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Anesthesia and the Brain

Part 1: Unconsciousness Under General Anesthetic is a Dynamic State

00:00:15.05 Hi. I'm Emery Brown.
00:00:17.00 I'm an anesthesiologist at Mass General Hospital,
00:00:19.10 a Professor of Anesthesia at Harvard Medical School,
00:00:21.18 and a Professor of Computational Neuroscience at MIT.
00:00:24.24 What I'd like to do today is talk to you a little bit about anesthesia,
00:00:28.11 and I've entitled this talk
00:00:30.12 "Unconsciousness Under General Anesthesia is a Dynamic State".
00:00:34.08 So, these are the main points which I'd like to share with you.
00:00:37.23 Under general anesthesia, the brain is not turned off.
00:00:41.06 It's actually quite active.
00:00:43.05 It's actually quite dynamic,
00:00:45.01 and I'm gonna show you that.
00:00:47.04 Anesthetics work by creating oscillations
00:00:50.14 -- rhythms in the brain --
00:00:53.04 that block the ability of various parts of the brain
00:00:56.11 to communicate.
00:00:57.17 We're gonna see that very dramatically.
00:01:01.08 The way we're going to see it is using the electroencephalogram,
00:01:04.05 the EEG.
00:01:07.07 It's a way to measure brainwaves.
00:01:08.11 And as a consequence of these oscillations,
00:01:10.22 we can use this to track the state of someone under anesthesia
00:01:14.20 and know whether he or she is sufficiently unconscious or not.
00:01:20.05 So, just a brief overview.
00:01:22.13 60 million people a year receive general anesthesia in the United States.
00:01:25.19 And about 250 million receive anesthesia worldwide.
00:01:30.10 Anesthesia revolutionized the practice of surgery.
00:01:35.04 But before I go on and tell you a little bit about the history,
00:01:36.23 let me just explain what I'm talking about.
00:01:39.00 What is general anesthesia?
00:01:40.27 So, it's a drug-induced reversible state,
00:01:42.17 and it has these four characteristics...
00:01:44.09 these five characteristics:
00:01:46.09 unconsciousness;
00:01:48.18 amnesia, meaning you don't remember what happens;
00:01:51.19 analgesia, you don't feel pain;
00:01:54.20 akinesia, you're not moving -- it makes it easier for the surgeons to operate;
00:01:59.04 and we do this by maintaining stability and control of the physiological systems:
00:02:03.06 respiration, body temperature, heart rate,
00:02:06.16 blood pressure.
00:02:08.21 And the key part is it's reversible.
00:02:11.02 So, we put you in this state, and we bring you out,
00:02:13.10 so that you can undergo surgery
00:02:16.10 or an invasive diagnostic procedure.
00:02:21.04 What's said very often is that anesthesia...
00:02:23.14 how it works is a mystery.
00:02:25.12 And I want to leave with the idea today that that's not the case.
00:02:28.11 It's not a mystery.
00:02:30.04 We have some very, very good ideas about how it works.
00:02:33.07 And as we gain a better understanding of how it works,
00:02:35.14 that allows us to take better care of patients.
00:02:37.15 So, before we go on,
00:02:39.17 let me give you a brief history of anesthesia.
00:02:41.19 So, William Morton conducted the first public demonstration
00:02:45.17 of ether as anesthesia
00:02:48.22 at Mass General Hospital back on October 16th, 1846.
00:02:54.19 Morton was a dentist.
00:02:58.09 And at the time, people did not take very good care of their teeth.
00:03:01.09 And he realized that he could install
00:03:03.21 a full set of dentures if he were...
00:03:06.01 if he could remove all the rotten teeth from a patient.
00:03:09.08 Now, as you can imagine,
00:03:11.13 this was... this would be very, very painful.
00:03:14.23 So, what he did was he was looking
00:03:17.20 for a way to put the patients in a state
00:03:20.01 so they could tolerate this dental procedure.
00:03:23.17 Surgery was in the same situation at the time.
00:03:26.20 There was no way to render someone insensate
00:03:29.05 to undergo surgery.
00:03:31.06 And because a lot of the surgeries
00:03:33.12 were performed because of infections,
00:03:35.12 a lot of the surgeries were amputations.
00:03:37.19 And surgeons like dentists were measured by their...
00:03:41.23 their quality was measured by how quickly they could carry out a procedure like this.
00:03:46.06 And supposedly, Morton could remove a tooth within...
00:03:48.24 under a minute.
00:03:51.02 So, through interactions with Charles Jackson,
00:03:53.16 who was a chemist at the time,
00:03:55.14 Morton learned about ether.
00:03:57.17 In addition, ether was, like, a social drug.
00:04:01.05 People used to have it, little vials of it,
00:04:04.06 on their counters.
00:04:07.01 And maybe after a meal, you'd sniff a little ether.
00:04:10.00 It would help you feel good after a meal.
00:04:12.17 And Morton realized that
00:04:17.02 if enough ether were sniffed or inhaled,
00:04:20.00 someone could be rendered insensate.
00:04:23.16 So, he proposed this idea of operating on someone
00:04:26.20 under ether to John Collins Warren,
00:04:29.01 who was a major surgeon
00:04:31.13 at Mass General Hospital back at the time.
00:04:34.03 So, on October 16th, 1846,
00:04:36.23 Gilbert Abbott was the patient who had a tumor on his neck
00:04:40.14 that John Collins Warren wanted to remove.
00:04:43.15 So, they... Morton built these flasks,
00:04:48.00 these very nice, solid glass flasks,
00:04:52.03 and he had sponges inside that were soaked with ether.
00:04:55.00 He held the flask in front of Abbott's face.
00:04:58.08 He inhaled the ether.
00:05:00.07 He was rendered insensate.
00:05:02.09 Warren performed the surgery.
00:05:05.11 And afterwards, he said, "This is no humbug,"
00:05:08.10 meaning this was the real deal.
00:05:11.01 And that was a revolutionary event.
00:05:15.03 A few days later, about a week later,
00:05:17.21 he contacted Oliver Wendell Holmes, Sr,
00:05:20.10 who was a professor at Harvard Medical School at the time
00:05:22.23 and he asked him, how should he name this phenomenon
00:05:25.09 that he had just produced?
00:05:28.10 And Oliver Wendell Holmes thought about it rather carefully.
00:05:32.08 He said... we should call it anesthesia,
00:05:35.13 meaning from the... coming from the Greek,
00:05:37.21 meaning "lack of sensation".
00:05:39.17 So, the adjective will be anesthetic.
00:05:42.09 And he went through a whole set of other terms, which he didn't...
00:05:45.02 which he said really didn't fit the bill.
00:05:48.24 And afterwards,
00:05:51.20 he also commented that we should pick this term carefully
00:05:54.19 because whatever term we use
00:05:57.00 will be with us now and forevermore.
00:05:59.15 And just to give you some idea,
00:06:01.17 that was October 18... October 16th, 1846,
00:06:05.22 so that's fall of... that's fall of the year.
00:06:10.03 By the end of the year, the practice
00:06:13.04 was being carried out in Europe as well.
00:06:16.10 So, you can see how quickly it spread
00:06:18.11 because it was a very, very important advance in medicine.
00:06:23.13 So, what do we do today?
00:06:25.22 Well, we still use ether.
00:06:27.19 On the left, you have diethyl ether.
00:06:30.10 On the right, you have sevoflurane,
00:06:32.22 which is just a fluorinated ether.
00:06:35.06 So, in some sense, we haven't...
00:06:37.08 we haven't come very far.
00:06:39.01 But it also speaks to how effective ether was,
00:06:41.01 in the fact that we can still use it today.
00:06:44.21 So, how do we actually do this?
00:06:48.23 Well, we don't just use a single drug anymore;
00:06:51.19 we use combinations of drugs.
00:06:54.09 So, for example, if we go back through
00:06:57.19 the various states that I said we'd like to try to achieve...
00:06:59.19 so, for analgesia, in addition to ether,
00:07:02.09 we would give you opioids.
00:07:05.11 I'm gonna talk about propofol.
00:07:07.04 So, to render you unconscious, we'd administer propofol,
00:07:10.17 and then we could also use the ethers the same way.
00:07:13.07 When someone is unconscious,
00:07:15.02 we feel that they also have amnesia as well,
00:07:18.16 and that tends pretty much always to be the case,
00:07:21.24 with rare exception.
00:07:23.19 So, the drugs which we use to make you unconscious
00:07:27.02 are sufficient to produce amnesia.
00:07:30.05 But if we wanted to give you a drug where you might just be sed...
00:07:33.06 you want to have the patient just be sedated
00:07:35.13 without being amnestic,
00:07:37.11 then we could use a benzodiazepine.
00:07:39.01 So, those are drugs like Valium, for example.
00:07:41.03 And then, in addition, we use drugs
00:07:43.15 which relax the muscles.
00:07:45.06 You might call them paralyzing agents.
00:07:47.02 The one that we don't use anymore
00:07:49.04 but was often heard about was curare.
00:07:52.05 And if you look at that list that I have there,
00:07:55.10 you see how ether is in every category.
00:07:57.15 Ether can do a little bit of everything,
00:07:59.16 and so that's why, you know, we were very fortunate
00:08:02.09 to find a drug that...
00:08:04.12 a single drug that, you know, would...
00:08:06.08 you know, could meet all these characteristics.
00:08:08.07 Now, this is wisdom in retrospect.
00:08:09.23 We didn't have these characteristics laid out.
00:08:11.15 This is how we currently define, you know, anesthesia.
00:08:14.15 And then, as I mentioned, stability of the physiologic systems
00:08:17.03 using hemodynamics for the things that are most profoundly affected,
00:08:20.01 that is, the blood flow and blood pressure.
00:08:22.13 Those are the things that are most profoundly affected,
00:08:24.23 so we have to give drugs to stabilize those as well.
00:08:27.04 So, that's how we deal with it.
00:08:28.23 We call this balanced general anesthesia.
00:08:30.14 So, you have a combination of drugs,
00:08:32.15 each of which kind of targets one or more aspects
00:08:35.12 of the state of anesthesia,
00:08:37.09 the general anesthesia that we want to achieve.
00:08:40.11 So, what I'm gonna talk about now is,
00:08:43.11 how does propofol induce unconsciousness?
00:08:47.10 And propofol is our most widely used anesthetic.
00:08:50.15 It's actually 2,6-diisopropylphenol,
00:08:54.19 and it's... it's very white,
00:08:56.24 and if you touch it, it feels very, very greasy.
00:08:59.19 And I have here John Glen, who was the discoverer of propofol.
00:09:04.18 He developed the molecule
00:09:07.01 when he was working at AstraZeneca.
00:09:10.18 And for this discovery,
00:09:12.18 he received the 2018 Lasker Award.
00:09:16.02 So, propofol is our most used anesthetic,
00:09:18.07 in the United States and worldwide.
00:09:20.15 So, I thought I would tell you a little bit about propofol
00:09:23.24 and, as I said,
00:09:25.22 how does propofol make you unconscious?
00:09:28.11 So, the first thing I have to tell you is just a little bit of...
00:09:31.10 a little bit of molecular biology, let's say...
00:09:36.08 just a little bit.
00:09:37.24 What propofol does... when you administer it,
00:09:40.05 it travels through the bloodstream and it finds the nerves.
00:09:43.00 It binds to a very specific type of receptor
00:09:46.07 called a GABA receptor.
00:09:48.07 Now, the GABA receptor is a receptor
00:09:50.06 that controls the flow of chloride ions into neurons.
00:09:54.24 Alright?
00:09:56.14 Chloride ions have a negative charge.
00:10:00.04 So, when a chloride ion...
00:10:01.24 if more enter into a cell,
00:10:04.02 they tend to shut the cell down,
00:10:05.24 because things become more negative.
00:10:07.23 It's difficult for the neuron to transmit the electrical impulses.
00:10:11.24 So, if you do this across enough nerve cells,
00:10:14.06 what you're going to see is...
00:10:16.00 there's always current flowing in the brain.
00:10:18.24 What this drug is doing
00:10:22.03 is it's causing alterations in those current flows.
00:10:24.05 And we're gonna get a good sense of what that looks like.
00:10:27.04 So, that's the first thing.
00:10:28.21 So, the propofol binds to these receptors,
00:10:32.11 these GABA receptors,
00:10:34.03 and sevoflurane does the same thing too.
00:10:36.02 It binds at other sites as well,
00:10:38.03 but let's say that both of them bind to GABA receptors.
00:10:42.10 Now, what's gonna happen is
00:10:44.22 the dynamics of the brain activity
00:10:47.17 are gonna change.
00:10:49.05 And let's get a... let's take a look at how...
00:10:51.01 what that's gonna look like.
00:10:53.02 So, here I've put up a schematic
