Ep48 "Why do brains become depressed?"

What is depression? Why are brains able to slip into it? Is depression detectable in animals? Do animals have options beyond fight or flight? And what does any of this have to do with measuring depression medications in city water supplies, reward pathways in the brain, the prevalence of tuberculosis, and zapping the head with magnetic stimulation? Join today's episode with David Eagleman and his guest -- psychiatrist Jonathan Downar -- for a deep dive into the brain science behind depression and what new solutions are on the horizon.

Episode Transcript

Speaker 1 (00:05):
What is depression and why are brains so easily able
to slip into it? Is depression detectable in animals? And
when we look across the animal kingdom do we see
options beyond fight or flight? And what does any of
this have to do with measuring depression medications in city

(00:25):
water supplies, or reward pathways in the brain, or the
prevalence of tuberculosis or zapping the head with magnetic stimulation.

Speaker 2 (00:37):
Welcome to Inner Cosmos with me David Eagleman.

Speaker 1 (00:40):
I'm a neuroscientist and an author at Stanford and in
these episodes we sail deeply into our three pound universe
to understand why and how our lives look the way
they do. Today's episode is about depression. We are going

(01:04):
to dive into the science behind it and we'll see
what new solutions are.

Speaker 2 (01:09):
On the horizon. So let me start by assuming way out.

Speaker 1 (01:13):
What fascinates me is not just what the brain can
accomplish in terms of our normal functioning, but also one
can't help but notice the fragility of the brain.

Speaker 2 (01:25):
I mean, just think about how easy it is to
lose consciousness when you hit your head.

Speaker 1 (01:30):
Or think about what happens when you drink alcohol and
your perception and your decision making changes, or you don't
get enough sleep, and how you behave and how you
decide these can become a little different. Or when you're
angry and you act differently, or if you consume psychedelic
drugs and your conscious experience changes entirely. What all this

(01:53):
tells us, I think, is that it's very easy for
the system to get knocked off its normal pathway. And
what's clear is that the brain puts an enormous amount
of effort into trying to stay operating in the normal range. Now,
given this context, one area that's fascinating and of massive

(02:15):
social importance is depression.

Speaker 2 (02:19):
This is a mood disorder.

Speaker 1 (02:21):
It affects how you feel, how you think, how you
handle your daily tasks, how you eat and sleep. People
with depression feel persistently sad. They often feel empty or anxious, pessimistic, hopeless, worthless, helpless,
and they lose interest in the things that used to

(02:43):
bring them joy. They're slowed down in all the aspects
of their life, and often there are thoughts of suicide. Now,
almost everyone has had someone in their life who has
suffered depression at some point, whether that's recognized or not.
And generally everyone's first intuition when they have a friend

(03:05):
or a loved one who becomes depressed is to talk
them out of it, to say, hey, things are okay,
snap out of it, look at the bright side. And
eventually you might be tempted to say, come on, just
toughen up. But the important lesson from centuries of psychiatry
and more recently neuroscience is that it's not so easy.

(03:27):
It's a physical problem. And that's why we talk about
mental illness nowadays exactly as we talk about a physical
illness like COVID or a broken leg, and that understanding
opens the door to different approaches, because a physical problem
invites physical solutions. Now, my father was a psychiatrist, and

(03:52):
he was always impressed that he could have a patient
who would be suffering from clinical depression and would lose
his job and maybe lose his spouse, and my father
can make a prescription like let's say prozac, and that
patient often could get out of bed again and then
get his job back and win his spouse back. Now,

(04:13):
how do we understand this, Well, it's an issue that
I talk about a lot, which is that we are
made up of small pieces and parts, And the thing
to appreciate is that you are the sum total of
all those pieces and parts.

Speaker 2 (04:26):
Whatever is going on.

Speaker 1 (04:28):
At this microscopic level is you and your mood and
your behavior. Now, why would anybody think that crazy statement
is true. Well, there are many things that we see
in the clinics every day which teach us this lesson.
People can get damage to their brains and they can
no longer understand how to use a mirror, or they

(04:50):
can no longer name furry animals, or they can no
longer see colors, or understand speech, or understand music or
any We have a million other things that we think
should just come for free in the world. Now, what
this exposes is that these are functions of the brain,
and even if a little bit of the brain is damaged,

(05:12):
then you can't perform that function anymore. Now, many of
the sorts of brain damage that you'll read about in
an exciting book about the brain, these are things that
most people won't see in their lifetimes. They won't know
any friend or relative who has these issues because they
are rare things to happen, and they usually involve damage

(05:34):
to a region of the brain from a tumor or
a stroke or a traumatic brain injury, and those things
represent big changes in the city of the brain, like
an entire block of New York City falling in an earthquake.
But there are much more subtle things that happen in
the brain as well, and these are changes that have
to do with the way the system runs, with its

(05:58):
tens of billions of neurons and trillions of synaptic connections.
So to return to the city analogy, imagine that instead
of big damage that you can see, the city still
looks the same, but parts of it are operating very
subtly differently. So the playwrights have all quit, and the

(06:19):
city planners have stopped planning, and the coffee shops are
closing two hours earlier, and all of this stuff impedes
the city's ability to thrive and be an active, well
functioning place for innovation and tourism. But it's all very subtle,
and if you looked at this from a drone flying

(06:39):
over the city, you really wouldn't see much of a difference.
It's small stuff that's happening at a small level, but
it changes the way that the city operates. And again,
who you are and how you see, the world comes
from the way that the city of your brain is operating.

