Ep48 rebroadcast "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.
Welcome to Inner Cosmos.

Speaker 2 (00:38):
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. I mean,
just think about how easy it is to lose.

Speaker 2 (01:28):
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. This is a mood disorder. 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,

(02:40):
and they lose interest in the things that used to
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
tough en up.

Speaker 2 (03:20):
But the important lesson.

Speaker 1 (03:21):
From centuries of psychiatry and more recently neuroscience is that
it's not so easy. 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

(03:43):
a physical problem invites physical solutions. Now, my father was
a psychiatrist, and 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,

(04:06):
and that patient often could get out of bed again
and then get his job back and win his spouse back. Now,
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.

Speaker 2 (05:15):
Now, many of the sorts.

Speaker 1 (05:17):
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 to a
region of the brain from a tumor or a stroke

(05:38):
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 tens

(05:58):
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 city planners

(06:20):
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 over

(06:40):
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.

Speaker 2 (06:48):
The way that the city operates.

Speaker 1 (06:51):
And again, who you are and how you see, the
world comes from the way that the city of your
brain is operating. 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

(07:14):
are separate from it or able to ride above it.
So if you've 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

(07:36):
pervasive and societally important examples of these kind of subtle
changes to the brain is with depression.

Speaker 2 (07:44):
And so for this episode, I decided.

Speaker 1 (07:47):
To call my colleague Jonathan Downer, who is an incredibly
insightful and empathic observer.

Speaker 2 (07:53):
Of the brain.

Speaker 1 (07:54):
He has an MD and specializes in psychiatry, and he
also has a PhD in neuroscience, and one of his
areas of expertise is depression. And as it turns out,
Jonathan 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

(08:17):
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 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,

(08:39):
or perhaps yourself. It's a shockingly common challenge. 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 to 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 around 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 and
planted for her Parkinson's disease. They implanted the electrodes, one
on one side and one on the other, and during

(09:37):
the 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

(09:58):
turned it on. Nothing high 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 at 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
had landed on some other pathways that projected out to
a completely different part of the frontal lobes, and every

(11:33):
time they turned on and off this part of the
frontal lobes, the person would instantly going out of the sadness.
Now 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 very directly that there

(11:55):
was a 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 pattern 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,

(12:15):
and maybe even 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 can you define depression clinical depression?

Speaker 3 (12:27):
Sure? 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

(12:48):
some 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 up long 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

(13:10):
entering 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 start chasing you, then you
have to go beyond freeze. You have to go into
this sort of the flight mode should 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,
and 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

(15:53):
drop in their mood when they have an immunization, as
their immune system fires up to sort to deal with
the infection. But 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

(16:14):
at least hopefully 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,

(16:35):
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 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

(17:04):
swim after the ship for a 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

(17:26):
that something about the situation changes, hope 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

(17:46):
the mouse or whatever, is placed inside an air 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.

(18:08):
What's interesting is that there are breeds of mice who
are prone to depression and prone too 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 test, which is really just
a way of tapping into how long before the animal
switches into this mode of folding and giving up and

(18:29):
waiting for something to change. That approach is a 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?

Speaker 2 (18:51):
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, in 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

(19:16):
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 it numbers
for depression and suicidality going up, it's sort of an
index of a number of people who feel like they
are losing it life and that there's no way out

(20:33):
for them. 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

(20:53):
I wouldn't say anyone has solved the mysteries of what
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?
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 be 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,

(22:38):
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 a or an effort in boosing
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 it's 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,

(23:48):
and 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. We are starting to get really great

(24:10):
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 or underactive, and can actually stimulate them and

(24:34):
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,
and for the last twenty years, people have been pioneering
and starting to come up with ways that they can

(24:56):
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 to 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,
and so it would be really really useful if they
could undergo a different form of treatment that was non invasive.

(25:20):
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
place it looks like a little ping pong paddle. It's
sort of placed against the scalp. You place it over

(25:41):
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
your thumb, and I were to press the button and

(26:03):
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 reasons 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
you can reduce the strength of the connections and areas

(26:24):
that I guess are overconnected. 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 injects 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 simulator 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. 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
evaluate possible futures. What's your interpretation of what happens when
somebody is depressed in terms of the futures that they
are simulating. So that's a fascinating question, and I think

(28:15):
there actually are some really lovely brain imaging studies that
we're 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. The default mode network is named that
because it seems to be one of the most you know,

(28:36):
it's the area of the brain that is on by
default when we're not doing anything else. So if you
or I are 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.

