even if your eye is on the switch

to make sure that that isn’t going to get turned on.

They’re just too precious.

They are your livelihood.

And earlier, we talked about deadlifts.

There are other forms of exercise.

There are things like tennis.

There’s drawing and painting,

a full range of things that one can do with their hands.

Use your imagination, folks.

Is it true that neurosurgeons

don’t do any really like heavy grip activity

because it can refine the motor circuits

in the brain and elsewhere

that can throw off their neurosurgery game?

I would say that many neurosurgeons

avoid activities that put their hands at risk.

Another one, by the way,

there’s an annual softball tournament

that 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 typical hard softball.

I don’t know why they call it softball.

And actually, two close colleagues of mine

have gotten injured at that tournament.

Maybe this is, it’s also, I must say,

I’m poking fun,

but for those of you who are going

in the medical profession,

it’s also one of the more,

how should I say this?

Well, I’m just gonna say it.

There’s a steep hierarchy of training in neurosurgery.

There’s a certain harshness that’s been conveyed to me

about the training,

much like astronaut training, to be totally fair.

And so maybe this is a tactic to weed out

either the younger or the older generation.

This is evolution, right?

We have to evolve and-

We are weak in medical training.

We have the weak, I guess.

Well, I can 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 that being said, I can tell you briefly,

is I think that, you know, it’s funny.

My mother came to me recently.

She has osteopenia.

And she told me, her doctor told her

she’s not allowed to do deadlifts.

And I was like, okay, that’s fine.

I’m not telling you you should do deadlifts.

I just don’t exactly understand the relationship.

But 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 confirm that I agree with you on the deadlifts

is when I was operating,

this was when I was at Stanford University operating.

And as I mentioned earlier,

we get an intraoperative CAT scan

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 is really bad.

It’s 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 we kind of had a little brief aside

and I learned he was a personal trainer

and his name was Zach.

And he said to me, 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, powerlifting.

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 powerlifting to everybody

for the exact reason you said.

And I’ve gotten hurt doing it, by the way.

But I do think, I wish I started a little younger

and I would argue that with close supervision

and very well, if you have a very experienced trainer,

which I would argue if you’re a neurosurgeon or an astronaut

or have a highly specialized profession

where you need your limbs to function,

dentists, things like that.

If you’re gonna take something on like this,

it really needs to be extremely carefully supervised.

And I can tell you that my trainer had a profound impact

on my life and my posture and my physical health.

And so we did deadlift, I’ll admit.

So when you brought it up, I kind of chuckled to myself,

but yes, 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 significantly.

And I miss him since I left California.

I have a new trainer in Philadelphia who’s great,

but, and I still deadlift occasionally with him,

but I can say I am opposed to deadlifting callously,

but if you’re extremely well monitored

by an experienced personal trainer or weightlifter,

I think it could be a great exercise.

Great, I love to be wrong in this case,

because I’m a huge proponent

and on the podcast you go on and on.

I mean, there’s so much data now pointing to the fact

that 180 to 200 minutes of zone two 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

or it’s really important just to offset

deterioration of muscles and 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 pointed out with proper form.

So even the neurosurgeons are doing this,

which I think is wonderful.

As a final question, 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 cause or it could be effect of the training,

but it’s obvious to me why one would want that trait

in their neurosurgeon.

I wouldn’t want a hyperactive,

certainly not an impulsive neurosurgeon,

given that the margins of error are so,

so tiny in spatial scale

and probably on the temporal scale too.

You don’t want people doing things in time

that are 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 arousal?

They can calm themselves in real time.

And here’s a specific question.

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 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 Tourette’s-like compulsions again.

But that one can kind of 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,

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 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 appreciate the earlier reference to neurosurgeons

as astronauts,

because I’ve also heard us compared to cowboys before,

and it’s a little bit less flattering.

Some of what we do surgically

really does require a substantial amount of confidence.

And that confidence hopefully comes

from years of training and experience.

You always worry that the confidence is sort of misplaced,

and that is problematic.

Luckily, you so rarely see that

because our training is so rigorous.

We have a board of,

American Board of Neurological Surgeons

that sort of allows and assesses surgeons

to continue practice and holds us to a really high bar.

I do think it tends to attract a certain personality.

In my subspecialty as a deep brain stimulation surgeon,

we call it stereotactic and functional neurosurgery.

Some people have likened us

to the neurologists with a scalpel.

