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Dec. 14, 2009 - Freedomain Radio - Stefan Molyneux
52:54
1533 Dr Greg Siegle Interview - Anxiety, Depression, Autism

Dr Siegle discusses the latest breakthroughs in brain imaging and mental health treatments.

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Hi everybody, this is Stefan Molyneux from Freedomain Radio.
I am here with the esteemed Dr.
Greg J. Siegel who is an associate professor at the Department of Psychiatry at the University of Pittsburgh School of Medicine and holds many other very, very important sounding positions which I won't go into here but which I'll throw in the description for the video.
And I contacted Dr.
Siegel because I'm very interested in bringing out the empirical research behind The newest approaches to treatment of mental ailments, mental illnesses, depression, anxiety and so on.
So I've been cornering and pestering and stalking people who have some really great empirical research and Dr.
Siegel came very top on that list.
So thank you so much for taking the time to have a chat.
Thanks so much for speaking with me.
You came out of the computer science field if I read your resume correctly.
That's true. That's very interesting.
So, I mean, you bring a kind of empiricism to the work that you're doing, which comes out of computer science.
I sort of co-ran a software company in another life, so computer science is very empirical and I think it's quite interesting that you bring, I think, that same level of empiricism and precision and, of course, some considerable computer skills to your work.
Has that had a big influence on how you approach the brain, I guess, as opposed to the more abstract topic of the mind?
Absolutely. It's actually had a huge influence on how I approach both the mind and the brain.
When I was in computer science, mostly I was working in the domain of artificial intelligence, which, as you know, it involves trying to simulate minds.
At one point, I sort of learned that the work I was doing was being used primarily to help people build more accurate missiles and decided to try and apply some of that same thinking to a domain in which we had a better shot at helping people.
So it was using some of the same technologies, the same cognitive modeling technologies, to understand what went on in depression.
We originally started by just trying to say, what would make somebody who's depressed respond very quickly to negative things?
Depressed people are very quick to say things are very negative.
And so we simulated some of the relevant brain processes, And got some simulations that kind of worked.
The odd thing happens when I let one of them run overnight by accident.
And turns out that it kept going and going and thinking about negative things all evening.
We came back the next morning and said, well, maybe we have something.
And then said, if this is true, we should be able to find it in people.
And that really started the whole empirical investigation of trying to understand what goes on when depressed people think about negative things over and over and ruminate.
Right, and I'm absolutely positive you've heard this joke before, but some part of me simply cannot resist that since you use computers to simulate depression, you really know what it means when a computer is down.
But let's perhaps continue with that, continue past that joke as if we hit something in the road and we'll just keep going.
But I'm sorry, I'm afraid I just could not resist.
And that was the first time I'd heard it.
No, really? Man, you work with some dry people, or perhaps you work with some very witty people and I'm not able to compete.
We'll see. So if I understand this correctly, this affective interference that you're talking about is the way in which negative emotional connotations get associated with memories that at the time were not specifically negative.
So if you say to a depressed person, well, why don't you go have lunch with a friend?
They'll say, oh, I'm not going to enjoy that.
I don't want to do that. But then if they actually go and do it, they find that their enjoyment is not correspondent to the emotional anticipation of the enjoyment, which is much less.
Is that a fair way of putting it or is that wide of the mark?
It's actually a very fair way of putting not only the phenomenon, but some of the ways we start to try and treat depression.
So the phenomenon is that depressed people think about some negative thing, and they activate brain regions that are associated with negative emotion.
Then they think about something else, and there's a principle in neuroscience called the Hebb rule that says when two regions are active at the same time, the connection between them grows stronger.
So if you're thinking about negative things or you're feeling very sad and you think about some new thing, you'll associate sadness with the new thing and you build up all of these very negative associations.
Part of the treatment then for depression would involve helping people to learn to break those associations by, for example, experiencing something that maybe shouldn't have a negative outcome and helping them to realize, wow, that didn't have a negative outcome.
My expectations were not consistent with what happened in reality and I could try reevaluating a bit.
Right, right. So it's almost to take an analogy, the brain is to some degree a muscular organ in that which we exercise develops.
And we understand that in terms of musical ability or language skills or whatever.
But it's almost like there's optimism and pessimism are two arms of the body.
And if all you do is lift weights with your pessimistic muscles, you will get these monster Schwarzenegger muscles on the one side, but your other arm will atrophy.
And it's sort of balancing those out so that you're not just using the strongest arm, so to speak.
Brilliant. Yeah, exactly.
I sit with my patients all the time and I ask them, so do you think you're really excellent at anything?
And they'll tell me over and over again, no, I'm not.
And so I say, okay, well, let's try this.
Give me the quickest negative association you could make with just things that I throw out.
And I'll say things like kittens that most people can't find something bad to say about it.
They'll say, oh, they pee on my carpet.
And I'll say, wait, you're very good at that.
Right. Kittens in a bag in the river, right?
Exactly. Right, right.
Yeah, no, depressed people can be very, very good at slowly draining your will to live, or sometimes not so slowly.
And that, of course, is the challenge.
It's the sort of battle of light and dark.
And so can you tell me a little bit about the ideology or the source of this kind of stuff?