(07:00):
In other words, the sum total of what's happening under
the hood your biology. And I think the reason this
is surprising is because we tend to think of ourselves
as being removed from our biology. You are separate from
it or able to ride above it. So if you've

(07:21):
ever known someone with depression, or had depression yourself, you
will know that you can't just say hey, come on,
cheer up, snap out of it. That doesn't suffice to
change the biology. And one of the most pervasive and
societally important examples of these kind of subtle changes to

(07:42):
the brain is with depression. And so for this episode,
I decided to call my colleague Jonathan Downer, who is
an incredibly insightful and empathic observer of the brain. He
has an MD and specializes in psychiatry, and he also
has a PhD in neurosci and one of his areas
of expertise is depression. And as it turns out, Jonathan

(08:06):
and I wrote a textbook together on cognitive neuroscience called
Brain and Behavior, and this is the textbook used at
Stanford and at universities worldwide. And the textbook covers a
lot of ground, but for today, I just want to
zoom in on depression. So I rang him up to
get his perspective on this issue that is not only

(08:27):
neuroscientifically important and fascinating, but also, unlike the strange deficits
that you might see only in a textbook, you almost
certainly know someone with depression, perhaps someone close to you,
or perhaps yourself.

Speaker 2 (08:40):
It's a shockingly common challenge.

Speaker 1 (08:43):
So let's dive in to understand it. So, Jonathan, how
did you get interested in studying depression?

Speaker 3 (08:55):
Well, it's a bit of an interesting story, David. You'd
have to go back about years too. When I was
a graduate student over at the Toronto Western Hospital. That
is a hospital that has a i guess a major
neurosurgical unit where they perform surgeries where they implant deep
brain stimulators, which are a bit like brain pacemakers, into

(09:15):
the brains of people with Parkinson's disease and other kinds
of neurological disorders. And in a round two thousand and two,
a patient came in who was a middle aged woman
who had previously suffered from depression but no longer. She
was coming in to have the deep brain stimulators implanted
for her Parkinson's disease. They implanted the electrodes, one on
one side and one on the other, and during the

(09:37):
surgery they turned them on to make sure that they
are succeeding in reducing the person's hand tremors or the
other tremors in their body that they're trying to have treated.
What was interesting is when they turned on the one
on one side, the opposite hands started to reduce in
its tremor and the tremor went away, which is exactly
what they expected to happen. On the other side, there
was something very strange happened as soon as they turned

(09:59):
it on. Nothing Hahigh up into her tremor whatsoever, and
instead she descended instantly into a deep despairing re experiencing
of her depression. It kicked him within seconds, and she
described it as a deep down, bad feeling in the
pit of my stomach. I wanted to cry, but I couldn't.
Someone could have come in to shoot me and I

(10:19):
wouldn't have cared. I couldn't have cared less. No, immediately
they turned the switch off again, and surprisingly, within seconds,
the sadness lifted again and they found themselves in a
very weird situation where every time they turned on this current,
the person would descend immediately within a few seconds into sadness,
and then every time they turned it off she would
be able to emerge within a few seconds. Again, it

(10:41):
was literally sadness the flip of the switch.

Speaker 2 (10:45):
Wow.

Speaker 1 (10:45):
And so that's what's got you started in researching that.

Speaker 2 (10:49):
So that's exactly it.

Speaker 3 (10:50):
So at the time I was doing my PhD using
a technology called functional functional MRI, which I'm sure you've
talked about on the podcast before, which is a way
of using MRI scanners to look at the brain activity
of people as various things happen. So the neuros versions
wanted to understand what was going on, So we went
down to where the functional MRIs were being done and

(11:12):
they turned on and off one of the switches on
the one side that affected the tremor, and they were
able to show a particular brain pathway that was affected
controlling the motor circuits of the brain, which was the
intended effect. On the other hemisphere, though the electrode was
just a few millimeters off and as a result, it
landed on some other pathways that projected out to a
completely different part of the front lobes, and every time

(11:33):
they turned on and off this part of the frontal lobes,
the person would instantly going out of the sadness. That
was happy news of the patient because they were able
to reposition the electrodes so that both electrodes did the
appropriate thing. But it got us thinking about what this
really meant about depression. All these theories at the time
that depression might be a chemical imbalance or this or that,
we really saw it very directly that there was a

(11:55):
question of the activity of the brain and that within seconds,
one pattern of activity the brain led to sadness, and
within seconds, if that padding of activity could somehow be
turned off, then the person's sadness would go away. And
that really got us thinking about whether we might start
being able to use things like brain stimulation to understand
what depression was about in the brain, and maybe even

(12:15):
to come up with a new generation of treatments that
work better than the medications and therapy of the time.

Speaker 2 (12:20):
Okay, terrific, So we'll talk about that.

Speaker 1 (12:23):
Let's start with you, can you define depression clinical depression?

Speaker 2 (12:27):
Sure?

Speaker 3 (12:28):
So, there are standardized definitions of depression that involve a
series of symptoms, the core of which is sad or
depressed mood most of the day most days, and the
second of which is a thing called anhedonia, which is
the inability to enjoy things or experience pleasure, a loss
of motivation, a loss of joy, a loss of the
brain's reward functions. In addition to that, there are some

(12:48):
standard symptoms that go along with that. Commonly, people will
have disturbances in their sleep or appetite, trouble with concentration,
They may have difficulty with their energy and fatigue levels,
and there are thoughts that come along of self harm
and suicide that there are obviously the most concerning parts
about the depression. So that's the standard sort of diagnostic
approach by which we determine whether somebody has been entering

(13:11):
into a period of depression. It's unfortunately, really common. At
any given time in North America, about five percent of
people are in the middle of a depressive episode, and
at least ten percent of people, perhaps more these days,
are going to go through an episode of depression at
some point in their lifetimes. Almost everybody will have somebody
they know who has been through depression or is going

(13:32):
through depression or will go through depression.

Speaker 1 (13:34):
So one of the things I want to talk about
is why this happens, What it is about the wiring
of the human brain that allows us to slip so
easily into that mode.

Speaker 2 (13:44):
What are your thoughts on that.

