Speaker 1: What is depression and why are brains so easily able
Speaker 1: to slip into it? Is depression detectable in animals? And
Speaker 1: when we look across the animal kingdom do we see
Speaker 1: options beyond fight or flight? And what does any of
Speaker 1: this have to do with measuring depression medications in city
Speaker 1: water supplies, or reward pathways in the brain, or the
Speaker 1: prevalence of tuberculosis or zapping the head with magnetic stimulation.
Speaker 2: Welcome to Inner Cosmos with me David Eagleman.
Speaker 1: I'm a neuroscientist and an author at Stanford and in
Speaker 1: these episodes we sail deeply into our three pound universe
Speaker 1: to understand why and how our lives look the way
Speaker 1: they do. Today's episode is about depression. We are going
Speaker 1: to dive into the science behind it and we'll see
Speaker 1: what new solutions are.
Speaker 2: On the horizon. So let me start by assuming way out.
Speaker 1: What fascinates me is not just what the brain can
Speaker 1: accomplish in terms of our normal functioning, but also one
Speaker 1: can't help but notice the fragility of the brain.
Speaker 2: I mean, just think about how easy it is to
Speaker 2: lose consciousness when you hit your head.
Speaker 1: Or think about what happens when you drink alcohol and
Speaker 1: your perception and your decision making changes, or you don't
Speaker 1: get enough sleep, and how you behave and how you
Speaker 1: decide these can become a little different. Or when you're
Speaker 1: angry and you act differently, or if you consume psychedelic
Speaker 1: drugs and your conscious experience changes entirely. What all this
Speaker 1: tells us, I think, is that it's very easy for
Speaker 1: the system to get knocked off its normal pathway. And
Speaker 1: what's clear is that the brain puts an enormous amount
Speaker 1: of effort into trying to stay operating in the normal range. Now,
Speaker 1: given this context, one area that's fascinating and of massive
Speaker 1: social importance is depression.
Speaker 2: This is a mood disorder.
Speaker 1: It affects how you feel, how you think, how you
Speaker 1: handle your daily tasks, how you eat and sleep. People
Speaker 1: with depression feel persistently sad. They often feel empty or anxious, pessimistic, hopeless, worthless, helpless,
Speaker 1: and they lose interest in the things that used to
Speaker 1: bring them joy. They're slowed down in all the aspects
Speaker 1: of their life, and often there are thoughts of suicide. Now,
Speaker 1: almost everyone has had someone in their life who has
Speaker 1: suffered depression at some point, whether that's recognized or not.
Speaker 1: And generally everyone's first intuition when they have a friend
Speaker 1: or a loved one who becomes depressed is to talk
Speaker 1: them out of it, to say, hey, things are okay,
Speaker 1: snap out of it, look at the bright side. And
Speaker 1: eventually you might be tempted to say, come on, just
Speaker 1: toughen up. But the important lesson from centuries of psychiatry
Speaker 1: and more recently neuroscience is that it's not so easy.
Speaker 1: It's a physical problem. And that's why we talk about
Speaker 1: mental illness nowadays exactly as we talk about a physical
Speaker 1: illness like COVID or a broken leg, and that understanding
Speaker 1: opens the door to different approaches, because a physical problem
Speaker 1: invites physical solutions. Now, my father was a psychiatrist, and
Speaker 1: he was always impressed that he could have a patient
Speaker 1: who would be suffering from clinical depression and would lose
Speaker 1: his job and maybe lose his spouse, and my father
Speaker 1: can make a prescription like let's say prozac, and that
Speaker 1: patient often could get out of bed again and then
Speaker 1: get his job back and win his spouse back. Now,
Speaker 1: how do we understand this, Well, it's an issue that
Speaker 1: I talk about a lot, which is that we are
Speaker 1: made up of small pieces and parts, And the thing
Speaker 1: to appreciate is that you are the sum total of
Speaker 1: all those pieces and parts.
Speaker 2: Whatever is going on.
Speaker 1: At this microscopic level is you and your mood and
Speaker 1: your behavior. Now, why would anybody think that crazy statement
Speaker 1: is true. Well, there are many things that we see
Speaker 1: in the clinics every day which teach us this lesson.
Speaker 1: People can get damage to their brains and they can
Speaker 1: no longer understand how to use a mirror, or they
Speaker 1: can no longer name furry animals, or they can no
Speaker 1: longer see colors, or understand speech, or understand music or
Speaker 1: any We have a million other things that we think
Speaker 1: should just come for free in the world. Now, what
Speaker 1: this exposes is that these are functions of the brain,
Speaker 1: and even if a little bit of the brain is damaged,
Speaker 1: then you can't perform that function anymore. Now, many of
Speaker 1: the sorts of brain damage that you'll read about in
Speaker 1: an exciting book about the brain, these are things that
Speaker 1: most people won't see in their lifetimes. They won't know
Speaker 1: any friend or relative who has these issues because they
Speaker 1: are rare things to happen, and they usually involve damage
Speaker 1: to a region of the brain from a tumor or
Speaker 1: a stroke or a traumatic brain injury, and those things
Speaker 1: represent big changes in the city of the brain, like
Speaker 1: an entire block of New York City falling in an earthquake.
Speaker 1: But there are much more subtle things that happen in
Speaker 1: the brain as well, and these are changes that have
Speaker 1: to do with the way the system runs, with its
Speaker 1: tens of billions of neurons and trillions of synaptic connections.
Speaker 1: So to return to the city analogy, imagine that instead
Speaker 1: of big damage that you can see, the city still
Speaker 1: looks the same, but parts of it are operating very
Speaker 1: subtly differently. So the playwrights have all quit, and the
Speaker 1: city planners have stopped planning, and the coffee shops are
Speaker 1: closing two hours earlier, and all of this stuff impedes
Speaker 1: the city's ability to thrive and be an active, well
Speaker 1: functioning place for innovation and tourism. But it's all very subtle,
Speaker 1: and if you looked at this from a drone flying
Speaker 1: over the city, you really wouldn't see much of a difference.
Speaker 1: It's small stuff that's happening at a small level, but
Speaker 1: it changes the way that the city operates. And again,
Speaker 1: who you are and how you see, the world comes
Speaker 1: from the way that the city of your brain is operating.
Speaker 1: In other words, the sum total of what's happening under
Speaker 1: the hood your biology. And I think the reason this
Speaker 1: is surprising is because we tend to think of ourselves
Speaker 1: as being removed from our biology. You are separate from
Speaker 1: it or able to ride above it. So if you've
Speaker 1: ever known someone with depression, or had depression yourself, you
Speaker 1: will know that you can't just say hey, come on,
Speaker 1: cheer up, snap out of it. That doesn't suffice to
Speaker 1: change the biology. And one of the most pervasive and
Speaker 1: societally important examples of these kind of subtle changes to
Speaker 1: the brain is with depression. And so for this episode,
Speaker 1: I decided to call my colleague Jonathan Downer, who is
Speaker 1: an incredibly insightful and empathic observer of the brain. He
Speaker 1: has an MD and specializes in psychiatry, and he also
Speaker 1: has a PhD in neurosci and one of his areas
Speaker 1: of expertise is depression. And as it turns out, Jonathan
Speaker 1: and I wrote a textbook together on cognitive neuroscience called
Speaker 1: Brain and Behavior, and this is the textbook used at
Speaker 1: Stanford and at universities worldwide. And the textbook covers a
Speaker 1: lot of ground, but for today, I just want to
Speaker 1: zoom in on depression. So I rang him up to
Speaker 1: get his perspective on this issue that is not only
Speaker 1: neuroscientifically important and fascinating, but also, unlike the strange deficits
Speaker 1: that you might see only in a textbook, you almost
Speaker 1: certainly know someone with depression, perhaps someone close to you,
Speaker 1: or perhaps yourself.