Because when we see people as adults, and there are lots of theories as to how it develops, you know, there's genetics, there's environment, there's a combination of the two.
Okay, there aren't that many theories.
I guess they're just three. But what are your thoughts about how this develops in terms of genetic predisposition, environment, or just, if we can use a very colloquial phrase, the bad habits of focusing on the negative that may just become self-reinforcing over time?
So, I guess we could start by suggesting that there's probably some genetic and some environmental contribution.
Few people would disagree with that at this point.
In terms of the genetic contribution, usually we're thinking of those as vulnerabilities.
So if you're put in the wrong situation with some genetic or other kind of vulnerability, you may tend to develop depression.
To give one example that people have been playing a lot with lately, there's a Variation of the serotonin transporter allele that you've probably heard about, where if you have two short copies of this allele, you Tend to activate a brain structure called the amygdala very quickly and easily in response to stimuli that could be perceived as threatening.
So if I show you a face that has a fearful expression, people with this short version of the serotonin transporter allele will tend to activate this brain structure that loosely is responsible for saying, gosh, that's bad.
Now, this might not be a bad thing.
If you live in an environment where things are very threatening, Having a system that could detect that very quickly and easily might be really adaptive.
That said, suppose you're now put in an environment where you've had some singular bad thing happen to you.
And reminders of that are everywhere and you're very good at detecting them.
All of a sudden you get to learning and perhaps over learning that bad thing and this combination of the genetic predisposition along with the environmental event could really have some negative consequences.
So we kind of think in that way about it being a diathesis stress model.
Can you just explain that last time?
Sorry, a diathesis, meaning a pre-existing vulnerability, and a stress, meaning some stressor that's happened that you wouldn't otherwise expect to have terribly negative consequences.
Right, right. And this, of course, is the challenge of learning, particularly at the base of the brain, which is that we do want to not have to learn everything over and over again.
Like, hey, these berries made me sick, and tomorrow, hey, these berries made me sick, right?
You don't want to... So you do want to adapt to negative stimuli, but at the same time, If your environment changes or if that, as you say, was a singular event, you don't want to extrapolate that to the future.
You know, like one clown was mean and therefore I must avoid all clowns for eternity.
But at the same time, we don't want to say to people, well, don't process your negative stimuli because, you know, life is a bowl of roses because it's not always.
So I think there is that real balance and that real challenge of wanting to accept and process negative stimuli but not necessarily being enslaved to extrapolating it too widely.
Absolutely. And this notion of overgeneral processing, overgeneral memory is very common in depression.
And I guess what's worse is that we shouldn't think of Emotional information processing as a static phenomenon.
When somebody processes emotional information, this area called the amygdala lights up and says, gosh, that's good or that's bad.
But then there's a lot of feedback between areas like that and another brain area called the hippocampus, which is responsible for episodic memory.
So you say, oh, that's bad.
And then you think of some bad thing that happened that's relevant.
Which makes you think, perhaps, oh, that's bad again.
And you could get stuck in this loop of, oh, that's bad, and I'll think about some bad thing, which makes me think about other bad things.
And this cascade is thought of as a spiral of depression.
Right, so there's some external stimuli that causes our fight or flight, which we then internalize by...
I mean, it's hard to say dwelling on it, because if we look at something technical like PTSD, it's not exactly a voluntary dwelling on it, because it occurs in dreams and it's involuntary, but we become almost our own self-magnifying negative stimuli, and we no longer are reliant upon the external cues for that internal response.
Exactly, and we've just become very good at thinking about that bad thing.
Typically, somebody who's depressed will Think about how they've offended somebody, for example.
And just about any information that comes into the stream of information processing could end up reminding them about how offensive they have been.
And so it's very easy to get stuck on that.
In terms of it being voluntary or involuntary, what we've found is that depressed people often don't even know they're ruminating.
When you catch them and say, are you doing it?
Oh yes, yes, they can identify it now.
But it's not a conscious, not a voluntary or volitional process.
And we find that areas like the amygdala, you show somebody an emotional bit of information, those areas turn on and they stay on for 30 seconds.
You try and interrupt them from being active with, you know, have people put numbers in order or something.
And you can decrease that activity for a few moments, but five seconds after they're done with that cognitive activity, that amygdala is back up and kicking and they'll tell you they're thinking about the negative thing again.
Right. Right, right.
And so it is, to a large degree, involuntary.
The pattern-making process of the environment, plus to some degree, as you say, the genetic susceptibility, has turned that into an involuntary process.
And until they become conscious of it, and I guess work their willpower to try and change it, it is very much, it's like your liver processing.
I don't know what the hell's going on down there.
It just happens, right?
But I guess once you become conscious of it, you have then more of a choice to interrupt that cycle.
Yeah, and I should mention that one of the most effective therapies for depression, cognitive therapy, is devoted toward first understanding thought-feeling interactions and just making very explicit.
Every time you have a negative thought, say, yeah, I understand that I'm doing that.
And then learning as almost a second step to challenge them.
A lot of people, as soon as they realize they're doing it, that's really the first step toward recovery.
Yeah, it's that injection of neocortical hamlet, right?
