WEBVTT - Rebroadcast Ep48 "Why do brains become depressed?" 0:00:05.160 --> 0:00:09.640 What is depression and why are brains so easily able 0:00:09.720 --> 0:00:14.680 to slip into it? Is depression detectable in animals? And 0:00:14.760 --> 0:00:17.040 when we look across the animal kingdom do we see 0:00:17.280 --> 0:00:21.119 options beyond fight or flight? And what does any of 0:00:21.120 --> 0:00:25.560 this have to do with measuring depression medications in city 0:00:25.600 --> 0:00:29.600 water supplies, or reward pathways in the brain, or the 0:00:29.600 --> 0:00:33.960 prevalence of tuberculosis or zapping the head with magnetic stimulation. 0:00:37.320 --> 0:00:39.519 Welcome to Inner Cosmos. 0:00:38.840 --> 0:00:39.920 With me David Eagleman. 0:00:40.040 --> 0:00:42.960 I'm a neuroscientist and an author at Stanford and in 0:00:43.000 --> 0:00:47.199 these episodes we sail deeply into our three pound universe 0:00:47.560 --> 0:00:51.000 to understand why and how our lives look the way 0:00:51.040 --> 0:01:04.360 they do. Today's episode is about depression. We are going 0:01:04.400 --> 0:01:07.160 to dive into the science behind it and we'll see 0:01:07.400 --> 0:01:09.160 what new solutions are. 0:01:09.040 --> 0:01:12.800 On the horizon. So let me start by assuming way out. 0:01:13.400 --> 0:01:17.080 What fascinates me is not just what the brain can 0:01:17.120 --> 0:01:21.560 accomplish in terms of our normal functioning, but also one 0:01:21.680 --> 0:01:25.600 can't help but notice the fragility of the brain. I mean, 0:01:25.680 --> 0:01:28.959 just think about how easy it is to lose. 0:01:28.720 --> 0:01:30.800 Consciousness when you hit your head. 0:01:30.880 --> 0:01:35.200 Or think about what happens when you drink alcohol and 0:01:35.240 --> 0:01:39.039 your perception and your decision making changes, or you don't 0:01:39.040 --> 0:01:41.800 get enough sleep, and how you behave and how you 0:01:41.840 --> 0:01:45.000 decide these can become a little different. Or when you're 0:01:45.120 --> 0:01:48.880 angry and you act differently, or if you consume psychedelic 0:01:48.960 --> 0:01:53.520 drugs and your conscious experience changes entirely. What all this 0:01:53.760 --> 0:01:56.480 tells us, I think, is that it's very easy for 0:01:56.560 --> 0:02:00.720 the system to get knocked off its normal pathway. And 0:02:00.760 --> 0:02:03.960 what's clear is that the brain puts an enormous amount 0:02:03.960 --> 0:02:10.520 of effort into trying to stay operating in the normal range. Now, 0:02:10.520 --> 0:02:15.799 given this context, one area that's fascinating and of massive 0:02:15.880 --> 0:02:21.280 social importance is depression. This is a mood disorder. It 0:02:21.280 --> 0:02:24.880 affects how you feel, how you think, how you handle 0:02:24.919 --> 0:02:28.360 your daily tasks, how you eat and sleep. People with 0:02:28.440 --> 0:02:40.359 depression feel persistently sad. They often feel empty or anxious, pessimistic, hopeless, worthless, helpless, 0:02:40.800 --> 0:02:43.800 and they lose interest in the things that used to 0:02:43.840 --> 0:02:47.560 bring them joy. They're slowed down in all the aspects 0:02:47.560 --> 0:02:52.280 of their life, and often there are thoughts of suicide. Now, 0:02:52.400 --> 0:02:55.720 almost everyone has had someone in their life who has 0:02:55.760 --> 0:02:59.280 suffered depression at some point, whether that's recognized or not. 0:03:00.200 --> 0:03:05.160 And generally everyone's first intuition when they have a friend 0:03:05.280 --> 0:03:08.639 or a loved one who becomes depressed is to talk 0:03:08.720 --> 0:03:11.880 them out of it, to say, hey, things are okay, 0:03:12.440 --> 0:03:14.840 snap out of it, look at the bright side. And 0:03:14.919 --> 0:03:18.400 eventually you might be tempted to say, come on, just 0:03:18.600 --> 0:03:19.240 tough en up. 0:03:20.040 --> 0:03:21.960 But the important lesson. 