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 1: Welcome to Inner Cosmos.
Speaker 2: 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. I mean,
Speaker 1: just think about how easy it is to lose.
Speaker 2: 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. This is a mood disorder. It
Speaker 1: affects how you feel, how you think, how you handle
Speaker 1: your daily tasks, how you eat and sleep. People with
Speaker 1: 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: tough en up.
Speaker 2: But the important lesson.
Speaker 1: From centuries of psychiatry and more recently neuroscience is that
Speaker 1: it's not so easy. It's a physical problem. And that's
Speaker 1: why we talk about mental illness nowadays exactly as we
Speaker 1: talk about a physical illness like COVID or a broken leg,
Speaker 1: and that understanding opens the door to different approaches, because
Speaker 1: a physical problem invites physical solutions. Now, my father was
Speaker 1: a psychiatrist, and he was always impressed that he could
Speaker 1: have a patient who would be suffering from clinical depression
Speaker 1: and would lose his job and maybe lose his spouse,
Speaker 1: and my father can make a prescription like let's say prozac,
Speaker 1: and that patient often could get out of bed again
Speaker 1: and then 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.
Speaker 2: Now, many of the sorts.
Speaker 1: Of brain damage that you'll read about in an exciting
Speaker 1: book about the brain, these are things that most people
Speaker 1: won't see in their lifetimes. They won't know any friend
Speaker 1: or relative who has these issues because they are rare
Speaker 1: things to happen, and they usually involve damage to a
Speaker 1: region of the brain from a tumor or a stroke
Speaker 1: or a traumatic brain injury, and those things represent big
Speaker 1: changes in the city of the brain, like an entire
Speaker 1: block of New York City falling in an earthquake. But
Speaker 1: there are much more subtle things that happen in the
Speaker 1: brain as well, and these are changes that have to
Speaker 1: do with the way the system runs, with its tens
Speaker 1: of billions of neurons and trillions of synaptic connections. So
Speaker 1: to return to the city analogy, imagine that instead of
Speaker 1: big damage that you can see, the city still looks
Speaker 1: the same, but parts of it are operating very subtly differently.
Speaker 1: So the playwrights have all quit, and the city planners
Speaker 1: have stopped planning, and the coffee shops are closing two
Speaker 1: hours earlier, and all of this stuff impedes the city's
Speaker 1: ability to thrive and be an active, well functioning place
Speaker 1: for innovation and tourism. But it's all very subtle, and
Speaker 1: if you looked at this from a drone flying over
Speaker 1: 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.
Speaker 2: The way that the city operates.
Speaker 1: And again, who you are and how you see, the
Speaker 1: world comes from the way that the city of your
Speaker 1: brain is operating. In other words, the sum total of
Speaker 1: what's happening under the hood your biology. And I think
Speaker 1: the reason this is surprising is because we tend to
Speaker 1: think of ourselves as being removed from our biology. You
Speaker 1: are separate from it or able to ride above it.
Speaker 1: So if you've ever known someone with depression, or had
Speaker 1: depression yourself, you will know that you can't just say hey,
Speaker 1: come on, cheer up, snap out of it. That doesn't
Speaker 1: suffice to change the biology. And one of the most
Speaker 1: pervasive and societally important examples of these kind of subtle
Speaker 1: changes to the brain is with depression.
Speaker 2: And so for this episode, I decided.
Speaker 1: To call my colleague Jonathan Downer, who is an incredibly
Speaker 1: insightful and empathic observer.
Speaker 2: Of the brain.