Speaker 2: It's a shockingly common challenge.
Speaker 1: So let's dive in to understand it. So, Jonathan, how
Speaker 1: did you get interested in studying depression?
Speaker 3: Well, it's a bit of an interesting story, David. You'd
Speaker 3: have to go back about years too. When I was
Speaker 3: a graduate student over at the Toronto Western Hospital. That
Speaker 3: is a hospital that has a i guess a major
Speaker 3: neurosurgical unit where they perform surgeries where they implant deep
Speaker 3: brain stimulators, which are a bit like brain pacemakers, into
Speaker 3: the brains of people with Parkinson's disease and other kinds
Speaker 3: of neurological disorders. And in a round two thousand and two,
Speaker 3: a patient came in who was a middle aged woman
Speaker 3: who had previously suffered from depression but no longer. She
Speaker 3: was coming in to have the deep brain stimulators implanted
Speaker 3: for her Parkinson's disease. They implanted the electrodes, one on
Speaker 3: one side and one on the other, and during the
Speaker 3: surgery they turned them on to make sure that they
Speaker 3: are succeeding in reducing the person's hand tremors or the
Speaker 3: other tremors in their body that they're trying to have treated.
Speaker 3: What was interesting is when they turned on the one
Speaker 3: on one side, the opposite hands started to reduce in
Speaker 3: its tremor and the tremor went away, which is exactly
Speaker 3: what they expected to happen. On the other side, there
Speaker 3: was something very strange happened as soon as they turned
Speaker 3: it on. Nothing Hahigh up into her tremor whatsoever, and
Speaker 3: instead she descended instantly into a deep despairing re experiencing
Speaker 3: of her depression. It kicked him within seconds, and she
Speaker 3: described it as a deep down, bad feeling in the
Speaker 3: pit of my stomach. I wanted to cry, but I couldn't.
Speaker 3: Someone could have come in to shoot me and I
Speaker 3: wouldn't have cared. I couldn't have cared less. No, immediately
Speaker 3: they turned the switch off again, and surprisingly, within seconds,
Speaker 3: the sadness lifted again and they found themselves in a
Speaker 3: very weird situation where every time they turned on this current,
Speaker 3: the person would descend immediately within a few seconds into sadness,
Speaker 3: and then every time they turned it off she would
Speaker 3: be able to emerge within a few seconds. Again, it
Speaker 3: was literally sadness the flip of the switch.
Speaker 2: Wow.
Speaker 1: And so that's what's got you started in researching that.
Speaker 2: So that's exactly it.
Speaker 3: So at the time I was doing my PhD using
Speaker 3: a technology called functional functional MRI, which I'm sure you've
Speaker 3: talked about on the podcast before, which is a way
Speaker 3: of using MRI scanners to look at the brain activity
Speaker 3: of people as various things happen. So the neuros versions
Speaker 3: wanted to understand what was going on, So we went
Speaker 3: down to where the functional MRIs were being done and
Speaker 3: they turned on and off one of the switches on
Speaker 3: the one side that affected the tremor, and they were
Speaker 3: able to show a particular brain pathway that was affected
Speaker 3: controlling the motor circuits of the brain, which was the
Speaker 3: intended effect. On the other hemisphere, though the electrode was
Speaker 3: just a few millimeters off and as a result, it
Speaker 3: landed on some other pathways that projected out to a
Speaker 3: completely different part of the front lobes, and every time
Speaker 3: they turned on and off this part of the frontal lobes,
Speaker 3: the person would instantly going out of the sadness. That
Speaker 3: was happy news of the patient because they were able
Speaker 3: to reposition the electrodes so that both electrodes did the
Speaker 3: appropriate thing. But it got us thinking about what this
Speaker 3: really meant about depression. All these theories at the time
Speaker 3: that depression might be a chemical imbalance or this or that,
Speaker 3: we really saw it very directly that there was a
Speaker 3: question of the activity of the brain and that within seconds,
Speaker 3: one pattern of activity the brain led to sadness, and
Speaker 3: within seconds, if that padding of activity could somehow be
Speaker 3: turned off, then the person's sadness would go away. And
Speaker 3: that really got us thinking about whether we might start
Speaker 3: being able to use things like brain stimulation to understand
Speaker 3: what depression was about in the brain, and maybe even
Speaker 3: to come up with a new generation of treatments that
Speaker 3: work better than the medications and therapy of the time.
Speaker 2: Okay, terrific, So we'll talk about that.
Speaker 1: Let's start with you, can you define depression clinical depression?
Speaker 2: Sure?
Speaker 3: So, there are standardized definitions of depression that involve a
Speaker 3: series of symptoms, the core of which is sad or
Speaker 3: depressed mood most of the day most days, and the
Speaker 3: second of which is a thing called anhedonia, which is
Speaker 3: the inability to enjoy things or experience pleasure, a loss
Speaker 3: of motivation, a loss of joy, a loss of the
Speaker 3: brain's reward functions. In addition to that, there are some
Speaker 3: standard symptoms that go along with that. Commonly, people will
Speaker 3: have disturbances in their sleep or appetite, trouble with concentration,
Speaker 3: They may have difficulty with their energy and fatigue levels,
Speaker 3: and there are thoughts that come along of self harm
Speaker 3: and suicide that there are obviously the most concerning parts
Speaker 3: about the depression. So that's the standard sort of diagnostic
Speaker 3: approach by which we determine whether somebody has been entering
Speaker 3: into a period of depression. It's unfortunately, really common. At
Speaker 3: any given time in North America, about five percent of
Speaker 3: people are in the middle of a depressive episode, and
Speaker 3: at least ten percent of people, perhaps more these days,
Speaker 3: are going to go through an episode of depression at
Speaker 3: some point in their lifetimes. Almost everybody will have somebody
Speaker 3: they know who has been through depression or is going
Speaker 3: through depression or will go through depression.
Speaker 1: So one of the things I want to talk about
Speaker 1: is why this happens, What it is about the wiring
Speaker 1: of the human brain that allows us to slip so
Speaker 1: easily into that mode.
Speaker 2: What are your thoughts on that.
Speaker 3: It's a really fascinating question, And I think to answer that,
Speaker 3: what we found is you can get a lot of
Speaker 3: the clue to that looking at evolution or a biology,
Speaker 3: because humans are not, by no means the only animals
Speaker 3: that can go into it a spare like syndrome, I
Speaker 3: mean depression. Most of us who have pets, and most
Speaker 3: of us of animals who have seen situations where animals
Speaker 3: can drop into a despair and stop eating and stop
Speaker 3: sleeping and do all the same things and don't enjoy
Speaker 3: the things they normally would. Something that looks a bit
Speaker 3: like depression is detectable in dogs and cats and elephants
Speaker 3: and zoo animals, and even in things like zebrafish, which
Speaker 3: are tiny little vertebrates. So evolution seems to have put
Speaker 3: a depression like mode there, you know, a very long
Speaker 3: time ago, and it's one of the oldest circuits in
Speaker 3: the brain. When we look at the circuitry that drives depression.
Speaker 3: What we find is it falls into a bigger category
Speaker 3: of circuits that help the brain to defend against threats.
Speaker 3: And in a nutshell, for every living thing, whether you're
Speaker 3: a fish or a raccoon or a human, there are
Speaker 3: sort of four main categories of things you can do
Speaker 3: if a threat comes along. So let's say you're a
Speaker 3: fish swimming along and a shark shows up. The first
Speaker 3: thing you can do is you can freeze and hope
Speaker 3: the shark doesn't see you, So that's freeze mode. If
Speaker 3: the shark sees you and starts chasing you, then you
Speaker 3: have to go beyond freeze. You have to go into
Speaker 3: this sort of the flight mode would be the escape mode,
Speaker 3: and if the shark corners you. We've all seen that.