0:03:21.680 --> 0:03:25.680 From centuries of psychiatry and more recently neuroscience is that 0:03:25.880 --> 0:03:29.400 it's not so easy. It's a physical problem. And that's 0:03:29.440 --> 0:03:33.960 why we talk about mental illness nowadays exactly as we 0:03:34.000 --> 0:03:37.880 talk about a physical illness like COVID or a broken leg, 0:03:38.720 --> 0:03:43.880 and that understanding opens the door to different approaches, because 0:03:43.920 --> 0:03:50.840 a physical problem invites physical solutions. Now, my father was 0:03:50.880 --> 0:03:54.520 a psychiatrist, and he was always impressed that he could 0:03:54.800 --> 0:03:58.160 have a patient who would be suffering from clinical depression 0:03:58.680 --> 0:04:01.640 and would lose his job and maybe lose his spouse, 0:04:01.680 --> 0:04:05.360 and my father can make a prescription like let's say prozac, 0:04:06.000 --> 0:04:09.160 and that patient often could get out of bed again 0:04:09.360 --> 0:04:13.200 and then get his job back and win his spouse back. Now, 0:04:13.240 --> 0:04:15.760 how do we understand this, Well, it's an issue that 0:04:15.800 --> 0:04:18.159 I talk about a lot, which is that we are 0:04:18.240 --> 0:04:21.840 made up of small pieces and parts, And the thing 0:04:21.880 --> 0:04:25.520 to appreciate is that you are the sum total of 0:04:25.560 --> 0:04:26.719 all those pieces and parts. 0:04:26.760 --> 0:04:27.800 Whatever is going on. 0:04:28.200 --> 0:04:32.839 At this microscopic level is you and your mood and 0:04:32.880 --> 0:04:37.239 your behavior. Now, why would anybody think that crazy statement 0:04:37.279 --> 0:04:40.279 is true. Well, there are many things that we see 0:04:40.320 --> 0:04:43.400 in the clinics every day which teach us this lesson. 0:04:43.960 --> 0:04:47.000 People can get damage to their brains and they can 0:04:47.040 --> 0:04:50.480 no longer understand how to use a mirror, or they 0:04:50.480 --> 0:04:54.120 can no longer name furry animals, or they can no 0:04:54.200 --> 0:04:59.600 longer see colors, or understand speech, or understand music or 0:04:59.760 --> 0:05:02.479 any We have a million other things that we think 0:05:02.560 --> 0:05:05.440 should just come for free in the world. Now, what 0:05:05.480 --> 0:05:09.360 this exposes is that these are functions of the brain, 0:05:09.560 --> 0:05:12.200 and even if a little bit of the brain is damaged, 0:05:12.680 --> 0:05:15.120 then you can't perform that function anymore. 0:05:15.880 --> 0:05:18.040 Now, many of the sorts. 0:05:17.640 --> 0:05:20.800 Of brain damage that you'll read about in an exciting 0:05:20.839 --> 0:05:23.480 book about the brain, these are things that most people 0:05:23.520 --> 0:05:28.279 won't see in their lifetimes. They won't know any friend 0:05:28.360 --> 0:05:31.599 or relative who has these issues because they are rare 0:05:31.680 --> 0:05:35.360 things to happen, and they usually involve damage to a 0:05:35.480 --> 0:05:38.360 region of the brain from a tumor or a stroke 0:05:38.440 --> 0:05:42.239 or a traumatic brain injury, and those things represent big 0:05:42.360 --> 0:05:45.880 changes in the city of the brain, like an entire 0:05:45.960 --> 0:05:49.440 block of New York City falling in an earthquake. But 0:05:49.480 --> 0:05:51.880 there are much more subtle things that happen in the 0:05:51.880 --> 0:05:54.680 brain as well, and these are changes that have to 0:05:54.720 --> 0:05:58.480 do with the way the system runs, with its tens 0:05:58.480 --> 0:06:03.240 of billions of neurons and trillions of synaptic connections. So 0:06:03.560 --> 0:06:06.360 to return to the city analogy, imagine that instead of 0:06:06.400 --> 0:06:10.200 big damage that you can see, the city still looks 0:06:10.279 --> 0:06:14.960 the same, but parts of it are operating very subtly differently. 0:06:15.480 --> 0:06:20.120 So the playwrights have all quit, and the city planners 0:06:20.120 --> 0:06:24.200 have stopped planning, and the coffee shops are closing two 0:06:24.240 --> 0:06:28.560 hours earlier, and all of this stuff impedes the city's 0:06:28.600 --> 0:06:33.200 ability to thrive and be an active, well functioning place 0:06:33.279 --> 0:06:37.320 for innovation and tourism. But it's all very subtle, and 0:06:37.400 --> 0:06:40.159 if you looked at this from a drone flying over 0:06:40.200 --> 0:06:42.680 the city, you really wouldn't see much of a difference. 