Speaker 3 (13:46):
It's a really fascinating question, And I think to answer that,
what we found is you can get a lot of
the clue to that looking at evolution or a biology,
because humans are not, by no means the only animals
that can go into it a spare like syndrome, I
mean depression. Most of us who have pets, and most
of us of animals who have seen situations where animals
can drop into a despair and stop eating and stop

(14:07):
sleeping and do all the same things and don't enjoy
the things they normally would. Something that looks a bit
like depression is detectable in dogs and cats and elephants
and zoo animals, and even in things like zebrafish, which
are tiny little vertebrates. So evolution seems to have put
a depression like mode there, you know, a very long
time ago, and it's one of the oldest circuits in

(14:28):
the brain. When we look at the circuitry that drives depression.
What we find is it falls into a bigger category
of circuits that help the brain to defend against threats.
And in a nutshell, for every living thing, whether you're
a fish or a raccoon or a human, there are
sort of four main categories of things you can do
if a threat comes along. So let's say you're a
fish swimming along and a shark shows up. The first

(14:50):
thing you can do is you can freeze and hope
the shark doesn't see you, So that's freeze mode. If
the shark sees you and starts chasing you, then you
have to go beyond freeze. You have to go into
this sort of the flight mode would be the escape mode,
and if the shark corners you. We've all seen that.
There are animals, you know, if you happen to get
a possum or a raccoon in your garage, there usually
will run away, But of course if they get cornered

(15:11):
and they feel like there's no way out, they will
fight very fiercely, and lots of animals do that. So
there is this third mode called fight. But the brain
needs a fourth mode to deal with situations that are unwinnable.
Sometimes you've tried freezing, you've tried fleeing, you've tried fighting.
But if at some point the brain decides you're not
going to win this fight and there's no running away,
there's no escaping, and you can't just ignore the problem,

(15:32):
the brain taps into a fourth mode that I'll call fold.
There's a passive threat defense mode where the instincts are
all about losing your confidence, running home and hiding in
your burrow and keeping your head down and hoping that
something changes. This is the mode that is turned on
when people are fighting off in illness or a major injury.
So if they have surgery or if they're fighting off
in illness. Some people will actually have a drop in

(15:53):
their mood when they have an immunization as their immune
system fires up to sort of to deal with the infection.
In any situation where the brain decides that it needs
to be hiding doubt in recovery and recovering and keeping
its head down, it will go into this fold mode.
Now that may be necessary to keep you out of
danger until the threat goes away, or at least hopefully

(16:15):
until the threat goes away. But the problem that comes
up in depression is when this becomes a self perpetuating
process and the circuits that drive fold mode, which is
a normal and useful defense mechanism for the threats we
can't win against. If those circuits get stuck in an
infinite feedback loop and just keep going and going, then
the person may still be stuck in depression weeks later,
months later, maybe even years later.

Speaker 1 (16:37):
You once give me an example of falling off a
ship in the middle of the night to illustrate this
fold mode.

Speaker 3 (16:44):
Yeah, so I wanted to. That's actually a great point.
So there are situations where we're we're going into this
mode is really useful, and every once in a while
we're reading the news about somebody who falls off the
back of a ship in the middle of the night
and then miraculously gets rescued in the morning. Now, if
you or I fell off the back of a ship
in the middle of the night, like a cruise ship
or something, we'd probably swim after the ship for a

(17:05):
while and scream for help and try and attract his attention.
But if it was really clear that the ship was
sailing away and no one could hear us, and we're
stuck in the middle of the sea, I mean we're
in a really bad situation. It's really risky, and this
is probably not going to work out well. But our
best chance of survival is actually to fold, to curl
up into a ball and just wait and save your
energy and hope that something about the situation changes, hope

(17:28):
you get rescued. That mode is the same mode that
we talk about when we talk about depression, and in fact,
when pharmaceutical companies are developing new medications for depression, one
of the ways that they'll do animal testing to see
if the molecule helps depression is whether a thing called
the forced swim test, and the forced swim test, the animal,
like the mouse or whatever, is placed inside an air

(17:50):
a little beaker where they have to swim around and
there's nothing to stand on. Now, mice are quite good swimmers,
and they're also quite good floaters, so they'll swim and
swim around, and eventually, at some point they'll realize that
they're not going to get out of this situation, and
so they stop swimming around and they just give up
and float. And at that point the experimenter will stop
the stop watch and see how many minutes that took.
What's interesting is that there are breeds of mice who

(18:11):
are prone to depression and prone to this are giving
up quickly, and most antidepressants, when the mice are on
the antidepressant still actually swim for a lot longer before
giving up. And so this forced swim tests, which is
really a way of tapping into how long before the
animal switches into this mode of folding and giving up
and waiting for something to change. That approach is a

(18:33):
long standing and standard way that people have searched for
new antidepressant medications over the last several decades.

Speaker 2 (18:40):
Okay, terrific.

Speaker 1 (18:41):
And so when we look at depression in this country
or around the world, what are the rates of depression? Like,
are things going up or down?

Speaker 3 (18:54):
Yeah, so it's unfortunate that, I mean, the encouraging thing
over the last few decades is that compared to say,
the nineteen eighties and the nineteen nineties when I started
doing brain imaging research, there's a lot less stigma around
mental health than there was, and that that's certainly very encouraging.
There are a lot more people seeking treatment than before,
and people are seeking treatments with medications and with psychotherapy

(19:15):
more more than ever. The problem is that this hasn't
changed the numbers at all. So despite the fact that
there's less stigma, despite the fact that people are coming
forward and taking antidepressants, and that in fact, antidepressants are
being used in sex quantities that they can be detected
with spectroscopes in the water supplies of cities and so on,
so they'll actually be able to go and they can

(19:36):
detect trace amounts of all these medications in city water supplies.
Despite all of this, the prevalence of depression and of
suicidal acts and suicidality has not gone down at all,
And in certain populations like younger folks under age twenty
and in the early twenties, the numbers for depression, anxiety,
and suicidality are going up rather than down. So we

(19:59):
definitely need to put the search on to understand how
depression works in the brain and really develop a new
generation of treatments because what we're having right now is
not moving the needle.

Speaker 2 (20:08):
Why do you suppose the numbers are going up?

Speaker 3 (20:12):
There are a lot of different possibilities for why that is.
I think we could probably have a whole other podcast
on what that is. In a nutshell, there are more
there seem to be more situations where people feel like
the fight is unwinnable. When I see that numbers for
depression and suicidality going up, it's sort of an index
of number of people who feel like they are losing
it life and that there's no way out for them.