There is nothing good or bad, but thinking makes it so.
There are obviously stimuli in the world that will affect us positively or negatively almost without control.
I mean, you get hit by a bullet that's going to be negative or whatever, right?
But there is a huge amount, especially in the modern world where we're not susceptible to that fight-or-flight mechanism nearly as much, there's a huge amount that If you understand that there are almost always thoughts that precede feelings, particularly very solid or deep feelings, that if you can get those thoughts, over time you can learn to turn them to something different, which has a huge whiplash effect down the road on the emotionality.
I want to introduce a second concept, because near as we can tell, depressed people have a second vulnerability factor, and there are also genetic predispositions that might give you this, but in healthy people, You process some emotional information.
You say, oh, that's bad.
And then there's a mechanism that would say, yes, that might be bad, but I have other things to do and to think about now.
And this mechanism that subserves executive control lets you go off and think about something different if that's what you want to do.
In depressed people, we found that these cortical mechanisms, specifically associated with activity in the dorsolateral prefrontal cortex, Don't turn on as much as in healthy people.
So not only are depressed people ruminating and thinking about negative things, but their brake system, which should help them interrupt doing that, is not functioning optimally.
So you could think about them in that sense like a car without brakes.
Right, going downhill with a rocket pack on the back or something like that.
Absolutely, absolutely. And this is always the challenge, and this is what fascinates me so much about the work that you're doing, that you say, well, this area of the brain is not lighting up the way that it should.
Yet, it's not just the brain because we have the mind.
It's hard to know, of course, whether that is something that is genetic or whether that's something that is genetic plus environment, plus perhaps a lack of introspection and a development of bad or cyclical habits.
That's the fascinating thing, that you're looking at something that can self-adjust in a way that no other organ in the body seems to be able to do.
Absolutely. I guess one qualification I'd put on that is even if there is a genetic predisposition, for example, to not have an efficient prefrontal cortex or to have a very efficient amygdala, it doesn't mean that you can't exercise those muscles, to use your analogy from before, and get better at, for example, interrupting rumination with executive control.
So even if somebody might not be predisposed to be the Most highly controlled person they might be able to at least pick themselves up by their bootstraps out of depression with sufficient training and what it would mean to engage in those processes.
Right. I mean, as I've talked about in my show to others, if you know that you have a family history of developing heart disease, you don't just give up then and eat foie gras and smoke cigars all day.
What you do is you say, oh crap, you know, I have a predisposition towards this, so I need to work extra hard in the opposite direction.
And the funny thing is that you, of course, can end up even healthier than if you'd never found out you had a family history of a tendency towards heart disease because you may end up eating better than average and exercising more than the average or whatever it is else that you would do or getting more Yes, absolutely. And that's one thing we're finding.
We've just started to look at what depressed people look like after therapy, scanning people's brains before and then after therapy again.
And sure enough, we find changes.
And these depressed people Well, one of the most interesting things we're starting to see is that they don't necessarily look just like healthy people, but they certainly look different than depressed people.
So perhaps you're giving them new skills, you're creating a new animal which is uniquely suited to dealing with the vulnerabilities of depression.
Yeah, now that's interesting because now the kind of therapy that you're talking about is largely cognitive-based therapy, which is really, as I understand it, really examining at a very core level The thoughts and impulses that lead to the emotions and not accepting the emotions as a cause, but rather as an effect of unconscious premises or values or perspectives that you sort of need to make conscious.
Check the rationality of and sort of that's a very, very brief summary of CBT. Is that the kind of therapy that you were mentioning earlier has the greatest effect with depressed people?
Yeah, or at least it has a proven strong effect with depressed people.
Right, right. Sorry, go ahead.
Just when we say a strong effect, so we're not too optimistic, probably 60% of people respond to it.
And we still have 40% of people for whom we're looking for other interventions.
Right, right. And we'll get to some of the work that you're doing in predicting which form of treatment would be best, which as you say, there's no other field that you don't do some sort of pre-screening to figure out the best treatment.
But when you say that the brains are different, this comes out of the fMRI work, I assume that you're mapping the actual activity within the brain in real time and seeing the differences.
So we have sort of three categories, the depressed pre-treatment, the depressed or hopefully less depressed post-treatment, and then the sort of average or normal.
I mean, we've talked a little bit about the elevated amygdala and depressed hypothalamus.
Did I get that right?
Or depressed frontal cortex?
Prefrontal cortex.
So what comes out of therapy for depressed people and what are the differences that you see between that and the average brain?
Well, so this is work where we're really just starting to look at it.
And I should let you know that the differences in depressed and healthy people before therapy we've published, the differences after, we're going to be submitting very soon for publication.
And so I don't want to say too much about it, but what I will say is that if you look at That it's not always a matter of what the regions are, but you also need to look at the time course.
So whereas healthy people may have a very quick recruitment of dorsolateral prefrontal cortex after an emotional stimulus, depressed people don't recruit that area very much at all.
Perhaps after therapy, depressed people who are no longer depressed are taking a little while to recruit that area.
So the time course of recruitment doesn't look just like healthy people, doesn't look like depressed people, but you could see they're working on, for lack of a better word, regulating that amygdala activity.