0:06:42.760 --> 0:06:47.200 It's small stuff that's happening at a small level, but 0:06:47.720 --> 0:06:49.279 it changes. 0:06:48.839 --> 0:06:51.080 The way that the city operates. 0:06:51.920 --> 0:06:55.040 And again, who you are and how you see, the 0:06:55.080 --> 0:06:58.600 world comes from the way that the city of your 0:06:58.640 --> 0:07:02.240 brain is operating. In other words, the sum total of 0:07:02.240 --> 0:07:06.400 what's happening under the hood your biology. And I think 0:07:06.440 --> 0:07:10.360 the reason this is surprising is because we tend to 0:07:10.440 --> 0:07:14.360 think of ourselves as being removed from our biology. You 0:07:14.360 --> 0:07:18.160 are separate from it or able to ride above it. 0:07:20.120 --> 0:07:23.200 So if you've ever known someone with depression, or had 0:07:23.240 --> 0:07:27.360 depression yourself, you will know that you can't just say hey, 0:07:27.360 --> 0:07:30.280 come on, cheer up, snap out of it. That doesn't 0:07:30.320 --> 0:07:36.240 suffice to change the biology. And one of the most 0:07:36.280 --> 0:07:41.480 pervasive and societally important examples of these kind of subtle 0:07:41.560 --> 0:07:44.440 changes to the brain is with depression. 0:07:44.840 --> 0:07:47.680 And so for this episode, I decided. 0:07:47.280 --> 0:07:50.880 To call my colleague Jonathan Downer, who is an incredibly 0:07:50.920 --> 0:07:54.080 insightful and empathic observer. 0:07:53.720 --> 0:07:54.320 Of the brain. 0:07:54.840 --> 0:07:58.160 He has an MD and specializes in psychiatry, and he 0:07:58.200 --> 0:08:01.560 also has a PhD in neuroscience, and one of his 0:08:01.720 --> 0:08:05.480 areas of expertise is depression. And as it turns out, 0:08:05.800 --> 0:08:09.920 Jonathan and I wrote a textbook together on cognitive neuroscience 0:08:09.960 --> 0:08:13.440 called Brain and Behavior, and this is the textbook used 0:08:13.440 --> 0:08:17.320 at Stanford and at universities worldwide. And the textbook covers 0:08:17.360 --> 0:08:20.040 a lot of ground, but for today, I just want 0:08:20.080 --> 0:08:23.760 to zoom in on depression. So I rang him up 0:08:23.800 --> 0:08:26.240 to get his perspective on this issue that is not 0:08:26.280 --> 0:08:32.160 only neuroscientifically important and fascinating, but also, unlike the strange 0:08:32.200 --> 0:08:35.040 deficits that you might see only in a textbook, you 0:08:35.120 --> 0:08:38.920 almost certainly know someone with depression, perhaps someone close to you, 0:08:39.120 --> 0:08:45.120 or perhaps yourself. It's a shockingly common challenge. So let's 0:08:45.200 --> 0:08:52.400 dive in to understand it. So, Jonathan, how did you 0:08:52.440 --> 0:08:54.600 get interested in studying depression? 0:08:55.800 --> 0:08:58.920 Well, it's a bit of an interesting story, David. You'd 0:08:58.960 --> 0:09:01.600 have to go back about years to when I was 0:09:01.640 --> 0:09:04.920 a graduate student over at the Toronto Western Hospital. That 0:09:05.080 --> 0:09:08.160 is a hospital that has a i guess a major 0:09:08.280 --> 0:09:12.720 neurosurgical unit where they perform surgeries where they implant deep 0:09:12.760 --> 0:09:15.920 brain stimulators, which are a bit like brain pacemakers, into 0:09:15.960 --> 0:09:18.840 the brains of people with Parkinson's disease and other kinds 0:09:18.880 --> 0:09:22.480 of neurological disorders. And in around two thousand and two, 0:09:22.559 --> 0:09:25.160 a patient came in who was a middle aged woman 0:09:25.280 --> 0:09:28.760 who had previously suffered from depression but no longer. She 0:09:28.880 --> 0:09:30.760 was coming in to have the deep brain stimulators and 0:09:30.840 --> 0:09:34.280 planted for her Parkinson's disease. They implanted the electrodes, one 0:09:34.320 --> 0:09:37.240 on one side and one on the other, and during 0:09:37.240 --> 