Speaker 2 (28:53):
There are two pathways by which we do that.

Speaker 3 (28:55):
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 problems in my life, things that
I should be motivated to go and sort out. And

(29:18):
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 can both pursue opportunities in the future,
and we can also avoid threats and problems and resolve them.

(29:41):
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 bit of a loop from the frontal
lobes going down into the reward and motivational structures of

(30:02):
the brain and as if it gets stuck in a loop.
What happens is the person experience is just finding that
even though there may be 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, 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

(30:24):
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 we call by the technical term ruminations. So in depression,
this non reward pathway has gotten stuck in a loop,

(30:45):
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 MINDFULSS 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 in 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 3 (34:11):
Yeah. 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

(34:32):
TMS 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 is 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

(34:55):
ABAD 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 area, so
instead of stimulating the first area they 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 is and apply some pulses of stimulation, not

(36:02):
to 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 1 (36:11):
That's your interpretation of what transcrinal meganing 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. In 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. I 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. He says, it's

(37:22):
like I 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 weakened. So the circuit's still there and functioning,

(37:43):
but it's not 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

(38:04):
so 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.

Speaker 1 (38:40):
And so this 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

(39:00):
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 with 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 signed and frustrated, going, why are you fighting
us on this? I keep trying to tell you all

(39:24):
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
now that we know where this motivational cerguit lives, now
that we know where this non reward circuit lives, we

(40:06):
can 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

(40:27):
reward circuit 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 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

(40:49):
of the epilepsy within the brain. 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 guy, 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,

(41:11):
they just let them have negative 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

(41:31):
activity that was present when the brain 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

(41:53):
flip thelip the lip, just to 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

(42:15):
if their heart 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.

Speaker 2 (42:36):
And there's a.

Speaker 3 (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've 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

(43:37):
feels like, well, 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 bought. Thisis a depression where you know,
serotonin had something to do with your mood, and if
your mood was low, it was maybe because your serotonin

(44:18):
was low. 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 U to
have GI emotions in the brain, stomach can regulate nausea,

(44:42):
and the visual cortex it can do visual things. And
so there's no such thing as it 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 a circuit in the brain and blip

(45:03):
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 they often find that because they've
been depressed for twenty years, you know that they don't

(45:26):
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 figure out how the person
will adapt to a life that has hope in it.

Speaker 1 (45:46):
Again, Yeah, so you once told me how you see
the battle against depression in the twenty first century from
a historical point of view. 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

(46:07):
given time is about five percent.

Speaker 3 (46:09):
Now. 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 be 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, 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 stimulators

(47:33):
and everybody, not everybody wants them and just throw our
up sersons 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 TMS

(47:56):
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 verse 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 part of their

(48:17):
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

(48:38):
and has not done well on 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

(48:59):
have a tool that is now capable of treating most
people with depression and getting at least half of them
out of 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 dig into one more thing, because
you had talked. I've heard you talk 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 is 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

(50:09):
away 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.

Speaker 2 (50:16):
The rest of it.

Speaker 3 (50:16):
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, and the prevalence of tuberculosis improved
because people's lives improved, you know, better food, cleaner water,

(50:37):
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 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

(51:00):
idea that depression is the thing that happens when the
brain has decided it's in a battle for survival that
it's not going to win. Then we look at the
prevalence of depression is a number of people who look
around at their lives and concluded that they are in
an unwinnable situation. 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

(51:22):
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 the brain, but also develop stronger
societies in which we just have fewer percentages of people

(51:43):
who are trapped and fights for survival that they feel
it can 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 the phrase is to kun olam, and
it has been described to me as a religious injunction

(52:05):
to repair the world.

Speaker 2 (52:08):
Yeah I can't.

Speaker 3 (52:09):
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 and reduce despair everywhere. And so when
I think about the pathway to takun Olam and what
neuroscience can contribute to it, and what you know brain

(52:29):
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 than you think.

(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 discus, 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.