So they're taking a while for it to ramp up.
And what is the time frame of treatment or post-treatment that is being measured here?
This would be 14 weeks of good cognitive behavior therapy followed by a scan immediately after treatment.
We published last year on a group of nine depressed people imaged a year after treatment and found that the gains they had in terms of both symptoms, decreased amygdala activity, and increased dorsolateral prefrontal recruitment We're all preserved a year after.
But not increased, is that right?
They were sort of preserved but not increased?
Well, we hadn't scanned those people right after treatment, so we don't know.
Right. And because, I mean, I just wonder if it's almost like you're learning a new language, 14 weeks is only going to take you so far.
But if you continue to practice it, I just, I mean, intuitively, which means nothing, it would seem to me that you would expect a continued improvement if they kept doing the work, whatever, journaling or self-talk, until it became more sort of automatic.
And this is supported by the data.
Depressed people after therapy often will continue to get better.
Right. Again, I've always found it to be sort of like a muscle.
If you continue to do the work, then you will continue to improve.
And after a while, it does become like learning a second language.
You can think and you don't really need to study it anymore.
But there is quite a time frame that you need to continue to apply.
It's not like, ooh, 14 weeks, you walk away, dust your hands, and like, ooh, this is as good as I can get.
It is the beginning, I think, of a retraining that should go on for longer.
So this is an interesting speculation, and it's exactly what we've believed.
We're hoping to show that this is true.
We're starting a study to try and look at this.
What I can tell you is that the data on this, the very limited data, are actually even weirder than that.
Excellent. Let me take us down a garden path for just a moment, okay?
I mentioned that there's this break system, the dorsolateral prefrontal cortex.
If you think that depression is a matter of the break system not working, perhaps rather than do all the good work of cognitive therapy, we could just help people to exercise their prefrontal cortex.
For example, Add numbers just so, so they're keeping numbers in memory, and add each number to the one before it, and exercise your mind in that way.
We've tried this with depressed people, and sure enough, they get better.
They get better above and beyond therapy and medication.
A group out in England, led by Adrian Wells and Costas Papagiorgio, took this even further.
I'm sorry to interrupt your flow.
You just blew my mind a little there, and I just want to make sure I understood it correctly.
So you gave depressed people over and above therapy and medication the results were better if they added sequences of numbers within their own minds?
Yeah, yeah. Ideally because they're exercising this atrophied muscle, they're using their prefrontal cortex in a way that they wouldn't otherwise do so.
Now, sorry, this is sort of like the icing on the cake of CBT or medication, or is this without either CBT or medication?
This was all in addition to medication.
Okay, good. So it's not like a substitute, but if you do this in addition to, then you'll get even better.
That's what we've published on.
We're trying desperately to get funded to see how well this thing does alone, but as you could imagine, we're having difficulty persuading the government that that would be an interesting thing to do.
Sure. I have no doubt that it would be an enormously difficult thing to challenge people on.
People get kind of oogie around mental health and a lot of people, especially if they themselves have had some issues or family issues with it, they like, you know, la la la, doesn't happen.
Who cares? You could, you know, let's move on to something like a broken bone that we can see.
Or at least in this case, we have good validated therapies.
Now you're telling me to do this thing that admittedly sounds a little bit crazy.
Do we really want to subject people who might kill themselves to that intervention?
And the rub has been persuading reviewers that, no, this could be a powerful enough intervention that we want to try it on its own.
Wow. Okay, so I'm so sorry.
You were then starting to talk about some other researchers.
I just want to make sure I understood that one fully.
Oh yeah, no, I think this is one of our most interesting results, so I'm happy to talk about that all day.
So Adrian Wells and Costas Papagiorgio just tried something like this.
They tried to help depressed people to learn to focus their attention.
For two weeks, they brought people out into the fields and said, pay attention to this sound or that sound.
When you would otherwise be ruminating, just learn to focus your attention when and where you want to.
After two weeks, they told them, now, you've had this intervention.
Please don't do that again for a year.
You know, we really don't want you to practice in this way.
We want to see how well it sticks.
Or I think actually the England trial, it was two to six weeks.
But then they brought them back a year later after asking them, please don't practice.
And all of the gains they had made, the decreased rumination, decreased depressive symptomatology, was all present a year later.
Wait, sorry.
I think you just gave me a double negative, and I want to make sure I understood that.
So the gains that they made, if they didn't practice, the gains were all lost.
No, no, no. It's the opposite.
Oh, good. Okay. So that's why I wanted to check on that.
So the gains were preserved even without practice.
That's correct. So in this particular intervention, the gains were preserved.
The insight, perhaps, and what I would hope we could get to as a field, is that if you are...
Not simply using the therapeutic interventions that we came up with back in the 60s, but really have gotten very specific about a mechanism and said, this is a brain mechanism which is disturbed in depression.
We're going to target that brain mechanism directly until you're using it.
We might then be able to let you go without as much practice.
We don't yet have enough data to say that out loud and jump up and down about it, but I'm hopeful that these sort of neuroscience-based interventions will let us have stronger preserved gains than some of the therapies we've used to date.
Right, right. Now, I would also like to touch on a topic that I guess we mentioned before the interview started, which was the degree to which you were going to do formal assessments prior to treating depression.