Speaker 3: There are animals, you know, if you happen to get
Speaker 3: a possum or a raccoon in your garage, there usually
Speaker 3: will run away, But of course if they get cornered
Speaker 3: and they feel like there's no way out, they will
Speaker 3: fight very fiercely, and lots of animals do that. So
Speaker 3: there is this third mode called fight. But the brain
Speaker 3: needs a fourth mode to deal with situations that are unwinnable.
Speaker 3: Sometimes you've tried freezing, you've tried fleeing, you've tried fighting.
Speaker 3: But if at some point the brain decides you're not
Speaker 3: going to win this fight and there's no running away,
Speaker 3: there's no escaping, and you can't just ignore the problem,
Speaker 3: the brain taps into a fourth mode that I'll call fold.
Speaker 3: There's a passive threat defense mode where the instincts are
Speaker 3: all about losing your confidence, running home and hiding in
Speaker 3: your burrow and keeping your head down and hoping that
Speaker 3: something changes. This is the mode that is turned on
Speaker 3: when people are fighting off in illness or a major injury.
Speaker 3: So if they have surgery or if they're fighting off
Speaker 3: in illness. Some people will actually have a drop in
Speaker 3: their mood when they have an immunization as their immune
Speaker 3: system fires up to sort of to deal with the infection.
Speaker 3: In any situation where the brain decides that it needs
Speaker 3: to be hiding doubt in recovery and recovering and keeping
Speaker 3: its head down, it will go into this fold mode.
Speaker 3: Now that may be necessary to keep you out of
Speaker 3: danger until the threat goes away, or at least hopefully
Speaker 3: until the threat goes away. But the problem that comes
Speaker 3: up in depression is when this becomes a self perpetuating
Speaker 3: process and the circuits that drive fold mode, which is
Speaker 3: a normal and useful defense mechanism for the threats we
Speaker 3: can't win against. If those circuits get stuck in an
Speaker 3: infinite feedback loop and just keep going and going, then
Speaker 3: the person may still be stuck in depression weeks later,
Speaker 3: months later, maybe even years later.
Speaker 1: You once give me an example of falling off a
Speaker 1: ship in the middle of the night to illustrate this
Speaker 1: fold mode.
Speaker 3: Yeah, so I wanted to. That's actually a great point.
Speaker 3: So there are situations where we're we're going into this
Speaker 3: mode is really useful, and every once in a while
Speaker 3: we're reading the news about somebody who falls off the
Speaker 3: back of a ship in the middle of the night
Speaker 3: and then miraculously gets rescued in the morning. Now, if
Speaker 3: you or I fell off the back of a ship
Speaker 3: in the middle of the night, like a cruise ship
Speaker 3: or something, we'd probably swim after the ship for a
Speaker 3: while and scream for help and try and attract his attention.
Speaker 3: But if it was really clear that the ship was
Speaker 3: sailing away and no one could hear us, and we're
Speaker 3: stuck in the middle of the sea, I mean we're
Speaker 3: in a really bad situation. It's really risky, and this
Speaker 3: is probably not going to work out well. But our
Speaker 3: best chance of survival is actually to fold, to curl
Speaker 3: up into a ball and just wait and save your
Speaker 3: energy and hope that something about the situation changes, hope
Speaker 3: you get rescued. That mode is the same mode that
Speaker 3: we talk about when we talk about depression, and in fact,
Speaker 3: when pharmaceutical companies are developing new medications for depression, one
Speaker 3: of the ways that they'll do animal testing to see
Speaker 3: if the molecule helps depression is whether a thing called
Speaker 3: the forced swim test, and the forced swim test, the animal,
Speaker 3: like the mouse or whatever, is placed inside an air
Speaker 3: a little beaker where they have to swim around and
Speaker 3: there's nothing to stand on. Now, mice are quite good swimmers,
Speaker 3: and they're also quite good floaters, so they'll swim and
Speaker 3: swim around, and eventually, at some point they'll realize that
Speaker 3: they're not going to get out of this situation, and
Speaker 3: so they stop swimming around and they just give up
Speaker 3: and float. And at that point the experimenter will stop
Speaker 3: the stop watch and see how many minutes that took.
Speaker 3: What's interesting is that there are breeds of mice who
Speaker 3: are prone to depression and prone to this are giving
Speaker 3: up quickly, and most antidepressants, when the mice are on
Speaker 3: the antidepressant still actually swim for a lot longer before
Speaker 3: giving up. And so this forced swim tests, which is
Speaker 3: really a way of tapping into how long before the
Speaker 3: animal switches into this mode of folding and giving up
Speaker 3: and waiting for something to change. That approach is a
Speaker 3: long standing and standard way that people have searched for
Speaker 3: new antidepressant medications over the last several decades.
Speaker 2: Okay, terrific.
Speaker 1: And so when we look at depression in this country
Speaker 1: or around the world, what are the rates of depression? Like,
Speaker 1: are things going up or down?
Speaker 3: Yeah, so it's unfortunate that, I mean, the encouraging thing
Speaker 3: over the last few decades is that compared to say,
Speaker 3: the nineteen eighties and the nineteen nineties when I started
Speaker 3: doing brain imaging research, there's a lot less stigma around
Speaker 3: mental health than there was, and that that's certainly very encouraging.
Speaker 3: There are a lot more people seeking treatment than before,
Speaker 3: and people are seeking treatments with medications and with psychotherapy
Speaker 3: more more than ever. The problem is that this hasn't
Speaker 3: changed the numbers at all. So despite the fact that
Speaker 3: there's less stigma, despite the fact that people are coming
Speaker 3: forward and taking antidepressants, and that in fact, antidepressants are
Speaker 3: being used in sex quantities that they can be detected
Speaker 3: with spectroscopes in the water supplies of cities and so on,
Speaker 3: so they'll actually be able to go and they can
Speaker 3: detect trace amounts of all these medications in city water supplies.
Speaker 3: Despite all of this, the prevalence of depression and of
Speaker 3: suicidal acts and suicidality has not gone down at all,
Speaker 3: And in certain populations like younger folks under age twenty
Speaker 3: and in the early twenties, the numbers for depression, anxiety,
Speaker 3: and suicidality are going up rather than down. So we
Speaker 3: definitely need to put the search on to understand how
Speaker 3: depression works in the brain and really develop a new
Speaker 3: generation of treatments because what we're having right now is
Speaker 3: not moving the needle.
Speaker 2: Why do you suppose the numbers are going up?
Speaker 3: There are a lot of different possibilities for why that is.
Speaker 3: I think we could probably have a whole other podcast
Speaker 3: on what that is. In a nutshell, there are more
Speaker 3: there seem to be more situations where people feel like
Speaker 3: the fight is unwinnable. When I see that numbers for
Speaker 3: depression and suicidality going up, it's sort of an index
Speaker 3: of number of people who feel like they are losing
Speaker 3: it life and that there's no way out for them.
Speaker 3: So it is a bit of a barometer of social
Speaker 3: health in that way. Some people have also attributed to
Speaker 3: increased stressors around social media use and so on, and
Speaker 3: some people have even attributed to things like changes in
Speaker 3: the composition of the bacteria that live within our guts,
Speaker 3: some of which appear to have a protective effect against depressions.
Speaker 3: So there are a lot of theories out there, but
Speaker 3: I wouldn't say anyone has solved the mysteries of what
Speaker 3: it is. There are lots of people posing everything from
Speaker 3: social factors to psychological factors to biological factors like literally
Speaker 3: write down to the bacteria in a person's gut.
Speaker 1: So what do you think about the pharmaceutical treatments for depression?
Speaker 2: Are they are they useful? Are they neutral?