Speaker 1: He has an MD and specializes in psychiatry, and he
Speaker 1: also has a PhD in neuroscience, and one of his
Speaker 1: areas of expertise is depression. And as it turns out,
Speaker 1: Jonathan and I wrote a textbook together on cognitive neuroscience
Speaker 1: called Brain and Behavior, and this is the textbook used
Speaker 1: at Stanford and at universities worldwide. And the textbook covers
Speaker 1: a lot of ground, but for today, I just want
Speaker 1: to zoom in on depression. So I rang him up
Speaker 1: to get his perspective on this issue that is not
Speaker 1: only neuroscientifically important and fascinating, but also, unlike the strange
Speaker 1: deficits that you might see only in a textbook, you
Speaker 1: almost certainly know someone with depression, perhaps someone close to you,
Speaker 1: or perhaps yourself. It's a shockingly common challenge. So let's
Speaker 1: dive in to understand it. So, Jonathan, how did you
Speaker 1: 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 to 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 around 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 and
Speaker 3: planted for her Parkinson's disease. They implanted the electrodes, one
Speaker 3: on one side and one on the other, and during
Speaker 3: the surgery they turned them on to make sure that
Speaker 3: they are succeeding in reducing the person's hand tremors or
Speaker 3: the other tremors in their body that they're trying to
Speaker 3: have treated. What was interesting is when they turned on
Speaker 3: the one on one side, the opposite hands started to
Speaker 3: reduce in its tremor and the tremor went away, which
Speaker 3: is exactly what they expected to happen. On the other side,
Speaker 3: there was something very strange happened as soon as they
Speaker 3: turned it on. Nothing high 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 at 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: had landed on some other pathways that projected out to
Speaker 3: a completely different part of the frontal lobes, and every
Speaker 3: time they turned on and off this part of the
Speaker 3: frontal lobes, the person would instantly going out of the sadness.
Speaker 3: Now that was happy news of the patient because they
Speaker 3: were able to reposition the electrodes so that both electrodes
Speaker 3: did the appropriate thing. But it got us thinking about
Speaker 3: what this really meant about depression. All these theories at
Speaker 3: the time that depression might be a chemical imbalance or
Speaker 3: this or that, we really saw very directly that there
Speaker 3: was a question of the activity of the brain and
Speaker 3: that within seconds, one pattern of activity the brain led
Speaker 3: to sadness, and within seconds, if that pattern of activity
Speaker 3: could somehow be turned off, then the person's sadness would
Speaker 3: go away. And that really got us thinking about whether
Speaker 3: we might start being able to use things like brain
Speaker 3: stimulation to understand what depression was about in the brain,
Speaker 3: and maybe even to come up with a new generation
Speaker 3: of treatments that work better than the medications and therapy
Speaker 3: of the time.
Speaker 2: Okay, terrific, So we'll talk about that.
Speaker 1: Let's start with can you define depression clinical depression?
Speaker 3: Sure? So, there are standardized definitions of depression that involve
Speaker 3: a series of symptoms, the core of which is sad
Speaker 3: or depressed mood most of the day most days, and
Speaker 3: the second of which is a thing called anhedonia, which
Speaker 3: is the inability to enjoy things or experience pleasure, a
Speaker 3: loss of motivation, a loss of joy, a loss of
Speaker 3: the brain's reward functions. In addition to that, there are
Speaker 3: some standard symptoms that go along with that. Commonly, people
Speaker 3: will 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 up long of self
Speaker 3: harm and suicide that there are obviously the most concerning
Speaker 3: parts about the depression. So that's the standard sort of
Speaker 3: diagnostic approach by which we determine whether somebody has been
Speaker 3: entering into a period of depression. It's unfortunately, really common.