I was speaking to another researcher recently who was saying that the tragedy of course is that If you put somebody on medication for depression, it can take, of course, 6 to 12 weeks for effects to show up or sometimes longer.
And it may not be right and you may need to tweak it or you may need to change it and so on.
So you might actually be 6 to 12 months before you come up with something that actually clicks with the person's individual physiology.
And he was saying that, you know, the ideal is to try and find some way to test ahead of time about what is going to be the most effective approach.
And I think that's a little bit different than the content of what you're talking about, but I think that you're quite keen on finding some way to get the most effective treatment the soonest, because saying six to twelve months to a depressed person, it's like dog years, you know?
It seems so long to somebody who's in that state of mind.
Yeah, and the consequences can be terrible.
If you have an ineffective intervention and the person is not properly monitored in that time, it could be fatal.
Depression is still the number one leading cause of days missed from work in this country.
It's terribly disruptive to families.
Every day that we can give somebody without depression is a huge gain economically, philosophically, and in terms of this person's health.
Right, right. So, I actually don't find it to be so far afield from what we've been talking about.
If you believe that this increased amygdala activity is integral to somebody's depression and decreased prefrontal control is integral to somebody's depression, and an intervention like cognitive therapy should work to interrupt these processes,
Then, you should be able, theoretically, to scan somebody's brain before treatment, and if they're a person with high amygdala activity, low dorsolateral prefrontal activity, or some of the more proximal mechanisms, the dorsolateral prefrontal cortex doesn't connect directly to the amygdala, but goes through a weigh station in the paragenual cingulate.
If those areas are not functioning, as healthy peoples do, Perhaps they're the ones who really need cognitive behavior therapy.
And indeed, we've published and now other groups have also published that the people who respond best to cognitive behavior therapy are the people with this increased amygdala activity, decreased prefrontal control.
Right. Right.
Right. Right.
And would they fall into the 60% that you mentioned earlier who benefit from most of this treatment would have those similar brain characteristics?
That's correct. Right.
Okay. Okay. And what's even more fascinating is we've got a whole set of papers that have been published recently suggesting that it's different mechanisms which predict response to medication.
So there are eight papers published now saying that in contrast to the cognitive therapy story, people with this increased rostral paragenual cingulate activity, the off switch for the amygdala, people who have increased activity in that area respond better to medication.
So that lets us get to a potential algorithm.
If I scan your brain today and you have decreased activity in that area in response to an emotional stimulus, perhaps you could do very well with cognitive therapy.
But if you have increased activity in that area relative to healthy people, well, perhaps you'd do better with medications.
Right, right, right.
Right, and again, I know that it's not black or white either or, but in terms of the immediate intervention, what you would do, what would be the highest priority to start with, that would be where you'd start, and then you'd see if there were other ways to make it longer lasting.
And of course, ideally, get the person off medication, if at all possible, in the longer run through some CBT, but that's the sort of surgical strike, first response approach, right?
That's right. It's a question of where would I start with the first intervention.
Right, right. How easy is it for people to get a hold of these kinds of brain scans?
I don't know. I mean, I know up here, I'm from Canada where MRIs are, you know, mythical beasts that you have to track down in some ways in a horrible way.
But if people do want to sort of go to their doctor, I know this is still a ways away, but how hard would it be for them to get time on an fMRI to get this kind of diagnostic tool ahead of time?
That's a great question, Stefan, and really it's very much at the heart of how valuable this kind of work is going to be in the coming years.
What I can tell you is that right now we are not at the state where we should be doing this clinically, mainly because it's hard even to compare data from one scanner to another.
That said, we're getting there.
We're getting there fast. The studies are being published every day, which are going to at least give us the technology for doing this.
In terms of then, how hard is it to get scanned?
Well, turns out that if you are suspected of having a brain lesion, or if you break your arm these days, people get you an MRI fairly quickly.
If you're suspected of having pneumonia, you're brought in very quickly for scans, so why not brains?
We now have, in America, CPT codes, insurance reimbursement codes for pre-surgical planning and pre-treatment planning.
Mostly it's used for epilepsy surgery.
So if you have somebody who has epilepsy and you want to give them an intervention, Like surgery, you want to make sure you're not taking out the brain areas that do language and that are associated with higher thought.
So you have people get an MRI and think about things and speak for a while and make sure that you've mapped out those areas so you can do your surgery around that.
We have the wherewithal to scan people for that now.
It depends on how much you think that scanning people before depression treatment is as valuable as that.
Oh, yeah. From my entrepreneur's hat, that is a really challenging but exciting business case to make.
Because depression isn't like a broken arm.
You can function. You can drag yourself through the day.
You can even be a doctor, I'm sure, and be depressed.
So there's not that saying, well, if it cuts two weeks off from work, then you pay this much less in insurance and the person starts paying insurance premiums that much sooner.
I think you'd have to make that case to the insurance companies.
And that would be, I mean, a very exciting way to translate that into something that would be actionable in a way that politics kind of isn't.
If you can make a strong business case to insurance companies about how this kind of preventative intervention We'll put cash back in the pocket within the quarter or within the second quarter.