(20:34):
So it is a bit of a barometer of social
health in that way. Some people have also attributed to
increased stressors around social media use and so on, and
some people have even attributed to things like changes in
the composition of the bacteria that live within our guts,
some of which appear to have a protective effect against depressions.
So there are a lot of theories out there, but
I wouldn't say anyone has solved the mysteries of what

(20:55):
it is. There are lots of people posing everything from
social factors to psychological factors to biological factors like literally
write down to the bacteria in a person's gut.

Speaker 1 (21:23):
So what do you think about the pharmaceutical treatments for depression?

Speaker 2 (21:27):
Are they are they useful? Are they neutral?

Speaker 3 (21:30):
Well, I would say that I can give you what
the numbers say. So if a person comes into their
family doctor with an episode of depression and they try
an antidepressant. There was a famous study about fifteen years
ago called star d Let out of the University of
Texas Southwestern and they found that about two thirds of
people could get to remission from depression after trying one

(21:53):
medication or two medications, or three medications or four medications
one after the other. But the numbers really drop precipit
so about one third of people would get better trying
the first medication they ever tried, only about one third
about a quarter of people would get better on the
second medication they tried. But by the time you've tried
two medications without success, the third and the fourth one
are down to, you know, around eight to twelve percent

(22:16):
success rates, not particularly high at all. So we're unfortunately
the situation where the medications tend to work by fairly
similar mechanisms in terms of boosting serotonin levels or boosting
nor at inefferent levels or dobamine levels and so on
and so. Yes, you try to influence the person's oppression
by influencing these neurotransmitters in the brain, but at least
one third of people don't get any benefit from them,

(22:37):
and unfortunately a lot of people relapse and a very
large percentage of people. About twenty five percent of people
stop taking medications early because of side effects. So I
don't want to run down medications because the upside is that,
you know, it's in some ways, it's quite remarkable that
you can take somebody who's despairing about where their life
is going, and all you ask them to do is

(22:58):
take ten seconds out of their day to take a
serotonin boosting medication or an or an effort in boosting
medication just at bedtime with their toothbrush, And it is
quite remarkable that just by doing that one little thing,
a certain percentity of people will emerge from depressed, dispar
and suicidality and be able to face the world again.
So that's the upside of it. The downside is that
there's also a very large number of people who don't

(23:18):
get better on the medications, and a very large number
of people who can't tolerate the medications.

Speaker 1 (23:22):
So tell me about recent breakthroughs that are understanding.

Speaker 3 (23:26):
So we're in what I would argue is actually one
of the most exciting periods of discovery within all of
within all of medicine, so psychiatry and in particular a
field called interventional psychiatry is now looking at all the
traditional disorders like depression, anxiety, and so on in terms
of brain circuitry and in terms of brain function, and

(23:48):
thanks to twenty five years of brain imaging research, we're
actually starting to get really lovely maps of where stuff
happens in the brain and what brain circuits are involved
in depression, anxiety, OCD, post traumatic stress disorder, or eating disorders,
pretty much most of the major categories of mental health disorders.

(24:08):
We are starting to get really great maps of what
areas of the brain are affected in them. The thing
that's making that knowledge useful is that we're also starting
to really take advantage now of a new generation of
brain stimulation treatments inspired by the kinds of cases that
I told you about at the beginning of our conversation,
which can go into those circuits which may be overactive

(24:31):
or underactive, and can actually stimulate them and reset them
back to their normal pattern of activity. So these new
generation of treatments are brain stimulation treatments, and what's important
about them is they're anatomically precise. Some of them, as
I mentioned before, involve implantable devices like deep brain stimulators,

(24:51):
and for the last twenty years, people have been pioneering
and starting to come up with ways that they can
actually implant little pacemakers in the brains of people who
have very serious forms of depression where nothing has worked,
and these deep brain stimulators have caused quite remarkable ability
of people that could turn around and immerge from their depression.
But of course we also have the issue that not
everybody wants to have a pacemaker and plant in their brain,

(25:13):
and so it would be really really useful if they
could undergo a different form of treatment that was non invasive.
And so the other kind of treatment that's really taking
off right now involves a treatment approved by the FDA
in two thousand and eight called transcranial magnetic stimulation. Transcranial
magnetic stimulation involves using a powerful focus magnetic pulse generator

(25:37):
placed it looks like a little ping pong paddle. It's
sort of placed against the scalp. You place it over
the target circuit that you want to stimulate, and with
the magnetic pulses you're able to actually stimulate and activate
target circuits in the brain without needing any surgery. They're
quite powerful, so even though they're magnetic pulses. These are
not fridge magnets. Like if you were to place this
paddle over the precise spot on your brain that moves

(26:00):
your thumb, and I were to press the button and
cause a couple of little pulses, you would actually see
your thumb or your hand move with every single pulse.
So these are ways of actually stimulating target reagions in
the brain. And by stimulating them over and over again
hundreds of times a day, you can gradually strengthen the
connections in areas of the brain that require strengthening, or

(26:22):
you can reduce the strength of the connections and areas
that I guess are over connected. And with these two approaches,
you can try to return the brain or reset the
brain back to its normal pattern of activity that occurs
when they are not in this mode of despair and folding.

Speaker 1 (26:39):
And how is this figured out? About which brain areas
to zap.

Speaker 3 (26:44):
So the work on this began all the way back
in the nineteen eighties when they started using pet scanners,
which inject a radioactive dye to look at the metabolism
of the brain, and they were able to compare the
brain activity of people with depression people who are not
in depression, and so the first maps of these came
out in the late nineteen eighties and early nineteen nineties,

(27:06):
and they pinpointed a set of areas in the frontal
lobes and also elsewhere in the brain that seemed to
be consistently underactive in people with depression. They also pinpointed
areas of the brain that were consistently overactive in people
with depression. Those ones appear to be deeper in and
this led to a new generation of treatments where people
use the transcranial magnetic stimulation devices to target the frontal

(27:29):
lobe areas near the surface because the magnetic pulses could
read them. They also went to the surgeons and began
using the deep brain stimulator electrodes, which despite their name
as stimulators, can actually be used to inhibit and disrupt
areas of the brain that are overactive, and so they
were able to implant these in the areas of the
brain that were deeper and overactive in depression and use

(27:51):
them to reset their activity.