Speaker 3: At any given time in North America, about five percent
Speaker 3: of people are in the middle of a depressive episode,
Speaker 3: and 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 start chasing you, then you
Speaker 3: have to go beyond freeze. You have to go into
Speaker 3: this sort of the flight mode should 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: and there's a passive threat defense mode where the instincts
Speaker 3: are all about losing your confidence, running home and hiding
Speaker 3: in your burrow and keeping your head down and hoping
Speaker 3: that something changes. This is the mode that is turned
Speaker 3: on when people are fighting off in illness or a
Speaker 3: major injury. So if they have surgery or if they're
Speaker 3: fighting off in illness. Some people will actually have a
Speaker 3: drop in their mood when they have an immunization, as
Speaker 3: their immune system fires up to sort to deal with
Speaker 3: the infection. But in any situation where the brain decides
Speaker 3: that it needs to be hiding doubt in recovery and
Speaker 3: recovering and keeping its head down, it will go into
Speaker 3: this fold mode. Now that may be necessary to keep
Speaker 3: you out of danger until the threat goes away, or
Speaker 3: at least hopefully until the threat goes away. But the
Speaker 3: problem that comes up in depression is when this becomes
Speaker 3: a self perpetuating process and the circuits that drive fold mode,
Speaker 3: which is a normal and useful defense mechanism for the
Speaker 3: threats we can't win against. If those circuits get stuck
Speaker 3: in an infinite feedback loop and just keep going and going,
Speaker 3: then 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 that's actually a great point. So there are
Speaker 3: situations where we're we're going into this mode is really useful,
Speaker 3: and every once in a while we're reading the news
Speaker 3: about somebody who falls off the back of a ship
Speaker 3: in the middle of the night and then miraculously gets
Speaker 3: rescued in the morning. Now, if you or I fell
Speaker 3: off the back of a ship in the middle of
Speaker 3: the night, like a cruise ship or something, we'd probably
Speaker 3: swim after the ship for a while and scream for
Speaker 3: help and try and attract his attention. But if it
Speaker 3: was really clear that the ship was sailing away and
Speaker 3: no one could hear us, and we're stuck in the
Speaker 3: middle of the sea, I mean, we're in a really
Speaker 3: bad situation. It's really risky, and this is probably not
Speaker 3: going to work out well. But our best chance of
Speaker 3: survival is actually to fold, to curl up into a
Speaker 3: ball and just wait and save your energy and hope
Speaker 3: that something about the situation changes, hope you get rescued.
Speaker 3: That mode is the same mode that we talk about
Speaker 3: when we talk about depression, and in fact, when pharmaceutical
Speaker 3: companies are developing new medications for depression, one of the
Speaker 3: ways that they'll do animal testing to see if the
Speaker 3: molecule helps depression is whether a thing called the forced
Speaker 3: swim test, and the forced swim test, the animal, like
Speaker 3: the mouse or whatever, is placed inside an air a
Speaker 3: little beaker where they have to swim around and there's
Speaker 3: 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 too are giving up quickly,
Speaker 3: and most antidepressants, when the mice are on the antidepressant
Speaker 3: still actually swim for a lot longer before giving up.
Speaker 3: And so this forced swim test, which is really just
Speaker 3: a way of tapping into how long before the animal
Speaker 3: switches into this mode of folding and giving up and
Speaker 3: waiting for something to change. That approach is a long
Speaker 3: standing and standard way that people have searched for new
Speaker 3: 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?
Speaker 2: Like, 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, in 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 it numbers
Speaker 3: for depression and suicidality going up, it's sort of an
Speaker 3: index of a number of people who feel like they
Speaker 3: are losing it life and that there's no way out
Speaker 3: for them. So it is a bit of a barometer
Speaker 3: of social health in that way. Some people have also
Speaker 3: attributed to increased stressors around social media use and so on,
Speaker 3: and some people have even attributed to things like changes
Speaker 3: in 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 1: 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 be inefferent levels or dobamine levels and so
Speaker 3: on and so. Yes, you try to influence the person's
Speaker 3: oppression by influencing these neurotransmitters in the brain, but at
Speaker 3: least 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 a or an effort in boosing
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 it's psychiatry, and in particular
Speaker 3: a field called interventional psychiatry is now looking at all
Speaker 3: the traditional disorders like depression, anxiety, and so on in
Speaker 3: terms of brain circuitry and in terms of brain function,
Speaker 3: and thanks to twenty five years of brain imaging research,
Speaker 3: we're actually starting to get really lovely maps of where
Speaker 3: stuff happens in the brain and what brain circuits are
Speaker 3: involved in depression, anxiety, OCD, post traumatic stress disorder, or
Speaker 3: eating disorders, pretty much most of the major categories of
Speaker 3: mental health disorders. We are starting to get really great
Speaker 3: maps of what areas of the brain are affected in them.