00:10:56.05 to show you what brain waves look like.
00:10:59.06 We call it the electroencephalogram, or the EEG.
00:11:02.06 And it's a measure of brain waves.
00:11:03.19 And all it is is just a very simple voltmeter.
00:11:07.09 If you put two electrodes on the scalp
00:11:12.08 and you connect it to...
00:11:14.04 you connect the electrodes to a voltmeter,
00:11:16.09 because there are currents always flowing in the brain,
00:11:20.06 you can measure potential differences.
00:11:22.13 And the potential differences
00:11:24.21 will be different across different parts of the brain,
00:11:26.21 because different parts of the brain
00:11:29.17 have different levels of activity at any given point in time.
00:11:31.17 Right?
00:11:33.07 So, this is a key... one of the first key ideas.
00:11:35.11 There are always currents flowing in the brain.
00:11:39.13 Alright?
00:11:41.15 And these currents appear as oscillations in the EEG,
00:11:43.16 when you put the... when you put these...
00:11:45.23 the EEG electrodes on someone's head.
00:11:48.23 Alright?
00:11:50.21 So, let me show you what this looks like
00:11:53.09 for someone receiving anesthesia.
00:11:55.01 So, we have EEG in our operating rooms
00:11:57.01 so we can measure the brainwaves of patients as they...
00:11:59.23 during the time that they're rec...
00:12:01.18 they're having surgery.
00:12:03.09 So, this is an EEG
00:12:05.21 that I recorded on a woman almost 6 years ago.
00:12:08.13 She was about to have thyroid surgery.
00:12:10.11 She was about 60 years of age.
00:12:13.05 She weighs about 80 kilograms.
00:12:15.21 And I'm going to give her propofol.
00:12:18.07 I'm gonna give her about 150 milligrams of it.
00:12:22.10 And we're gonna watch her brain waves
00:12:24.12 as they change in real-time.
00:12:26.18 So, there are four brain waves that you see there,
00:12:30.00 four electrodes.
00:12:31.17 So, there are two on the...
00:12:33.15 two on the left and two on the right.
00:12:36.02 That's why you see four traces there.
00:12:38.07 And we're just gonna watch what happens
00:12:40.19 as she receives the propofol.
00:12:42.10 I'll talk you through it.
00:12:44.09 Alright?
00:12:46.02 So, at the... at the moment, nothing's happening.
00:12:47.22 So, that's just her lying there,
00:12:49.10 kind of at rest.
00:12:50.22 And if you've never seen an EEG before,
00:12:52.18 those are eye blinks.
00:12:54.07 Okay?
00:12:55.22 Now, what's gonna happen now... I'm gonna inject the propofol,
00:12:58.01 and propofol burns when it goes in,
00:12:59.24 particularly if you inject it into a small vein
00:13:02.04 like the one on the back of my hand here.
00:13:04.17 So, that's what's happening,
00:13:07.04 and so she's tensing up like this.
00:13:08.21 She's tensing up.
00:13:10.17 And you see that there's a lot of noise, alright?
00:13:13.08 Now, that's actually gonna be good from a pedagogical standpoint,
00:13:15.15 because you're gonna be able to see exactly
00:13:18.03 when the drug takes effect.
00:13:19.19 So, give me another 6 or 7 seconds here.
00:13:21.22 So, look at all that noise.
00:13:23.13 She's tensing up... she's tensing up.
00:13:25.14 Now, watch what happens right... here... boom.
00:13:28.06 See those oscillations? Right?
00:13:31.06 They're gonna get bigger.
00:13:33.09 The drug is taking over.
00:13:35.12 It's turned off her brainstem,
00:13:37.10 and now she's become unconscious.
00:13:39.05 Right?
00:13:41.07 And now watch, they're gonna get even more profound...
00:13:43.15 they're gonna go flat...
00:13:46.09 and then burst.
00:13:48.16 Flat... and then burst.
00:13:51.17 So, she is now in a drug-induced coma.
00:13:55.07 She has to be in a state like that so she can en...
00:13:57.22 so she can undergo surgery.
00:14:00.08 Alright?
00:14:01.21 So, let's just go back and look at this.
00:14:03.18 Alright?
00:14:05.07 So, here's what I just showed you.
00:14:07.24 That was her at A. She was awake.
00:14:09.20 And let's say those oscillations are about 5 microvolts or so, alright?
00:14:14.04 Then, you saw her go down to this state here,
00:14:16.06 the sedative state,
00:14:17.12 where you saw those very regular oscillations,
00:14:19.08 sort of a...
00:14:22.02 slightly larger amplitude but very regular.
00:14:23.24 There were about 12-16 per second.
00:14:25.15 We call those beta oscillations, right?
00:14:29.06 Then, she skipped over D and she went right to...
00:14:33.11 she went right to E.
00:14:35.01 We saw large, slow oscillations, right?
00:14:37.00 And a rule of thumb when you see slow oscillations,
00:14:40.16 think that the brainstem,
00:14:42.10 or the lower part of the brain, has been inactivated.
00:14:44.10 The cent... the center that has the arousal systems.
00:14:47.15 So, that's probably the propofol
00:14:49.21 reaching those centers and turning them off.
00:14:52.16 Then, she went into burst suppression.
00:14:54.05 So, burst suppression is a very profound state
00:14:56.11 of brain inactivation.
00:14:58.14 We see it in deep states of anesthesia,
00:15:00.05 as I'm showing you here,
00:15:01.22 but also in coma, when patients are hypothermic.
00:15:05.23 So, it's a profound state in which the brain is shut off.
00:15:08.23 And you saw she went right into that
00:15:11.07 within less than a minute.
00:15:13.02 And then, the only thing that would be deeper
00:15:14.16 is if she were in the state which we call isoelectric.
00:15:18.05 You see, like, between the bursts there, it's flat.
00:15:20.19 So, if she were just totally flat,
00:15:22.16 she would be in this state there.
00:15:24.09 The state that you didn't see was this one.
00:15:26.18 It's a combination of what we call slow oscillations,
00:15:29.04 meaning there's less than 1 cycle per second,
00:15:32.13 or about 0.1-1 cycle per... cycles per second,
00:15:37.00 and alpha oscillations,
00:15:39.17 which are roughly around 10 cycles per second...
00:15:41.17 we'll just say 10 as a rule of thumb, alright?
00:15:43.13 So, you see, indeed, there... there's a combination of them.
00:15:48.00 You see you have very low frequency oscillations, like this,
00:15:51.11 and riding on top, you have these higher frequency oscillations.
00:15:54.19 And that's a typical pattern for propofol.
00:15:57.08 If you give a young person, someone 18-35, propofol,
00:16:00.20 that's the way... that's the brain dynamic you would see.
00:16:04.17 And the one state that I didn't talk about is this additional one here:
00:16:07.10 paradoxical excitation.
00:16:10.15 It turns out that at low doses,
00:16:13.07 anesthetics can actually cause excitation.
00:16:18.04 It's called paradoxical
00:16:20.13 because you have a drug which is supposed to render you insensate
00:16:24.18 or render you unconscious,
00:16:27.03 but it excites you.
00:16:28.16 And you go, wow, that's paradoxical.
00:16:30.13 But if you think about it,
00:16:32.11 we have a lot of intuition about this already.
00:16:34.02 Alcohol, for example.
00:16:36.04 A little bit of alcohol and you're in a state of paradoxic excitation.
00:16:40.10 Too much alcohol, and you're in a state of
00:16:43.13 an isoelectric brain.
00:16:45.09 So, we have more insight to it than we realize.
00:16:48.18 So, in order to really appreciate
00:16:52.15 how we've come to understand
00:16:54.11 what happens to the brain under anesthesia,
00:16:56.07 I'm gonna do a little tutorial here on signal processing.
00:16:59.06 Alright?
00:17:00.12 Because we want to understand the oscillations
00:17:02.03 -- we want to understand their structure --
00:17:03.21 so we need some signal processing techniques
00:17:05.16 to do that.
00:17:07.06 So, what I have here is a raw EEG trace.
00:17:09.07 Let's say I'm recording that at one of the electrodes.
00:17:11.16 And I can see it's got oscillations
00:17:14.02 of different amplitudes and frequencies in there.
00:17:17.15 Let's see...
00:17:20.07 so, if I knew what frequencies I wanted to pick out,
00:17:23.11 then I could build a filter and I could extract those.
00:17:28.03 Let's say I knew that there was an oscillation
00:17:30.07 about every 10... at 10 cycles per second.
00:17:32.07 I could build a filter that would pull out the 10 cycle per second oscillation.
00:17:36.24 If I knew it was around 1 cycle per second,
00:17:39.02 I could build a filter to do that.
00:17:41.12 But because this is such a dynamic process
00:17:43.17 and it's changing through time,
00:17:45.07 that's impractical,
00:17:47.02 because it won't stay at a fixed frequency.
00:17:50.24 So, what we use is what's called the spectrum.
00:17:53.06 And what the spectrum does
00:17:55.06 is it takes a signal
00:17:57.01 and it shows you how big the oscillation is,
00:18:00.23 the amplitude of every oscillation,
00:18:02.19 within a given frequency range.
00:18:05.00 So, in this particular case, here,
00:18:06.20 I'm taking a frequency range
00:18:08.22 from about 1 up to about 30.
00:18:10.13 And that's that signal that I have over there,
00:18:12.18 and I'm showing you its spectrum.
00:18:14.09 So, look... you see there's a very large low frequency component there.
00:18:17.20 So, if you look to the left of the graph,
00:18:20.00 there's a big spike on the left of the graph,
00:18:22.13 right... right over here.
00:18:26.16 And then, if you look in the middle there,
00:18:28.12 around 10 or so,
00:18:30.11 there's another big spike around 10.
00:18:31.24 And that's exactly those two components
00:18:34.03 that I showed you there before.
00:18:35.22 Alright?
00:18:37.09 And beyond 20, there's really nothing.
00:18:39.23 So, that's for that one 10-second trace of EEG.
00:18:43.11 Okay?
00:18:44.23 Now... but we need to do this over time.
00:18:47.10 So, if we take a 10-second trace,
00:18:50.02 we compute the spectrum,
00:18:51.16 and then we move it along,
00:18:54.11 and we compute it again,
00:18:56.07 we'll actually get, like, a three-dimensional structure,
00:18:59.07 because we'll have time on one axis,
00:19:02.14 the frequency that we're looking at on the other axis,
00:19:05.13 and then the... on the y axis...
00:19:09.19 on the y axis is going to be the amplitude,
00:19:14.01 or how big the signal is.
00:19:16.08 So, if we go back here to the spectrum
00:19:18.17 up in the second figure, there,
00:19:21.02 you see there's a large low frequency component,
00:19:25.13 a large 1-Hertz component there.
00:19:28.13 And there's a large,
00:19:30.15 but not as large... about 10-Hertz component.
00:19:33.08 And so, as we move this over time,
00:19:35.19 as we took successive 10-Hertz signals...
00:19:37.12 excuse me, successive 10 cycles...
00:19:41.05 10-second segments
00:19:43.15 and we made the spectrogram here...
00:19:45.24 this is what it looks like in three dimensions.
00:19:48.12 So, you see you have a mountain range to the left,
00:19:52.14 a valley, another mountain range,
00:19:54.15 and then it's like the ocean out beyond.
00:19:57.07 Alright?
00:19:58.22 So, this is impractical to display in the operating room,
00:20:02.12 so we typically display it this way.
00:20:04.17 So, it's like we're flying over the top of the mountain and the valley.
00:20:09.14 And the lower panel is the lower mountain range,
00:20:15.17 the middle, yellow panel is the middle mountain...
00:20:19.16 the second mountain range,
00:20:21.16 and the blue area up at the top
00:20:24.09 is essentially the ocean.
00:20:26.05 So, again, just to recap, what we're doing is...
00:20:29.05 we have a way of watching how the oscillations change through time.
00:20:32.05 And this is called the spectrogram
00:20:34.17 when it's over time,
00:20:36.20 or just the spectrum if it's just a single... single segment.
00:20:39.12 Alright?
00:20:41.03 So... so, let's look at it.
00:20:42.00 So, this is me, now, in the operating room.
00:20:44.05 And I'm measuring this on a patient that I'm taking care of.
00:20:46.18 This is a 19-year-old woman
00:20:49.05 who was having a short procedure.
00:20:50.18 So, I gave her propofol,
00:20:52.09 and then I gave her a propofol infusion to keep her unconscious.
00:20:55.19 So, you can see in the beginning, there,
00:20:58.21 you have these slow oscillations.
00:21:02.02 And then the slow oscillations
00:21:04.02 turn into slow and alpha oscillations.
00:21:06.22 So, you have initially just waves like this.
00:21:10.17 Then you have waves that have a second wave
00:21:13.13 riding on top.
00:21:14.24 So, you see there are two bands in the spectrum:
00:21:17.04 one at 10 cycles per second,
00:21:19.00 the top red band,