0:09:39.440 the surgery they turned them on to make sure that 0:09:39.480 --> 0:09:42.920 they are succeeding in reducing the person's hand tremors or 0:09:42.960 --> 0:09:45.360 the other tremors in their body that they're trying to 0:09:45.400 --> 0:09:48.440 have treated. What was interesting is when they turned on 0:09:48.520 --> 0:09:51.560 the one on one side, the opposite hands started to 0:09:51.720 --> 0:09:53.840 reduce in its tremor and the tremor went away, which 0:09:53.840 --> 0:09:56.960 is exactly what they expected to happen. On the other side, 0:09:56.960 --> 0:09:58.840 there was something very strange happened as soon as they 0:09:58.840 --> 0:10:01.920 turned it on. Nothing high into her tremor whatsoever, and 0:10:02.000 --> 0:10:08.880 instead she descended instantly into a deep despairing re experiencing 0:10:08.920 --> 0:10:11.960 of her depression. It kicked him within seconds, and she 0:10:12.040 --> 0:10:14.280 described it as a deep down, bad feeling in the 0:10:14.280 --> 0:10:17.400 pit of my stomach. I wanted to cry, but I couldn't. 0:10:18.080 --> 0:10:19.559 Someone could have come in to shoot me and I 0:10:19.600 --> 0:10:23.199 wouldn't have cared. I couldn't have cared less. No, immediately 0:10:23.240 --> 0:10:26.720 they turned the switch off again, and surprisingly, within seconds, 0:10:26.720 --> 0:10:29.920 the sadness lifted again and they found themselves in a 0:10:30.000 --> 0:10:33.360 very weird situation where every time they turned on this current, 0:10:33.520 --> 0:10:36.960 the person would descend immediately within a few seconds into sadness, 0:10:37.280 --> 0:10:39.400 and then every time they turned it off she would 0:10:39.480 --> 0:10:41.679 be able to emerge within a few seconds. Again. It 0:10:41.720 --> 0:10:43.920 was literally sadness at the flip of the switch. 0:10:45.120 --> 0:10:45.440 Wow. 0:10:45.480 --> 0:10:48.720 And so that's what's got you started in researching that. 0:10:49.440 --> 0:10:50.400 So that's exactly it. 0:10:50.480 --> 0:10:53.800 So at the time I was doing my PhD using 0:10:53.800 --> 0:10:57.040 a technology called functional functional MRI, which I'm sure you've 0:10:57.040 --> 0:11:00.600 talked about on the podcast before, which is a way 0:11:00.640 --> 0:11:03.280 of using MRI scanners to look at the brain activity 0:11:03.400 --> 0:11:06.280 of people as various things happen. So the neuros versions 0:11:06.480 --> 0:11:09.120 wanted to understand what was going on, So we went 0:11:09.160 --> 0:11:11.760 down to where the functional MRIs were being done and 0:11:12.559 --> 0:11:14.640 they turned on and off one of the switches on 0:11:14.679 --> 0:11:16.720 the one side that affected the tremor, and they were 0:11:16.760 --> 0:11:19.400 able to show a particular brain pathway that was affected 0:11:19.600 --> 0:11:21.960 controlling the motor circuits of the brain, which was the 0:11:22.000 --> 0:11:25.360 intended effect. On the other hemisphere, though the electrode was 0:11:25.400 --> 0:11:27.640 just a few millimeters off and as a result, it 0:11:27.640 --> 0:11:30.719 had landed on some other pathways that projected out to 0:11:30.800 --> 0:11:33.280 a completely different part of the frontal lobes, and every 0:11:33.360 --> 0:11:35.120 time they turned on and off this part of the 0:11:35.120 --> 0:11:37.760 frontal lobes, the person would instantly going out of the sadness. 0:11:38.280 --> 0:11:40.080 Now that was happy news of the patient because they 0:11:40.080 --> 0:11:43.040 were able to reposition the electrodes so that both electrodes 0:11:43.080 --> 0:11:46.240 did the appropriate thing. But it got us thinking about 0:11:46.760 --> 0:11:49.920 what this really meant about depression. All these theories at 0:11:49.960 --> 0:11:52.440 the time that depression might be a chemical imbalance or 0:11:52.480 --> 0:11:55.079 this or that, we really saw very directly that there 0:11:55.120 --> 0:11:57.600 was a question of the activity of the brain and 0:11:57.640 --> 0:12:00.640 that within seconds, one pattern of activity the