0:00

This is the BBC. This

0:03

podcast is supported by advertising outside

0:06

the UK. Hello,

0:08

Curios. Another show. Penultimate

0:10

one of this particular run,

0:12

and it's a very mysterious one today.

0:14

Another one in the category of stuff

0:16

that don't really understand.

0:18

mean, kind of giving away the entire episode there,

0:20

Adam? Sure. It's not a secret. It

0:24

is Mavo that we knock

0:26

people out with drugs and don't

0:28

know how we're doing it.

0:29

So this is an episode we should explain. It's

0:31

about and aesthetics and how they work.

0:40

Today's investigation is an absolute

0:42

knockout literally.

0:43

Yes. By the end of this, you should be blissfully

0:46

unaware of the pain you've been because we had a

0:48

question coming from two different listeners.

0:50

Alicia Nissan, a train driver in New South

0:52

Wales Australia, and Neil Morton from

0:55

Sterling in Scotland, and they both

0:57

emailed curious cases at bbc dot co dot

0:59

u k asking how do anesthetics

1:01

work? I know this one. Someone in a white

1:03

coat inject you and you wake up

1:05

handcuffed to an arangotang in the cargo hold

1:08

of a plane on its way to

1:08

Jakarta. Case solved. Pretty

1:11

sure that was your stag too that you're describing

1:13

there. Now, how do they actually

1:15

work? So how what's going on

1:17

in the body? Have you ever had one, by the way? I

1:19

have in anger. No. Not

1:21

that. In

1:22

a hospital environment, yes. Just once,

1:24

I loved it. I absolutely loved it. I

1:26

see something I was doomed to have taken out

1:29

the sensation as the

1:32

stuff runs up your arm and then waking up

1:35

several hours later, not with 4

1:37

teeth short and not knowing what the hell of harm.

1:39

I know you've had one -- Mhmm. --

1:41

because you phoned

1:43

me. Video called me

1:46

about five minutes after waking up. To

1:48

tell me about something to do with work.

1:51

Not a hundred percent coherently. I have to

1:53

confess. Yeah. I mean, that's I mean,

1:55

things that I think you're in your true estate. When

1:57

you're when you're coming up from random

1:58

aesthetic. My true estate is workaholic.

2:01

I'm

2:02

coherent, workaholic, working, workaholic.

2:04

Is that alright. Well, let's make things a little bit

2:06

less in coherent because we have two experts

2:09

joining us today. We have doctor Fiona Donald,

2:11

who's president of the Royal College of Anesthetists.

2:14

Yeah, that qualification seems

2:15

appropriate. And we also have Anil Seth,

2:17

professor of Cognizant neuroscience at the University

2:19

of Sussex and general consciousness

2:22

guru. And let's with

2:24

you. Being under

2:26

a general anesthetic, that is not

2:28

the same as being

2:30

asleep. Right? So what is the

2:32

difference? It really isn't the same. I've

2:34

had a number of general anesthetics. And

2:36

what's always struck me is how different it

2:38

is. When you go to sleep, and

2:40

you wake up again. There's always a sense

2:42

of some time having

2:43

passed. You know, you know, it's roughly been

2:45

a few hours. But

2:47

under Anna sees you, It's not

2:49

just the experience of absence. It's

2:51

the absence of any experience.

2:53

You could have been under for five minutes

2:55

five hours or or fifty years even.

2:57

The the ends just join

2:58

up, you're gone, and then you're back.

3:01

It's

3:01

a it's a kind of preemination of the

3:03

of the oblivion that might have

3:05

been there before you were born or maybe after

3:07

you

3:07

die. Goodness. That, I mean, that is quite a profound

3:09

thought for right at the top of curious cases, but let's

3:11

go with it. So we're not gonna spend

3:13

much time talking about the nature of consciousness because

3:15

that's a whole series in

3:17

itself. But it's the absence of

3:20

self. You do. You see you you kinda

3:22

cease to exist. I think that's right. I think

3:24

you just go away entirely. The

3:26

brain Now it's still going, it's

3:29

still doing stuff. Your body is still alive. It's

3:31

it's really, I think it's one of the best inventions

3:33

ever. And it just turns

3:35

the self off, but more than the it turns off

3:37

any experience and experience of

3:39

the outside world, and of course, the experience

3:41

of the surgeon cutting into your

3:43

body, which is why it's such a brilliant invention.

3:45

And it's also when you need someone

3:47

like Fiona to be in the

3:49

room with you. Fiona, I know that you you

3:51

do a lot of work dishing out the drugs But

3:53

have you ever undergone a genoa and set it yourself?

3:56

Yes, I have. Just once again, I agree.

3:58

It is really different to going

4:00

to sleep. And you just lose that

4:03

time completely. And the other thing

4:05

is that so at the end

4:07

of my operation, when I was in the recovery

4:09

room, my parents had a long conversation with the

4:11

anesthetist, and we discussed

4:13

many things of which I have no

4:15

memory. I've I've really enjoyed

4:17

the last gentleman in Caesar I had

4:19

because it wasn't 4 an emergency operation,

4:21

it was a planned

4:22

surgery, a relatively minor one.

4:24

And I still remember talking to the

4:26

anesthesiologist on way in and asking

4:28

him all sorts of probably for him unexpected

4:31

questions about exactly what what I was

4:33

getting and what the timescale was going

4:35

to be. And

4:35

then really trying to pay attention

4:39

to what happened at the moment that the

4:41

anesthetic

4:41

went. And Adam, you mentioned that you feel that

4:43

cold.

4:44

That will So that really

4:45

really weird sensation and shit, isn't it

4:47

from the inside? But now it doesn't mean that you

4:49

as a professor of consciousness must be singularly

4:52

the worst patient and an

4:54

anesthetist wants to meet on the way

4:55

in. Tell me everything about

4:58

what's happening. You know what? The

5:00

anesthetist always has a last word because

5:02

I can just be gambling on, but they

5:04

they turn the tap on and undergone. Now

5:07

count back backwards. Oh, bye

5:08

bye. Fiona, do they actually do the count backwards

5:10

thing? Because I they did it with me and I remember thinking

5:12

I'm gonna do this and I got to about seven.

5:14

I witnessed my son having some surgery

5:16

one

5:16

time, and they asked him to count backwards from ten,

5:19

and he didn't get to ten.