We tend to be a bit more intellectual.

Maybe bedside manner is a little bit friendlier.

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 busy, busy, busy.

There are some of these kind of reputations going around,

but I agree with you.

There’s a sort of a common feature

of a calmness across neurosurgeons.

And there’s some of my, obviously my favorite people,

my closest friends, and I can relate with them

probably because of that, sort of a big picture.

They don’t get sort of flustered.

They tend to be really good at figuring out

how to have quality time because we work really hard.

Our hours are significant.

And so the time with our families, our friends,

is less than we would like it to be.

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.

Even just texting with some of my friends

that are neurosurgeons, a great friend of mine

just became chairman at Duke,

and just connecting with him by text, which takes seconds,

we feel connected.

And I think that’s a trait amongst neurosurgeons.

We sort of know how to cut to the chase in a way

and prioritize our time.

It’s a skill that we probably have innately,

but it’s also part of the training.

When we are interns now,

there’s a lot of work hour regulations

that is probably quite appropriate, by the way.

I think our hours before were bordering on,

not necessarily, let’s just say they were not ideal

for mental health and sleep,

which we know are very important components.

Certainly, we had no time for meditation.

I definitely did not.

I wish I did.

Now, knowing what I know about meditation,

my wife’s a health coach.

I get it, I see it, I practice it myself with her.

I see the value.

I wish I had that tool when I was in training

because it’s stressful.

Even with the work hour restrictions,

we still don’t sleep very much.

We’re still at work a lot,

80 hours a week.

Throughout the entire career?

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.

That’s also a huge problem,

probably more of a problem.

And I’m joking a little bit.

I don’t necessarily think we’re abused,

but certainly our hours are significant.

But they come a bit more here and there.

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,

like you, those days tend to be a bit gentler

unless I’m grant writing.

Those days can be long, as you know.

So to answer your question,

I do think we’re sort of self-selected for it,

but I also think it’s part of the training.

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.

We learn to cope with our stress

and be efficient and prioritize things

despite the stress of it all.

And I think we take from that this sort of calm demeanor.

And perhaps it’s just amplifies

what we’re probably drawn to.

Because before we come to neurosurgery,

we might rotate in neurosurgery.

We might spend a month pretending to be a neurosurgeon,

learning from residents and faculty

that are practicing the specialty.

But prior to actually starting your training,

you never experienced anything

like being a resident in neurosurgery,

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.

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 your 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,

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.

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.

It is your toughest year because you’re young

and you’re inexperienced

and you don’t know what you don’t know.

And 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 just have to learn a lot

and you’re on call by yourself in the hospital.

And it’s a real challenge.

And I think that, personally,

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 Penn, at HUP, where I currently practice now.

And I remember I would see patients

anywhere from sort of the ground floor,

where the trauma bay was, or the ER,

all the way up to Founders 12th, the 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

and it became a great habit to have.

The problem with that, though,

was I paired that, unfortunately,

with 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,

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 attribute that to poor decision-making,

inexperience, 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 fiancee 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,

and 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 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 think that I’ve always related with the problems

that our patients have to a certain extent.

And when I’ve been most vulnerable,

which is when I was working the hardest

with the least amount of sleep,

I related with it the most.

And yes, exercise for me has always been my tool.

More recently, exercise, some strength training

I think is important compared with cardio.

I don’t do enough of either, but I definitely do some,

and that helps.

Meditation helps me a bit.

I do that every night before I go to sleep.

I use an app for it.

It’s probably not the best way to do meditation, but-

If it keeps you doing it regularly,

it’s the best way to do it.

Andrew, I couldn’t agree with you more.

It’s one of those things

where I look forward to it every night.

And 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, and she does the same to me

because I think we both value it.

I think that’s been very helpful.

And I didn’t have that tool probably when I needed it most,

but I have it now and it’s very helpful.

I really appreciate you sharing those tools

that a number of people, 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.

I hope so.

Well, certainly you need to be a physician

before you can become a neurosurgeon.

So, and 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 what you’ve shared today.

I really appreciate your mentioning

of the emphasis and appreciation on quality time.

I very much see this as quality time.

I know that our listeners 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.

You’re doing marvelous work.

We’ll point people to various places

they can find you online.

And should they need the help of your clinic,

to your clinic and your laboratory as well.

So on behalf of everybody 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

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and to his clinic,

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♪♪