Speaker 3: Well, I would say that I can give you what
Speaker 3: the numbers say. So if a person comes into their
Speaker 3: family doctor with an episode of depression and they try
Speaker 3: an antidepressant. There was a famous study about fifteen years
Speaker 3: ago called star d Let out of the University of
Speaker 3: Texas Southwestern and they found that about two thirds of
Speaker 3: people could get to remission from depression after trying one
Speaker 3: medication or two medications, or three medications or four medications
Speaker 3: one after the other. But the numbers really drop precipit
Speaker 3: so about one third of people would get better trying
Speaker 3: the first medication they ever tried, only about one third
Speaker 3: about a quarter of people would get better on the
Speaker 3: second medication they tried. But by the time you've tried
Speaker 3: two medications without success, the third and the fourth one
Speaker 3: are down to, you know, around eight to twelve percent
Speaker 3: success rates, not particularly high at all. So we're unfortunately
Speaker 3: the situation where the medications tend to work by fairly
Speaker 3: similar mechanisms in terms of boosting serotonin levels or boosting
Speaker 3: nor at inefferent levels or dobamine levels and so on
Speaker 3: and so. Yes, you try to influence the person's oppression
Speaker 3: by influencing these neurotransmitters in the brain, but at least
Speaker 3: one third of people don't get any benefit from them,
Speaker 3: and unfortunately a lot of people relapse and a very
Speaker 3: large percentage of people. About twenty five percent of people
Speaker 3: stop taking medications early because of side effects. So I
Speaker 3: don't want to run down medications because the upside is that,
Speaker 3: you know, it's in some ways, it's quite remarkable that
Speaker 3: you can take somebody who's despairing about where their life
Speaker 3: is going, and all you ask them to do is
Speaker 3: take ten seconds out of their day to take a
Speaker 3: serotonin boosting medication or an or an effort in boosting
Speaker 3: medication just at bedtime with their toothbrush, And it is
Speaker 3: quite remarkable that just by doing that one little thing,
Speaker 3: a certain percentity of people will emerge from depressed, dispar
Speaker 3: and suicidality and be able to face the world again.
Speaker 3: So that's the upside of it. The downside is that
Speaker 3: there's also a very large number of people who don't
Speaker 3: get better on the medications, and a very large number
Speaker 3: of people who can't tolerate the medications.
Speaker 1: So tell me about recent breakthroughs that are understanding.
Speaker 3: So we're in what I would argue is actually one
Speaker 3: of the most exciting periods of discovery within all of
Speaker 3: within all of medicine, so psychiatry and in particular a
Speaker 3: field called interventional psychiatry is now looking at all the
Speaker 3: traditional disorders like depression, anxiety, and so on in terms
Speaker 3: of brain circuitry and in terms of brain function, and
Speaker 3: thanks to twenty five years of brain imaging research, we're
Speaker 3: actually starting to get really lovely maps of where stuff
Speaker 3: happens in the brain and what brain circuits are involved
Speaker 3: in depression, anxiety, OCD, post traumatic stress disorder, or eating disorders,
Speaker 3: pretty much most of the major categories of mental health disorders.
Speaker 3: We are starting to get really great maps of what
Speaker 3: areas of the brain are affected in them. The thing
Speaker 3: that's making that knowledge useful is that we're also starting
Speaker 3: to really take advantage now of a new generation of
Speaker 3: brain stimulation treatments inspired by the kinds of cases that
Speaker 3: I told you about at the beginning of our conversation,
Speaker 3: which can go into those circuits which may be overactive
Speaker 3: or underactive, and can actually stimulate them and reset them
Speaker 3: back to their normal pattern of activity. So these new
Speaker 3: generation of treatments are brain stimulation treatments, and what's important
Speaker 3: about them is they're anatomically precise. Some of them, as
Speaker 3: I mentioned before, involve implantable devices like deep brain stimulators,
Speaker 3: and for the last twenty years, people have been pioneering
Speaker 3: and starting to come up with ways that they can
Speaker 3: actually implant little pacemakers in the brains of people who
Speaker 3: have very serious forms of depression where nothing has worked,
Speaker 3: and these deep brain stimulators have caused quite remarkable ability
Speaker 3: of people that could turn around and immerge from their depression.
Speaker 3: But of course we also have the issue that not
Speaker 3: everybody wants to have a pacemaker and plant in their brain,
Speaker 3: and so it would be really really useful if they
Speaker 3: could undergo a different form of treatment that was non invasive.
Speaker 3: And so the other kind of treatment that's really taking
Speaker 3: off right now involves a treatment approved by the FDA
Speaker 3: in two thousand and eight called transcranial magnetic stimulation. Transcranial
Speaker 3: magnetic stimulation involves using a powerful focus magnetic pulse generator
Speaker 3: placed it looks like a little ping pong paddle. It's
Speaker 3: sort of placed against the scalp. You place it over
Speaker 3: the target circuit that you want to stimulate, and with
Speaker 3: the magnetic pulses you're able to actually stimulate and activate
Speaker 3: target circuits in the brain without needing any surgery. They're
Speaker 3: quite powerful, so even though they're magnetic pulses. These are
Speaker 3: not fridge magnets. Like if you were to place this
Speaker 3: paddle over the precise spot on your brain that moves
Speaker 3: your thumb, and I were to press the button and
Speaker 3: cause a couple of little pulses, you would actually see
Speaker 3: your thumb or your hand move with every single pulse.
Speaker 3: So these are ways of actually stimulating target reagions in
Speaker 3: the brain. And by stimulating them over and over again
Speaker 3: hundreds of times a day, you can gradually strengthen the
Speaker 3: connections in areas of the brain that require strengthening, or
Speaker 3: you can reduce the strength of the connections and areas
Speaker 3: that I guess are over connected. And with these two approaches,
Speaker 3: you can try to return the brain or reset the
Speaker 3: brain back to its normal pattern of activity that occurs
Speaker 3: when they are not in this mode of despair and folding.
Speaker 1: And how is this figured out? About which brain areas
Speaker 1: to zap.
Speaker 3: So the work on this began all the way back
Speaker 3: in the nineteen eighties when they started using pet scanners,
Speaker 3: which inject a radioactive dye to look at the metabolism
Speaker 3: of the brain, and they were able to compare the
Speaker 3: brain activity of people with depression people who are not
Speaker 3: in depression, and so the first maps of these came
Speaker 3: out in the late nineteen eighties and early nineteen nineties,
Speaker 3: and they pinpointed a set of areas in the frontal
Speaker 3: lobes and also elsewhere in the brain that seemed to
Speaker 3: be consistently underactive in people with depression. They also pinpointed
Speaker 3: areas of the brain that were consistently overactive in people
Speaker 3: with depression. Those ones appear to be deeper in and
Speaker 3: this led to a new generation of treatments where people
Speaker 3: use the transcranial magnetic stimulation devices to target the frontal
Speaker 3: lobe areas near the surface because the magnetic pulses could
Speaker 3: read them. They also went to the surgeons and began
Speaker 3: using the deep brain stimulator electrodes, which despite their name
Speaker 3: as stimulators, can actually be used to inhibit and disrupt
Speaker 3: areas of the brain that are overactive, and so they
Speaker 3: were able to implant these in the areas of the
Speaker 3: brain that were deeper and overactive in depression and use
Speaker 3: them to reset their activity.
Speaker 1: So I recently did an episode on how brains simulate
Speaker 1: the future. This is one of the main jobs of
Speaker 1: brains is to simulate and.
Speaker 2: Evaluate possible futures.
Speaker 1: What's your interpretation of what happens when somebody is depressed
Speaker 1: in terms of the futures that they are simulating.