I think that would be a very exciting team up with an economist or something and find some way to make that case.
Because we all know that the financial burden of depression and anxiety and other forms of mental illness runs into the tens of billions of dollars a year, if not more, just within the United States.
So anything which can be done to lower this burden, which is one of the most common burdens that people face before they get old in terms of their well-being, That would be just a huge breakthrough in sort of quality of life and economic advantage.
This is absolutely true.
And actually, I spend a whole bunch of my time these days talking to insurance companies about this.
I'll give you a little bit of the odyssey, which is, before I applied for my last grant from the government, I went to insurance companies and said, OK, so what do you guys need For me to believe me and start doing scans before treatment.
What kind of effects, what kind of samples do you need?
And they told me, they said straight out, if you can get effects this big and this many people, we would consider it.
We would consider reimbursing for a pre-treatment scan for depression.
So in my grant, I actually wrote down those numbers and quoted them and said, look, this is what they're telling me.
Please just give me the money to do that.
And the grant got funded.
Now, Actually making it a reality, it's going to be happening sooner than you might think.
The costs, and one of the prime reasons is that the costs of scanning is coming down.
I've worked with economists on this.
Right now, you can buy a brain scanner, an MRI, magnetic resonance imaging system, for about $800,000 US. If you believe that that's amortized over three years, And that you're scanning every day, all day, full duty cycle.
That brings the cost of the scanning, along with hiring a technician to do the scans, down somewhere in the neighborhood of between $100 and $200 an hour.
Right, right. I can do the pretreatment scan for under an hour, so it's $100.
Right. And I bet you, if you were to say to any depressed person, even without the insurance, you know, would you be willing to spend $100 to cut your treatment time in half?
I mean, I know that that's an outlandish claim and with all the caveats you could imagine, I mean, they would be like, only $100?
I would have given you 10 times, you know, because it is such a difficult state of mind to be in.
Exactly. And even in rural areas, we're frequently spending more than $100 for tests for conditions that are not life-threatening.
Well, that's fascinating.
And I mean, it is tough to make these quality of life arguments.
You need to make the economic arguments.
But of course, you know, money makes the world go round and that's not a bad thing.
But I think if you can marry the, of course, you know, that's right.
I'm just pointing it out more for my listeners.
To marry the economic argument with the quality of life issue is doing a huge amount of good in the world.
And I mean, I think you should be incredibly proud of Of your pragmatism in this approach, right?
Of getting that out of the lab and into the hands of people who so desperately need it.
Thank you so much. This is what we're trying to do.
I can tell you that at least I'm hopeful in that the National Institute of Mental Health has just reorganized around a strategic plan, which has the third objective is to develop better interventions that incorporate the Diverse needs and circumstances of people with mental illness and specifically that means tailoring treatments for the individual.
And so really the government and the country here are behind doing that kind of work.
It's just leaving us to try and make it go at this point.
Now, I was wondering if you could also just touch on the two other areas that popped into my mind, which is nothing in particular, but the two other areas where this kind of work, I could think, would be very interesting.
We've been talking about depression, which of course is the evil twin of anxiety, which is another thing where I'm sure it's something to do with a lack of suppressors and over-excitability of some part of the brain, or a part that should turn on for specific situations but then stays on too long.
And of course, the one that is more rare but is more, I guess, visible within people's minds, which is schizophrenia, whether the work that you're doing has any applicability to anxiety and schizophrenia.
Okay, sure.
So, anxiety is a close cousin of depression.
Many people even feel that it's hard to differentiate one from the other.
So, absolutely.
Many of the brain mechanisms seem similar, though I'll suggest that there's a fundamental difference in anxiety that's been identified, I guess, first by a guy named Tom Borkovic, which was that people with anxiety really Are uncomfortable with these negative emotions and they'll do what they can to avoid them.
And often we think of anxiety as a disorder of avoidance.
So whereas depressed people ruminate and wallow in what's bad, depressed or anxious people are characterized often by worry of, how can I avoid allowing this bad thing to happen?
Both rumination and avoidance are these perseverative, going over and over bad things cognitions, but anxiety is so concentrated on the future.
Now, near as we can tell, there are probably some very similar brain mechanisms that are associated with this increased and overactive amygdala, for example, in depression and anxiety, though there are potentially some critical differences.
For example, with Chris Larsen, we took Anxious people who specifically had a phobia of snakes or spiders, and we showed them pictures of spiders in the brain scanner.
And sure enough, they had highly increased amygdala activity, but it shut off very quickly, like they were avoiding the pictures.
And since then, people have found that anxious people will also even look away from the pictures.
So sorry, even when the pictures are up, they get a spike in fight or flight, and then they suppress or that is suppressed even with the picture still up?
Yeah, it's the flight part of it.
So perhaps there are these differences.
The place where I think the similarity becomes most critical is when you look at kids.
Often depressed kids don't turn into depressed adults.
They'll turn into something else, externalizing adults, you know, people with conduct problems and such.
But anxious kids very often will later turn into depressed adults.
And near as we could tell, many of the processes that are going on in anxious kids, this worry is training for how to ruminate and how to go over negative things, and they'll later turn into depressed adults.