Speaker 3: The thing that's making that knowledge useful is that we're
Speaker 3: also starting to really take advantage now of a new
Speaker 3: generation of brain stimulation treatments inspired by the kinds of
Speaker 3: cases that I told you about at the beginning of
Speaker 3: our conversation, which can go into those circuits which may
Speaker 3: be overactive or underactive, and can actually stimulate them and
Speaker 3: reset them back to their normal pattern of activity. So
Speaker 3: these new generation of treatments are brain stimulation treatments, and
Speaker 3: what's important about them is they're anatomically precise. Some of them,
Speaker 3: as 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 to 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: place 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 reasons 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 overconnected. 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 injects 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 simulator 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. So I recently did an
Speaker 3: episode on how brains simulate the future. This is one
Speaker 3: of the main jobs of brains is to simulate and
Speaker 3: evaluate possible futures. What's your interpretation of what happens when
Speaker 3: somebody is depressed in terms of the futures that they
Speaker 3: are simulating. So that's a fascinating question, and I think
Speaker 3: there actually are some really lovely brain imaging studies that
Speaker 3: we're done on this about ten years ago, led by
Speaker 3: Adam Gazzale and some other folks over at UCSF. What
Speaker 3: they noticed was that perhaps in your discussion you talked
Speaker 3: about a network of areas in the brain called the
Speaker 3: default mode network. The default mode network is named that
Speaker 3: because it seems to be one of the most you know,
Speaker 3: it's the area of the brain that is on by
Speaker 3: default when we're not doing anything else. So if you
Speaker 3: or I are sitting in a room quietly and there's
Speaker 3: nothing going on, our default mode network turns on. And
Speaker 3: as we've all experienced that involved what happens in our
Speaker 3: minds is our brains start thinking about the past and
Speaker 3: thinking about the future and making plans and thinking about
Speaker 3: what may take place.
Speaker 2: There are two pathways by which we do that.
Speaker 3: There's a so called reward pathway where our brain thinks
Speaker 3: about opportunities and things we might start to want or
Speaker 3: desire to get us up out of our seats and
Speaker 3: get going. But there's also a second pathway called the
Speaker 3: non reward pathway, whose job it is entirely to think
Speaker 3: about non rewarding outcomes. Things could go wrong, fires I
Speaker 3: have to put out problems in my life, things that
Speaker 3: I should be motivated to go and sort out. And
Speaker 3: we need both of those to work in balance. So
Speaker 3: we both need the ability to come up with ideas
Speaker 3: for opportunities and things that we desire to do, but
Speaker 3: we also need to be guided by all the problems
Speaker 3: in life, all the things that we really need to
Speaker 3: be motivated to take care of. And with a balance
Speaker 3: between those two, we can both pursue opportunities in the future,
Speaker 3: and we can also avoid threats and problems and resolve them.
Speaker 3: The problem and depression occurs when this so called non
Speaker 3: reward pathway, whose whole job is to think about all
Speaker 3: negative consequences, things that are going wrong, things that could
Speaker 3: screw up, It can get trapped into sort of self
Speaker 3: perpetuating feedback loop. So the circuit in the brain is
Speaker 3: arranged as a bit of a loop from the frontal
Speaker 3: lobes going down into the reward and motivational structures of
Speaker 3: the brain and as if it gets stuck in a loop.
Speaker 3: What happens is the person experience is just finding that
Speaker 3: even though there may be ninety nine things that are
Speaker 3: going well in the person's life, their brain will find
Speaker 3: the one thing that's going wrong and it will get
Speaker 3: stuck on it, and it will just loop on it
Speaker 3: over and over and over again. I think most of
Speaker 3: us know somebody as family, friends, colleagues, maybe even ourselves
Speaker 3: who tend to do that, who are always really good
Speaker 3: at spotting the one problem and getting stuck on it.