5:20

I don't know. I've I don't have to say,

5:22

I just tend to sort chat in mainly

5:25

to people as they're

5:27

drifting off just to sort of have a kind of reassuring

5:29

noise in the background. I've not used

5:31

the number of things, but I think people do still do

5:33

it. And and we always win, as

5:35

I know

5:35

says. Yeah. You

5:37

always win. I think I think the last time I had,

5:39

it was definitely I think I

5:41

got about three numbers in before

5:43

oblivion took

5:44

over. I mean,

5:45

people people try and count really quickly. It's

5:47

not a problem.

5:49

The ecosystem. But you've been I mean,

5:51

that conversation when you come around, there is

5:53

something kind of interesting about that.

5:55

Do people say mad

5:57

stuff? Do people generally come up

5:59

with a

6:00

blank blank blank 4 that? Bong

6:01

crew's ideas as they're coming around.

6:03

They

6:04

I think they might be a little

6:06

bit more distributed than than

6:08

normal. But in general, they

6:11

make sense. And so that sort of lulls you into a

6:13

4 sense of security that you think you're having

6:15

a really good conversation with

6:17

them. And what

6:18

what do we

6:19

know about the pharmacology of what is actually

6:21

going on? That that that loss of self that

6:23

Anna was describing there. Do we do

6:25

we understand what's going on

6:28

in terms of the drugs? So, yeah, I

6:30

don't think we've got a full understanding of,

6:32

you know, how every drug drug works,

6:34

but we do know quite a bit.

6:36

So there's been there's been a lot of theories over the

6:38

years, but I think the sort of most

6:40

recent theories are that is around ion

6:43

gated channels and

6:45

that's gabot channels. So gabaries

6:48

gamma aminobutary acid. And

6:50

it's probably just – it's probably not just one

6:52

thing. But in general, what's happening is

6:54

that by interacting with those receptors,

6:56

they're kind of reducing the amount

6:58

of excitation matter transmission

7:01

of signals essentially so

7:03

that you then lose

7:04

consciousness. I okay. I'm

7:06

just I mean, I heard some stuff about ions.

7:08

I heard some stuff about receptors, but

7:10

what I did hear there was that people

7:12

aren't sure about how this

7:15

thing works. Have I have I understood that correctly

7:17

that people have been up general aesthetics

7:19

without knowing what they're doing.

7:21

So I wouldn't be quite like that.

7:24

I I would say that we generally know, you know,

7:26

we know how they're gonna work, and we know the effects taken

7:28

to have and the side effects and how to manage

7:30

things. But I think the

7:32

complete exact mechanism of

7:34

exactly how general anesthetics work

7:36

hasn't been completely worked at yet.

7:38

Okay. Let let me let me see if I've understood

7:41

this then. So in your brain, you've got

7:43

Nuance firing around all over the place.

7:45

And you want to get something

7:47

that stands in the way and stops the

7:49

receptors picking up on those

7:52

neurons

7:52

firing. Think that's the sort of thing.

7:54

So what it does is blocks a

7:57

receptor where that transmission might occur

7:59

and thereby causes the effect

8:01

to get and that

8:02

happens, as I say, at the gamba receptors. And

8:04

we also know that it happens at NMDA

8:06

receptors. Yeah. No. I do wanna ask you about,

8:08

like, just the practicalities of it

8:10

because all four of us. And I expect many

8:12

of the listeners have had general anesthetics at some

8:14

point. What happens?

8:17

You know, how do you apply the drugs? What

8:19

happens after we go

8:20

under? So we first of all have

8:22

to pop a little tube

8:25

into one of the veins so that we can

8:27

give the drugs into the veins because most of the

8:29

drugs that we give going through the through the veins,

8:31

and people would just gradually

8:33

drift off to sleep. And then you

8:35

can either keep people asleep by

8:37

getting them to breathe gases that will

8:39

keep them asleep, or you can

8:41

continue with the drugs through the vein.

8:43

And then at the end, you just stop the

8:45

drugs and then they wake

8:46

up. It's magic. It's basically

8:49

magic. It just sounds a bit like magic. I mean, what

8:51

you're what you're describing here is essentially

8:53

it sounds like you put pumps of magic of veins then

8:55

and then magical things happen. But

8:57

okay. The drugs that you're giving, this cocktail

8:59

of drugs that you're giving, do you also

9:01

have to Are there

9:03

different physiological things that you need to

9:05

control? I'm thinking about swallowing and breathing

9:08

while you're under. That's a really

9:10

interesting question. And people will

9:12

generally continue to breathe under

9:14

anesthetic for themselves unless

9:16

you paralyze their muscles so

9:18

then they can't breathe and then you have to take

9:20

over their breathing. So you're going

9:22

to take over that breathing and we

9:24

have ventilators that we use,

9:26

but a lot of anesthetics are done

9:28

with people just continuing to breathe

9:30

for themselves. What about swallowing? What about

9:32

sort of clearing your

9:35

throat of saliva? So people

9:37

don't generally swallow under anesthetic.

9:40

Because you're at a a kind of deep level

9:43

of loss of consciousness such that

9:45

you you wouldn't necessarily swallow. If people

9:47

are swallowing, might be assigned

9:49

that they're a bit

9:51

lighter under the anesthetic than you would

9:52

like. Okay. So

9:53

did people ever wake up? Does that ever

9:56

happen? You know, if you haven't been there where someone

9:59

So this, again, is an important

10:01

issue in anesthesia, and we talk

10:03

about accidental awareness under general

10:05

anesthesia. And that's

10:07

where someone is unintentionally awake.

10:10

Now, that doesn't happen very

10:12

often at all, and we have

10:14

and monitoring that we can use. So we have

10:17

clinical monitoring where we're looking at the patient because

10:19

we're always with the patient when they're

10:21

asleep. But we also have brain

10:23

monitors that we can use to look at the brain

10:25

activity, and that gives us a very good

10:27

idea of whether the anesthetic

10:29

is deep

10:29

enough, not too deep because, of course, you don't want to

10:32

give people too much answer to either. Must

10:34

be a very serious thing to to

10:36

to need to avoid. I mean, I imagine quite

10:38

life if somebody were to wake up while they're

10:40

having major abdominal surgery.

10:42

It's not so much that it's life threatening,

10:45

it's it's horrible

10:48

and it it can lead to

10:50

post traumatic stress --

10:51

Mhmm. -- for sorts

10:52

of very unpleasant sequelae.