00:21:20.22 and then a lower one, which is between
00:21:23.07 about 1-4 cycles per second,
00:21:25.09 and that's the slow or delta band.
00:21:28.20 So, this is a typical signature of propofol.
00:21:31.10 If you give a young person propofol
00:21:33.09 and you measure their brain waves,
00:21:35.05 this is how propofol alters their brain waves.
00:21:38.13 Alright?
00:21:39.21 And these oscillations are very strong.
00:21:41.15 Let me just give you a sense.
00:21:43.06 Remember a few slides ago,
00:21:44.21 I was telling you that the...
00:21:46.18 when you're awake, your EEG is about 5 microvolts.
00:21:49.21 These oscillations, now,
00:21:51.19 are between 20-50 microvolt in adults,
00:21:54.21 and they can be as high as 1000 microvolts in kids.
00:21:58.14 So, you go from a state like... you go from a state like this, okay?,
00:22:02.06 to something like this.
00:22:06.06 Alright?
00:22:08.02 So, you can already start to see...
00:22:09.17 if you need to be in a state like this to communicate,
00:22:12.01 and now I put in oscillations that are like this,
00:22:14.01 it's gonna be very, very difficult
00:22:16.10 for the parts of the brain to communicate.
00:22:17.21 Alright?
00:22:19.08 So, this starts to give you some intuition
00:22:20.24 about how the drugs are affecting the brain.
00:22:23.22 So, I've told you a little bit about the structure
00:22:26.10 and the EEG rhythms
00:22:28.14 that you see in time with propofol.
00:22:30.07 Now I want to tell you about what they look like in space,
00:22:33.01 where space is across the head.
00:22:36.20 So, if you place EEG electrodes
00:22:39.15 across the entire head,
00:22:42.13 you can record the different patterns that the drug produces
00:22:45.20 at different locations across the scalp.
00:22:49.02 So, to make this clear,
00:22:51.13 what I'm going to be describing,
00:22:53.01 I need to do a little bit of...
00:22:54.15 I need to give you a little bit of history from anesthesia
00:22:57.05 and also a little bit of history from neuroscience.
00:23:00.08 So, there's an oscillation
00:23:02.15 which is called an alpha oscillation
00:23:05.24 that is very... that's very easy to produce.
00:23:08.05 If you just stand here like this and you close your eyes,
00:23:11.16 and I place electrodes at the back of your head,
00:23:14.06 I'll record a 10-Hertz oscillation.
00:23:16.21 It's very, very strong,
00:23:19.15 and pretty much everybody has it.
00:23:21.09 Maybe about 5-10% of people don't.
00:23:23.09 And we tend to lose it, maybe,
00:23:26.16 as we get older.
00:23:28.10 So, this is an illustration of this.
00:23:30.04 So, what I've done here is
00:23:32.22 I have a volunteer subject
00:23:34.08 who's lying there with his eyes closed.
00:23:36.09 And each of those sites, there
00:23:38.14 -- there are 64 in all; I'm only showing you 44 of them --
00:23:41.10 is a location where I'm computing the spectrogram,
00:23:45.06 like I just talked about in the previous slide,
00:23:47.17 so I can show you what the oscillations are like
00:23:50.15 across his head.
00:23:52.02 So, as you see, most of it's blue,
00:23:53.17 meaning he has oscillations going on,
00:23:56.08 but the amplitude is not that high.
00:23:59.18 But look at the back -- look at the bottom of the slide there.
00:24:02.08 You see he has those two red strips.
00:24:04.15 So, those two red strips are
00:24:08.13 his eyes-closed alpha oscillation.
00:24:09.14 Remember, as I said, he's lying there like this with his eyes closed,
00:24:11.18 and he's producing this very, very regular 10-Hertz oscillation.
00:24:15.04 Right now.
00:24:16.18 So, that's the neuroscience piece.
00:24:19.03 In anesthesia, John Mitchenfelder and John Tinker
00:24:22.16 showed, in 1977, using monkeys,
00:24:25.19 that this alpha oscillation would start at the back of the head,
00:24:30.17 and when you anesthetize someone
00:24:32.06 -- in this case, monkeys --
00:24:33.17 it would move to the front.
00:24:36.04 And as long as you kept the animal anesthetized,
00:24:39.24 it stayed in the front of the head, okay?
00:24:42.23 And now, what we're gonna see is that
00:24:46.06 not only does it stay in the front of the head
00:24:48.14 but when you turn the...
00:24:50.03 in this case, the propofol, off,
00:24:52.01 it's gonna migrate... migrate back.
00:24:53.20 So, this forward movement of the alpha oscillation
00:24:55.12 from the back of the head to the front
00:24:57.06 is what we call anteriorization.
00:24:59.04 Alright?
00:25:00.16 And... but also, when you turn the drug off,
00:25:03.00 that oscillation moves backwards.
00:25:06.11 So, we're gonna do a controlled experiment here.
00:25:09.15 This is a volunteer subject.
00:25:11.04 We're gonna give him increasing doses of propofol.
00:25:14.01 We're gonna increase the dose, roughly every 14 minutes or so,
00:25:17.16 up to a level that...
00:25:20.01 where he should be profoundly unconscious.
00:25:22.01 Then we're gonna back it down.
00:25:23.17 So, it's gonna take about..
00:25:25.13 a little over an hour for him to reach the highest point,
00:25:28.08 and then it'll take about another hour for him to come down.
00:25:33.03 So, this is going to be a little over two hours,
00:25:34.19 what I'm gonna show you in just this compressed video here.
00:25:37.19 And you're gonna see this alpha oscillation
00:25:40.10 move from the back of his head to the front.
00:25:42.11 And when we turn the drugs off,
00:25:44.10 it's gonna move backward.
00:25:46.07 So, I'm gonna play this now.
00:25:49.10 So, you see the oscillation in the back.
00:25:52.06 The drug infusion hasn't started... it just started.
00:25:55.04 Now, watch how it breaks up in the back.
00:25:59.06 You see it breaks up.
00:26:01.18 Now, you see it's concentrating in the front.
00:26:03.13 It's very, very intense in the front of the head.
00:26:06.06 And if you look from the center of the head back,
00:26:08.15 there's nothing going on -- maybe just slow oscillations.
00:26:11.19 And now, here's the highest level, five.
00:26:14.18 It's really intense there at five.
00:26:16.15 It's all in the front.
00:26:19.00 Now, watch what happens when we turn the drug off.
00:26:21.18 When we turn the drug off, it moves backwards.
00:26:26.02 So, it moved forward, concentrated in the front,
00:26:28.14 then moved backwards.
00:26:31.00 That's anteriorization.
00:26:32.15 So, there's a temporal dynamic as well as a spatial dynamic
00:26:36.05 to the way the drug -- in this case, propofol --
00:26:38.09 is affecting the brain.
00:26:39.21 Alright?
00:26:40.24 So, now... we've seen enough phenomenology.
00:26:43.15 Let's talk mechanism.
00:26:45.03 Let's try to understand what's going on.
00:26:46.24 So, here's what's happening.
00:26:49.13 Neurons that have GABA receptors are everywhere throughout the brain
00:26:52.11 and the central nervous system.
00:26:53.24 So, I've drawn three key sites here:
00:26:56.18 up in the cortex, in the thalamus,
00:26:58.23 and also down in the brainstem.
00:27:01.05 And what do they do?
00:27:02.15 They create inhibitory networks.
00:27:04.06 Alright?
00:27:06.10 So, when you administer propofol
00:27:08.13 or another anesthetic which is...
00:27:10.01 acts on these GABAergic receptors,
00:27:12.13 they just go to all the sites
00:27:15.15 where these receptors are,
00:27:18.13 and they start creating their actions.
00:27:21.00 Alright?
00:27:22.10 But now, what we see is...
00:27:24.03 so, this is...
00:27:25.15 this is anatomy, which we can write out
00:27:28.12 without doing any experiments,
00:27:30.01 because this has been known for years.
00:27:32.05 Okay?
00:27:33.11 So, the propofol is gonna find these sites
00:27:36.03 where the GABA is,
00:27:37.18 and it's gonna affect how the neurons that have these receptors...
00:27:40.10 it's gonna affect their activity.
00:27:41.24 And I'll tell you one little factoid.
00:27:45.18 The neurons which have...
00:27:47.13 which are inhibitory act as kind of routers,
00:27:49.17 like routers in a computer network.
00:27:52.13 They sort of control the excitatory neurons,
00:27:54.14 with a ratio about 1:8 or 1:10.
00:27:59.00 So, if you control those routers, right?,
00:28:00.23 you're gonna control large areas of brain activity.
00:28:06.04 Alright?
00:28:07.16 So, that's kind of the setup... that's the anatomy of the setup.
00:28:10.10 Now... so, here's what happens.
00:28:12.16 So, I can write down that anatomy.
00:28:15.05 I go to the operating room, and this is what I see.
00:28:18.01 So, how does that anatomy give me this pattern, here?
00:28:20.08 That's the question I want to try to answer for you now.
00:28:23.05 So, I did an experiment that I just showed you the resul...
00:28:25.24 a little bit of... a few of the results of,
00:28:28.12 and I see an oscillation like this.
00:28:30.03 Now, I have to tell you one more little factoid
00:28:32.10 about the results from this experiment that I didn't mention before,
00:28:34.16 and that is, when you see that 10-Hertz oscillation
00:28:38.14 concentrate in the front of the head,
00:28:40.18 it's what we call coherent.
00:28:42.18 By coherent, I mean that
00:28:45.13 if you measured the correlation
00:28:48.07 between a site in the front of the head, here,
00:28:50.03 and a site in the front of the head, here,
00:28:52.01 that correlation is about 0.9.
00:28:53.21 In other words, all the oscillations there
00:28:57.10 are moving and sync, together.
00:28:58.21 Alright?
00:29:00.07 So, that says that, maybe,
00:29:02.01 they're being produced by some central area
00:29:05.24 or some central focus.
00:29:07.11 Alright?
00:29:08.22 So, what do we think is going on?
00:29:13.04 So... here's what we think is happening.
00:29:17.12 So, this is someone who's conscious.
00:29:21.00 And when you're conscious,
00:29:23.03 you have broadband communication,
00:29:25.00 going freely back and forth
00:29:27.12 between various parts of the brain.
00:29:30.00 In this particular case, I'm drawing the thalamus,
00:29:31.15 which is roughly in the center of the brain,
00:29:33.11 and it's a major way station.
00:29:36.15 All sorts of information comes to the thalamus:
00:29:38.12 sensory information, auditory information,
00:29:40.15 pain information, visual information.
00:29:43.17 So, it's a central way station.
00:29:45.20 So, if you wanted to tie up one area of the brain
00:29:48.00 and make someone unconscious,
00:29:49.07 the thalamus would be high on the list,
00:29:51.07 and arguably at the top of the list.
00:29:53.09 Now, it's richly connected to the frontal cortex,
00:29:57.09 the area we think about typically for reasoning,
00:29:59.24 if you would.
00:30:02.02 Alright?
00:30:03.13 So, normally, as the arrow indicates,
00:30:05.07 there's broadband communication between the thalamus and the cortex,
00:30:09.03 and you have an EEG pattern that looks small,
00:30:11.21 like the one I just showed you.
00:30:13.20 Now you administer propofol.
00:30:16.20 And you see a pattern that looks like this.
00:30:20.16 You see the large, slow oscillations
00:30:22.16 and the 10-Hertz oscillations riding on top.
00:30:25.24 And so, what was broadband communication going freely back and forth
00:30:31.01 now turns into this 10-Hertz oscillation,
00:30:33.16 like this, right?
00:30:35.16 So, what do we think is happening?
00:30:38.07 When you see the 10-Hertz oscillation appear,
00:30:41.18 what our modeling studies
00:30:43.20 -- our mathematical modeling studies --
00:30:46.18 have taught us is that
00:30:49.16 it's most likely an oscillation going back and forth
00:30:52.10 between the thalamus and cortex
00:30:54.07 at about 10 cycles per second.
00:30:55.18 We've now verified that by doing experiments
00:30:57.20 in rodents to show that that's indeed the case.
00:31:01.18 So, if you should be communicating like this
00:31:05.11 in a broadband fashion to have consciousness,
00:31:10.12 and all of a sudden you can...
00:31:12.06 the oscillations come in like this
00:31:15.07 at a regular 10-Hertz cycle,
00:31:17.10 it's gonna disrupt the ability for these two parts of the brain to communicate,
00:31:20.11 and put you in a state
00:31:24.16 where the parts of the brain wouldn't be able to exchange information,
00:31:27.06 hence unconsciousness.
00:31:29.11 Alright?
00:31:30.16 So, that's we think is happening.
00:31:32.16 But what's interesting...
00:31:34.14 look at that trace down there.
00:31:36.05 You see the 10-Hertz oscillation there.
00:31:38.06 But you also see this large, slow oscillation.