Speaker 3: But in depression it becomes true to a pathological extent
Speaker 3: where they get so stuck on it that even with effort,
Speaker 3: they cannot pull themselves out of the negative circle of thoughts,
Speaker 3: which 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 MINDFULSS 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 in 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 3: Yeah. I'm really glad you brought that up, because I
Speaker 3: think that actually lines up really well with a very
Speaker 3: recent discovery that's still quite new about what is happening
Speaker 3: for people who are trying a second form of OURTMS
Speaker 3: that kicks in when the first one doesn't work. So
Speaker 3: when I start rTMS repetitive transcranial magnetic stimulation, it's effectively
Speaker 3: TMS treatment but using these repetitive pulses. So some people
Speaker 3: will call it rTMS, and some people will simply just
Speaker 3: abbreviate it to TMS. But we're talking about using this
Speaker 3: non invasive stimulation. So when a person goes through and
Speaker 3: does the treatment using the standard parameters that I talked about,
Speaker 3: sometimes it works, and yet there is a percentage of
Speaker 3: people where it doesn't work. What we've noticed that those
Speaker 3: people tend to have higher scales on rumination negative ruminations
Speaker 3: ABAD 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 area, so
Speaker 3: instead of stimulating the first area they talk about, they
Speaker 3: go to a different brain area which actually sits within
Speaker 3: 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 is and apply some pulses of stimulation, not
Speaker 3: to strengthen the pathway that's not what we want, but
Speaker 3: to disrupt and weaken the connections through a neuroplasticity to
Speaker 3: the point where the person can now pull themselves out again.
Speaker 1: That's your interpretation of what transcrinal meganing 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. In 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. I 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. He says, it's
Speaker 3: like I walked up to the top of this escalator,
Speaker 3: I saw where it was going, and I realized I
Speaker 3: didn't want to go down there, and so my brain
Speaker 3: just kept going. And I think what's interesting on the
Speaker 3: brain imaging studies, of course, is if you scan people
Speaker 3: before and after, what you find is exactly what you described,
Speaker 3: that the connections between within this circuit are actually getting
Speaker 3: disrupted and weakened. So the circuit's still there and functioning,
Speaker 3: but it's not getting stuck in this attractor state or
Speaker 3: this loop. So I think it actually lines up really
Speaker 3: well with the account you just described. In the one case,
Speaker 3: plasticity being used to strengthen the person's ability to control
Speaker 3: their thoughts. But if that doesn't work in the other case,
Speaker 3: you can then go directly to the area that's stuck
Speaker 3: in a loop in the first place and use another
Speaker 3: form of plasticity to weaken those connections and loosen them
Speaker 3: so 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.
Speaker 1: And so this idea of being able to help somebody
Speaker 1: buy let's say, loosening up circuits in the brain, doing
Speaker 1: other things, you know, getting someone out of an attractor
Speaker 1: state non invasively is so promising. What do you predict
Speaker 1: is going to be the field in forty years from
Speaker 1: 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 with 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 signed and frustrated, going, why are you fighting
Speaker 3: us on this? I keep trying to tell you all
Speaker 3: the things that are good in life and reminds you
Speaker 3: of them, and it's almost like you want your brain
Speaker 3: wants to just go to the one negative thing and
Speaker 3: 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: now that we know where this motivational cerguit lives, now
Speaker 3: that we know where this non reward circuit lives, we
Speaker 3: can do all kinds of interventions. And you asked, what's
Speaker 3: it going to look like in forty years. I don't
Speaker 3: think there's going to be any one treatment that is
Speaker 3: just universally what people use I'll give you an example
Speaker 3: of that. So recently, a couple of years ago, a
Speaker 3: team that you see San Francisco, led by Catherine Scangos
Speaker 3: and colleagues. They were able to go to this non
Speaker 3: reward circuit in the brain that I talked about, and
Speaker 3: they took people who had very severe depression and they
Speaker 3: did something that I think is very kind of futuristic.
Speaker 3: First of all, they brought them into a special monitoring
Speaker 3: ward in the hospital and they implanted little electrodes in
Speaker 3: their brain and let them stay in the hospital for
Speaker 3: several days or weeks. Normally, that's what you'll do in
Speaker 3: epilepsy patients if you were trying to find the source
Speaker 3: of the epilepsy within the brain. You'll put electrodes all
Speaker 3: over the brain and you'll let them sit and you
Speaker 3: wait for them to have seizures, and then you go
Speaker 3: back and reconstruct where they came from so you can
Speaker 3: perform a surgery. And this guy, they said, well, you
Speaker 3: know the folks of depression, these folks are really depressed.