10:54

So obviously, we do everything

10:56

we can to avoid

10:57

that. And as I say, it is very rare. So

10:59

I want

10:59

the public to be reassured. Quite

11:02

much more terrifying than waking up in a

11:04

house or not being able to So I was wondering

11:07

whether you were gonna mention that because that's the

11:09

other terrifying thing about, you

11:11

know, these these sort of incidents of

11:13

awareness during anesthesia, which is that

11:15

the person may often be

11:17

paralyzed as well, so not able

11:19

to demonstrate that they're, in

11:21

fact, awake. Which is I think some of

11:23

the older and Fiona, you can correct me if I'm wrong, but I

11:25

think some of the older methods here involved

11:28

basically putting a turn a k on so

11:30

that the parallel, the kura

11:32

Ray didn't affect one

11:34

limb so that if the person did wake

11:36

up, they would be able to you

11:37

know, wave with their left hand to

11:40

say that that I'm awake. Yeah. The

11:41

isolated forearm 4. Yeah. Yeah.

11:43

The

11:43

isolated forearm technique. Yeah. So

11:45

what this so hang on. Let me make sure I understand

11:47

this then. So historically, I

11:50

mean, back when people didn't know how

11:52

anesthetics worked, you could

11:55

be conscious, but paralyzed, physically

11:58

physically placid, but

12:01

but but totally awake in your mind. And

12:03

unable to signal to surgeons and those around

12:05

you that that this was going

12:06

on. And so how long ago we talked?

12:09

I mean, you you said this is a it was like a standard

12:11

thing,

12:11

Fiona. I mean, I've never seen the

12:13

isolated form technique. So it's an ancient, you

12:15

know, it's a historical

12:16

technique. The most

12:19

serious forms of awareness under general anesthesia, which

12:21

are extremely rare rare, are the ones

12:23

where people are completely

12:25

awake, but paralyzed.

12:28

Now that does still happen

12:29

-- Mhmm. -- and that is a generally

12:32

a medical error, but

12:34

it's very, very rare. And the fact that we've

12:36

got all the machinery that we've got now that makes

12:38

it much, much less likely to

12:40

happen

12:40

now. And of course, I mean, that's

12:43

I don't wanna trivialize this too much, but, of course,

12:45

your job is not done as soon as the person

12:47

is is is knocked out. You don't sit there,

12:49

you know, playing solitaire on your phone for the rest

12:51

of the surgery. You're monitoring

12:54

four changes in in

12:55

physiology. Right? That's right. So before

12:58

we start, we wire

13:00

people up to lots of monitors to look at

13:02

all their physiological variables,

13:04

heart rate. Their oxygen

13:06

levels, their blood pressure. And

13:08

obviously, what a surgeon is

13:10

doing will have an effect on that as well as what

13:12

we're giving. So sometimes we need

13:14

to give drugs to help keep things

13:16

like the blood pressure normal or sometimes

13:18

we just need to give a little bit more pain

13:20

killer or something like that.

13:20

You mentioned their fioner about not

13:24

giving too much anesthetic. I

13:27

mean, imagine these these drugs are pretty

13:29

potent, but But what would happen if

13:31

you were to give somebody too much? Does it

13:33

affect when they wake up? So the

13:35

main anesthetic that we use is a

13:37

drug called pro perform. I mean, all

13:39

antipsychotics generally will drop the blood pressure

13:41

anyway, but it could drop the blood pressure more than you'd

13:43

like. It might slow down

13:45

someone's breathing more than you'd like.

13:47

But equally, we know that particularly in the elderly

13:49

in the frail or people who are

13:52

generally unwell, those

13:54

effects can be exacerbated. And

13:56

so you really want to make sure that you're

13:58

in that sweet spot where you're giving

14:00

enough anesthetic to make sure

14:02

that they're obviously asleep during

14:04

the during the

14:05

operation, but not causing Jimmy's

14:07

side effects. You're

14:08

walking a tight rope then it sounds like

14:11

we're skilled professionals, and we

14:13

do this a lot. And and so, actually,

14:15

it's not as much as a type on a type of as

14:17

it sounds. But we do, you know, we do need to

14:19

pay very close attention to what's going

14:21

on. I mean, I I can't I still can't

14:23

quite get over the idea. That an

14:26

entire career in administering drugs

14:28

to people and still not really be totally

14:30

sure about the ways in which it's

14:31

working. Yeah. I can I can I

14:34

can see where you're coming from? I mean,

14:36

I think the thing is that they have

14:38

a consistent way of

14:40

working So when you give the drug, it has a consistent

14:42

way of working. And so you you

14:45

recognize that that is happening. So I'm not

14:47

sure that you actually need

14:49

to know the molecular basis

14:51

of what's happening in order to be able to

14:53

use those drugs. I mean, there are lots of

14:55

things we do in life where we don't know the

14:57

the full mechanism of of why

14:59

why someone's

15:00

working. You

15:01

could still play ball sports before Newton came

15:03

along and explain gravity to us. Absolutely.

15:09

So obviously, one of the roles of

15:11

the police statistics is to is

15:13

to monitor physiology and that includes monitoring

15:15

brain activity as Fiona mentioned. Now

15:17

we're gonna delve deep into the brain now

15:19

because we wanna know what's going on in the

15:21

brain during a general

15:21

anesthetic. And what

15:24

that can tell us about awareness

15:26

and alertness and how

15:28

consciousness normally works. And to kick us

15:30

off, we spoke to an old friend of yours,

15:32

Adam. Irene Tracy. You remember her? Yeah.

15:34

Wow. She's no friend of

15:35

mine. Oh, come on

15:36

now. Irene is a professor of

15:39

anesthetic neuroscience at Oxford University.