brain led 0:12:00.640 --> 0:12:03.520 to sadness, and within seconds, if that pattern of activity 0:12:03.559 --> 0:12:06.280 could somehow be turned off, then the person's sadness would 0:12:06.280 --> 0:12:08.880 go away. And that really got us thinking about whether 0:12:09.200 --> 0:12:11.200 we might start being able to use things like brain 0:12:11.240 --> 0:12:15.160 stimulation to understand what depression was about in the brain, 0:12:15.240 --> 0:12:16.920 and maybe even to come up with a new generation 0:12:17.000 --> 0:12:19.959 of treatments that work better than the medications and therapy 0:12:19.960 --> 0:12:20.439 of the time. 0:12:20.760 --> 0:12:22.840 Okay, terrific, So we'll talk about that. 0:12:23.559 --> 0:12:26.760 Let's start with can you define depression clinical depression? 0:12:27.720 --> 0:12:31.040 Sure? So, there are standardized definitions of depression that involve 0:12:31.200 --> 0:12:33.840 a series of symptoms, the core of which is sad 0:12:33.920 --> 0:12:36.760 or depressed mood most of the day most days, and 0:12:36.840 --> 0:12:39.400 the second of which is a thing called anhedonia, which 0:12:39.440 --> 0:12:42.320 is the inability to enjoy things or experience pleasure, a 0:12:42.320 --> 0:12:44.679 loss of motivation, a loss of joy, a loss of 0:12:44.679 --> 0:12:47.960 the brain's reward functions. In addition to that, there are 0:12:48.080 --> 0:12:50.880 some standard symptoms that go along with that. Commonly, people 0:12:50.960 --> 0:12:54.640 will have disturbances in their sleep or appetite, trouble with concentration, 0:12:55.520 --> 0:12:58.120 They may have difficulty with their energy and fatigue levels, 0:12:58.760 --> 0:13:01.000 and there are thoughts that come up long of self 0:13:01.000 --> 0:13:03.520 harm and suicide that there are obviously the most concerning 0:13:03.559 --> 0:13:07.080 parts about the depression. So that's the standard sort of 0:13:07.120 --> 0:13:10.560 diagnostic approach by which we determine whether somebody has been 0:13:10.960 --> 0:13:14.480 entering into a period of depression. It's unfortunately, really common. 0:13:14.520 --> 0:13:17.240 At any given time in North America, about five percent 0:13:17.240 --> 0:13:20.319 of people are in the middle of a depressive episode, 0:13:20.520 --> 0:13:23.480 and at least ten percent of people, perhaps more these days, 0:13:23.559 --> 0:13:25.880 are going to go through an episode of depression at 0:13:25.880 --> 0:13:29.320 some point in their lifetimes. Almost everybody will have somebody 0:13:29.440 --> 0:13:32.200 they know who has been through depression or is going 0:13:32.200 --> 0:13:34.240 through depression or will go through depression. 0:13:34.559 --> 0:13:36.000 So one of the things I want to talk about 0:13:36.120 --> 0:13:39.040 is why this happens, What it is about the wiring 0:13:39.080 --> 0:13:41.560 of the human brain that allows us to slip so 0:13:41.679 --> 0:13:43.960 easily into that mode. 0:13:44.679 --> 0:13:45.640 What are your thoughts on that. 0:13:46.440 --> 0:13:50.560 It's a really fascinating question, And I think to answer that, 0:13:50.600 --> 0:13:52.320 what we found is you can get a lot of 0:13:52.320 --> 0:13:54.839 the clue to that looking at evolution or a biology, 0:13:55.400 --> 0:13:57.640 because humans are not, by no means the only animals 0:13:57.679 --> 0:13:59.520 that can go into it a spare like syndrome, I 0:13:59.520 --> 0:14:01.959 mean depression. Most of us who have pets, and most 0:14:01.960 --> 0:14:05.200 of us of animals who have seen situations where animals 0:14:05.240 --> 0:14:07.559 can drop into a despair and stop eating and stop 0:14:07.600 --> 0:14:09.760 sleeping and do all the same things and don't enjoy 0:14:09.760 --> 0:14:12.600 the things they normally would. Something that looks a bit 0:14:12.640 --> 0:14:16.119 like depression is detectable in dogs and cats and elephants 0:14:16.240 --> 0:14:19.720 and zoo animals, and even in things like zebrafish, which 0:14:19.720 --> 0:14:23.640 are tiny little vertebrates. So evolution seems to have put 0:14:23.680 --> 0:14:26.760 a depression like mode there, you know, a very long 0:14:26.800 --> 0:14:28.960 time ago, and it's one of the oldest circuits in 0:14:28.960 --> 0:14:32.480 the brain. When we look at the circuitry that drives depression. 