Speaker 3: So that's a fascinating question, and I think there actually
Speaker 3: are some really lovely brain imaging studies that were done
Speaker 3: on this about ten years ago, led by Adam Gazzale
Speaker 3: and some other folks over at UCSF. What they noticed
Speaker 3: was that perhaps in your discussion you talked about a
Speaker 3: network of areas in the brain called the default mode network.
Speaker 3: The default mode network is named that because it seems
Speaker 3: to be one of the most you know, it's the
Speaker 3: area of the brain that is on by default when
Speaker 3: we're not doing anything else. So if you or I
Speaker 3: were sitting in a room quietly and there's nothing going on,
Speaker 3: our default mode network turns on. And as we've all
Speaker 3: experienced that involved what happens in our minds is our
Speaker 3: brains start thinking about the past and thinking about the
Speaker 3: future and making plans and thinking about what may take place.
Speaker 3: There are two pathways by which we do that. There's
Speaker 3: a so called reward pathway where our brain thinks about
Speaker 3: opportunities and things we might start to want or desire
Speaker 3: to get us up out of our seats and get going.
Speaker 3: But there's also a second pathway called the non reward pathway,
Speaker 3: whose job it is entirely to think about non rewarding outcomes.
Speaker 3: Things could go wrong, fires I have to put out
Speaker 3: problems in my life, things that I should be motivated
Speaker 3: to go and sort out. And we need both of
Speaker 3: those to work in balance. So we both need the
Speaker 3: ability to come up with ideas for opportunities and things
Speaker 3: that we desire to do, but we also need to
Speaker 3: be guided by all the problems in life, all the
Speaker 3: things that we really need to be motivated to take
Speaker 3: care of. And with a balance between those two, we
Speaker 3: can both pursue opportunities in the future, and we can
Speaker 3: also avoid threats and problems and resolve them. The problem
Speaker 3: and depression occurs when this so called non reward pathway,
Speaker 3: whose whole job is to think about all negative consequences,
Speaker 3: things that are going wrong, things that could screw up,
Speaker 3: It can get trapped into sort of self perpetuating feedback loop.
Speaker 3: So the circuit in the brain is arranged as a
Speaker 3: bit of a loop from the frontal lobes going down
Speaker 3: into the reward and motivational structures of the brain and
Speaker 3: as if it gets stuck in a loop. What happens
Speaker 3: is the person experience is just finding that even though
Speaker 3: there maybe ninety nine things that are going well in
Speaker 3: the person's life, their brain will find the one thing
Speaker 3: that's going wrong and it will get stuck on it,
Speaker 3: and it will just loop on it over and over
Speaker 3: and over again. I think most of us know somebody
Speaker 3: as family, friends, colleagues, maybe even ourselves who tend to
Speaker 3: do that, who are always really good at spotting the
Speaker 3: one problem and getting stuck on it. But in depression
Speaker 3: it becomes true to a pathological extent where they get
Speaker 3: so stuck on it that even with effort, they cannot
Speaker 3: pull themselves out of the negative circle of thoughts, which
Speaker 3: we call by the technical term ruminations. So in depression,
Speaker 3: this non reward pathway has gotten stuck in a loop,
Speaker 3: and what the person experiences is an endless circle of
Speaker 3: ruminations and self criticism and thoughts about all the possible
Speaker 3: futures that will go wrong and all the past things
Speaker 3: that have gone wrong. And it just becomes very difficult
Speaker 3: to pull yourself out of this even when you need to.
Speaker 1: And so what is the transcranial magnetic stimulation doing when
Speaker 1: you are hitting a particular area, is it giving a
Speaker 1: second bite at the apple for that area to rewire?
Speaker 1: Is it simply making the area more plastic so that
Speaker 1: it has an opportunity to wire up in a more
Speaker 1: beneficial way the next time around.
Speaker 3: So I'll give you our best guess as to what's
Speaker 3: happening right now. As with many things in psychiatry, we
Speaker 3: discovered that these things worked long before we actually figured
Speaker 3: out why they worked. But the original areas of the
Speaker 3: brain that we stimulated were targeted because they just seem
Speaker 3: to be underactive in depression. So the theory was, look,
Speaker 3: they're underactive, let's use this brain stimulator. Let's stimulate them,
Speaker 3: let's turn them back on, and then all will be well.
Speaker 3: Later on, we discovered that what these areas really seem
Speaker 3: to be associated with is courage and resilience. In other words,
Speaker 3: people who happened just by chance to have more gray
Speaker 3: matter or more gray matter in these areas, they're more
Speaker 3: resilient distress. They have better ability to cope. These brain
Speaker 3: areas in the frontal lobes are engaged every time we
Speaker 3: do a thing called cognitive control, which is our ability
Speaker 3: to self regulate our thoughts and our behaviors and emotions.
Speaker 3: In fact, for those of you who've tried MINDFULSS meditation,
Speaker 3: if you've ever sat in a chair and tried to
Speaker 3: not ruminate and tried to focus on your breathing. Every
Speaker 3: time you notice that your mind is wandering, and you
Speaker 3: shut down the ruminations and come back to your breathing again,
Speaker 3: you turn on this network of areas. It looks like
Speaker 3: what we're doing with TMS is actually not so much
Speaker 3: pushing happiness into the brain or pulling anxiety out, but
Speaker 3: more generally strengthening the very same network that is activated
Speaker 3: when you do mindfulness meditation. And so when I talk
Speaker 3: to patients about what it's like for them after the
Speaker 3: TMS has worked, they talk a lot about how something
Speaker 3: stressful happen this week, and normally it would have ruined
Speaker 3: my whole week, but I noticed that I just got
Speaker 3: over it. I kind of thought about it and realized
Speaker 3: it wasn't as bad as and I was able to
Speaker 3: kind of cope with it. They describe it as having
Speaker 3: more coping capacity, And so it looks like the effects
Speaker 3: of TMS on depression, at least with the standard areas,
Speaker 3: might be somewhat indirect You're not so much pushing happiness
Speaker 3: in or taking anxiety out, but you are strengthening a
Speaker 3: sort of mental muscle for cognitive control. And as a result,
Speaker 3: people just generally get better at self regulating their thoughts
Speaker 3: and behaviors and emotions, and they can cope with more stress,
Speaker 3: so things don't feel quite as defeating, things don't look
Speaker 3: quite as bad.
Speaker 1: I've been sort of playing with a different interpretation slightly
Speaker 1: about it, which is that you are, to phrase it colloquially,
Speaker 1: you're sort of loosening up a network that has found
Speaker 1: itself getting into a particular way, a particular structure, and
Speaker 1: what you're doing is reintroducing plasticity to that area so
Speaker 1: that you have a chance of things running correctly through there.
Speaker 1: And with TMS, as we know, sometimes the first treatment
Speaker 1: doesn't work, but the second treatment does. My view on
Speaker 1: that is that it's possible that after the first time,
Speaker 1: the system reconverges into to some pathological wiring, and then
Speaker 1: you know, if you do it again, you're getting another
Speaker 1: chance to have it find better wiring.
Speaker 2: Yeah.
Speaker 3: I'm really glad you brought that up, because I think
Speaker 3: that actually lines up really well with a very recent
Speaker 3: discovery that's still quite new about what is happening for
Speaker 3: people who are trying a second form of OURTMS that
Speaker 3: kicks in when the first one doesn't work. So when
Speaker 3: I start rTMS, repetitive transcranial magnetic stimulation, it's effectively TMS
Speaker 3: treatment but using these repetitive pulses. So some people will
Speaker 3: call it rTMS, and some people will simply just abbreviate
Speaker 3: it to TMS. But we're talking about using this non
Speaker 3: invasive stimulation. So when a person goes through and does
Speaker 3: the treatment using the standard parameters that I talked about,
Speaker 3: sometimes it works, and yet there's a percentage of people
Speaker 3: where it doesn't work. What we've noticed that those people
Speaker 3: tend to have higher scales on rumination negative ruminations. A
Speaker 3: Bad Life and a Lovely study came out by a
Speaker 3: group led by Andy Lukter at You where he was
Speaker 3: able to identify that these people have higher rumination scores.