15:41

And listeners might remember

15:43

her because she runs a

15:45

little torturelobe and

15:47

she stabbed and electrocuted and

15:49

burnt Adam with

15:50

Chili's. 4, nothing we

15:53

can't get we can't get sign off or anything. No. I

15:54

think there was a heat gun involved in the chill shot. Okay. Anyway,

15:57

it was all part of our episode on

15:59

Pain. And I seemed to

16:01

recall. You quite liked it. Well, wait. I mean,

16:03

a little bit. Okay. Anyway,

16:05

we expect Irene about an exciting

16:07

experiment that she did. To

16:09

explore how patterns of brain activity

16:11

change as doses of anesthetic

16:13

increase and that involved

16:15

putting people in little EEG caps

16:17

like swimming cats with electrodes

16:18

inside, as well as looking at

16:20

their brain activity in a

16:22

scanner. We actually did what we call a multimodal

16:25

imaging experiments, so we had people with those

16:27

swimming cap on the e g kit,

16:29

and we put them inside

16:31

our large brain imaging scanner. Whilst

16:33

the subjects have been bombarded with

16:36

painful stimuli, an auditory stimuli.

16:38

So we were seeing how the brain was reacting to

16:40

that. But what we did then was

16:42

started to infuse in the anesthetic agent,

16:44

propofol, but instead of just squirting it

16:46

in, we very, very slowly gave

16:48

the anesthetic. So instead of taking them into

16:50

deep unawareness in fifteen

16:52

seconds, we took about thirty minutes to take

16:54

them down. Allowing

16:56

each person's brain to react

16:58

to that increasing dose of anesthetic

17:00

and to switch off in the way

17:02

that that brain wanted to. Now I've

17:04

spent thirty years looking at people's brains

17:06

and I know that people's brains

17:08

are very different and the brain is what

17:10

we're switching off during general anesthesia.

17:13

And so what we were looking for in the analysis

17:15

was, are there common things that are

17:17

happening to everybody in terms of how

17:20

the brain switching off and other things that are unique to each

17:22

person's brain. So

17:24

we stumbled across this incredible

17:26

serendipitous finding that

17:28

when people were having

17:30

an increasing dose of anesthetic. The

17:32

dose was carrying going up or pop up. And as

17:34

it went up, everybody mounted these slow

17:36

waves. And then suddenly, one person

17:38

would reach a limit and they wouldn't make any more.

17:40

And even though the dose of anesthetic kept on

17:42

going up, that was it for

17:45

them. And then the next subject did exactly the same,

17:47

but maybe they reached a different level that was

17:49

maybe a little bit more or a little bit less.

17:51

But when they reached their own

17:54

individualized maximum level of slow

17:56

waves. We realized the brain had gone

17:58

into what I call perceptual

18:00

unawareness. It was sort of lights

18:02

out. So even though the signals were coming

18:04

in, they were not being routed to the right

18:06

bits of the brain. So we're very excited

18:08

about this as a potential new device

18:10

that we could create that could really

18:12

help anesthetist deliver in

18:14

a more titrated and bespoke

18:16

way, just the right amount of anesthetic.

18:18

Okay, Anne or there's a lot going on there and a

18:21

lot to unpack from my

18:23

friend Irene. So basics

18:24

first. When she talks about mounting slow

18:27

waves, what what what what is

18:29

Irene talking about? She's

18:31

talking about these very slow oscillations

18:33

in overall brain activity.

18:35

The brain is always oscillating.

18:38

It's it's activity flows, it comes and it goes, it goes up and it

18:40

goes down, and it does this at various

18:42

different frequencies. There's

18:44

the alpha rhythm, which is very

18:46

prominent usually over the

18:48

visual cortex at the back of the brain.

18:50

This is an oscillation at about ten

18:52

hertz, ten cycles per second.

18:54

But what Irene is talking about are

18:56

delta oscillations. These are much

18:58

slow at about one to four

19:00

cycles per second. And what

19:02

she observed in her as a brilliant experiment

19:04

just to infuse the anesthetic very

19:05

slowly, is that these

19:08

delta waves, these very slow

19:10

waves those become much more prominent

19:12

and this hints at an underlying

19:14

mechanism for anesthesia and loss

19:16

of consciousness in

19:18

general. Which which has been called cortical by

19:20

stability. And what does that mean? That just means

19:22

that the the brain can be in

19:24

two different states. It can be in its normal

19:27

active states. And then it can be in very

19:29

quiescent, very low level, not much

19:31

going on state. And basically, these

19:33

these slow waves, these delta oscillations,

19:36

they show that the brain is periodically,

19:38

you know, a few times every second, just

19:41

entering this state of a very

19:44

little

19:44

activity. And what that means is each individual neuron,

19:46

each individual brain cell, there's

19:48

it sort of forgets what it's doing,

19:51

and it's normally getting inputs from a bunch of other neurons. And

19:53

then in these down states, these low states,

19:55

everything goes quiet. And

19:58

the neuron just stops. And then

20:00

when it restarts, it's like, well,

20:02

what was happening? And it starts just behaving a

20:04

little bit randomly. And what

20:06

this means is that the overall

20:08

patterns of 4 flow and

20:11

communication throughout the brain are

20:13

broken. And that's what we really see at a whole

20:15

brain level. We see

20:17

an interruption of how different parts of the

20:19

brain speak to each other.

20:19

That's really interesting because you're saying that we

20:22

see that at your own level, at a at a brain

20:24

level, but also as we started the

20:26

program talking about having a chat with Hannah when she

20:28

just woken up from her last general and

20:30

aesthetic, it also works at a sort of personality

20:32

level. You've had a pause

20:34

in your personality and you wake up slightly

20:36

confused. Yeah. That's

20:37

right. And, yeah, your

20:38

neurons forget and you forget as well. There's a

20:40

nice parallel there. And she

20:43

seems to be talking about there being a

20:45

sort of threshold that there's lots of

20:47

variants. It seemed to be very

20:49

individualized at which point

20:51

the drug turns your brain

20:51

off. Yeah. I think that's interesting. It's not that

20:54

surprising, really. I mean, we all have different brains,

20:56

so it's very likely that we're

20:58

going to respond to anesthetics in different ways. I mean, that's part

21:01

of the art of Anesthesia that Fionio

21:03

was talking

21:03

about. You can't just

21:05

know exactly

21:05

how much anesthetic it's gonna take to keep

21:08

someone at that fine balance

21:10

between just enough and not

21:12

too much So looking for

21:14

a signature in the brain that can

21:16

tell us when someone is

21:18

anesthetized, when they've lost consciousness, just

21:21

at that threshold, that's that's an extremely useful

21:23

thing to be able to

21:24

do. That's an

21:25

interesting point there, Fiona, that Animal

21:28

makes. Do you notice this this this variation

21:30

in different

21:30

individuals, the level of anesthetic that they

21:33

each require? Yeah. Yeah. New people

21:35

are different with certainly,

21:37

it takes quite a long time for them to go off to sleep and they're quite

21:39

restless as they're going off to sleep whereas other

21:41

people will go to sleep quite

21:43

quickly. Seemingly with the same amount

21:45

of drug. So, yeah, probably not a variation. One

21:47

of the things that we know about pain

21:49

thresholds from the episode

21:52

back a few series ago with involved me being tortured

21:54

by Irene is that we know that 4

21:56

localized pain, for topical pain,

21:59

that people vary, and we know that my

22:01

colleague sitting across from me with her

22:03

ginger

22:03

hair. Ginger's need

22:04

more and asbestos. She's actually have a higher

22:06

pain threshold. That is is

22:08

supposed to be true. Yes.