0:14:32.480 --> 0:14:35.160 What we find is it falls into a bigger category 0:14:35.240 --> 0:14:38.160 of circuits that help the brain to defend against threats. 0:14:38.960 --> 0:14:41.040 And in a nutshell, for every living thing, whether you're 0:14:41.040 --> 0:14:43.440 a fish or a raccoon or a human, there are 0:14:44.040 --> 0:14:46.120 sort of four main categories of things you can do 0:14:46.160 --> 0:14:47.840 if a threat comes along. So let's say you're a 0:14:47.880 --> 0:14:50.520 fish swimming along and a shark shows up. The first 0:14:50.520 --> 0:14:52.840 thing you can do is you can freeze and hope 0:14:52.840 --> 0:14:55.080 the shark doesn't see you, So that's freeze mode. If 0:14:55.160 --> 0:14:56.920 the shark sees you and start chasing you, then you 0:14:56.960 --> 0:14:58.520 have to go beyond freeze. You have to go into 0:14:58.520 --> 0:15:01.000 this sort of the flight mode should be the escape mode, 0:15:01.920 --> 0:15:04.480 and if the shark corners you, we've all seen that. 0:15:04.480 --> 0:15:06.240 There are animals, you know, if you happen to get 0:15:06.240 --> 0:15:09.360 a possum or a raccoon in your garage, there usually 0:15:09.360 --> 0:15:11.160 will run away, But of course if they get cornered 0:15:11.200 --> 0:15:12.680 and they feel like there's no way out, they will 0:15:12.680 --> 0:15:15.800 fight very fiercely, and lots of animals do that. So 0:15:15.920 --> 0:15:18.960 there is this third mode called fight. But the brain 0:15:19.000 --> 0:15:21.840 needs a fourth mode to deal with situations that are unwinnable. 0:15:22.080 --> 0:15:25.680 Sometimes You've tried freezing, you've tried fleeing, you've tried fighting. 0:15:26.000 --> 0:15:27.760 But if at some point the brain decides you're not 0:15:27.760 --> 0:15:29.680 going to win this fight and there's no running away, 0:15:29.720 --> 0:15:32.240 there's no escaping, and you can't just ignore the problem, 0:15:32.640 --> 0:15:35.080 the brain taps into a fourth mode that I'll call fold, 0:15:35.360 --> 0:15:38.400 and there's a passive threat defense mode where the instincts 0:15:38.400 --> 0:15:41.320 are all about losing your confidence, running home and hiding 0:15:41.400 --> 0:15:43.640 in your burrow and keeping your head down and hoping 0:15:43.680 --> 0:15:47.320 that something changes. This is the mode that is turned 0:15:47.360 --> 0:15:49.240 on when people are fighting off in illness or a 0:15:49.280 --> 0:15:51.360 major injury. So if they have surgery or if they're 0:15:51.360 --> 0:15:53.320 fighting off in illness. Some people will actually have a 0:15:53.400 --> 0:15:55.480 drop in their mood when they have an immunization, as 0:15:55.520 --> 0:15:58.560 their immune system fires up to sort to deal with 0:15:58.600 --> 0:16:01.920 the infection. But in any situation where the brain decides 0:16:01.960 --> 0:16:04.760 that it needs to be hiding doubt in recovery and 0:16:05.360 --> 0:16:07.920 recovering and keeping its head down, it will go into 0:16:07.920 --> 0:16:11.880 this fold mode. Now that may be necessary to keep 0:16:11.920 --> 0:16:14.480 you out of danger until the threat goes away, or 0:16:14.480 --> 0:16:17.200 at least hopefully until the threat goes away. But the 0:16:17.200 --> 0:16:19.600 problem that comes up in depression is when this becomes 0:16:19.760 --> 0:16:23.960 a self perpetuating process and the circuits that drive fold mode, 0:16:24.000 --> 0:16:27.000 which is a normal and useful defense mechanism for the 0:16:27.040 --> 0:16:29.720 threats we can't win against. If those circuits get stuck 0:16:29.760 --> 0:16:32.080 in an infinite feedback loop and just keep going and going, 0:16:32.440 --> 0:16:34.760 then the person may still be stuck in depression weeks later, 0:16:35.000 --> 0:16:36.720 months later, maybe even years later. 