Speaker 1 (27:53):
So I recently did an episode on how brains simulate
the future. This is one of the main jobs of
brains is to simulate and.

Speaker 2 (28:02):
Evaluate possible futures.

Speaker 1 (28:04):
What's your interpretation of what happens when somebody is depressed
in terms of the futures that they are simulating.

Speaker 3 (28:11):
So that's a fascinating question, and I think there actually
are some really lovely brain imaging studies that were done
on this about ten years ago, led by Adam Gazzale
and some other folks over at UCSF. What they noticed
was that perhaps in your discussion you talked about a
network of areas in the brain called the default mode network.

(28:32):
The default mode network is named that because it seems
to be one of the most you know, it's the
area of the brain that is on by default when
we're not doing anything else. So if you or I
were sitting in a room quietly and there's nothing going on,
our default mode network turns on. And as we've all
experienced that involved what happens in our minds is our
brains start thinking about the past and thinking about the
future and making plans and thinking about what may take place.

(28:53):
There are two pathways by which we do that. There's
a so called reward pathway where our brain thinks about
opportunities and things we might start to want or desire
to get us up out of our seats and get going.
But there's also a second pathway called the non reward pathway,
whose job it is entirely to think about non rewarding outcomes.
Things could go wrong, fires I have to put out

(29:14):
problems in my life, things that I should be motivated
to go and sort out. And we need both of
those to work in balance. So we both need the
ability to come up with ideas for opportunities and things
that we desire to do, but we also need to
be guided by all the problems in life, all the
things that we really need to be motivated to take
care of. And with a balance between those two, we

(29:35):
can both pursue opportunities in the future, and we can
also avoid threats and problems and resolve them. The problem
and depression occurs when this so called non reward pathway,
whose whole job is to think about all negative consequences,
things that are going wrong, things that could screw up,
It can get trapped into sort of self perpetuating feedback loop.
So the circuit in the brain is arranged as a

(29:56):
bit of a loop from the frontal lobes going down
into the reward and motivational structures of the brain and
as if it gets stuck in a loop. What happens
is the person experience is just finding that even though
there maybe ninety nine things that are going well in
the person's life, their brain will find the one thing
that's going wrong and it will get stuck on it,

(30:17):
and it will just loop on it over and over
and over again. I think most of us know somebody
as family, friends, colleagues, maybe even ourselves who tend to
do that, who are always really good at spotting the
one problem and getting stuck on it. But in depression
it becomes true to a pathological extent where they get
so stuck on it that even with effort, they cannot
pull themselves out of the negative circle of thoughts, which

(30:38):
we call by the technical term ruminations. So in depression,
this non reward pathway has gotten stuck in a loop,
and what the person experiences is an endless circle of
ruminations and self criticism and thoughts about all the possible
futures that will go wrong and all the past things
that have gone wrong. And it just becomes very difficult
to pull yourself out of this even when you need to.

Speaker 1 (31:00):
And so what is the transcranial magnetic stimulation doing when
you are hitting a particular area, is it giving a
second bite at the apple for that area to rewire?
Is it simply making the area more plastic so that
it has an opportunity to wire up in a more
beneficial way the next time around.

Speaker 3 (31:20):
So I'll give you our best guess as to what's
happening right now. As with many things in psychiatry, we
discovered that these things worked long before we actually figured
out why they worked. But the original areas of the
brain that we stimulated were targeted because they just seem
to be underactive in depression. So the theory was, look,
they're underactive, let's use this brain stimulator. Let's stimulate them,

(31:41):
let's turn them back on, and then all will be well.
Later on, we discovered that what these areas really seem
to be associated with is courage and resilience. In other words,
people who happened just by chance to have more gray
matter or more gray matter in these areas, they're more
resilient distress. They have better ability to cope. These brain
areas in the frontal lobes are engaged every time we

(32:04):
do a thing called cognitive control, which is our ability
to self regulate our thoughts and our behaviors and emotions.
In fact, for those of you who've tried MINDFULSS meditation,
if you've ever sat in a chair and tried to
not ruminate and tried to focus on your breathing. Every
time you notice that your mind is wandering, and you
shut down the ruminations and come back to your breathing again,
you turn on this network of areas. It looks like

(32:26):
what we're doing with TMS is actually not so much
pushing happiness into the brain or pulling anxiety out, but
more generally strengthening the very same network that is activated
when you do mindfulness meditation. And so when I talk
to patients about what it's like for them after the
TMS has worked, they talk a lot about how something
stressful happen this week, and normally it would have ruined

(32:47):
my whole week, but I noticed that I just got
over it. I kind of thought about it and realized
it wasn't as bad as and I was able to
kind of cope with it. They describe it as having
more coping capacity, And so it looks like the effects
of TMS on depression, at least with the standard areas,
might be somewhat indirect You're not so much pushing happiness
in or taking anxiety out, but you are strengthening a

(33:07):
sort of mental muscle for cognitive control. And as a result,
people just generally get better at self regulating their thoughts
and behaviors and emotions, and they can cope with more stress,
so things don't feel quite as defeating, things don't look
quite as bad.

Speaker 1 (33:20):
I've been sort of playing with a different interpretation slightly
about it, which is that you are, to phrase it colloquially,
you're sort of loosening up a network that has found
itself getting into a particular way, a particular structure, and
what you're doing is reintroducing plasticity to that area so

(33:41):
that you have a chance of things running correctly through there.
And with TMS, as we know, sometimes the first treatment
doesn't work, but the second treatment does. My view on
that is that it's possible that after the first time,
the system reconverges into to some pathological wiring, and then

(34:04):
you know, if you do it again, you're getting another
chance to have it find better wiring.

Speaker 2 (34:10):
Yeah.