Speaker 3: They then move the coil to a different areas, so
Speaker 3: instead of stimulating the first area that to talk about,
Speaker 3: they go to a different brain area which actually sits
Speaker 3: within this non reward circuit that we were talking about before,
Speaker 3: and instead of trying to stimulate and strengthen it. Sure enough,
Speaker 3: what they do is they try and inhibit and disrupt
Speaker 3: the activity of this area. So they are trying to
Speaker 3: disrupt and break up the feedback loop that they call
Speaker 3: the non reward attractor state. It's in fact a professor
Speaker 3: named Edmund Rolls out of Cambridge by the way just described,
Speaker 3: He came up with a theory of depression which is
Speaker 3: very similar to what you describe. He called it the
Speaker 3: non reward attractor theory of depression. That non reward circuit.
Speaker 3: The more it runs and the more it dwells on things,
Speaker 3: the more it strengthens the connections in and of itself,
Speaker 3: so it becomes self strengthening, self perpetuating, and you're just
Speaker 3: going to get stuck in this so called attractor state
Speaker 3: and not be able to get out of it. The
Speaker 3: solution with TMS would be to put the coil over
Speaker 3: those areas and apply some pulses of stimulation, not to
Speaker 3: strengthen the pathway that's not what we want, but to
Speaker 3: disrupt and weaken the connections through a neuroplasticity to the
Speaker 3: point where the person can now pull themselves out again.
Speaker 2: That's your interpretation.
Speaker 1: Of what transcrinial megaing stimulation does, right.
Speaker 3: Yeah, so we're still figuring this out. But what we
Speaker 3: think is that for some people, when you strengthen the
Speaker 3: first circuit and they regain their cognitive control, that circuit
Speaker 3: is connected to the non reward circuit, so they can
Speaker 3: then use their cognitive control to do this work themselves
Speaker 3: of popping themselves out at this tractor state and other people,
Speaker 3: for whatever reason, these two pathways aren't really very well connected,
Speaker 3: so they kind of operate independently. So you strengthen the
Speaker 3: first pathway, they get more coping capacity, but the problem
Speaker 3: is they're still stuck in these negative terminations. Then you
Speaker 3: bring them back again you move the stimulator over to
Speaker 3: this other pathway. I actually had a patient who described
Speaker 3: as saying this for your first treatment didn't work, but
Speaker 3: the second one you gave me over this non reward pathway.
Speaker 3: He said, I'm definitely one of those people you talked
Speaker 3: about who always finds the one negative thing the room.
Speaker 3: And if I see it, it's like a negative he said,
Speaker 3: it's like an escalator. I'm forcing it on the escalator
Speaker 3: and ride it down, down, down, all the way to
Speaker 3: the bottom. And then I'm just stuck there. That could
Speaker 3: be stuck there for days or weeks. And after I
Speaker 3: finished the course of treatment, something really horrible happened, and
Speaker 3: I thought, oh boy, here we go. I'm going to
Speaker 3: be dragged down the escalator, and it just didn't happen.
Speaker 3: I noticed the way he said it.
Speaker 2: It's like I.
Speaker 3: Walked up to the top of this escalator, I saw
Speaker 3: where it was going, and I realized I didn't want
Speaker 3: to go down there, and so my brain just kept going.
Speaker 3: And I think what's interesting on the brain imaging studies,
Speaker 3: of course, is if you scan people before and after,
Speaker 3: what you find is exactly what you described, that the
Speaker 3: connections between within this circuit are actually getting disrupted and weekend,
Speaker 3: so the circuit's still there and functioning, but it's not
Speaker 3: getting stuck in this attractor state or this loop. So
Speaker 3: I think it actually lines up really well with the
Speaker 3: account you just described. In the one case, plasticity being
Speaker 3: used to strengthen the person's ability to control their thoughts.
Speaker 3: But if that doesn't work in the other case, you
Speaker 3: can then go directly to the area that's stuck in
Speaker 3: a loop in the first place and use another form
Speaker 3: of plasticity. To weaken those connections and loosen them so
Speaker 3: the person can come out of it again.
Speaker 1: This is very cool because originally with depression, I mean,
Speaker 1: I think it's always been this way historically, that people,
Speaker 1: let's say loved ones who are with somebody who's depressed,
Speaker 1: feel like, hey, we should just be able to talk
Speaker 1: to the person out of this, just say hey, look
Speaker 1: at the bright side and so on.
Speaker 2: That doesn't work. And so this.
Speaker 1: Idea of being able to help somebody buy let's say,
Speaker 1: loosening up circuits in the brain, doing other things, you know,
Speaker 1: getting someone out of an attractor state non invasively is
Speaker 1: so promising. What do you predict is going to be
Speaker 1: the field in forty years from now when you're elderly.
Speaker 3: Oh wow, that's really interesting. I'll get to that in
Speaker 3: a moment, but I want to just come back and
Speaker 3: highlight that I think you've really hit the nail on
Speaker 3: the head of this, that every one of us has
Speaker 3: tried to talk someone who's despairing out of the respair.
Speaker 3: We've all tried to do it, and we've all been
Speaker 3: sort of stimied and frustrated, going, why are you fighting
Speaker 3: us on this? Like I keep trying to tell you
Speaker 3: all the things that are good in life and reminds
Speaker 3: you of them, and it's almost like you want your
Speaker 3: brain wants to just go to the one negative thing
Speaker 3: and stuck there. You've had that experience in talking to somebody.
Speaker 3: I'm sure we all have, and it comes back to
Speaker 3: exactly that lesson that depression is a kind of motivated state.
Speaker 3: It's the brain is turning this on because it thinks
Speaker 3: that it needs to be in this survival mechanism of
Speaker 3: just folding and giving up. It thinks that that's its
Speaker 3: best chance of survival. And so it's a highly motivated state.
Speaker 3: And you will not be able to talk somebody out
Speaker 3: of it because their motivational circuitry literally has been hijacked
Speaker 3: by the depression, and so just talking people out of
Speaker 3: it doesn't work terribly well. But as you say, now
Speaker 3: that we know where this motivational cirguit lives, now that
Speaker 3: we know where this non reward circuit lives, we can
Speaker 3: do all kinds of interventions. And you asked, what's it
Speaker 3: going to look like in forty years. I don't think
Speaker 3: there's going to be any one treatment that is just
Speaker 3: universally what people use. I'll give you an example of that.
Speaker 3: So recently, a couple of years ago, a team that
Speaker 3: you see San Francisco, led by Catherine Scangos and colleagues.
Speaker 3: They were able to go to this non reward circuit
Speaker 3: in the brain that I talked about, and they took
Speaker 3: people who had very severe depression and they did something
Speaker 3: that I think is very kind of futuristic. First of all,
Speaker 3: they brought them into a special monitoring ward in the
Speaker 3: hospital and they implanted the little electrodes in their brain and
Speaker 3: let them stay in the hospital for several days or weeks. Normally,
Speaker 3: that's what you'll do in epilepsy patients if you were
Speaker 3: trying to find the source of the epilepsy within the brain.
Speaker 3: You'll put electrodes all over the brain and you'll let
Speaker 3: them sit and you wait for them to have seizures,
Speaker 3: and then you go back and reconstruct where they came
Speaker 3: from so you can perform a surgery. And this guys,
Speaker 3: they said, well, you know the folks of depression, these
Speaker 3: folks are really depressed. They can't function, their suicidal you know,
Speaker 3: they really need something just as drastic as this. So
Speaker 3: they brought them in, they implanted the electrodes but instead
Speaker 3: of waiting for seizures, they just let them have negative
Speaker 3: thoughts and using a little app on their tablet, they
Speaker 3: could constantly rate what their brain was thinking about, and
Speaker 3: so you could see what kind of brain activity was
Speaker 3: going on when they were having positive thoughts or negative thoughts.