0:16:37.680 --> 0:16:40.680 You once give me an example of falling off a 0:16:40.760 --> 0:16:42.840 ship in the middle of the night to illustrate this 0:16:42.920 --> 0:16:43.480 fold mode. 0:16:44.400 --> 0:16:47.840 Yeah, so that's actually a great point. So there are 0:16:47.880 --> 0:16:51.960 situations where we're we're going into this mode is really useful, 0:16:52.040 --> 0:16:54.760 and every once in a while we're reading the news 0:16:54.760 --> 0:16:56.640 about somebody who falls off the back of a ship 0:16:56.640 --> 0:16:58.920 in the middle of the night and then miraculously gets 0:16:58.920 --> 0:17:01.080 rescued in the morning. Now, if you or I fell 0:17:01.080 --> 0:17:02.200 off the back of a ship in the middle of 0:17:02.240 --> 0:17:04.520 the night, like a cruise ship or something, we'd probably 0:17:04.560 --> 0:17:06.560 swim after the ship for a while and scream for 0:17:06.600 --> 0:17:08.639 help and try and attract his attention. But if it 0:17:08.680 --> 0:17:10.560 was really clear that the ship was sailing away and 0:17:10.560 --> 0:17:12.320 no one could hear us, and we're stuck in the 0:17:12.359 --> 0:17:14.920 middle of the sea, I mean, we're in a really 0:17:14.960 --> 0:17:17.199 bad situation. It's really risky, and this is probably not 0:17:17.240 --> 0:17:19.439 going to work out well. But our best chance of 0:17:19.480 --> 0:17:23.480 survival is actually to fold, to curl up into a 0:17:23.480 --> 0:17:26.160 ball and just wait and save your energy and hope 0:17:26.280 --> 0:17:29.240 that something about the situation changes, hope you get rescued. 0:17:30.000 --> 0:17:32.120 That mode is the same mode that we talk about 0:17:32.119 --> 0:17:35.880 when we talk about depression, and in fact, when pharmaceutical 0:17:35.960 --> 0:17:38.639 companies are developing new medications for depression, one of the 0:17:38.640 --> 0:17:40.720 ways that they'll do animal testing to see if the 0:17:40.800 --> 0:17:43.679 molecule helps depression is whether a thing called the forced 0:17:43.720 --> 0:17:46.520 swim test, and the forced swim test, the animal, like 0:17:46.560 --> 0:17:50.159 the mouse or whatever, is placed inside an air a 0:17:50.160 --> 0:17:52.040 little beaker where they have to swim around and there's 0:17:52.040 --> 0:17:54.240 nothing to stand on. Now, mice are quite good swimmers, 0:17:54.280 --> 0:17:56.240 and they're also quite good floaters, so they'll swim and 0:17:56.240 --> 0:17:59.040 swim around, and eventually, at some point they'll realize that 0:17:59.040 --> 0:18:00.760 they're not going to get out of this situation, and 0:18:00.800 --> 0:18:02.520 so they stop swimming around and they just give up 0:18:02.560 --> 0:18:05.840 and float. And at that point the experimenter will stop 0:18:05.840 --> 0:18:08.119 the stop watch and see how many minutes that took. 0:18:08.560 --> 0:18:11.760 What's interesting is that there are breeds of mice who 0:18:11.760 --> 0:18:14.200 are prone to depression and prone too are giving up quickly, 0:18:15.440 --> 0:18:18.800 and most antidepressants, when the mice are on the antidepressant 0:18:18.840 --> 0:18:21.520 still actually swim for a lot longer before giving up. 0:18:21.680 --> 0:18:24.320 And so this forced swim test, which is really just 0:18:24.400 --> 0:18:26.520 a way of tapping into how long before the animal 0:18:26.560 --> 0:18:29.199 switches into this mode of folding and giving up and 0:18:29.240 --> 0:18:33.960 waiting for something to change. That approach is a long 0:18:34.000 --> 0:18:37.240 standing and standard way that people have searched for new 0:18:37.520 --> 0:18:40.440 antidepressant medications over the last several decades. 0:18:40.880 --> 0:18:41.800 Okay, terrific. 0:18:41.960 --> 0:18:46.280 And so when we look at depression in this country 0:18:46.680 --> 0:18:50.879 or around the world, what are the rates of depression? 