Speaker 3 (34:11):
I'm really glad you brought that up, because I think
that actually lines up really well with a very recent
discovery that's still quite new about what is happening for
people who are trying a second form of OURTMS that
kicks in when the first one doesn't work. So when
I start rTMS, repetitive transcranial magnetic stimulation, it's effectively TMS

(34:33):
treatment but using these repetitive pulses. So some people will
call it rTMS, and some people will simply just abbreviate
it to TMS. But we're talking about using this non
invasive stimulation. So when a person goes through and does
the treatment using the standard parameters that I talked about,
sometimes it works, and yet there's a percentage of people
where it doesn't work. What we've noticed that those people
tend to have higher scales on rumination negative ruminations. A

(34:55):
Bad Life and a Lovely study came out by a
group led by Andy Lukter at You where he was
able to identify that these people have higher rumination scores.
They then move the coil to a different areas, so
instead of stimulating the first area that to talk about,
they go to a different brain area which actually sits
within this non reward circuit that we were talking about before,

(35:17):
and instead of trying to stimulate and strengthen it. Sure enough,
what they do is they try and inhibit and disrupt
the activity of this area. So they are trying to
disrupt and break up the feedback loop that they call
the non reward attractor state. It's in fact a professor
named Edmund Rolls out of Cambridge by the way just described,
He came up with a theory of depression which is
very similar to what you describe. He called it the

(35:39):
non reward attractor theory of depression. That non reward circuit.
The more it runs and the more it dwells on things,
the more it strengthens the connections in and of itself,
so it becomes self strengthening, self perpetuating, and you're just
going to get stuck in this so called attractor state
and not be able to get out of it. The
solution with TMS would be to put the coil over
those areas and apply some pulses of stimulation, not to

(36:02):
strengthen the pathway that's not what we want, but to
disrupt and weaken the connections through a neuroplasticity to the
point where the person can now pull themselves out again.

Speaker 2 (36:11):
That's your interpretation.

Speaker 1 (36:12):
Of what transcrinial megaing stimulation does, right.

Speaker 3 (36:15):
Yeah, so we're still figuring this out. But what we
think is that for some people, when you strengthen the
first circuit and they regain their cognitive control, that circuit
is connected to the non reward circuit, so they can
then use their cognitive control to do this work themselves
of popping themselves out at this tractor state and other people,
for whatever reason, these two pathways aren't really very well connected,
so they kind of operate independently. So you strengthen the

(36:38):
first pathway, they get more coping capacity, but the problem
is they're still stuck in these negative terminations. Then you
bring them back again you move the stimulator over to
this other pathway. I actually had a patient who described
as saying this for your first treatment didn't work, but
the second one you gave me over this non reward pathway.
He said, I'm definitely one of those people you talked
about who always finds the one negative thing the room.

(37:00):
And if I see it, it's like a negative he said,
it's like an escalator. I'm forcing it on the escalator
and ride it down, down, down, all the way to
the bottom. And then I'm just stuck there. That could
be stuck there for days or weeks. And after I
finished the course of treatment, something really horrible happened, and
I thought, oh boy, here we go. I'm going to
be dragged down the escalator, and it just didn't happen.
I noticed the way he said it.

Speaker 2 (37:21):
It's like I.

Speaker 3 (37:22):
Walked up to the top of this escalator, I saw
where it was going, and I realized I didn't want
to go down there, and so my brain just kept going.
And I think what's interesting on the brain imaging studies,
of course, is if you scan people before and after,
what you find is exactly what you described, that the
connections between within this circuit are actually getting disrupted and weekend,
so the circuit's still there and functioning, but it's not

(37:43):
getting stuck in this attractor state or this loop. So
I think it actually lines up really well with the
account you just described. In the one case, plasticity being
used to strengthen the person's ability to control their thoughts.
But if that doesn't work in the other case, you
can then go directly to the area that's stuck in
a loop in the first place and use another form
of plasticity. To weaken those connections and loosen them so

(38:05):
the person can come out of it again.

Speaker 1 (38:24):
This is very cool because originally with depression, I mean,
I think it's always been this way historically, that people,
let's say loved ones who are with somebody who's depressed,
feel like, hey, we should just be able to talk
to the person out of this, just say hey, look
at the bright side and so on.

Speaker 2 (38:38):
That doesn't work. And so this.

Speaker 1 (38:41):
Idea of being able to help somebody buy let's say,
loosening up circuits in the brain, doing other things, you know,
getting someone out of an attractor state non invasively is
so promising. What do you predict is going to be
the field in forty years from now when you're elderly.

Speaker 3 (39:03):
Oh wow, that's really interesting. I'll get to that in
a moment, but I want to just come back and
highlight that I think you've really hit the nail on
the head of this, that every one of us has
tried to talk someone who's despairing out of the respair.
We've all tried to do it, and we've all been
sort of stimied and frustrated, going, why are you fighting
us on this? Like I keep trying to tell you

(39:23):
all the things that are good in life and reminds
you of them, and it's almost like you want your
brain wants to just go to the one negative thing
and stuck there. You've had that experience in talking to somebody.
I'm sure we all have, and it comes back to
exactly that lesson that depression is a kind of motivated state.
It's the brain is turning this on because it thinks
that it needs to be in this survival mechanism of
just folding and giving up. It thinks that that's its

(39:46):
best chance of survival. And so it's a highly motivated state.
And you will not be able to talk somebody out
of it because their motivational circuitry literally has been hijacked
by the depression, and so just talking people out of
it doesn't work terribly well. But as you say, now
that we know where this motivational cirguit lives, now that
we know where this non reward circuit lives, we can

(40:06):
do all kinds of interventions. And you asked, what's it
going to look like in forty years. I don't think
there's going to be any one treatment that is just
universally what people use. I'll give you an example of that.
So recently, a couple of years ago, a team that
you see San Francisco, led by Catherine Scangos and colleagues.
They were able to go to this non reward circuit

(40:28):
in the brain that I talked about, and they took
people who had very severe depression and they did something
that I think is very kind of futuristic. First of all,
they brought them into a special monitoring ward in the
hospital and they implanted the little electrodes in their brain and
let them stay in the hospital for several days or weeks. Normally,
that's what you'll do in epilepsy patients if you were
trying to find the source of the epilepsy within the brain.