00:31:41.05 Alright?
00:31:42.12 I didn't explain that.
00:31:44.15 You get two oscillations, there, with propofol:
00:31:47.10 the 10-Hertz oscillation
00:31:48.20 and the slower delta oscillation.
00:31:51.02 Let me talk about that now.
00:31:54.10 So, here's what we think is happening.
00:31:56.20 So, this was the... this was the alpha oscillation,
00:32:00.13 and the slow oscillation.
00:32:02.14 And I wanted to put this up again, because you see...
00:32:05.14 you see how the alpha oscillation and the slow oscillation
00:32:08.00 are just as strong --
00:32:10.01 they're just as red, so they're just as intense.
00:32:12.21 The alpha oscillation is in the front of the head.
00:32:15.05 It's coherent.
00:32:17.23 It turns out that the slow oscillation
00:32:21.08 -- and we could see this if we go back and look at the video I showed you --
00:32:23.21 is everywhere.
00:32:26.09 And instead of being coherent,
00:32:28.01 it seems to be quite incoherent.
00:32:29.22 It's not connected.
00:32:31.15 In other words, the various sites where it's occurring
00:32:34.16 don't seem to be connected,
00:32:37.00 at least as far as the human EEG is concerned.
00:32:38.16 Alright?
00:32:40.05 So, what do we think is going on there?
00:32:42.20 Well, we got some insight into what's happening there
00:32:45.11 from an experiment that we did
00:32:48.13 in patients with epilepsy.
00:32:50.01 So, patients that have intractable epilepsy...
00:32:53.02 after they failed all medical therapies,
00:32:55.06 they actually come for surgery.
00:32:58.09 The surgeon and the neurologist
00:33:00.17 work very hard to locate the part of the brain
00:33:02.07 that they think is causing the disturbance,
00:33:05.21 and once they feel that they've identified it,
00:33:08.06 they'll conduct a surgery to remove that area of the brain.
00:33:13.24 So, the way they do that is
00:33:16.07 the patient comes in,
00:33:18.14 gets electrodes implanted, like the ones I'm showing there,
00:33:20.17 in the area of the brain where they think the seizures are occurring,
00:33:26.04 they stay in the hospital for 5-7 days,
00:33:29.12 off of medication
00:33:31.16 so they've had enough seizures
00:33:33.13 so they can triangulate what the location
00:33:34.19 of the seizure foci or focus may be,
00:33:37.02 then they'll come back the operating room
00:33:39.16 to have the electrodes removed.
00:33:42.00 Then, in a subsequent operation,
00:33:44.07 they'll have the seizure focus removed.
00:33:46.06 Alright?
00:33:47.21 So, when a patient comes back to the operating room a second time
00:33:51.22 to have the electrodes removed,
00:33:55.01 we have a natural experiment from an anesthesia standpoint,
00:33:57.12 because the person has to receive general anesthesia
00:33:59.23 to have the electrodes removed.
00:34:02.17 So, what we do is we just record
00:34:04.15 the neural activity to try to learn
00:34:06.23 what happens when you give someone ana...
00:34:08.21 when you give someone anesthesia,
00:34:10.14 recording not from the scalp, now,
00:34:13.06 but directly from the brain.
00:34:14.18 So, these were some very, very insightful studies.
00:34:19.15 It was the PhD thesis of one of my graduate students,
00:34:22.12 Laura Lewis.
00:34:24.00 So, if you look on the left, there,
00:34:25.19 you see the conscious state.
00:34:28.10 You see the oscillations, like I was showing you before.
00:34:30.20 They're low amplitude
00:34:33.06 with, you know, kind of high frequency.
00:34:35.19 And the bottom li... the line below that shows you what the neurons are doing.
00:34:38.08 The neurons are spiking...
00:34:40.19 pretty much wherever they want to.
00:34:42.05 They can do whatever they want.
00:34:43.12 They can communicate freely.
00:34:46.10 Now look on the right.
00:34:48.04 The slow oscillations have taken over.
00:34:50.20 Alright?
00:34:52.16 And the colors on the traces
00:34:56.16 correspond to the locations on the brain
00:34:58.22 that I'm showing you below.
00:35:00.16 So, you see a red trace,
00:35:02.21 you see a blue trace,
00:35:04.11 and you see a green trace.
00:35:06.04 And then, below that, you see these little histograms.
00:35:09.03 You see little bunches of activities.
00:35:11.00 So, look what happened.
00:35:12.12 When the person was... when the person was awake and conscious,
00:35:15.19 the neurons were spiking wherever they wanted to.
00:35:18.11 But now, when propofol takes over,
00:35:20.03 see how the neurons can only spike now...
00:35:22.11 little bunches... see the histograms...
00:35:25.00 they spike now... they spike now.
00:35:27.01 So, this is a neuron that's recorded
00:35:29.02 next to where that red electrode is sitting.
00:35:31.04 Now, if we were to look at a neuron
00:35:33.19 that's recorded next to the green electrode,
00:35:35.19 whereas the red electrode... the red...
00:35:37.18 the neuron next the red electrode is spiking here,
00:35:40.04 the one next to the green electrode is spiking here.
00:35:42.05 It's like this. It's like this.
00:35:44.15 So, if it's important for neurons
00:35:47.14 near the red electrode to communicate
00:35:49.18 with neurons near the green electrode,
00:35:51.09 that's gonna be very difficult to happen,
00:35:53.13 because they're spiking at different times.
00:35:55.24 They're out of phase, right?
00:35:58.15 So, now, imagine you have this happening across the entire head.
00:36:04.08 You can see it's gonna be very difficult
00:36:06.01 for parts of the brain to communicate,
00:36:07.14 hence another potential mechanism
00:36:10.12 to make someone unconscious.
00:36:13.07 So, we've done two, right?
00:36:15.04 We had the alpha oscillation,
00:36:17.06 which was in the front of the head, right?,
00:36:24.10 and we think it represents strong coupling
00:36:26.23 between the thalamus and cortex,
00:36:28.17 restricting communication.
00:36:30.05 But then, all across the head,
00:36:32.17 the slow oscillation is creating these...
00:36:35.07 these little islands,
00:36:37.12 making it very difficult for neighboring areas of the brain to communicate.
00:36:42.24 Then there's the anteriorization,
00:36:44.21 which you can see is...
00:36:46.12 you have an oscillation that moved
00:36:47.17 from the back of the head to the front.
00:36:49.23 So, these are three potential mechanisms
00:36:51.08 through which propofol could be making you unconscious.
00:36:53.15 Now, why is this important?
00:36:55.08 It's important scientifically
00:36:57.03 because it helps us understand something about brain dynamics.
00:36:58.23 But it's also important practically.
00:37:01.09 Because anesthesiology is often criticized
00:37:05.22 when we have events of patients being aware under anesthesia
00:37:08.20 and the anesthesiologist didn't know it.
00:37:11.13 So, if someone came to me and said,
00:37:14.17 Emery, you know, the last time I had surgery, I had awareness.
00:37:18.01 I was awake and the anesthesiologist didn't know it.
00:37:21.07 And I'd say, well, that's not gonna happen.
00:37:23.00 So, I'd use the EEG.
00:37:25.12 I would administer propofol,
00:37:29.05 or one of the other agents,
00:37:30.24 until I saw dynamics like the ones I'm showing you here.
00:37:34.00 And if anything I've suggested is even approximately correct,
00:37:36.15 I have a way of knowing when a person
00:37:38.21 is sufficiently unconscious
00:37:40.16 such that he or she wouldn't have awareness.
00:37:42.21 Part of the reason that this problem still persists today,
00:37:46.19 even in 2019,
00:37:48.22 is that most anesthesia care
00:37:53.01 is given without using the EEG in the way that I'm suggesting.
00:37:55.22 So, this is an easy issue to fix,
00:37:58.21 but it's a way of fixing it
00:38:01.24 not just by using patterns
00:38:03.23 but also understanding the dynamics
00:38:05.20 that sort of underlie those patterns.
00:38:08.08 I want to make one final point:
00:38:10.24 general anesthesia is not sleep.
00:38:13.07 An anesthesiologist might say to a patient,
00:38:15.09 Excuse me, Mr. Smith.
00:38:18.23 I'm gonna have you go off to sleep for your surgery.
00:38:21.12 And you can understand why he or she might not say,
00:38:26.00 Excuse me, Mr. Smith.
00:38:28.01 I'm gonna put you in a drug-induced, reversible coma.
00:38:30.12 That would not be very reassuring to the patient.
00:38:33.02 By the same token, we shouldn't say sleep,
00:38:35.00 because anesthesia is not sleep.
00:38:36.13 And I've drawn this out here.
00:38:38.03 So, if you look at the first row, there,
00:38:40.03 I'm showing you what it looks like when...
00:38:43.20 the EEG in patients that are awake.
00:38:46.05 So, on the left you have just a normal EEG.
00:38:47.19 And on the right, there's that eyes-closed alpha oscillation.
00:38:50.17 You see that nice, regular 10-Hertz oscillation.
00:38:53.00 So, those are two awake states.
00:38:54.21 Down the left column,
00:38:56.20 what I'm showing you is the states of anesthesia
00:38:59.16 that I showed you before.
00:39:01.05 Down the right column,
00:39:02.20 I'm showing the stages of sleep.
00:39:05.05 Remember, sleep has two big components.
00:39:08.03 It goes non-REM, REM,
00:39:11.09 non-REM, REM.
00:39:13.08 You cycle through them...
00:39:15.11 so, non-rapid eye movement sleep,
00:39:17.04 rapid eye movement sleep.
00:39:18.17 You cycle between REM and non-REM
00:39:20.10 roughly every 90 minutes.
00:39:22.00 You do it about 4-6 times a night.
00:39:23.19 And you typically awake from the state of REM.
00:39:28.00 So, if you think about what's happening,
00:39:30.11 you're going...
00:39:32.08 this is a normal physiologic oscillation
00:39:34.03 that transpires
00:39:36.17 between two oscillatory states.
00:39:40.01 The non-REM state usually has slower oscillations,
00:39:43.04 and the REM state has higher-frequency oscillations.
00:39:45.18 And they have different physiologic characteristics.
00:39:48.16 Roughly speaking, the brain is more active during REM sleep,
00:39:50.22 whereas in non-REM sleep it's less active.
00:39:53.17 The body is more relaxed during REM sleep.
00:39:57.00 The body is potentially more active
00:40:00.05 during non-REM sleep.
00:40:01.20 So, there are two different conditions.
00:40:04.12 What happens when we give you anesthesia?
00:40:07.07 We bring you down to one of the states on the right,
00:40:09.18 and we hold you there.
00:40:11.04 So, you're just sitting there doing this.
00:40:13.10 You're not going through
00:40:15.20 a normal REM/non-REM oscillation state.
00:40:19.18 And in fact, no single drug could make you have the oscillations,
00:40:24.09 or produce the oscillations,
00:40:26.07 between REM and non-REM sleep.
00:40:29.15 So, when we take drugs to help us sleep,
00:40:33.03 the idea is perhaps they sedate us,
00:40:35.17 and then our natural sleeping tendencies
00:40:38.23 or systems take over.
00:40:40.11 But remember, those medications themselves
00:40:43.22 don't allow us to have normal sleep.
00:40:48.03 Moreover, general anesthesia is definitely not sleep.
00:40:51.18 So, using those drugs to try to produce sleep
00:40:54.14 is not a good idea.
00:40:58.11 So, these are the main points which I've made.
00:41:01.07 As I've tried to show you,
00:41:03.22 under general anesthesia, the brain is dynamic;
00:41:05.19 it's not turned off.
00:41:09.07 I've shown you how anesthetics create arou...
00:41:11.19 altered arousal states.
00:41:13.15 In this particular case,
00:41:15.12 how propofol creates unconsciousness
00:41:16.22 by generating oscillations and sustaining them.
00:41:19.09 And we believe that it's these oscillations
00:41:21.17 which are impairing the communication between brain regions,
00:41:24.22 therefore rendering a patient unconscious
00:41:27.05 or, in other situations, insensate,
00:41:29.21 with other drugs.
00:41:32.15 And as I've shown you, these oscillations
00:41:34.20 are readily visible on an electroencephalogram,
00:41:37.03 so that suggests that we have a way of monitoring patients
00:41:40.18 under anesthesia
00:41:42.18 so we can know how unconscious they are,
00:41:45.02 we can decide if we need to get more or less of an anesthetic.
00:41:48.02 And I think this is a very important practice
00:41:50.16 which could make the use of these anesthetics
00:41:54.03 even safer today.
00:41:57.01 So, I want to thank you for listening.
00:41:59.04 And in the next segment,
00:42:02.10 I'm gonna tell you...
00:42:03.20 take you even further into the world of the dynamics
00:42:06.04 of the brain under anesthesia.