Speaker 3: And by doing that and using a machine learning algorithm,
Speaker 3: they were able to detect the electrodes that showed particular
Speaker 3: pattern of abnormal activity that was present when the brain
Speaker 3: got sucked into those negative ruminations. When they did that,
Speaker 3: they were then able to implant a deep brain stimulator
Speaker 3: in that and it was a closed loop system, so
Speaker 3: it was attached to a tiny little computer that would
Speaker 3: that would detect when the brain had gone into this
Speaker 3: abnormal rhythm of negative thoughts and it would just disrupt
Speaker 3: the activity with about five or six seconds of stimulation.
Speaker 3: So we just flip the blip the blip, just to
Speaker 3: like when you tap on a microphone to break a
Speaker 3: feedback loop. It was literally just tapping on that microphone
Speaker 3: and saying, hey, stop it. We've used this approach in
Speaker 3: the heart for a long time, so people have heart
Speaker 3: rhythm problems, can wear things called implantable, have a surgery
Speaker 3: to have an implantable a cardiac defibrillator, so something like
Speaker 3: the defibrillator padals that you might see in the airport,
Speaker 3: but this is actually implanted inside. So if their heart
Speaker 3: ever gets stuck in an abnormal rhythm that might be fatal,
Speaker 3: the device will automatically detect that the heart's in that
Speaker 3: rhythm and just give a few blips to reset it.
Speaker 3: So interestingly, they were doing the same thing in the brain,
Speaker 3: these folks that effectively created an implantable brain defibrillator, and
Speaker 3: so it was detecting when this abnormal pattern comes along,
Speaker 3: they blip it for a few seconds. And there's a
Speaker 3: lovely article in the New York Times a couple of
Speaker 3: years ago where they interviewed the patient describe what it
Speaker 3: was like, and they talked about it as being a
Speaker 3: sort of you're about to get sucked down into these
Speaker 3: negative thoughts, and she said, suddenly the rational side of
Speaker 3: you comes on and those negative emotions can be separated
Speaker 3: from your real situation. What was encouraging is that this
Speaker 3: seems to this process of implanting these stimulators seems to
Speaker 3: work even in people who have had depression for decades
Speaker 3: and have tried every other treatment available, multiple medications, therapies, TMS,
Speaker 3: even electric convulsive therapy, all kinds of things. So people
Speaker 3: have really gotten nowhere with the other treatments using this
Speaker 3: targeted intelligent approach. I think that really is sort of
Speaker 3: the prototype of what the future looks like.
Speaker 1: Yeah, I think one of the most amazing things about this.
Speaker 1: Many listeners will already sort of be aware of this research,
Speaker 1: but generally we think of ourselves and our personalities and
Speaker 1: our thoughts and our emotions as something different from let's
Speaker 1: say our heart and how is our heart functioning? And
Speaker 1: you can defibrillate the heart, but the brain it feels like, well,
Speaker 1: that's me, that's just who I am, and so on.
Speaker 1: And it's sort of an amazing revelation that many people
Speaker 1: have when they start seeing this sort of data to
Speaker 1: understand that we are physical creatures, and when you do
Speaker 1: things to change the physical structure, that changes who you
Speaker 1: are in that moment.
Speaker 3: I think that's spot on, And that comes back to
Speaker 3: the story we told at the beginning of why it
Speaker 3: was so interesting for me as a as a young
Speaker 3: researcher that you know, at that time many years ago,
Speaker 3: we really there were the default idea was this thing
Speaker 3: called the serotonin bothesis of depression, where you know, serotonin
Speaker 3: had something to do with your mood, and if your
Speaker 3: mood was low, it was maybe because your serotonin was low.
Speaker 3: You you know, didn't have enough serotonin in your soup.
Speaker 3: So we should get out a serotonin shaker and we
Speaker 3: should shake some put some more serotonin into your soup,
Speaker 3: and that will somehow just you know, make your mood
Speaker 3: get better. But it turns out, of course, it's not
Speaker 3: as simple as that, the serotonin is not mood. Serotonin
Speaker 3: in you know, in your in your GI tract will
Speaker 3: will cause your you know, to have to have GI
Speaker 3: emotions in the brain. Stomach can regulate nausea, and the
Speaker 3: visual cortex it can do visual things. And so there's
Speaker 3: no such thing as a really where mood is just
Speaker 3: boiled down to not having enough of a molecule in place.
Speaker 3: But when we looked at those cases, as you said,
Speaker 3: where people who had been depressed for so long that
Speaker 3: they thought it was just part of who they were,
Speaker 3: they then have this experience where you literally just take
Speaker 3: a circuit in the brain and blip it and reset it,
Speaker 3: and the person immediately in their thoughts is no longer
Speaker 3: getting stuck in the negative thoughts and can look past
Speaker 3: the one thing that's going wrong to the other ninety
Speaker 3: nine things that are going right through that clear sort
Speaker 3: of logical way, And you're right, people do really find
Speaker 3: it as a revelation, and people who improve on these
Speaker 3: they often find that because they've been depressed for twenty years,
Speaker 3: you know that they don't It can be actually quite
Speaker 3: a lot of work to sit down with a person
Speaker 3: and figure out how to reconstruct their life based on
Speaker 3: the premise that they actually get up every day and
Speaker 3: feel good and ready to do things. They have spent
Speaker 3: twenty years building a life around disability, so it's not
Speaker 3: something where so there often can be quite a lot
Speaker 3: of work done over months or years to try and
Speaker 3: figure out how the person will adapt to a life
Speaker 3: that has hope in it. Again, Yeah, so you.
Speaker 1: Once told me how you see the battle against depression
Speaker 1: in the twenty first century from a historical point of view.
Speaker 3: Yeah, so, I mean, let's come back to those we
Speaker 3: talked about earlier on where we said that there's the
Speaker 3: prevalence of depression over the lifetime is maybe ten percent,
Speaker 3: and the prevalence at any given time is about five percent.
Speaker 2: Now.
Speaker 3: There are lots of diseases in the history of medicine
Speaker 3: where the prevalence has come down a lot, So people
Speaker 3: used to be a lot of people. Tuberculosis, that's come
Speaker 3: down a lot, and we're now making progress against malaria.
Speaker 3: We're making progress against various forms of hepatitis. We're making
Speaker 3: progress against stomach alsers that used to sometimes be fatal
Speaker 3: if they progress. And for each of these things we
Speaker 3: now have effective treatments and the prevalence has come down.
Speaker 3: Even for HIV, something that was once untreatable and uncontrollable
Speaker 3: is now turned into something that is controllable, and that
Speaker 3: over time we may be able to get the prevalences down.
Speaker 3: So the dream for us, I think for the twenty
Speaker 3: first century would view that we would like, you know,
Speaker 3: at the end of our careers forty years from now,
Speaker 3: as you said, we'd like to be able to look
Speaker 3: back at the prevalence of depression and anxiety and other
Speaker 3: mental health disorders and say, look at that we used
Speaker 3: to be at five or ten percent, and look how
Speaker 3: much numbers come down since then. Millions of people who
Speaker 3: had no pathway forward now see. Depression is something that
Speaker 3: is treatable, and employers no longer look at depression as
Speaker 3: something that would disqualify you from being hired for a job.