22:09

No. That's local anesthetic. That's local

22:12

pain. Does it does this does this sort

22:14

of variation transfer into

22:15

general, into Britain, the brain waves that we're talking about?

22:17

I think

22:18

it's more around pain

22:20

than actual anesthesia. You

22:24

know what? Even so I need to

22:26

I need to can't be full of drugs

22:28

enough to knock out a small

22:29

horse. That's a Right. Yes.

22:32

Wow. Anyway, but that that individual

22:35

variation wanna go back to thinking about what's happening

22:37

in the brain, Anil, that that

22:39

that must give us clues to what the actual physiology,

22:41

what the neurochemistry, what

22:44

what neurochemistry is happening in the brain

22:46

when consciousness is switched off if there is so

22:48

much variance between

22:49

people. There's a lot of variance. I think

22:52

there's important levels to think about how an

22:54

aesthetics work. One is this very

22:56

basic level of what anesthetic

22:58

chemicals doing to the neurons or to the

23:01

synapses, the connections between neurons.

23:03

And here,

23:03

a really important

23:04

clue comes from the fact that anesthetics

23:07

don't just work on humans. They work on pretty

23:09

much anything that's

23:10

alive. They work on mice. They work

23:13

on insects. They work on

23:15

fruit flies.

23:16

They work on bacteria, and they even work

23:18

on plants. Now you have these

23:20

these plants called mimosaputica,

23:22

the so called don't touch me plant touch

23:25

me not plant. And if you touch it, please

23:27

retract. If you infuse

23:29

a plant like that with with

23:31

anesthetics, it loses the ability to respond.

23:33

So anesthetics at some

23:35

level work on something that's shared

23:37

across pretty much everything that's

23:39

alive. And

23:40

that might be, as we were talking about earlier, it might

23:42

be something very, very fundamental to do

23:44

with the

23:45

membranes of the surfaces of cells

23:47

and how their shapes are formed and so

23:49

on. No. Do you think do you

23:50

think we should start an instantizing carrots

23:53

before we cut into

23:53

them? Well, I

23:54

mean, I I think you should. Yeah.

23:57

I

23:57

think Yes.

24:00

Wow. Anyway, you wanna go back

24:02

to thinking about what's happening in the brain

24:04

that

24:05

is

24:05

it possible to even score levels

24:07

of consciousness? How do we actually do we is

24:09

there a metric? Do we how do we know

24:11

how conscious one is? There are

24:13

a number of metrics that as Fiano was

24:16

mentioning, that brain monitoring has been

24:18

happening in operating here. This is a very

24:20

long time to try and keep track of

24:22

the level of

24:23

anesthesia. And there's actually been some very

24:26

exciting research that has developed

24:28

new kinds of consciousness or

24:30

anesthesia meters

24:30

that go a little bit beyond just

24:33

measuring how strong

24:36

particular waves

24:36

are like these delta oscillations in

24:38

the brain.

24:38

So there are it's a kind of a new

24:41

generation of consciousness meters that

24:43

have been tested under anesthesia, but also

24:45

under other ways of losing

24:47

consciousness like sleep or in people with with

24:49

severe brain injury as well. And these

24:51

are all based on measuring the

24:53

complexity of the

24:55

brain dynamics under these

24:57

different

24:57

conditions. And by complexity, I mean

24:59

something very intuitive here. Like, so when

25:02

the brain is doing something, very

25:04

very predictable. Yeah. Just repeated

25:06

patterns over and over again, that's

25:08

very low complexity. And when the

25:10

brain is behaving completely randomly, like

25:12

every neuron during its own

25:13

thing, every neuron for itself.

25:15

That's also not very complex either.

25:19

Complexity in this sense is this balance between

25:21

simplicity in predictability and

25:24

randomness. And a new approach that's

25:26

that's been pioneered for the last twenty years

25:28

or so has been measuring

25:31

levels of brain complexity. And

25:33

one really good way of

25:35

doing this is a very impressive way I think it's very

25:37

it's very cool actually. Is by using a

25:39

combination of EG, which

25:41

we've already talked about, which measures the tiny

25:43

electrical field generated by

25:45

brain

25:45

cells. And a method

25:48

called TMS transcranial

25:50

magnetic stimulation. And this is

25:52

basically put a big magnet by

25:55

the

25:55

brain turn it on very briefly, and

25:57

it and it injects a pulse of energy

25:59

into the brain. And you don't notice

26:01

this. It just activates the

26:03

the brain through

26:04

the skull. And you can see the response

26:07

to the this activation in the EEG.

26:09

It's a bit like banging on the

26:11

brain with an electrical hammer and listening

26:13

to the echo. And what

26:16

you find is that by measuring

26:18

the complexity of the echo, is it is

26:20

it just like throwing a

26:22

stone into pond and there's a there's a single response, but

26:24

it all dies out very quickly. That

26:27

goes along with unconscious states.

26:29

But if the echo is complex, like you throw a

26:32

few stones into the pond and all these waves

26:34

are bouncing around and you just see this

26:36

complicated patterns, that

26:38

come and go over space and

26:40

time. That's indicative

26:42

of a conscious state. And what's

26:44

really exciting is that researchers have been able to put a

26:47

number to this complexities. And

26:49

this number seems to

26:51

be able to track conscious level,

26:53

both in anesthesia, but also in

26:56

sleep and and after brain injury and

26:58

and many other conditions

26:59

too. And this gives us a clue

27:02

about everyday consciousness as well. We

27:04

need this we

27:05

need these complex interactions where different parts

27:07

of the brain speak to each other

27:09

in different ways. In order to

27:11

be

27:11

conscious? So there's I

27:14

mean, in summary, still quite a lot we don't

27:16

understand. I think there's still a lot to

27:18

to I didn't mention this at the beginning of but

27:20

I'm actually having a general understanding tomorrow.