Part 2: The Dynamics of the Brain Under Anesthesia

00:00:14.09 Hi. I'm Emery Brown.
00:00:16.10 I am a Professor at Harvard Medical School,
00:00:19.05 an anesthesiologist at Mass General Hospital,
00:00:21.19 and a Professor of Computational Neuroscience at MIT.
00:00:25.07 And in this presentation,
00:00:27.09 I'm gonna tell you about the dynamics of the anesthetized brain.
00:00:31.13 In the previous presentation,
00:00:33.22 I showed that a primary way through which anesthetics work
00:00:37.06 is by producing oscillations, or dynamics,
00:00:40.23 that disrupt brain communication.
00:00:42.19 The brain isn't turned off.
00:00:44.15 And I'm gonna expand on that theme
00:00:46.07 and show you what other things we've learned about anesthetics
00:00:49.08 as they act in the brain.
00:00:51.08 And so, here's a brief overview.
00:00:53.07 I'm gonna go back over a little bit of what I told you in the first lecture,
00:00:56.13 like what general anesthesia is,
00:00:59.20 and then what I want to show you is an idea
00:01:02.17 which I call Bremer's principle:
00:01:04.13 all anesthesia... all anesthetics, pardon me,
00:01:06.18 produce slow delta oscillations.
00:01:09.17 And then, I'm gonna show you a little bit
00:01:12.11 about what happens to the response to anesthesia
00:01:15.05 as a function of age.
00:01:17.00 And then I'm gonna introduce an idea called reanimation.
00:01:20.21 In anesthesiology, we typically think about anesthetizing patients...
00:01:26.17 you're rendering them into the state of anesthesia
00:01:27.23 so that they can have surgery,
00:01:30.03 and when they... the coming out is passive.
00:01:33.12 We turn the agents off, and we let them come out.
00:01:36.01 But maybe we could turn the brain back on,
00:01:37.23 and that's what we're calling reanimation.
00:01:39.20 So, what is general anesthesia?
00:01:43.05 So, it's a drug-induced, reversible state
00:01:45.14 that consists of unconsciousness;
00:01:48.19 amnesia, meaning you don't remember;
00:01:50.23 analgesia, means you don't... meaning you don't feel pain;
00:01:54.23 akinesia, meaning you're not moving as the surgeons are operating;
00:01:57.03 with stability and control of the principle physiologic systems.
00:02:00.18 And as I said before, we have some good ideas, now,
00:02:05.20 about how anesthesia works.
00:02:07.09 We think it works by producing oscillations
00:02:09.18 that disrupt how the parts of the brain communicate.
00:02:12.20 And that's what I showed you in the previous lecture,
00:02:15.22 with propofol as an example.
00:02:19.07 Propofol binds to GABA receptors.
00:02:23.19 These receptors are on neurons.
00:02:26.08 Neurons then alter the way in which they spike.
00:02:29.08 And on a gross level, what that does is
00:02:32.02 it alters the current flows in the brain.
00:02:34.10 By altering these current flows... by altering...
00:02:37.06 by altering these current flows,
00:02:40.11 you change how the various parts of the brain communicate.
00:02:44.02 And what I'm showing you here in this diagram
00:02:46.04 is the targets for GABA.
00:02:48.23 These GABA receptors are everywhere in the brain.
00:02:51.24 And I’m showing you three principal regions:
00:02:53.19 up in the cortex, up front;
00:02:56.04 in the middle, there, in the thalamus;
00:02:57.21 and down in the brainstem.
00:02:59.21 So, the substrate on which these drugs can...
00:03:02.11 these drugs can act is basically everywhere throughout the brain
00:03:06.11 and central nervous system.
00:03:08.10 So, they bind, they generate these changes in dynamics,
00:03:12.20 and it looks something like this.
00:03:14.08 So, when someone is conscious,
00:03:17.05 your brainwaves look like this,
00:03:19.10 and two of the... two of the principal brain regions
00:03:22.02 that we discussed before were the thalamus and cortex.
00:03:26.18 The thalamus, again, being the central way station,
00:03:29.22 which transmits and receives information,
00:03:33.09 all types of brain information:
00:03:35.20 sensation, auditory information,
00:03:39.11 pain information, visual information.
00:03:43.09 And the cortex, which is...
00:03:45.14 the frontal cortex, which you usually think of as being there...
00:03:47.17 associated with or controlling reasoning.
00:03:51.06 So, if the two areas are communicating
00:03:53.19 when someone's conscious,
00:03:55.14 there's just a free flow of information
00:03:57.12 back and forth between the two,
00:03:59.02 and the brain waves, measured by the EEG,
00:04:01.22 look something like I'm showing you there:
00:04:04.02 low amplitude, relatively high frequency.
00:04:06.05 You administer a drug like propofol,
00:04:08.14 and those low amplitude, high frequency oscillations
00:04:12.12 turn into large amplitude, low frequency oscillations.
00:04:16.07 In this case, there are two of them.
00:04:18.10 You see you have a low osc... a low frequency oscillation
00:04:20.13 like this
00:04:22.23 and then a... still a larger amp... an amp...
00:04:24.23 an oscillation of about the same amplitude riding on top.
00:04:27.05 One is at about 1-4 cycles per second,
00:04:30.00 and the other is about 10 cycles per second.
00:04:32.20 The slower one is called the slower delta oscillation.
00:04:35.06 The faster one is called the alpha oscillation.
00:04:38.12 And it looks like this.
00:04:41.00 Instead of having a nice, free flow of information
00:04:43.13 back between the thalamus and cortex,
00:04:45.09 the alpha oscillation is producing
00:04:47.20 this very rhythmic communication
00:04:53.12 between the thalamus and cortex,
00:04:55.08 which makes it... which changes the way
00:04:57.21 these two brain regions communicate,
00:04:59.14 and we believe is one of the ways in which the drugs
00:05:02.09 are making patients unconscious.
00:05:04.02 So... and I showed you before
00:05:07.21 that in the operating room, it would look something like this.
00:05:10.14 You would see what we call a spectrogram.
00:05:14.18 We break the oscillations down into their freq...
00:05:17.21 by frequencies so we can see
00:05:20.19 how strong the components are at the different frequencies.
00:05:23.07 And if you look here, on this particular graph...
00:05:26.02 this was a young woman I took care of
00:05:28.16 who was 19 years old.
00:05:30.07 She was having a short operation.
00:05:32.01 I gave her propofol.
00:05:33.16 And in the beginning, she had slow oscillations.
00:05:36.15 Then the slow oscillations turned into slow oscillations
00:05:39.08 as well as alpha oscillations,
00:05:41.09 where you see the two red bands there.
00:05:43.10 The hig... upper red band is the 10-Hertz oscillation.
00:05:45.24 The lower red band are the slow oscillations,
00:05:48.03 which are between, as I said,
00:05:50.12 about 1-4 cycles per second.
00:05:52.19 And this is the signature of propofol
00:05:56.08 in a young person.
00:05:58.05 And this way of displaying the oscillations
00:06:02.12 makes it easier to see the characteristics of them
00:06:05.14 than just showing the trace that...
00:06:07.16 as it might be on the... on the...
00:06:09.11 the raw trace as it might appear on the monitor.
00:06:11.17 Alright?
00:06:13.08 So, what I want to show you now is...
00:06:15.24 I showed you the propofol produced slow oscillations,
00:06:19.20 but it turns out that each of the anesthetics we use
00:06:22.08 also produce the slow oscillations
00:06:24.13 because they all have targets in the brainstem.
00:06:26.14 Now, why do I say this?
00:06:28.16 So, for this, I'll have to go back to 1935.
00:06:31.17 And a Belgian physiologist named Frederic Bremer
00:06:34.15 did a series of experiments.
00:06:36.15 In the first set of experiments, he...
00:06:40.05 he did these in cats.
00:06:42.00 He severed the spinal cord from the brainstem and brain,
00:06:45.12 at A, there.
00:06:47.08 And he measured the EEG of the cats
00:06:50.04 in those conditions.
00:06:52.01 And he saw what appeared to be
00:06:54.00 an awake-appearing EEG.
00:06:55.19 And he called this state “encephale isole”,
00:06:59.10 meaning "the isolated encephalon."
00:07:02.11 Then he did a second set of experiments
00:07:05.04 in another set of cats,
00:07:07.02 in which he severed the brainstem, together with the spinal cord,
00:07:11.07 from the brain.
00:07:13.07 And he termed this preparation the "cerveau isole" --
00:07:18.18 brain and... "isolated cerebrum".
00:07:21.00 And then, what he saw was slow delta oscillations
00:07:24.11 in the EEG.
00:07:25.24 So, this gave us the idea
00:07:28.06 that somewhere in the brainstem
00:07:31.01 were the centers which were responsible
00:07:33.04 for arousal or driving what appears to be
00:07:35.21 the awake state.
00:07:37.13 So, the corollary of that is
00:07:39.21 if you take away the inputs coming from these areas of the brain,
00:07:42.21 and you're measuring EEG,
00:07:44.17 what you'll see is slow oscillations.
00:07:47.01 And that's indeed what the anesthetics demonstrate.
00:07:50.08 So, we'll just go through a couple of examples.
00:07:52.23 Here's a drug called dexmedetomidine,
00:07:55.05 which we use mostly for sedation
00:07:57.14 or as an anesthetic adjunct...
00:07:59.23 sedation in the intensive care unit
00:08:01.21 or as an anesthetic adjunct in the operating room.
00:08:04.19 And in the first panel,
00:08:07.09 I'm showing you a pattern which we frequently see,
00:08:10.04 where you have what are called spindles.
00:08:12.02 They look like the alpha oscillations,
00:08:13.14 but they're a little lighter.
00:08:15.08 They don't have the same sort of regular rhythm.
00:08:18.10 They're sort of evanescent.
00:08:20.02 They're like this... chhu chhu chhu... chhu chhu chhu.
00:08:22.07 The alpha oscillations... chhu chhu chhu chhu chhu chhu chhu.
00:08:26.06 And at the same time, you see there's slow oscillations
00:08:28.24 there as well.
00:08:30.15 So, what's interesting about this drug
00:08:34.05 is it produces a state which looks very much like non-REM sleep.
00:08:38.10 So, in the upper panel
00:08:40.09 where you see the spindles and the slow oscillations,
00:08:44.01 that looks very much like non-REM stage 2 sleep.
00:08:47.17 And in the lower panel,
00:08:49.16 where you just have pretty much predominantly slow oscillations,
00:08:52.09 that looks like non-REM stage 3 sleep.
00:08:55.13 Alright? Or slow wave sleep.
00:08:58.08 And you can see, there's just a large slow wave pattern
00:09:01.14 down at the bottom of the slide there.
00:09:03.07 Now, why would this happen?
00:09:05.07 Well, it turns out that dexmedetomidine
00:09:07.23 targets areas which are believed to help control sleep,
00:09:13.00 and one of the areas down in the brainstem
00:09:15.14 is the locus coeruleus, which is this area that comes out of the brainstem here
00:09:21.06 and travels to the cortex.
00:09:23.17 It travels to the central thalamus.
00:09:27.20 It travels to the basal forebrain.
00:09:29.24 And if you... the drug takes away the inputs that...
00:09:36.07 that this region...
00:09:38.02 that this nucleus transmits to those areas.
00:09:40.24 By taking them away, you're creating like...
00:09:43.27 you're doing chemically what Bremer did with...
00:09:47.17 with experiments.
00:09:49.20 You're taking away those inputs going to the thalamus and cortex.
00:09:54.17 And lo and behold, you see the slow oscillations
00:09:56.03 that I just showed you.
00:09:57.19 So, that's how this particular drug produces the slow oscillations.
00:10:02.14 This is nitrous oxide, laughing gas.
00:10:05.14 This is an actual recording from a patient
00:10:07.24 in the operating room,
00:10:09.25 where we turn... we switched from using sevoflurane and ether
00:10:14.16 to laughing gas.
00:10:16.21 And we do that very often
00:10:20.03 to wake the patient up, because the...
00:10:22.23 it's much easier to...
00:10:25.25 it's much easier to remove the nitrous oxide
00:10:28.08 -- have them breathe it off --
00:10:30.29 then it is, let's say, the ether.
00:10:32.20 So, it's a technique that we commonly use at our hospital
00:10:34.17 when we're waking patients up.
00:10:36.15 But what was so interesting about this
00:10:39.00 is we had never really paid attention
00:10:41.03 to what was happening in the EEG.
00:10:42.19 This is just something we did.
00:10:44.02 So, when you look at the EEG,
00:10:45.23 you see almost perfect sine waves.
00:10:49.21 And they're actually perfect in this particular case...
00:10:52.04 sine waves that are about 2...
00:10:55.18 their... their period is about 1 second or so.
00:11:02.15 So, they go up and down about...
00:11:04.19 or, I mean... their period is about a half a second.
00:11:07.18 They go up and down about 2 times in a second.
00:11:10.04 So, this is amazing.
00:11:12.07 I mean, think about it.
00:11:14.02 You saw what the other EEG activity looked like.
00:11:16.01 It's like... these drugs...
00:11:18.03 this drug is producing, like, almost perfect sinusoidal oscillations.
00:11:23.19 Now, what's interesting about this is it comes on, b
00:11:27.14 ut it doesn't last.