So we're looking at... Sorry, I just want to make sure I get that.
So the depressed kids don't necessarily become depressed adults, but the anxious kids will often become depressed adults.
Yeah. Okay. And there is some data saying a lot of depressed kids do become depressed adults, but the story in anxiety is particularly clear, where these kids...
Very often become the depressed adults.
So we're looking now at scanning anxious kids' brains.
Do they look more like depressed adults?
And then if we give cognitive behavior therapy to these anxious kids, can we prevent them from turning into depressed adults?
Right. Yeah, because, I mean, brains in kids are a little bit reversed in some ways because you put a stimulant into a kid's brain and they actually become lethargic, right?
I mean, that's the ADHD medication debate.
So that's interesting that there's sort of a mirror image of what might occur as an adult.
Well, it's interesting.
The stimulant story is particularly interesting in that when we've been scanning depressed kids, In a number of articles, it's looking like whereas depressed adults are characterized by this increased amygdala activity, depressed kids are characterized by decreased amygdala activity.
Now, if you look at a typical antidepressant, this affects the neurotransmitter serotonin.
You put the amygdala in a dish of serotonin and it kind of shuts off.
Depressed adults with an overactive amygdala, you give them something that decreases serotonin function all of a sudden, or increases serotonin receptor function, and of course you could decrease amygdala activity.
Depressed kids, that might not be the relevant intervention.
In contrast, if these kids have decreased amygdala activity, maybe you need something for them that stimulates them, that makes that amygdala function even more than it was.
Perhaps something more like a stimulant would be what they need.
So perhaps this mirror image story could lead us to different interventions for depressed adults and depressed or anxious, for that matter, kids.
Yeah, I mean, the thought that pops into my mind, if you don't mind indulging Rank Amateur Hour, the thought that pops into my mind is that If you are avoidant as a child, then you avoid, I think, accumulating many of the rich experiences that children should, right?
By exploring and making mistakes and falling over and, you know, swinging the bat and missing.
They won't want to go up to bat.
And so in a sense, they don't get the richness of the childhood experience.
And so they feel that loss later on.
It's just a possibility, but that's what popped into my head.
Absolutely. I think that's really hugely true.
If you don't have all the experiences that would let you learn coping mechanisms, that would let you learn how good the world is to fall back on later, what you've learned is mostly how to avoid things.
You go into your adult life with that being mostly what you know how to do, and it might be a very difficult adult life that you lead.
Right. And you will, of course, be unconsciously comparing yourself, as we all do to varying degrees of efficacy, unconsciously comparing yourself with other people who seem to have a much easier time coping with life stressors because, of course, they may not have been anxious and avoidant as children, kind of thrown themselves into the blender and realized that it doesn't actually hurt that much.
Absolutely. Right.
That's very interesting. Very interesting.
And I know that we're going kind of far afield, but I was just wondering, I was talking to a researcher recently who blew my mind, as these conversations always do, about the degree to which a researcher is finding that certain kinds of talk therapy can actually have some effect on schizophrenia.
And my, again, admittedly amateur understanding was that schizophrenia was resistant to talk therapy.
But if talk therapy can help Adjust the brain patterns to something closer to normal and obviously schizophrenia have brain patterns that are quite far from normal Do you feel that or do you think that this approach that you're taking might have some efficacy in that realm as well?
Yeah, so this is a really interesting question.
Let me point out two potential similarities of schizophrenia and depression.
The first involves these Attractors that we've been speaking of.
That is depressed people think of some negative thing, some environmental input, and that reminds them of some other bad thing that they've learned very well, which they continue to spin on.
Schizophrenia is highly characterized by delusions and all sorts of things seem to lead back to those delusions.
So if somebody with schizophrenia sees somebody outside their department or their apartment and they have a delusion that they're being followed by the government, it could very easily trigger that delusion.
Perhaps that same sort of over-learning has gone on in schizophrenia.
And I'm not the first one to say this.
The computational modeling work that led us to understanding depression came very directly out of some computational modeling work of schizophrenia as having these very well-learned attractors.
So that's one similarity.
The second similarity, as I've mentioned, this decreased prefrontal control, the ability to think about what you want to, when you want to, as a function of the dorsolateral prefrontal cortex that we've discussed in depression.
Is also present in spades in schizophrenia.
There are large numbers of articles saying that people with schizophrenia do poorly on executive control tasks.
When you image their brain, there's decreased recruitment of the dorsolateral prefrontal cortex on hard tasks, or perhaps increased recruitment of that area on easy tasks because they're very inefficient at using it.
As such, perhaps some of these new cognitive training interventions that we've been talking about could also be effective for schizophrenia.
At this point, there are any number of trials funded, not only for cognitive behavior therapy for schizophrenia, which has proven, or at least in the initial trials, has done very well with schizophrenia, but also these neuroscience-based interventions to train prefrontal control in that group.
Right. Well, I mean, that would be a huge boon because that, I mean, is an absolutely debilitating and horrifying illness for those who experience it.
And, of course, everyone around them goes through just hell with that.
So anything that can be done with that would be enormous.
Absolutely. Okay, I've got one last, you know, since you're catching all the curveballs, I'll throw one more.