27:23

So I'm not sure whether I'm gonna be

27:25

more fearful after this

27:27

conversation or less. I think I'm gonna

27:29

ask, though, Fiona, for the 4 little drug that they give you

27:31

that makes you feel like you've had three gin and tonics

27:33

before I go in.

27:36

Thank you so much to our guests. Anoseth

27:38

and Theona Donald.

27:41

So Professor Fry,

27:43

when it comes to the question of how anesthetics

27:46

actually work. Can we say k solved?

27:48

Absolutely not doctor Rutherford. Real

27:50

doctors use them every day and no

27:52

one quite knows what magic chemistry is happening

27:54

in our

27:54

brains. We fully lose a sense of

27:56

self though, our consciousness is

27:59

erased temporarily. Anesthetics

28:01

involve blocking certain neurochemical

28:03

pathways and putting the brain into a

28:05

holding path of slow

28:06

brainwaves. But precisely

28:08

how anesthesia actually works remains

28:10

one of science's great mysteries.

28:12

I woke

28:16

up during an operation once.

28:19

Did you? Mhmm. AGA general answer. No. It was

28:21

like twilight. I think that's what they call it.

28:23

It's essentially where they they give you local

28:26

anesthetic and then they heavily sedate you.

28:28

It's lower risk.

28:31

So this is when I had some

28:33

an operation on my lymphedema, which

28:36

I spoke about a number of times in

28:38

Anyway, what happened was I

28:40

woke up and then I wanted

28:42

to see what was going on so I sat up

28:45

and, like, had a look. And I don't really remember seeing

28:47

that much, but I do remember the reaction

28:49

of everyone in the

28:50

room. They were like, oh, no. And then they pushed me

28:53

back down. Crikey. I mean, we

28:55

should reassure the listeners that that

28:57

is a different

28:58

process. Yeah. Yeah. Yeah. To general

29:01

understanding, And it was very it was I it's subcutaneous.

29:03

Right? So -- Yeah. -- it's very superficial.

29:05

I probably could have got away without even being

29:06

sedated. That's sedation

29:07

process. Just 4 being a

29:08

wimp. Still not III

29:11

also file that in the category of suboptimal.

29:14

There's so many interesting things about

29:16

this. And I I know that, you know, is one of

29:18

the sciences great mysteries that

29:20

this thing that use day in, day out, and

29:23

and we don't have a fundamental

29:25

understanding of what what is happening

29:27

in this in this weirdness. There's

29:29

there's another thing that we didn't quite get to in the show, which I

29:31

think is fascinating. Irene and Tracy was

29:33

talking about the the natural variants, how

29:35

people are different, and people's brains are

29:38

different. And a

29:40

while back, I was involved in a project talking

29:42

about the genetic differences and reactions

29:45

to anesthetics. And

29:47

there's a really interesting category.

29:49

There's one particular anesthetic

29:51

which is which is used

29:53

acetylcholine eschar as it's called and it's

29:56

it's addressing a system which

29:58

is so you can intubate people. So during

30:00

anesthetics, you need to get a tube down down

30:02

their throat and our throats generally don't like that

30:03

happening. Mhmm. So you give a local

30:06

anesthetic which suppresses the muscles, and

30:08

it normally lasts about

30:10

five

30:10

minutes. But in the late seventies,

30:13

early eighties in India, A doctor

30:15

started to notice that some of their

30:18

patients were going in

30:20

for voluntary operations.

30:23

And they were not

30:25

waking up from their anesthetics for up

30:27

to five or six hours.

30:29

And then

30:30

they wake up and they're absolutely fine. Right?

30:32

So it wasn't clinically problematic.

30:35

So they went through this process of trying to

30:37

understand which bit of the anesthetic cocktail

30:39

was causing this, and this particular group of people was

30:41

reacting to. And it was in fact this

30:44

substance alconate's bit of the

30:46

anesthetic cocktail

30:46

mix, which is first suppressing the

30:49

the gag reflex.

30:50

And then they noticed that it was only happening

30:52

in one particular group of people

30:55

and that so in India,

30:57

there's still a lot of cost based.

30:59

In dogami, it's cool. So, you know,

31:02

different groups of people that

31:04

don't necessarily into breed with each other.

31:05

Mhmm. That's a very bad way to explain it. Yeah.

31:08

But it may I mean, it makes it I mean, like,

31:10

there's all sorts of extremely

31:13

problematic cultural history

31:15

associated with this, but but ultimately

31:18

ultimately you have groups that that

31:20

tend to marry and have children within their

31:22

own

31:22

groups. Exactly. That's

31:23

exactly right. That's a much better way of explaining

31:25

that. You're welcome. You know

31:26

what? I can see she's just hearing on Eugenics.

31:30

Wait a minute. Just explain genetics

31:32

and race to me. I think you did. Anyway,

31:34

so what what was noticed was it was

31:36

one particular

31:36

cast. It was It was Just just to be

31:38

clear, anyone that doesn't know how

31:41

heavily addicted Adam is when

31:42

he's on. It would work on genetic. He has a

31:44

radio four series at the moment called Bad Blood on you

31:46

on you tanks. I'm just popping the

31:48

word Eugenics in as a

31:49

law. It's important to just say it makes a

31:52

plan eighty percent of my work here. Anyway,

31:54

the point is that this one group of people at

31:56

Voicea Cast, which is like a

31:58

merchant cast in in India,

32:01

all of the people that were were weren't waking up

32:03

for 456

32:05

hours. From this particular pseudo code, anesthetics,

32:07

were all from this one

32:10

group. And so it was

32:12

it was worked out that there

32:14

was a particular genetic mutation in the chemical pathway,

32:16

the metabolic pathway, which

32:19

is processing this

32:21

particular anesthetic, and it only

32:23

exists in this one particular group. So

32:25

when you notice things like that, you

32:27

can you can go back through history and work

32:29

out when that mutation occurred, and we think it occurred

32:31

about two thousand years ago,

32:33

existed for two thousand years

32:35

with absolutely zero effects because

32:37

no one was being anesthetized with

32:39

Colleen Estores. Oh,

32:41

crazy. And then all of a sudden, you see, oh,

32:43

there you go. So that's a When we

32:45

when we were talking about that, I was thinking about that because both

32:48

Anil and I have Indian

32:50

heritage, but

32:52

I I wonder what what mutations have

32:54

already happened that it that that that

32:56

have not yet revealed themselves because

32:58

we're not yet drinking the draft

33:01

Yeah. That that that will show themselves

33:03

to be. Well, alcohol is is a good

33:05

example of that because there's there's

33:07

natural variation in alcohol

33:10

dehydrogenase. Which is the

33:12

the enzyme that processes our goal.