(40:50):
You'll put electrodes all over the brain and you'll let
them sit and you wait for them to have seizures,
and then you go back and reconstruct where they came
from so you can perform a surgery. And this guys,
they said, well, you know the folks of depression, these
folks are really depressed. They can't function, their suicidal you know,
they really need something just as drastic as this. So
they brought them in, they implanted the electrodes but instead
of waiting for seizures, they just let them have negative

(41:12):
thoughts and using a little app on their tablet, they
could constantly rate what their brain was thinking about, and
so you could see what kind of brain activity was
going on when they were having positive thoughts or negative thoughts.
And by doing that and using a machine learning algorithm,
they were able to detect the electrodes that showed particular
pattern of abnormal activity that was present when the brain

(41:33):
got sucked into those negative ruminations. When they did that,
they were then able to implant a deep brain stimulator
in that and it was a closed loop system, so
it was attached to a tiny little computer that would
that would detect when the brain had gone into this
abnormal rhythm of negative thoughts and it would just disrupt
the activity with about five or six seconds of stimulation.
So we just flip the blip the blip, just to

(41:54):
like when you tap on a microphone to break a
feedback loop. It was literally just tapping on that microphone
and saying, hey, stop it. We've used this approach in
the heart for a long time, so people have heart
rhythm problems, can wear things called implantable, have a surgery
to have an implantable a cardiac defibrillator, so something like
the defibrillator padals that you might see in the airport,
but this is actually implanted inside. So if their heart

(42:15):
ever gets stuck in an abnormal rhythm that might be fatal,
the device will automatically detect that the heart's in that
rhythm and just give a few blips to reset it.
So interestingly, they were doing the same thing in the brain,
these folks that effectively created an implantable brain defibrillator, and
so it was detecting when this abnormal pattern comes along,
they blip it for a few seconds. And there's a

(42:37):
lovely article in the New York Times a couple of
years ago where they interviewed the patient describe what it
was like, and they talked about it as being a
sort of you're about to get sucked down into these
negative thoughts, and she said, suddenly the rational side of
you comes on and those negative emotions can be separated
from your real situation. What was encouraging is that this
seems to this process of implanting these stimulators seems to

(42:58):
work even in people who have had depression for decades
and have tried every other treatment available, multiple medications, therapies, TMS,
even electric convulsive therapy, all kinds of things. So people
have really gotten nowhere with the other treatments using this
targeted intelligent approach. I think that really is sort of
the prototype of what the future looks like.

Speaker 1 (43:17):
Yeah, I think one of the most amazing things about this.
Many listeners will already sort of be aware of this research,
but generally we think of ourselves and our personalities and
our thoughts and our emotions as something different from let's
say our heart and how is our heart functioning? And
you can defibrillate the heart, but the brain it feels like, well,

(43:39):
that's me, that's just who I am, and so on.
And it's sort of an amazing revelation that many people
have when they start seeing this sort of data to
understand that we are physical creatures, and when you do
things to change the physical structure, that changes who you
are in that moment.

Speaker 3 (43:58):
I think that's spot on, And that comes back to
the story we told at the beginning of why it
was so interesting for me as a as a young
researcher that you know, at that time many years ago,
we really there were the default idea was this thing
called the serotonin bothesis of depression, where you know, serotonin
had something to do with your mood, and if your
mood was low, it was maybe because your serotonin was low.

(44:18):
You you know, didn't have enough serotonin in your soup.
So we should get out a serotonin shaker and we
should shake some put some more serotonin into your soup,
and that will somehow just you know, make your mood
get better. But it turns out, of course, it's not
as simple as that, the serotonin is not mood. Serotonin
in you know, in your in your GI tract will
will cause your you know, to have to have GI

(44:39):
emotions in the brain. Stomach can regulate nausea, and the
visual cortex it can do visual things. And so there's
no such thing as a really where mood is just
boiled down to not having enough of a molecule in place.
But when we looked at those cases, as you said,
where people who had been depressed for so long that
they thought it was just part of who they were,
they then have this experience where you literally just take

(45:01):
a circuit in the brain and blip it and reset it,
and the person immediately in their thoughts is no longer
getting stuck in the negative thoughts and can look past
the one thing that's going wrong to the other ninety
nine things that are going right through that clear sort
of logical way, And you're right, people do really find
it as a revelation, and people who improve on these

(45:21):
they often find that because they've been depressed for twenty years,
you know that they don't It can be actually quite
a lot of work to sit down with a person
and figure out how to reconstruct their life based on
the premise that they actually get up every day and
feel good and ready to do things. They have spent
twenty years building a life around disability, so it's not
something where so there often can be quite a lot
of work done over months or years to try and

(45:43):
figure out how the person will adapt to a life
that has hope in it. Again, Yeah, so you.

Speaker 1 (45:49):
Once told me how you see the battle against depression
in the twenty first century from a historical point of view.

Speaker 3 (45:57):
Yeah, so, I mean, let's come back to those we
talked about earlier on where we said that there's the
prevalence of depression over the lifetime is maybe ten percent,
and the prevalence at any given time is about five percent.

Speaker 2 (46:09):
Now.

Speaker 3 (46:09):
There are lots of diseases in the history of medicine
where the prevalence has come down a lot, So people
used to be a lot of people. Tuberculosis, that's come
down a lot, and we're now making progress against malaria.
We're making progress against various forms of hepatitis. We're making
progress against stomach alsers that used to sometimes be fatal
if they progress. And for each of these things we

(46:29):
now have effective treatments and the prevalence has come down.
Even for HIV, something that was once untreatable and uncontrollable
is now turned into something that is controllable, and that
over time we may be able to get the prevalences down.
So the dream for us, I think for the twenty
first century would view that we would like, you know,
at the end of our careers forty years from now,
as you said, we'd like to be able to look

(46:50):
back at the prevalence of depression and anxiety and other
mental health disorders and say, look at that we used
to be at five or ten percent, and look how
much numbers come down since then. Millions of people who
had no pathway forward now see. Depression is something that
is treatable, and employers no longer look at depression as