Speaker 3: They can't function, their suicidal you know, they really need
Speaker 3: something just as drastic as this. So they brought them in,
Speaker 3: they implanted the electrodes but instead of waiting for seizures,
Speaker 3: they just let them have negative thoughts and using a
Speaker 3: little app on their tablet, they could constantly rate what
Speaker 3: their brain was thinking about, and so you could see
Speaker 3: what kind of brain activity was going on when they
Speaker 3: were having positive thoughts or negative thoughts. And by doing
Speaker 3: that and using a machine learning algorithm, they were able
Speaker 3: to detect the electrodes that showed particular pattern of abnormal
Speaker 3: activity that was present when the brain got sucked into
Speaker 3: those negative ruminations. When they did that, they were then
Speaker 3: able to implant a deep brain stimulator in that and
Speaker 3: it was a closed loop system, so it was attached
Speaker 3: to a tiny little computer that would that would detect
Speaker 3: when the brain had gone into this abnormal rhythm of
Speaker 3: negative thoughts and it would just disrupt the activity with
Speaker 3: about five or six seconds of stimulation. So we just
Speaker 3: flip thelip the lip, just to like when you tap
Speaker 3: on a microphone to break a feedback loop. It was
Speaker 3: literally just tapping on that microphone and saying, hey, stop it.
Speaker 3: We've used this approach in the heart for a long time.
Speaker 3: So people have heart rhythm problems, can wear things called implantable,
Speaker 3: have a surgery to have an implantable a cardiac defibrillator,
Speaker 3: so something like the defibrillator padals that you might see
Speaker 3: in the airport, but this is actually implanted inside. So
Speaker 3: if their heart ever gets stuck in an abnormal rhythm
Speaker 3: that might be fatal, the device will automatically detect that
Speaker 3: the heart's in that rhythm and just give a few
Speaker 3: blips to reset it. So interestingly, they were doing the
Speaker 3: same thing in the brain, these folks that effectively created
Speaker 3: an implantable brain defibrillator, and so it was detecting when
Speaker 3: this abnormal pattern comes along, they blip it for a
Speaker 3: few seconds.
Speaker 2: 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've had depression for decades and
Speaker 3: 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
Speaker 1: this Many listeners will already sort of be aware of
Speaker 1: this research, but generally we think of ourselves and our
Speaker 1: personalities and our thoughts and our emotions as something different
Speaker 1: from let's say our heart and how is our heart functioning,
Speaker 1: And you can defibrillate the heart, but the brain it
Speaker 1: feels like, well, that's me, that's just who I am,
Speaker 1: and so on. And it's sort of an amazing revelation
Speaker 1: that many people have when they start seeing this sort
Speaker 1: of data to understand that we are physical creatures and
Speaker 1: when you do things to change the physical structure, that
Speaker 1: changes who you 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 bought. Thisis a depression where you know,
Speaker 3: serotonin had something to do with your mood, and if
Speaker 3: your mood was low, it was maybe because your serotonin
Speaker 3: was low. You you know, didn't have enough serotonin in
Speaker 3: your soup. So we should get out a serotonin shaker
Speaker 3: and we should shake some put some more serotonin into
Speaker 3: your soup, and that will somehow just you know, make
Speaker 3: your mood get better. But it turns out, of course,
Speaker 3: it's not as simple as that, the serotonin is not mood.