What about autism?
Autism. I know, that's the big, ugly, nasty, complex, who knows what question, but if you could spin a few thoughts, I would appreciate it.
Yeah, I mean, it's a terribly pervasive disorder.
It's terribly debilitating.
I guess I'll point to just one bit of research done by a guy named Steve Porges, which I find utterly fascinating.
We've been talking about the amygdala a lot, and the amygdala is this brain structure that recognizes things as bad or threatening.
Now, if you have a high level of vulnerability to the amygdala activating in all sorts of cases when it shouldn't activate, you could imagine that somebody would become frightened of a lot of things in their environment, yeah?
Yeah. All right.
What Steve Porter...
Oh, and Richie Davidson's group has actually found for a long time People thought that people with autism had very little in the way of emotional reactivity.
Richie Davidson scanned a bunch of brains of kids with autism and found that their amygdala was highly reactive to pictures, especially pictures of people's eye whites.
The amygdala is a highly evolutionary structure geared toward detecting threat in our environment.
And if you show just the whites of people's eyes, you get amygdala activity.
This happens in spades.
In people with autism, they react a lot to these sort of wide eyes.
We know that kids with autism can't look at people's eyes.
Right, right. Here's the work by Steve Porges, which, if we haven't blown your mind yet...
I'm putting a helmet on, so go ahead.
I would say this is some of the most exciting work I've been hearing about lately.
He says, why would the amygdala be overactive in these kids?
Well, one thing we know is they have a lot of trouble processing sound, especially like the human speech sounds.
They have a They have a very difficult time when that's played for them.
The medial temporal areas, the meat in the grain matter surrounding the amygdala, should ideally inhibit it.
Sounds inhibit those medial temporal areas.
At least this is Porges' theory.
And what he says is that these kids with autism are hearing sounds which have shut off their ability to inhibit the amygdala.
So here's his intervention.
You ready? He habituates the medial temporal lobe.
He'll play a sound in a very narrow bandwidth for these kids.
Something like almost a flute sound is a very narrow sine wave.
Once these kids calm down to hearing that, it'll widen the bandwidth just a little and habituate them to that.
He'll widen the bandwidth more and more and more.
When it reaches, when the sounds he's playing reach the bandwidth of human speech, these kids look up into people's eyes and they start interacting in a much more normal way with their parents, with their guardians and people around them.
Yeah, because they're not experiencing human speech like you and I would experience a saber-toothed tiger so they can absorb and handle the stimuli.
That's right. And ideally, perhaps this amygdala is now inhibited like healthy people's amygdala would be inhibited, and they can handle these more normal interactions, like looking at the whites of people's eyes.
Okay, well, I'll give you that, Greg.
Brain surgery with a pan flute has completely blown my mind.
I will absolutely give you that as a mind-blowing.
I'm going to play the little clip from Scannerist just when this part comes up, because that is really an astounding finding.
I think so.
Wow. Wow.
Wow. Well, listen, I really appreciate your time.
I don't want to take your entire evening away, but I really do appreciate your time.
And with your permission, I'll link people to some of the work that you've done, because I think it's completely fascinating.
And whatever I can do to put the skyhooks of media into the ivory towers of academia and haul out some of the findings, I'm happy to do.
I think what's going on in this particular area, it's amazing.
It's even over the past 10 to 15 years, it seems to have just erupted in its functional findings.
I just think what you guys are doing is I don't think there's anything more important that someone can be doing at the moment in terms of, you know, if we can just get the technology of the brain to match the technology of destruction that we have, you know, there's a race of humanity against our capacity for destruction.
And the more that we can help people to heal their minds and avoid the negative stimuli, you know, there's sort of hippie aspects of love and togetherness and intimacy that is more possible to people with more functional minds.
And I think that you guys are whipping the horses of love.
And we are racing, I think, to some degree, the horses of destruction, and anything I can do to give you guys a head start, I'm happy to do.
Well, thank you so much, Stefan.
This has really been great to talk to you.
I want to leave just with three thoughts from today, just to sum up.
One, what we've suggested is that depression is, first and foremost, a brain disorder.
It's a mind's disorder, and that mind can be measured as brain functions.
So the people who think that Yeah, autism and schizophrenia are for real, but depression is, oh, that's just in your head.
Well, yes, but it's a brain disorder.
Second, treatments for depression, both medications and psychotherapy, affect those aspects of brain function that are disrupted in depression.
So psychotherapy, CBT, is treating the brains of depressed people.
And third, what we've suggested is if you believe the first two, Then the next generation of interventions could be directed very directly at saying, so what's going on in the brain of depressed people and how do we treat that more specifically so we don't, for example, need all the side effects of the medications we currently have or the diffuseness of some therapies.
We're starting to look right at how do we affect the brain very directly.
Right, right.
And break a cycle that if these people are parents, then it will give them better coping and management and patient skills with their own children, which has an escalating positive effect.
It's like we're just reversing the downward spiral of depression intergenerationally to more of an upward spiral.
And I think that's just a magnificent thing to be involved in.
Absolutely. Well, thank you so much.
This has been terrific. I appreciate that.
Thank you so much, Greg. Take care.
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