(47:11):
something that would disqualify you from being hired for a job.
Oh you have depression, that's okay and not the end
of the world. Just go in and get the course
of treatment and we'll see you. We'll see you back
in a week or two. So you know, this will
help to erode the stigma, and I think we'll really
get to see the numbers coming down on this. Are
we going to get those millions of people better with
deep brain stimulators alone? No, of course not. We're not
going to be implanting millions and millions of deep brain

(47:33):
stimulators and everybody, not everybody wants them and just throw
on up serasons to do that. But I think we
do have a real opportunity using the non invasive forms
of brain stimulation like TMS, which are getting you know,
very very good as well. So your colleague over at
over at Stanford are one of my good friends. Nolan
Williams was instrumental in developing a radical new form of

(47:55):
TMS treatment that could take a person from severe depression
on money day all the way down to being in
remission in literally five days. The secret was to do
two things. The first was not to do a treatment
once a day traditionally, but to do up to ten
treatments a day, so that a person can have thirty
or forty or fifty treatments in a week and that's
definitely enough TMS sessions to get them better. The second

(48:17):
part of their trick was actually performed some brain imaging
in the person so you could see what pathways to
be targeting and then fine tune and personalized where the
coil is. Through some combination of those two things, they
seem to be hitting very high success rates that are
north of fifty percent. So we have a tool now
with TMS that if you know someone who has struggled
with depression or anxiety and has not done well on

(48:39):
therapy or medications, that's a lot of people. They can
go anywhere in the United States right now to a
TMS clinic and they can undergo a course of transcradial
magnetic simulation. And with the most recent FD protocols, we
believe that we can get more than fifty percent of
people to remission even if nothing else has worked. So
we do think we have a tool that is now

(49:00):
capable of treating most people with depression and getting at
least half of them out of the depression, maybe more.
The trick is going to be to scale that. So
it's scaling up so that everyone in the country will
have access to this treatment. Once we're there, I think
we will absolutely see improvements in the prevalence in our lifetimes.

Speaker 1 (49:18):
It's great, Hey, just think into one more thing, because
you'd talked I've heard you talked before about tuberculosis and
the parallel there.

Speaker 3 (49:28):
Yeah, so that's an interesting thing. It is possible. I
guess that our battle against depression in the twenty first
century is really a little bit like the battle against
tuberculosis in the nineteenth and the twentieth century. One of
the pioneers of modern medicine the nineteenth century physician Sir
William Osler. He, of course saw many patients in his

(49:48):
career with tuberculosis coming from the poorer areas of town,
the overcrowded areas and so on, the places where living
conditions were terrible, where sanitation was terrible, and as a result,
he described tuberculosis as primarily quote a social disease with
a medical aspect. In other words, yes, we can treat
it medically, but fundamentally, tuberculosis isn't going to go away

(50:10):
until people have better living conditions, until you don't have
eight people living in one room, until people aren't with
bad food, and all the rest of it. So, in fact,
although tuberculosis drugs were developed in the twentieth century and
save millions of lives when they're invented, the reality is
that the rates of tuberculosis were coming down decades before
any of these drugs were ever ruled out to reach people,

(50:31):
and the prevalence of tuberculosis improved because people's lives improved,
you know, better food, cleaner water, less crowded living conditions,
less dire poverty, less desperation, And I think we're going
to see that a very similar thing is happening here.
It's not that we won't be able to use new
technologies like brain stimulation to pull people out of despair,
but it's also possible that a key to getting people

(50:52):
out of despair will be to understand depression also as
to some degree a social disease with a medical aspect.
If we go back to the idea that depression is
the thing that happens when the brain has decided it's
in a battle for survival that it is not going
to win. Then we look at the prevalence of depression
as a number of people who look around at their
lives and concluded that they are in an unwinnable situation.

(51:14):
And I believe in the same way that we part
of the pathway to getting people out of depression and
reducing its prevalence will be improving the conditions of people's lives.
They're the degree to which they feel secure, a degree
to which they don't feel like they're going to lose
their housing or to be under threat of violence. The
first places in the world to overcome depression will be
the ones that don't just develop better technologies to reset

(51:38):
the brain, but also develop stronger societies in which we
just have fewer percentages of people who are trapped in
fights for survival that they feel like it never seem
to win. And I guess that's maybe. There is a
concept which one of my colleagues introduced me to from
the history of Judaism, and it's a lovely phrase that
I guess really carry around with me all day. It's

(52:00):
the phrase is to kun olam, and it has been
described to me as a religious injunction to repair the world. Yeah,
I can't. I think you and I have also discussed
this in the past as well. Yeah, so yeah, when
we talk about resetting the brain, I think that falls
within the larser of battles to try and improve the
lot of humanity and reduce the reduce despair everywhere. And

(52:23):
so when I think about the pathway to takun Olam
and what neuroscience can contribute to it, and what you
know brain stimulation can contribute to it, I think it
has an essential role in reducing the number of people
who face the world in despair, and that will be
an essential component of this much larger injunction to repair
the world, which I think we can all relate to.

Speaker 1 (52:48):
I spend many of these episodes talking about the extraordinary
things that the brain does well, but it's equally important
to talk about what happens when the brain gets off,
because some percentage of your friends and loved ones are
going to have to battle depression at some point, and
it might be a slightly higher percentage.

Speaker 2 (53:10):
Than you think.

Speaker 1 (53:11):
The brain is incredible, but fragile, and what we see
from depression is that it's relatively easy for it to
slip out of its optimal operating range. Happily, neuroscience labs
all over the world are working to understand this, and
researchers and companies are generating new approaches, as with transcranial

(53:36):
magnetic stimulation, such that as we move forward, we will
have increasingly better ways to get things back on track.
Go to Eagleman dot com slash podcast for more information
and to find further reading. Send me an email at

(53:57):
podcasts at eagleman dot com with questions or discuss ession
and I'll be making monthly episodes in which I address
those and check out and subscribe to Inner Cosmos on
YouTube for videos of each episode and to leave comments
until next time. I'm David Eagleman, and this is Inner Cosmos.