Speaker 3: Serotonin in you know, in your in your GI tract
Speaker 3: will will cause your you know, to have U to
Speaker 3: have GI emotions in the brain, stomach can regulate nausea,
Speaker 3: and the visual cortex it can do visual things. And
Speaker 3: so there's no such thing as it really where mood
Speaker 3: is just boiled down to not having enough of a
Speaker 3: molecule in place. But when we looked at those cases,
Speaker 3: as you said, where people who had been depressed for
Speaker 3: so long that they thought it was just part of
Speaker 3: who they were, they then have this experience where you
Speaker 3: literally just take a circuit in the brain and blip
Speaker 3: it and reset it, and the person immediately in their
Speaker 3: thoughts is no longer getting stuck in the negative thoughts
Speaker 3: and can look past the one thing that's going wrong
Speaker 3: to the other ninety nine things that are going right
Speaker 3: through that clear sort of logical way, And you're right,
Speaker 3: people do really find it as a revelation, and people
Speaker 3: who improve on these they often find that because they've
Speaker 3: been depressed for twenty years, you know that they don't
Speaker 3: It can be actually quite a lot of work to
Speaker 3: sit down with a person and figure out how to
Speaker 3: reconstruct their life based on the premise that they actually
Speaker 3: get up every day and feel good and ready to
Speaker 3: do things. They have spent twenty years building a life
Speaker 3: around disability, so it's not something where so there often
Speaker 3: can be quite a lot of work done over months
Speaker 3: or years to try and figure out how the person
Speaker 3: will adapt to a life that has hope in it.
Speaker 1: Again, Yeah, so you once told me how you see
Speaker 1: the battle against depression in the twenty first century from
Speaker 1: a historical point of view. Yeah, so, I mean, let's
Speaker 1: come back to those we talked about earlier on where
Speaker 1: we said that there's the prevalence of depression over the
Speaker 1: lifetime is maybe ten percent, and the prevalence at any
Speaker 1: given time is about five percent.
Speaker 3: Now. There are lots of diseases in the history of
Speaker 3: medicine where the prevalence has come down a lot, So
Speaker 3: people used to be a lot of people. Tuberculosis, that's
Speaker 3: come 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 be 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, not the end of
Speaker 3: the world. Just go in and get the course of
Speaker 3: treatment and we'll see you. We'll see you back in
Speaker 3: a week or two. So you know, this will help
Speaker 3: to erode the stigma, and I think we'll really get
Speaker 3: to see the numbers coming down on this. Are we
Speaker 3: going to get those millions of people better with deep
Speaker 3: brain stimulators alone? No, of course not. We're not going
Speaker 3: to be implanting millions and millions of deep brain stimulators
Speaker 3: and everybody, not everybody wants them and just throw our
Speaker 3: up sersons to do that. But I think we do
Speaker 3: have a real opportunity using the non invasive forms of
Speaker 3: brain stimulation like TMS, which are getting you know, very
Speaker 3: very good as well. So your colleague over at over
Speaker 3: at Stanford are one of my good friends. Nolan Williams
Speaker 3: was instrumental in developing a radical new form of TMS
Speaker 3: treatment that could take a person from severe depression on
Speaker 3: money day all the way down to being in remission
Speaker 3: in literally five days. The secret was to do two things.
Speaker 3: The verse was not to do a treatment once a
Speaker 3: day traditionally, but to do up to ten treatments a day,
Speaker 3: so that a person can have thirty or forty or
Speaker 3: fifty treatments in a week and that's definitely enough TMS
Speaker 3: sessions to get them better. The second part of their
Speaker 3: trick was actually performed some brain imaging in the person
Speaker 3: so you could see what pathways to be targeting and
Speaker 3: then fine tune and personalized where the coil is. Through
Speaker 3: some combination of those two things, they seem to be
Speaker 3: hitting very high success rates that are north of fifty percent.
Speaker 3: So we have a tool now with TMS that if
Speaker 3: you know someone who has struggled with depression or anxiety
Speaker 3: and has not done well on therapy or medications, that's
Speaker 3: a lot of people. They can go anywhere in the
Speaker 3: United States right now to a TMS clinic and they
Speaker 3: can undergo a course of transcradial magnetic simulation. And with
Speaker 3: the most recent FD protocols, we believe that we can
Speaker 3: get more than fifty percent of people to remission even
Speaker 3: if nothing else has worked. So we do think we
Speaker 3: have a tool that is now capable of treating most
Speaker 3: people with depression and getting at least half of them
Speaker 3: out of depression, maybe more. The trick is going to
Speaker 3: be to scale that. So it's scaling up so that
Speaker 3: everyone in the country will have access to this treatment.