00:11:29.03 It lasts from somewhere between 3-12 minutes,
00:11:32.08 and then it transitions to higher-frequency oscillations.
00:11:36.22 But in this state, the person is probably profoundly unconscious.
00:11:42.23 And what we think is transpiring is that the drug...
00:11:45.24 again we'll apply Bremer's principle:
00:11:47.29 we should look for something coming out of the brainstem
00:11:51.02 to explain this.
00:11:53.06 So, coming out of the brainstem
00:11:56.21 is a very important pathway
00:11:59.17 called the parabrachial nucleus.
00:12:01.15 This nucleus releases glutamate,
00:12:04.07 and it's... it uses glutamate as its neurotransmitter.
00:12:07.27 So, it's believed that nitrous oxide
00:12:10.08 blocks this release of glutamate.
00:12:14.00 So, there's the target in the brainstem.
00:12:15.26 This drug is preventing the transmission of information
00:12:20.27 from the brainstem to the thalamus and cortex.
00:12:24.15 And again, by Bremer's principle,
00:12:25.26 we predict we'd see slow oscillations,
00:12:27.20 and that's indeed what we... what we find.
00:12:29.18 So, a final example: ketamine.
00:12:31.15 Ketamine is a drug that we widely use in anesthesia
00:12:34.25 to treat pain.
00:12:36.23 It produces hallucinations
00:12:38.25 and, in recent years,
00:12:41.18 it's found to be very useful in helping certain patients
00:12:45.07 that have chronic depression
00:12:47.18 receive almost immediate relief from their depressive symptoms.
00:12:51.02 And ketamine produces a very interesting pattern.
00:12:54.24 If you just give low-dose ketamine,
00:12:57.04 the dose range in which someone hallucinates,
00:13:00.21 you'll just see high-frequency oscillations
00:13:02.24 like I'm showing here in the top panel.
00:13:04.21 You'll see high-frequency oscillations.
00:13:06.08 You wouldn't see those... those large blips at all.
00:13:09.06 You just see high-frequency oscillations.
00:13:11.15 But when you give a larger dose,
00:13:13.16 so that someone could be essentially anesthetized,
00:13:15.08 you get a combination of the high-frequency patterns
00:13:18.19 and the low-frequency patterns.
00:13:20.26 And the two alternate.
00:13:22.21 It goes high-frequency, low-frequency,
00:13:24.17 high-frequency, low-frequency.
00:13:26.24 And that's what I'm showing you here.
00:13:29.02 And again, by Bremer's principle...
00:13:32.07 these slow osc...
00:13:34.00 these low-frequency oscillations
00:13:36.24 should have a brain stem origin.
00:13:38.07 And it's roughly the same argument that we used for...
00:13:41.20 it's roughly the same argument that we used for nitrous oxide.
00:13:48.02 This ketamine also acts by blocking glutamate...
00:13:53.01 the release of glutamate,
00:13:54.26 probably in the brainstem from the parabrachial nucleus,
00:13:56.22 and in this case goi...
00:13:59.14 the connections going up to the thalamus,
00:14:01.02 the connections going up to the cortex...
00:14:02.24 they're severed,
00:14:04.17 and that's probably what's producing these slow oscillations,
00:14:06.23 slow or delta oscillations.
00:14:09.24 It's not... they have different properties with resp...
00:14:13.07 compared with nitrous oxide,
00:14:15.04 as far as the... the high-frequency oscillations are concerned,
00:14:19.19 because, there, that's a very, very specific effect of ketamine,
00:14:22.20 acting to inhibit inhibitory neurons
00:14:27.26 before it inhibits the excitatory neurons.
00:14:31.14 So, there's a little bit of subtlety there.
00:14:33.03 But the main point that I want to make here
00:14:35.06 is that ketamine, just like propofol, just like dexmedetomidine,
00:14:38.07 produces slow oscillations,
00:14:40.03 and there seems to be a brainstem mechanism.
00:14:43.22 So, let me tell you about anesthesia...
00:14:46.21 the response of the brain to anesthesia
00:14:49.17 as a function of age.
00:14:51.03 So, this is... this is a...
00:14:56.07 the spectrogram of a 30-year-old gentleman
00:14:58.24 who's under propofol anesthesia.
00:15:00.20 You can see the very strong alpha oscillations
00:15:02.26 and the slow oscillations.
00:15:04.21 We've talked about that.
00:15:07.08 Now, here is someone who's 57.
00:15:10.17 Like, the 57-year-old gentleman
00:15:13.00 could be the 30-year-old gentleman's father.
00:15:14.29 They both have slow oscillations;
00:15:16.22 they both have alpha oscillations.
00:15:18.02 And if you look carefully, you see how the...
00:15:20.14 the alpha oscillations seem to be a little bit weaker
00:15:22.20 in the older gentleman than in the younger gentleman,
00:15:24.20 but they're still there. They're still present.
00:15:26.17 And there's another little subtle difference.
00:15:28.06 They're at a slightly lower frequency band,
00:15:30.00 maybe more like 8-12, as opposed to the younger person's band...
00:15:33.15 oscillations being between 10-15.
00:15:36.07 But nevertheless, they're there.
00:15:38.07 Look at this, though.
00:15:40.21 Here's a woman who's 81 years old.
00:15:42.20 This was a lady I took care of
00:15:44.27 who had a tumor on her chest the size of an American football,
00:15:48.15 and it took the thoracic surgeons the better part of
00:15:51.00 six and a half hours to remove the tumor.
00:15:53.27 I was using the EEG to monitor her.
00:15:57.19 And you can see she has very weak alpha oscillations,
00:16:02.00 very weak slow oscillations.
00:16:04.08 And in addition to that,
00:16:06.14 you see how everything is blue above.
00:16:08.04 So, there's a very profound absence of oscillations,
00:16:12.00 let's say, in the gamma range,
00:16:13.24 usually 25 to, let's say, 40 Hertz or so,
00:16:16.28 where we usually think about... rhythms that are used for communication
00:16:20.28 would normally be found.
00:16:22.27 So, she has an absence of the normal communication rhythms,
00:16:26.15 and she has these very, very weak alpha oscillations
00:16:30.03 and... and slow oscillations.
00:16:32.15 And one of the good things about using the EEG
00:16:34.22 as I was taking care of her...
00:16:36.06 I was able to titrate the drugs very precisely to her EEG
00:16:40.01 and know exactly when she was receiving enough anes...
00:16:43.06 enough of the anesthetics to be unconscious.
00:16:46.25 Now, here's the part which is sobering.
00:16:49.05 This gentleman here is about
00:16:53.00 the same age as the gentleman to...
00:16:55.06 on the... on the left.
00:16:58.00 They're about the same age: one is 56, one is 57.
00:17:02.00 The 57-year-old's EEG looks
00:17:06.06 more like the 30-year-old's,
00:17:08.07 whereas the 56-year-old's EEG looks more like the 81-year-old.
00:17:11.03 And you look at this, and you go, wow, that's interesting.
00:17:13.26 What's going on?
00:17:15.22 Well, we age differently physically.
00:17:17.08 Perhaps our brains age differently as well?
00:17:20.24 It makes sense.
00:17:24.04 And... but what's... what's even more intriguing about it
00:17:26.23 is that we might discover it under anesthesia.
00:17:28.29 So, here's one way to think about it.
00:17:30.21 So, forget about anesthesia for the purpose
00:17:33.05 of rendering somebody into a state so they can undergo surgery.
00:17:35.19 Think of this as an experiment.
00:17:37.08 What we're gonna do is give you a stimulus.
00:17:40.04 In this case, the stimulus is a drug
00:17:42.29 that'll make your brain oscillate.
00:17:44.22 Okay?
00:17:46.07 So, when you're young, you can oscillate...
00:17:49.28 your brain oscillates like this.
00:17:51.15 And as you get older,
00:17:53.06 the oscillations become weaker.
00:17:55.28 And the point at which they become weaker,
00:17:58.00 or the rate at which they become weaker,
00:17:59.24 in some sense probably depends upon brain health, right?
00:18:02.17 So, let's take this a little bit further.
00:18:05.20 So, you... you can probably guess
00:18:07.21 what the kids look like.
00:18:08.28 So, there's a 3-year-old.
00:18:11.24 There's a 14-year-old.
00:18:13.26 Right?
00:18:15.15 You can see that you have the same patterns
00:18:18.22 across all the age groups.
00:18:20.15 It's just that the power across the different bands
00:18:23.19 changes as a function of age.
00:18:26.25 And here's a nice little summary of that, here.
00:18:29.21 So, this is just an empirical observation
00:18:33.08 that we did, that we made,
00:18:35.17 where we just looked at the amplitude of the oscillation...
00:18:39.06 the maximum amplitude of the oscillation
00:18:41.14 as a function of age.
00:18:43.06 And if you look there,
00:18:45.07 you see there's a peak about 6-8 years of age,
00:18:48.00 and then after that, it's all downhill, right?
00:18:50.25 And the... the 81-year-old woman
00:18:53.07 is way out to the... is way out to the right.
00:18:57.23 So, the brain is changing its response to anesthesia.
00:19:03.08 And one of the implications of this for us is that
00:19:07.19 as we take care of patients,
00:19:09.03 we have to... we should take this into account
00:19:11.05 as we dose our drugs,
00:19:14.02 and it helps us understand... and it helps us understand
00:19:16.25 the responses of the brain to anesthesia,
00:19:18.19 and helps us... and helps us choose our drugs differently.
00:19:22.28 So, what happens if you're even younger?
00:19:28.00 You know, the youngest person I showed you there
00:19:30.21 was about 3 years of age.
00:19:33.24 So, here's a 3-month-old.
00:19:35.23 So, the 3-month-old just has slow oscillations everywhere --
00:19:40.04 no alpha oscillations or anything like that.
00:19:42.18 And then, seemingly, something magical happens
00:19:45.27 at 4 months of age.
00:19:48.16 At 4 months of age, you actually
00:19:52.03 start to see the oscillations over the entire head.
00:19:54.04 And, again... why would this be picked up under anesthesia
00:20:00.16 and not... as opposed to anoth... some other... some other...
00:20:03.28 or in an... as opposed to in an experimental setup?
00:20:07.02 And again, it's one of these things
00:20:09.23 where we just haven't paid attention
00:20:11.18 to the responses of the brain to anesthesia
00:20:13.14 the same way we've... we've looked at how the brain responds
00:20:16.17 to other... other phenomena.
00:20:18.08 And what this suggests is that
00:20:22.04 there are some developmental changes that occur
00:20:25.04 in those first 3 months
00:20:27.14 that are reflected in how the [patient] responds
00:20:30.26 to the anesthetic.
00:20:32.29 So, suggesting that.. you know, anesthesia
00:20:36.07 not only is something for making it possible to undergo surgery,
00:20:39.19 but it may also be a tool for studying
00:20:42.28 the brain and its circuits.
00:20:45.18 So... but just to fill out the point about the...
00:20:48.16 the aging brain...
00:20:51.16 so, what happened to the aging brain?
00:20:54.01 Why is that 81-year-old woman's EEG...
00:20:57.26 why does it have lower amplitude oscillations
00:21:01.27 than, let's say, the 30-year-old's?
00:21:03.22 Well, all you have to do is take a neuron
00:21:05.28 and think about its various parts,
00:21:08.03 and then think about what happens to those parts
00:21:11.05 as the brain ages.
00:21:12.21 So, first of all, as we get older, we produce less neurotransmitter.
00:21:16.01 As we get older, the dendrites,
00:21:18.03 which receive information from other neurons...
00:21:20.29 they don't retract and extend as much...
00:21:24.00 their dynamics are actually decreased.
00:21:27.04 The myelin sheath -- the insulation along the neuron --
00:21:31.17 breaks down so the transmission of the action potentials,
00:21:34.16 the electrical impulses,
00:21:36.25 is... degrades.
00:21:39.20 The mitochondria, the powerhouse of the... of the cell,
00:21:43.21 decrease in function.
00:21:45.22 And also, the cells lose volume.
00:21:49.19 And on a macro level,
00:21:52.03 this would look like a decrease...
00:21:53.24 like an increase in the ventricular size,
00:21:55.17 if we were to look at an older person on an MRI image.
00:22:00.18 So, you don't have to involve...
00:22:04.07 invoke anything like dementia or Alzheimer's.
00:22:07.14 Just think of an aging neuron.
00:22:09.20 And you have cables,
00:22:11.04 which essentially have been around for 81 years,
00:22:14.04 and the fidelity with which they can transmit signals
00:22:17.07 just declines,
00:22:18.22 because each of the components of the cable is 81 years...
00:22:21.15 is 81 years old.
00:22:24.04 So, let's talk about reanimation.
00:22:29.04 As I said, we give you drugs...
00:22:31.22 or, we give a patient drugs
00:22:33.26 in order to render him or her unconscious, insensate,
00:22:37.04 so they can tolerate surgery.
00:22:38.28 But the really important thing is waking someone up,
00:22:41.01 because, as I like to say,
00:22:42.23 anyone can knock you out.
00:22:44.17 Anesthesiologists bring you back.
00:22:46.04 The New York Times did a piece on our laboratory
00:22:48.06 a few years ago,
00:22:49.21 and this was one of the Letters to the Editor.
00:22:51.03 It read, "I had my corrective surgery for...