0:18:51.040 --> 0:18:52.960 Like, are things going up or down? 0:18:54.040 --> 0:18:57.560 Yeah, so it's unfortunate that, I mean, the encouraging thing 0:18:57.560 --> 0:19:00.280 over the last few decades is that compared to say, 0:19:00.280 --> 0:19:02.800 the nineteen eighties, in the nineteen nineties when I started 0:19:02.800 --> 0:19:05.600 doing brain imaging research, there's a lot less stigma around 0:19:05.640 --> 0:19:08.240 mental health than there was, and that that's certainly very encouraging. 0:19:08.560 --> 0:19:10.880 There are a lot more people seeking treatment than before, 0:19:11.320 --> 0:19:15.840 and people are seeking treatments with medications and with psychotherapy 0:19:16.000 --> 0:19:18.600 more more than ever. The problem is that this hasn't 0:19:18.640 --> 0:19:21.520 changed the numbers at all. So despite the fact that 0:19:21.560 --> 0:19:24.040 there's less stigma, despite the fact that people are coming 0:19:24.119 --> 0:19:27.080 forward and taking antidepressants, and that in fact, antidepressants are 0:19:27.119 --> 0:19:29.800 being used in sex quantities that they can be detected 0:19:29.920 --> 0:19:34.760 with spectroscopes in the water supplies of cities and so on, 0:19:34.800 --> 0:19:36.320 so they'll actually be able to go and they can 0:19:36.359 --> 0:19:41.000 detect trace amounts of all these medications in city water supplies. 0:19:41.720 --> 0:19:44.840 Despite all of this, the prevalence of depression and of 0:19:44.880 --> 0:19:48.560 suicidal acts and suicidality has not gone down at all, 0:19:48.920 --> 0:19:53.199 And in certain populations like younger folks under age twenty 0:19:53.240 --> 0:19:55.960 and in the early twenties, the numbers for depression, anxiety, 0:19:56.000 --> 0:19:59.080 and suicidality are going up rather than down. So we 0:19:59.119 --> 0:20:02.400 definitely need to put the search on to understand how 0:20:02.400 --> 0:20:04.640 depression works in the brain and really develop a new 0:20:04.680 --> 0:20:07.520 generation of treatments because what we're having right now is 0:20:07.560 --> 0:20:08.520 not moving the needle. 0:20:08.800 --> 0:20:10.640 Why do you suppose the numbers are going up? 0:20:12.119 --> 0:20:14.720 There are a lot of different possibilities for why that is. 0:20:15.720 --> 0:20:17.960 I think we could probably have a whole other podcast 0:20:18.000 --> 0:20:20.880 on what that is. In a nutshell, there are more 0:20:21.000 --> 0:20:23.520 There seem to be more situations where people feel like 0:20:23.560 --> 0:20:26.240 the fight is unwinnable. When I see that it numbers 0:20:26.240 --> 0:20:28.639 for depression and suicidality going up, it's sort of an 0:20:28.640 --> 0:20:30.399 index of a number of people who feel like they 0:20:30.400 --> 0:20:33.560 are losing it life and that there's no way out 0:20:33.600 --> 0:20:35.720 for them. So it is a bit of a barometer 0:20:36.000 --> 0:20:38.960 of social health in that way. Some people have also 0:20:38.960 --> 0:20:42.400 attributed to increased stressors around social media use and so on, 0:20:42.480 --> 0:20:45.160 and some people have even attributed to things like changes 0:20:45.200 --> 0:20:48.119 in the composition of the bacteria that live within our guts, 0:20:48.440 --> 0:20:51.280 some of which appear to have a protective effect against depressions. 0:20:51.320 --> 0:20:53.760 So there are a lot of theories out there, but 0:20:53.800 --> 0:20:55.840 I wouldn't say anyone has solved the mysteries of what 0:20:55.880 --> 0:20:58.680 it is. There are lots of people posing everything from 0:20:58.720 --> 0:21:04.000 social factors to psychological factors to biological factors like literally 0:21:04.000 --> 0:21:16.359 write down to the bacteria in a person's gut. 0:21:23.440 --> 0:21:26.320 So what do you think about the pharmaceutical treatments for depression? 0:21:27.040 --> 0:21:30.040 Are they are they useful? Are they neutral? 0:21:30.760 --> 0:21:32.800 Well, I would say that I can give you what 0:21:32.800 --> 0:21:35.359 the numbers say. So if a person comes into their 0:21:35.400 --> 0:21:38.280 family doctor with an episode of depression and they try 0:21:38.280 --> 0:21:41.360