33:14

And it's distributed in wildly

33:16

different ways around the

33:16

world. And it only has

33:19

an effect if you drink if you

33:21

drink.

33:21

And that and that's a big part of the history of

33:24

scientific racism in fact. Oh, it's

33:26

happened. I've got to it.

33:28

Really took fifty five series.

33:31

Yeah. But that's for another time. Should we

33:33

do

33:33

some Curio correspondence? Curio

33:35

correspondence, which comes before, 4. Wait.

33:38

Wait. Wait. How much?

33:40

Correspondence. What are

33:43

you

33:43

saying? It's just

33:46

been suggested that one of our things.

33:49

Emma, our studio manager who's just that. I

33:51

don't know Adam and I, we've

33:53

now got to the stage of curiousness is where we've done

33:55

an episode on every conceivable

33:57

thing, including an episode on

33:59

singing. And if you'd listened to that, you know that it is not

34:01

wise to ask, particularly

34:04

me. But

34:04

also, Adam Kisill bang on about being

34:07

4 after I that used to a chorister. Let's do

34:09

correspondence. There's no there's a theme tune. So I

34:11

I left a pause then for the theme tune, but there

34:13

isn't one. There isn't

34:16

one. So a couple of episodes ago,

34:18

we did a Phantasia, the concept of the blind minds I knew.

34:20

Inability to visualize in your

34:22

head -- Mhmm. -- and both

34:25

was to the tests online, and

34:28

then I came up with a hyper

34:29

visualizer, and I think you were

34:31

pretty good visualizer. An

34:34

AFAN average. I think I was I was

34:36

bang average. A Fantastic Put

34:38

People. I can't I still can't remember how

34:40

to pronounce that. Fantastic. Yeah.

34:41

That's right. It's fantastic.

34:42

But lots and lots of people were

34:45

stunned -- Yeah. -- to realize

34:47

as this program went out that they

34:49

themselves were a fantastic and had thought

34:51

that as people all around them were saying picture in your

34:53

mind's eye, they thought it was metaphorical and

34:56

didn't realize that

34:58

other people could actually

35:00

picture things in their minds

35:01

eye. And there were so many

35:04

so many emails that came in about

35:06

this. Yeah.

35:06

And Twitter was awash with it as well. It's quite

35:08

it's very interesting now because it's not a well known phenomenon. And yet,

35:10

three percent,

35:11

you know. Yeah. And

35:14

didn't know about it. But

35:16

anyway, so there there isn't an

35:18

afantasian network. So if if if this is

35:20

something that you've come across, then then get in touch

35:22

with those guys. If you just just share your

35:24

experiences and support, Yeah. Loads of

35:25

correspondence. This one from Martin Christmas,

35:28

rather lovely. My wife, Kate, and I have just had

35:30

the most incredible evening.

35:32

I had no idea that A Frantasia even

35:34

existed and had always assumed

35:36

the phrase mind's eye was a metaphor.

35:38

We've had a lovely evening laughing

35:40

about how our our mad differences

35:42

that we never even knew despite being

35:44

married for ten

35:45

years. I wonder if it's, you know, you could

35:47

actually explain some of the joys

35:50

and maybe not joys in

35:52

relationships when

35:53

when when when discovering that you've got a condition that no one knew

35:56

about. How extraordinary. I mean,

35:57

it's like one in thirty people. One

35:59

in thirty three

36:01

percent? percent. Don't call me professional

36:04

mathematician for

36:04

nothing. Okay. Should

36:05

we take care of

36:08

the week?

36:10

Asperious, totally unique heat. Rutherford

36:15

and fries, Curio.

36:19

Of the week.

36:26

We got a letter in from Greg Wilson. proposed

36:28

an exchange of badges,

36:31

badges, badges -- Oh, right. -- not the

36:33

mammals. Right. I don't.

36:36

As I know

36:36

that you are fans of Matt Damon.

36:38

How does he know

36:41

that? I think

36:42

he's And we

36:44

ever saw them again.

36:45

One getting. You may recognize us as

36:47

the employer of his character

36:49

in goodwill hunting. You may recognize us as

36:51

the employer of his character in

36:54

goodwill. What

36:54

Okay. So either right. So he was

36:57

a builder at one point? Yes.

37:00

But he also was at university. He was at a

37:01

janitor. Janitor. In the university? Yes.

37:04

And he kept solving mathsy things on

37:06

glass, which is how mathematicians aren't

37:08

sold. No. No.

37:09

No. No. No. No. No. No. No. No. No.

37:11

There was no glass. It was a mirror

37:13

in

37:13

the toilet. Do you know what? I've got to be

37:15

careful about correcting you about

37:18

films because I did it in an episode recently and I was

37:19

wrong. Where are you? Yes. Okay.

37:21

There is

37:22

a mirror. I accept there's a mirror, but I don't think that counts

37:24

as glass. That's a mirror. No.

37:26

I think he does it with with a

37:27

chalkboard. Right. You're right. And I think it's and

37:29

4 you're right

37:30

about the mirror. Let's let's call that one square

37:32

draw. What did you get wrong?

37:35

It was when I said, cherry cherrypot fire was about

37:37

the four minute mile, it wasn't. It was

37:39

about Harold Abrahams running in the Olympics

37:41

years before Roger Bannister. I can see you

37:43

looking confused about whether you should be smug that I got it wrong and

37:46

absolute lack of interest in what I'm

37:47

saying. No. It was more that I thought it was

37:49

about Roman races.

37:52

So something like

37:54

the niche

37:55

the, like, nuanced differences between your

37:57

two things. But men on

37:59

Twitter did enjoy pointing it out.

38:02

So men on Twitter.

38:03

Okay.

38:03

Are you ready? Yeah.