00:22:55.26 due to 'infantile paralysis' -- likely polio -- in 1949.
00:23:00.16 The bill for the anesthesiologists was $400.
00:23:02.08 My mother was horrified, but my father calmed her when he said
00:23:04.08 it was probably $50 for the procedure,
00:23:06.21 but I gladly... but I gladly pay the other $350
00:23:10.03 because he knew how to wake her up."
00:23:12.01 Right? The important thing is not just anesthetizing the patient
00:23:15.21 but bringing them back.
00:23:17.00 Also, as I mentioned,
00:23:19.05 at the moment this is a passive process.
00:23:21.04 We time how we turn off the drugs,
00:23:22.20 and we let the person come back.
00:23:24.27 My colleague, Ken Solt,
00:23:27.06 at Mass General Hospital and Harvard Medical School,
00:23:28.28 has been studying how to turn the brain back on.
00:23:31.15 And I just want to show you an example of that.
00:23:34.20 So, he's been testing this idea in rats.
00:23:37.15 So, here's a gnat...
00:23:39.02 a rat who's been anesthetized for about 20 minutes.
00:23:41.20 And what Ken is going to do...
00:23:44.01 he's gonna give him an injection of methylphenidate.
00:23:47.01 Methylphenidate is Ritalin,
00:23:48.24 the same Ritalin that we use to treat ADHD.
00:23:50.27 So, he injects the Ritalin.
00:23:52.28 Remember, we don't turn the anesthesia off.
00:23:54.23 And what he does is... he now flushes it into the animal,
00:23:57.22 and look what happens.
00:24:04.06 He comes to.
00:24:07.26 Now, for this experimental paradigm,
00:24:12.01 the animal has to turn over
00:24:14.19 in order for us to really grade him
00:24:17.16 as having woken up by... by this particular protocol.
00:24:21.08 And he's managed to get his feet caught there in the wires.
00:24:24.20 But you can see he's making very, very purposeful, very determined...
00:24:28.05 a very determined effort to turn himself over.
00:24:31.03 And he does make it; I've seen the end of the video.
00:24:35.22 Alright?
00:24:36.28 So... the... you can do it.
00:24:40.22 Come on... a little more...
00:24:43.07 uhhh, he made it.
00:24:44.05 Okay, phew.
00:24:45.25 That was close, there, for a while.
00:24:48.20 Alright.
00:24:50.03 So, before we talk science,
00:24:52.04 let's talk about what I call science from
00:24:54.07 the "word on the street."
00:24:56.01 So, this is an article that appeared in the New York Times
00:24:59.00 back in April of 2015.
00:25:00.19 It was the story of this woman who has a startup company.
00:25:03.14 And her investors tell her that they want
00:25:06.14 a new financial plan on their debt...
00:25:07.29 on their desk first thing in the morning.
00:25:10.02 She calls up her dealer.
00:25:13.14 He brings a bag of pills to her apartment in New York.
00:25:18.00 And she gives him a wad of cash.
00:25:19.23 She gulps down one of the pills,
00:25:21.25 and then, after thinking about it,
00:25:23.26 she decides to take another one of the pills.
00:25:27.03 And then shortly thereafter,
00:25:29.17 you see what it says there...
00:25:31.08 several minutes later, she felt her brain snap to attention.
00:25:34.03 She pushed up her glasses and worked,
00:25:36.01 essentially, for the next seven hours straight.
00:25:39.08 And so, this is something of which we see a lot of,
00:25:41.07 and that's what this article is about:
00:25:42.24 people abusing these stimulants.
00:25:46.01 People in regular jobs taking these as a matter of course.
00:25:49.04 This is not a good idea.
00:25:50.22 It's actually very, very dangerous.
00:25:52.08 But what I want to point out here is...
00:25:54.03 you see where she said,
00:25:55.23 "She felt her brain snap to attention."
00:25:58.24 Maybe this is an idea that we could use
00:26:01.01 when patients' brains have been discombobulated
00:26:03.08 with anesthetics to help return to a function...
00:26:06.07 a normally functioning state.
00:26:08.14 Because, particularly with older patients,
00:26:12.03 the likelihood of having some sort of brain dysfunction,
00:26:14.19 ranging from delirium to postoperative cognitive dysfunction
00:26:17.08 that could last for several months,
00:26:20.21 is fairly high -- depending on what study you want to look at,
00:26:22.17 between 20-40, maybe even 50%,
00:26:25.01 in some form or another.
00:26:26.18 So, maybe one of the things that we should do is...
00:26:30.02 in addition to monitoring the brain better with the EEG,
00:26:32.21 is come up with some ideas to turn the brain back on.
00:26:36.01 So, I'm gonna show you an example of that.
00:26:38.14 Now, remember, that rat...
00:26:41.06 he got up, but could he function?
00:26:43.23 Right? Could he actually execute a task?
00:26:47.14 So, to test that idea,
00:26:49.07 Ken did a second study.
00:26:51.08 So, first what he did was he trained the rat
00:26:55.28 to go back and press the correct lever,
00:26:58.17 a correct touchpad,
00:27:01.14 and then, if he pressed the correct touchpad,
00:27:03.04 he could turn around behind himself
00:27:05.06 and get a reward.
00:27:07.00 So, he comes up, he presses the correct touchpad,
00:27:08.25 he gets a reward.
00:27:10.18 Alright?
00:27:12.00 So, what Ken does now is he anesthetizes the rat.
00:27:15.25 And while he's anesthetized...
00:27:18.04 so, the rat is trained to execute this task.
00:27:19.28 He anesthetizes him.
00:27:21.24 And before he anesthetizes him,
00:27:23.14 he implants an electrode in his ventral tegmental area.
00:27:26.17 So, the ventral tegmental area,
00:27:28.21 as I'll show you in a bit,
00:27:30.16 is an area which is responsible for reward,
00:27:32.03 but it's also responsible for arousal.
00:27:34.26 So, what he does is he anesthetizes the rat,
00:27:38.01 stimulates the ventral tegmental area...
00:27:40.06 now, you're gonna see... the animal is gonna wake up.
00:27:42.20 We don't turn the anesthesia off.
00:27:45.18 He's gonna wake up.
00:27:47.06 And then, what he's going to do is he's gonna go back to work.
00:27:49.06 He realizes, oh, I'm in the box where I can get my reward,
00:27:51.02 so he goes back to work.
00:27:53.00 And we're gonna let him work for a few minutes,
00:27:55.00 and then what Ken is going to do...
00:27:56.29 he's gonna turn the stimulation off,
00:27:59.05 and the animal is going to become anesthetized again.
00:28:02.08 So, Ken is actually controlling this animal's level of arousal.
00:28:05.15 Here, let me play the video for you.
00:28:07.29 So, there's the animal.
00:28:09.19 There's no stimulation on.
00:28:11.06 He's actually anesthetized.
00:28:12.25 And you can see the cable there.
00:28:14.26 That connects to the stimulating electrode that's in his ventral tegmental area.
00:28:17.26 So, now, in just a second,
00:28:19.25 Ken is gonna turn the stimulation on.
00:28:21.06 So, he turns the stimulation on.
00:28:23.23 The animal comes to.
00:28:25.02 The anesthesia is not turned off, remember.
00:28:27.01 He goes to the reward box
00:28:29.02 but, just like in life, there's no free lunch,
00:28:31.00 so he has to work.
00:28:32.16 So, he hits the correct... he hits the correct symbol,
00:28:36.07 and he comes back and gets a reward.
00:28:37.29 Now, he turns around again.
00:28:39.24 Ken changed the stimulation to 20 Hertz.
00:28:42.21 He hits the correct symbol.
00:28:44.14 He's a little wobbly, but he's doing what he was trained to do.
00:28:47.15 Alright?
00:28:49.24 Now... he turns around a second time, here.
00:28:53.06 I think he... he gets this one wrong.
00:28:55.06 Yeah, he got that wrong.
00:28:56.20 So, the light tells me got it wrong.
00:28:57.28 Right? So, now he turns around again.
00:28:59.28 So, now, he's gonna turn around for another trial.
00:29:03.06 And watch what happens.
00:29:04.22 Ken's gonna turn the stimulation off.
00:29:06.20 So, the trial is set. The lights come on.
00:29:08.27 Ken turns of stimulation off...
00:29:12.08 and he's back out again.
00:29:14.04 So, he was only awake because Ken was stimulating
00:29:18.15 his ventral tegmental area.
00:29:20.14 Right?
00:29:22.02 So, what's happening here?
00:29:23.27 So, how does Ritalin work?
00:29:25.15 Well, Ritalin works by increasing dopamine in the brain.
00:29:31.04 It increases dopamine in this pathway
00:29:33.06 called the mesocortical pathway,
00:29:36.06 meaning this pathway going from the midbrain,
00:29:40.00 out to the cortex, up there. Alright?
00:29:43.16 So, that's different from the nigrostriatal pathway,
00:29:46.24 which I've also shown there,
00:29:48.29 which is the one implicated in Parkinson's disease.
00:29:51.15 Right?
00:29:53.10 So, this mesocortical pathway is also important in reward,
00:29:58.04 but it's important in cognition.
00:29:59.19 So, when you're taking...
00:30:02.12 or, when a patient is taking Ritalin,
00:30:04.28 hey're actually taking advantage of this particular pathway, here.
00:30:09.16 And Ritalin blocks the reuptake of dopamine...
00:30:10.03 so, dopamine is removed from the brain by being taken back up
00:30:15.13 into the cells that released it.
00:30:16.27 And so, if you block that,
00:30:18.18 you keep the level of dopamine in the brain high.
00:30:21.10 And then, the other way that you can...
00:30:23.22 you can create this effect is by giving Ritalin,
00:30:26.18 or, as Ken was doing in this experiment electrically,
00:30:29.14 by electrically stimulating the ventral tegmental area directly,
00:30:32.15 or with elec... with electricity or optogenetically.
00:30:37.03 So, this is an idea... this idea of giving Ritalin is a...
00:30:40.12 is something that Ken is studying
00:30:43.10 as a way to turn the brain back on after anesthesia.
00:30:47.25 So, what have I told you?
00:30:49.19 As I said, the brain under anesthesia
00:30:51.17 is not turned off.
00:30:53.04 It's actually quite dynamic.
00:30:56.03 I've shown you a little bit more about
00:30:58.01 how the oscillations are likely to be a mechanism
00:31:02.10 through which the drugs
00:31:05.17 produce altered states of arousal, in particular unconsciousness,
00:31:08.04 and that all the anesthetics
00:31:11.24 produce slow oscillations because they have targets in the brainstem
00:31:14.04 that take away inputs going up the thalamus and cortex.
00:31:19.00 You can see why,
00:31:21.15 because these oscillations are so readily visible in the EEG
00:31:24.24 and they change systematically with age,
00:31:27.04 that this offers a very compelling paradigm for being able to...
00:31:31.21 for tracking the state of patients' brains under anesthesia,
00:31:34.20 and also designing control systems.
00:31:37.10 And I've shown you a little bit about reanimation,
00:31:38.28 turning the brain back on.
00:31:41.18 And as I said before,
00:31:43.12 this may be a way to not only speed recovery
00:31:44.29 but maybe would help reduce
00:31:47.17 the incidence of postoperative cognitive dysfunction and delirium,
00:31:49.18 which frequently occurs in elderly patients after anesthesia and surgery.
00:31:53.20 So, I've told you about the implications of studying anesthesia
00:31:56.17 for the sake of anesthesia.
00:31:58.14 But the implications are even broader.
00:32:00.18 Because anesthesia connects very broadly
00:32:02.29 with a number of issues and problems
00:32:06.19 in clinical neuroscience.
00:32:09.25 And I've just listed a few here.
00:32:11.26 So, for example, I have epilepsy up there.
00:32:15.14 We have an anesthetic drug like methyl... methyl...
00:32:18.19 ahem, excuse me...
00:32:20.16 like methohexital, which is a barbiturate.
00:32:23.26 At low doses, it actually induces seizures.
00:32:26.01 But in higher doses, you can use it to treat a seizure.
00:32:29.02 Or I have locked-in syndrome there.
00:32:32.16 If you give a combination of droperidol and fentanyl,
00:32:36.10 it produces a locked-in syndrome in patients.
00:32:39.11 Right?
00:32:40.26 It's like this sort of...
00:32:43.28 this very powerful antidopaminergic state
00:32:45.27 that's created by the combination of those two drugs.
00:32:49.00 Or as another illustration,
00:32:50.22 I mentioned ketamine earlier,
00:32:52.14 being used to treat pain.
00:32:54.03 It's a model for schizophrenia.
00:32:57.12 And now it's being used to treat chronic depression.
00:33:00.25 And if you think about what we just talked about
00:33:03.17 -- waking someone up from anesthesia;
00:33:05.12 it's a drug-induced, reversible coma --
00:33:07.19 maybe some of these ideas could be applied to help bring people out of coma,
00:33:12.18 help increase their level... their level of arousal.
00:33:16.23 So, what I'm showing you is that we think about...
00:33:19.11 as we think about anesthesia as a neuroscience phenomena,
00:33:21.24 we take seriously studying the neurophysiology of anesthesia.
00:33:25.01 It's very clear that we can improve care of patients
00:33:28.13 requiring anesthesia for surgery.
00:33:31.24 But I think there even broader implications
00:33:34.13 for using this as a way to study the brain,
00:33:36.25 and then for maybe finding solutions
00:33:39.25 to other problems, or related problems,
00:33:43.10 in clinical neuroscience.
00:33:45.00 So, thank you very much.