Speaker 3: Once we're there, I think we will absolutely see improvements
Speaker 3: in the prevalence in our lifetimes.
Speaker 1: It's great, Hey, just dig into one more thing, because
Speaker 1: you had talked. I've heard you talk before about tuberculosis
Speaker 1: and 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 is primarily quote a social disease
Speaker 3: with a medical aspect. In other words, yes, we can
Speaker 3: treat it medically, but Fundamentally, tuberculosis isn't going to go
Speaker 3: away until people have better living conditions, until you don't
Speaker 3: have eight people living in one room, until people aren't
Speaker 3: with bad food, and all.
Speaker 2: The rest of it.
Speaker 3: So in fact, although tuberculosis drugs were developed in the
Speaker 3: twentieth century and save millions of lives when they're invented,
Speaker 3: the reality is that the rates of tuberculosis were coming
Speaker 3: down decades before any of these drugs were ever ruled
Speaker 3: out to reach people, and the prevalence of tuberculosis improved
Speaker 3: because people's lives improved, you know, better food, cleaner water,
Speaker 3: less crowded living conditions, less dire poverty, less desperation, And
Speaker 3: I think we're going to see that a very similar
Speaker 3: thing is happening here. It's not that we won't be
Speaker 3: able to use new technologies like brain stimulation to pull
Speaker 3: people out of despair, but it's also possible that a
Speaker 3: key to getting people out of despair will be to
Speaker 3: understand depression also as to some degree a social disease
Speaker 3: with a medical aspect. If we go back to the
Speaker 3: idea that depression is the thing that happens when the
Speaker 3: brain has decided it's in a battle for survival that
Speaker 3: it's not going to win. Then we look at the
Speaker 3: prevalence of depression is a number of people who look
Speaker 3: around at their lives and concluded that they are in
Speaker 3: an unwinnable situation. And I believe in the same way
Speaker 3: that we part of the pathway to getting people out
Speaker 3: of depression and reducing its prevalence will be improving the
Speaker 3: conditions of people's lives. They're the degree to which they
Speaker 3: feel secure, a degree to which they don't feel like
Speaker 3: they're going to lose their housing or to be under
Speaker 3: threat of violence. The first places in the world to
Speaker 3: overcome depression will be the ones that don't just develop
Speaker 3: better technologies to reset the brain, but also develop stronger
Speaker 3: societies in which we just have fewer percentages of people
Speaker 3: who are trapped and fights for survival that they feel
Speaker 3: it can never seem to win. And I guess that's maybe.
Speaker 3: There is a concept which one of my colleagues introduced
Speaker 3: me to from the history of Judaism, and it's a
Speaker 3: lovely phrase that I guess really carry around with me
Speaker 3: all day. It's the phrase is to kun olam, and
Speaker 3: it has been described to me as a religious injunction
Speaker 3: to repair the world.
Speaker 2: Yeah I can't.
Speaker 3: I think you and I have also discussed this in
Speaker 3: the past as well. Yeah, so yeah, when we talk
Speaker 3: about resetting the brain, I think that falls within the
Speaker 3: larser of battles to try and improve the lot of
Speaker 3: humanity and reduce and reduce despair everywhere. And so when
Speaker 3: I think about the pathway to takun Olam and what
Speaker 3: neuroscience can contribute to it, and what you know brain
Speaker 3: stimulation can contribute to it, I think it has an
Speaker 3: essential role in reducing the number of people who face
Speaker 3: the world in despair, and that will be an essential
Speaker 3: component of this much larger injunction to repair the world,
Speaker 3: 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 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 discus, and
Speaker 1: I'll be making monthly episodes in which I address those
Speaker 1: and check out and subscribe to Inner Cosmos on YouTube
Speaker 1: for videos of each episode and to leave comments until
Speaker 1: next time. I'm David Eagleman, and this is Inner Cosmos.