Speaker 3: Oh you have depression, that's okay and not the end
Speaker 3: of the world. Just go in and get the course
Speaker 3: of treatment and we'll see you. We'll see you back
Speaker 3: in a week or two. So you know, this will
Speaker 3: help to erode the stigma, and I think we'll really
Speaker 3: get to see the numbers coming down on this. Are
Speaker 3: we going to get those millions of people better with
Speaker 3: deep brain stimulators alone? No, of course not. We're not
Speaker 3: going to be implanting millions and millions of deep brain
Speaker 3: stimulators and everybody, not everybody wants them and just throw
Speaker 3: on up serasons to do that. But I think we
Speaker 3: do have a real opportunity using the non invasive forms
Speaker 3: of brain stimulation like TMS, which are getting you know,
Speaker 3: very very good as well. So your colleague over at
Speaker 3: over at Stanford are one of my good friends. Nolan
Speaker 3: Williams was instrumental in developing a radical new form of
Speaker 3: TMS treatment that could take a person from severe depression
Speaker 3: on money day all the way down to being in
Speaker 3: remission in literally five days. The secret was to do
Speaker 3: two things. The first was not to do a treatment
Speaker 3: once a day traditionally, but to do up to ten
Speaker 3: treatments a day, so that a person can have thirty
Speaker 3: or forty or fifty treatments in a week and that's
Speaker 3: definitely enough TMS sessions to get them better. The second
Speaker 3: part of their trick was actually performed some brain imaging
Speaker 3: in the person so you could see what pathways to
Speaker 3: be targeting and then fine tune and personalized where the
Speaker 3: coil is. Through some combination of those two things, they
Speaker 3: seem to be hitting very high success rates that are
Speaker 3: north of fifty percent. So we have a tool now
Speaker 3: with TMS that if you know someone who has struggled
Speaker 3: with depression or anxiety and has not done well on
Speaker 3: therapy or medications, that's a lot of people. They can
Speaker 3: go anywhere in the United States right now to a
Speaker 3: TMS clinic and they can undergo a course of transcradial
Speaker 3: magnetic simulation. And with the most recent FD protocols, we
Speaker 3: believe that we can get more than fifty percent of
Speaker 3: people to remission even if nothing else has worked. So
Speaker 3: we do think we have a tool that is now
Speaker 3: capable of treating most people with depression and getting at
Speaker 3: least half of them out of the depression, maybe more.
Speaker 3: The trick is going to be to scale that. So
Speaker 3: it's scaling up so that everyone in the country will
Speaker 3: have access to this treatment. Once we're there, I think
Speaker 3: we will absolutely see improvements in the prevalence in our lifetimes.
Speaker 1: It's great, Hey, just think into one more thing, because
Speaker 1: you'd talked I've heard you talked before about tuberculosis and
Speaker 1: the parallel there.
Speaker 3: Yeah, so that's an interesting thing. It is possible. I
Speaker 3: guess that our battle against depression in the twenty first
Speaker 3: century is really a little bit like the battle against
Speaker 3: tuberculosis in the nineteenth and the twentieth century. One of
Speaker 3: the pioneers of modern medicine the nineteenth century physician Sir
Speaker 3: William Osler. He, of course saw many patients in his
Speaker 3: career with tuberculosis coming from the poorer areas of town,
Speaker 3: the overcrowded areas and so on, the places where living
Speaker 3: conditions were terrible, where sanitation was terrible, and as a result,
Speaker 3: he described tuberculosis as primarily quote a social disease with
Speaker 3: a medical aspect. In other words, yes, we can treat
Speaker 3: it medically, but fundamentally, tuberculosis isn't going to go away
Speaker 3: until people have better living conditions, until you don't have
Speaker 3: eight people living in one room, until people aren't with
Speaker 3: bad food, and all the rest of it. So, in fact,
Speaker 3: although tuberculosis drugs were developed in the twentieth century and
Speaker 3: save millions of lives when they're invented, the reality is
Speaker 3: that the rates of tuberculosis were coming down decades before
Speaker 3: any of these drugs were ever ruled out to reach people,
Speaker 3: and the prevalence of tuberculosis improved because people's lives improved,
Speaker 3: you know, better food, cleaner water, less crowded living conditions,
Speaker 3: less dire poverty, less desperation, And I think we're going
Speaker 3: to see that a very similar thing is happening here.
Speaker 3: It's not that we won't be able to use new
Speaker 3: technologies like brain stimulation to pull people out of despair,
Speaker 3: but it's also possible that a key to getting people
Speaker 3: out of despair will be to understand depression also as
Speaker 3: to some degree a social disease with a medical aspect.
Speaker 3: If we go back to the idea that depression is
Speaker 3: the thing that happens when the brain has decided it's
Speaker 3: in a battle for survival that it is not going
Speaker 3: to win. Then we look at the prevalence of depression
Speaker 3: as a number of people who look around at their
Speaker 3: lives and concluded that they are in an unwinnable situation.
Speaker 3: And I believe in the same way that we part
Speaker 3: of the pathway to getting people out of depression and
Speaker 3: reducing its prevalence will be improving the conditions of people's lives.
Speaker 3: They're the degree to which they feel secure, a degree
Speaker 3: to which they don't feel like they're going to lose
Speaker 3: their housing or to be under threat of violence. The
Speaker 3: first places in the world to overcome depression will be
Speaker 3: the ones that don't just develop better technologies to reset
Speaker 3: the brain, but also develop stronger societies in which we
Speaker 3: just have fewer percentages of people who are trapped in
Speaker 3: fights for survival that they feel like it never seem
Speaker 3: to win. And I guess that's maybe. There is a
Speaker 3: concept which one of my colleagues introduced me to from
Speaker 3: the history of Judaism, and it's a lovely phrase that
Speaker 3: I guess really carry around with me all day. It's
Speaker 3: the phrase is to kun olam, and it has been
Speaker 3: described to me as a religious injunction to repair the world. Yeah,
Speaker 3: I can't. I think you and I have also discussed
Speaker 3: this in the past as well. Yeah, so yeah, when
Speaker 3: we talk about resetting the brain, I think that falls
Speaker 3: within the larser of battles to try and improve the
Speaker 3: lot of humanity and reduce the reduce despair everywhere. And
Speaker 3: so when I think about the pathway to takun Olam
Speaker 3: and what neuroscience can contribute to it, and what you
Speaker 3: know brain stimulation can contribute to it, I think it
Speaker 3: has an essential role in reducing the number of people
Speaker 3: who face the world in despair, and that will be
Speaker 3: an essential component of this much larger injunction to repair
Speaker 3: the world, which I think we can all relate to.
Speaker 1: I spend many of these episodes talking about the extraordinary
Speaker 1: things that the brain does well, but it's equally important
Speaker 1: to talk about what happens when the brain gets off,
Speaker 1: because some percentage of your friends and loved ones are
Speaker 1: going to have to battle depression at some point, and
Speaker 1: it might be a slightly higher percentage.
Speaker 2: Than you think.
Speaker 1: The brain is incredible, but fragile, and what we see
Speaker 1: from depression is that it's relatively easy for it to
Speaker 1: slip out of its optimal operating range. Happily, neuroscience labs
Speaker 1: all over the world are working to understand this, and
Speaker 1: researchers and companies are generating new approaches, as with transcranial
Speaker 1: magnetic stimulation, such that as we move forward, we will
Speaker 1: have increasingly better ways to get things back on track.
Speaker 1: Go to Eagleman dot com slash podcast for more information
Speaker 1: and to find further reading. Send me an email at
Speaker 1: podcasts at eagleman dot com with questions or discuss ession
Speaker 1: and I'll be making monthly episodes in which I address
Speaker 1: those and check out and subscribe to Inner Cosmos on
Speaker 1: YouTube for videos of each episode and to leave comments
Speaker 1: until next time. I'm David Eagleman, and this is Inner Cosmos.