Videos in this Talk
  • Part 1: Unconsciousness Under General Anesthetic is a Dynamic State
    Part 1: Unconsciousness Under General Anesthetic is a Dynamic State
    Audience:
    • Student
    • Researcher
    • Educators of H. School / Intro Undergrad
    • Educators of Adv. Undergrad / Grad
  • Part 2: The Dynamics of the Brain Under Anesthesia
    Part 2: The Dynamics of the Brain Under Anesthesia
    Audience:
    • Student
    • Researcher
    • Educators
    • Educators of H. School / Intro Undergrad
    • Educators of Adv. Undergrad / Grad
Speaker: Emery Brown
Total Duration: 1:14:28
Recorded: August 2019
All Talks in Neuroscience

Talk Overview

What happens to your brain when you are under general anesthesia? Dr. Emery Brown explains that under general anesthesia your brain is not turned off but is very dynamic. Electrical oscillations in the brain can be recorded using an electroencephalogram (EEG).  Brown shows how oscillations induced by anesthesia interfere with normal communication between different regions of the brain. By following oscillations of different frequencies, it is possible to monitor and adjust a patient’s level of unconsciousness under anesthesia.

All general anesthetics act in the brain stem region to induce slow brain oscillations. Brown shares EEG spectrograms that clearly show that the brain response to anesthesia varies with age. Younger brains show strong oscillations while those of older brains show weaker oscillations.  Interestingly, not all brains “age” at the same rate. By using EEG spectrogram to visualize brain dynamics, anesthesiologists can optimize drug dosage for individual patients. Brown closes his talk by presenting recent research suggesting that it may be possible to “turn the brain back on” after general anesthesia as a way to speed patient recovery.

Speaker Bio

Emery Brown

Emery Brown

Dr. Emery Brown is an expert in understanding the neurophysiological basis for how general anesthesia works and passionate about his desire to pass this understanding on to others.  Recent technological advances allow large amounts of data to be recorded from the brain. Brown’s lab is developing statistical tools and algorithms to analyze and interpret this… Continue Reading

Playlist: Bench to Bedside

Related Resources

Purdon PL, Sampson A, Pavone K, Brown EN. (2015) Clinical Electroencephalography for Anesthesiologists: Part I: Background and Basic Signatures Anesthesiology 123 (4) 937-60.

Cornelissen L, Kim SE, Purdon PL, Brown EN, Berde CB (2015). Age-dependent electroencephalogram (EEG) patterns during sevoflurane general anesthesia in infants. Elife.;4:e06513.

Purdon PL, Pavone KJ, Akeju O, et al. (2015) The Ageing Brain: Age-dependent changes in the electroencephalogram during propofol and sevoflurane general anaesthesia. Br J Anaesth. 2015;115 Suppl 1(Suppl 1):i46–i57.

Brown EN, Pavone KJ, Naranjo M. (2018) Multimodal General Anesthesia: Theory and Practice. Anesth Analg. 127(5):1246–1258.

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