38:04

What is it? Mhmm. Okay. Mhmm. Okay. It's

38:06

too bad. Here you go. Here you go. And

38:10

they say e over c

38:11

squared. Oh,

38:12

I know what it is. What it is? I know what

38:14

it is. Let me see if I can work it out.

38:17

So so we should read it out. It's an equation. It says

38:19

e over c squared times square root

38:21

of minus one times

38:24

p v over NRR

38:26

icon I do

38:27

this? Mhmm. Right. E is energy. But

38:30

what's an

38:30

equation with e

38:31

and c squared

38:34

in it? Equals m c squared

38:35

to c is the square the the speed of light? Yes. So

38:37

what's the other letter

38:38

in the m? Yeah. So m equals

38:41

E0C squared.

38:43

M equals e over c

38:45

squared. Yeah.

38:45

The middle bit, square root of minus one

38:48

is an imaginary number, which is

38:50

next week's show. Correct? The square root of minus

38:52

one is minus one. No, one?

38:54

I don't know. It's I. Come on. Oh,

38:56

I. Yeah. Imagine number. Thank you, Descartes.

39:00

So IEMI.

39:02

Now what's p v over in our

39:04

PV pressure? Think think

39:07

what's the question? E equals m c squared.

39:09

No. PVPV over n. What's what's actually Is

39:12

that an an electrical one? No.

39:15

TV pressure. Volume, voltage. Yes. Volume.

39:18

Volume. Oh, is this hook's

39:19

lock? Oil's lock. No. Oh,

39:20

I don't know. And the ideal gas

39:22

sequase embarrassing. What are -- -- radius of a

39:25

circle,

39:25

of a spear. I don't know if I think

39:27

Why don't we stop? What

39:31

else do you get with gases? What other

39:33

smell? Look,

39:33

it says MI, and they're an

39:36

employer. MI An

39:39

employer, five. Mission

39:42

Impossible. M is

39:44

equals

39:45

a t come on. Equals NRT

39:48

time. MIT. MIT. MIT.

39:50

MIT. Matt Damon worked. Will Hunting

39:52

worked at MIT? Well

39:55

done, sir. Look.

39:57

Frankly, the thing that I've

40:00

noticed that the most about this is

40:02

that Greg

40:04

spent seventeen dollars and eighty five cents in airmailing

40:06

list to

40:07

us. Yeah. Thank you, Greg. I

40:09

mean, I struggled to get through it with a

40:11

lot of hand holding

40:14

by my colleague there. But I enjoyed that. I enjoyed

40:16

that. That's cool. Also, neither us work

40:18

at MIT. You can't have a badge.

40:21

Yes, you

40:23

can. I'm saying that you can. She's

40:25

the VTO. She used the VTO. We have to we

40:27

do have something else that's connected to Matt

40:30

Damon because Duncan McMillan shared the surprising news with

40:32

us. Every

40:33

year, Steven Soderberg.

40:36

Soderberg. Who's

40:38

that?

40:38

Steven Soderberg is like one of the great living directors. Yeah.

40:41

Yeah. He's made amazing

40:43

films like that all of the oceans,

40:45

films, oceans eleven. That's

40:48

great. Twelve and thirteen, not so much. But also complete

40:50

classics like, I believe you made magic

40:52

mic, which is brewing film, and

40:55

the one about the pandemic

40:58

that happened before the pandemic where Glynis

41:00

Contagion --

41:01

Mhmm. -- is superb director. What's

41:03

going on

41:03

here? Aaron Brokovich. He made

41:06

Aaron Brokovich. That's cool. Oh,

41:06

he's cool. Oh, and and and one of the films he made with Matt Damon was

41:09

the the biography of

41:11

Leverage, which is

41:13

Excellent. Okay. Cool. Alright. So anyway, this

41:16

guy, this this man, mister

41:18

Stephen, he summarizes everything that he's read and watched every

41:20

year, and he consumes a lot. the

41:22

twenty ninth of January last year, he

41:24

read the complete guide to absolutely

41:26

everything, which is mine in and Adam's

41:29

book. No way.

41:31

I thought you

41:31

should know if you don't already. We didn't know. Adam

41:34

very clearly did not know. That

41:36

is no way. I clicked on

41:38

the link. Holy smokes.

41:40

He's like one of my favorite directs of

41:42

all

41:42

time. Is he? And he's read

41:44

one of your books.

41:47

One hour book. Wow. And you were in Where

41:50

is that? I can't see that. I can't see that. I

41:52

can't see that. I've made it. Yeah.

41:55

You know what? That's cool. That is re that is

41:57

really cool. You know what

41:59

though? What I've noticed is that he's got

42:01

basically something every single day, apart from

42:03

the day when he red

42:05

art book where he

42:08

doesn't have anything for five

42:10

entire days

42:11

afterwards. He was just Yeah. Washing. Yeah. Lying it to wash it.

42:13

I'm looking over the list here. It's really interesting.

42:15

But also, a couple of days later, he watched

42:17

Beavers and But Head do

42:20

the universe. Lovely,

42:22

Skye. Steven Soderberg, if

42:24

you're listening to this show, having read our

42:27

book, I love your

42:28

films. And I want to be your friend. And

42:30

I'm sorry to know who you were, but I I mean, I'm I'll happily be your friend

42:32

too. Watch jaws on

42:35

the fourth of September. 4. Adam's

42:38

just reading the list of everything that he's read now.

42:41

There's a question. Okay. This is let's

42:43

let's let's leave it We'll

42:45

leave in the post. Next week, we're talking about the

42:47

maturing numbers. Bay one. Glass onion, he

42:50

watch. All about eef RRR. That was

42:52

really good. The thick of it. Oh my

42:53

god. I love

42:53

this so much. That is the best things

42:56

that ever happened

42:58

to me. I'm

43:06

Paris Lays. Welcome to the

43:08

flip side from BBC

43:10

4 Radio In each

43:13

episode, I'll tell two stories from opposite sides

43:15

of the coin. A new

43:18

science to ask questions

43:20

about elements of the

43:22

human

43:22

experience. That we sometimes take for 4.

43:26

Turns out that this person that

43:27

I sublet my

43:30

apartment to he was, you know, a scammer. I see now

43:32

I am the

43:33

person that I was when I was

43:35

on the Internet at thirteen. It's

43:38

lies and it's covered with lips