Hello, my name is George Mashour. I'm a faculty member at the University of Michigan in the Department of Anesthesiology, as well as the Department of Neurosurgery, also a faculty in the Neuroscience Graduate Program here. And today, I'm going to give you a lecture on the interfaces of sleep and anesthesia. So as an anesthesiologist, I want to let you know why we care or why we should care about sleep neurobiology. First of all, sleep neurobiology may be intimately involved with the big question in anesthesiology, namely, how do general anesthetics work? We've been using them since the 19th century, but we still don't have a precise understanding of their mechanism. In addition to that fundamental scientific question, there are also a number of clinical concerns. Postoperative, postsurgical complications that are related to sleep, another reason why we need to understand sleep neurobiology. And finally, we as physicians do a great job of sleep depriving our patients in the intensive care unit, even on the general medical ward, so we really need to understand that interface of sleep and anesthesiology. So today, I'm going to be exploring three questions. Do sleep and anesthesia have a shared phenotype? That is, do they look alike? Do they have a shared underlying mechanism? And finally, do they have a shared function? And that's something that my lab has done some work on. So first, let me state the obvious. Sleep and anesthesia do not have a trivial identity relationship. That is, they're distinct states. We know this in the field of sleep neurobiology and anesthesiology. But I think the public has a better grasp of this due to the death of Michael Jackson, which occurred due to an overdose of propofol. And evidently, he was taking propofol, a commonly used intravenous anesthetic to help him with sleep. And of course, the state of anesthesia is different than sleep. And really, this is a dramatic example of why that's the case. Now despite the fact that sleep and anesthesia are different, we very commonly use sleep as a metaphor for general anesthesia. And if you were to walk around some operating rooms today at the University of Michigan, you'd hear anesthesiologists saying, we're going to be sending you off to sleep now. You're going to have a pleasant nap. You're going to have wonderful dreams, and you wake up, and you're going to be feeling good. So why do we do that? Well, first of all, sleep is the experiential basis for our knowledge of unconsciousness, and in particular, reversible unconsciousness. Every patient, every one of you watching this lecture has gone to sleep and woken up. And further more, they're positive connotations of health and restoration. We tend to feel good after we're sleeping. So it's much more reassuring to tell a patient, you're going to be going off to sleep now as supposed to something like, I'm about to induce a reversible pharmacologic coma. That's not so reassuring. So we tend to use sleep as a metaphor for general anesthesia. So when did this metaphor come about? Well, I can't tell you precisely. But if you go back to the Bible, even the first book of Genesis, you will see, and the Lord God caused a deep sleep to fall upon Adam, and he slept. And he took one of his ribs, and closed up the flesh in its place. Now independently of whether your belief system is rooted in the Judeo-Christian tradition, I think you can agree that based on this, the concept of surgical anesthesia as a kind of deep sleep is an ancient one. So we use sleep as a metaphor for anesthesia. Is that because they look alike? Do they have a shared phenotype? Well again, sleep and anesthesia are distinct states that have distinct traits or are comprised of distinct traits. Anesthesia, as I mentioned before is something that's pharmacologic. We're inducing this pharmacologic coma. It's also irreversible. That doesn't mean it's permanent, but it's irreversible with respect to a noxious stimulus, for example, the surgeon's scalpel. Sleep on the other hand is a spontaneous process. It's endogenous, the brain is generating sleep. It's also easily reversible. If I were to put a scalpel on you while you were sleeping, you would probably wake up pretty quickly. And finally, sleep is homeostatic. We need sleep. I don’t think anybody could make the claim that we need a general anesthetic. So despite these distinct traits, there are also a number of shared traits. And some of these traits are considered canonical or essential for a good general anesthetic. First of all, hypnosis, we're disconnected from our environment or we're unconscious. Analgesia, we have some pain relief or decreased sensitivity to pain. Amnesia, we can't remember what's going on during dreamless sleep or during an anesthetic. And finally immobility, certainly during REM sleep we have a REM paralysis. And during a successful general anesthetic, we don't want a patient moving around on the table during a surgery. Now if we extend that concept of phenotype to the electrophysiologic level, we can also see some similarities between sleep and anesthesia. This slide actually comes from a paper by Dr. Lydic's group, one of the course directors. And you can see that the slow waves of non-rapid eye movement sleep, non-REM, look quite similar to the slow waves induced by the anesthetic halothane. And furthermore, you can see spindle formations both during non-REM sleep, as well as halothane. Now the spindles during anesthesia aren't exactly the same as those during sleep, but they have striking similarities. In terms of slow waves during sleep and anesthesia, that's been recently studied in a more formal way. And there are a number of striking homologies or similarities. The authors of this article saw slow waves on all unconscious states. They spanned a large number of electroencephalographic channels. They had a consistent frequency and distribution. And they generally started at the front of the brain, and were propagated posteriorly to the back of the brain. So I've told you that sleep is used as a metaphor for general anesthesia. And that's probably driven because there's a shared phenotype that these two states look alike. So this begs the question are there underlying mechanisms that are the same between sleep and anesthesia that are driving these phenotypic similarities? This actually was a hypothesis, that's now referred to as the shared circuits hypothesis, that was put forth by one the the course directors Dr. Ralph Lydic. Dr. Helen Baghdoyan, also very much a part of this line of investigation. And in the mid-1990s they suggested, thus it is highly probable that neuronal mechanisms, which have evolved for regulating naturally occurring states are preferentially involved in generating some traits characteristic of anesthetic-induced states. So to understand that, we need to talk a little bit about the neurobiology of sleep-wake control. And this is a slide pointing out some of the key nodes in the subcortical region of the brain that are important for driving sleep. And these can roughly be broken up into arousal centers. So these are centers that are promoting cortical arousal. And you have the LC, the locus coeruleus which transmits norepinephrine. The LDT/PPT, that's the laterodorsal and pedunculopontine tegmentum, they transmit acetylcholine. So these kinds of arousal centers are critical for keeping the brain awake. And there are a number of different centers that have different neurotransmitter systems. It's a redundant system which is important. We wouldn't want to be unconscious just because one of these centers was knocked out. But of course, we don't spend all of our time awake. And you can see with the red dots are some important sleep promoting centers. So in particular, the ventrolateral preoptic nucleus which transmits GABA and galanin, this is located in the hypothalamus. And this was an interesting target to think about anesthetic mechanisms. So here's the center in the brain that seems to turn on when you go to sleep. It seems to control sleep. Could it be a center that's important in controlling anesthesia? And it was shown about ten years ago in 2003 that c-Fos, which is a marker of metabolic activity, was increased in the ventrolateral preoptic nucleus or VLPO. So there's an associated increase. And more recently, the laboratory of Dr. Kelz has shown that VLPO, and in particular the sleep promoting neurons within VLPO are turned on by the anesthetic isoflurane. The graph that you're seeing is looking at a lesioning of the VLPO to see what it does to anesthetic sensitivity. And what you're seeing here is that when you have an acute lesion, that's the solid red line, there's a shift to the right of the dose response curve. That means you need more of the drug to get the same behavioral effect. In other words, animals who have an acute lesion of VLPO become resistant to the effects of anesthesia, suggesting that the VLPO plays a role in anesthetic mechanism. But importantly, if you look at a more chronic lesion at 24 days, and that's in the dashed red line, there's a left-ward shift. And that means that the animals become hypersensitive to the effects of the anesthetic. So why should this be the case? Why do we have this bimodal response? Well, what's happening in the intervening period is that the animals are developing tremendous sleep deprivation because they're not able to go to sleep without the VLPO. And so what happens likely is that other centers promoting anesthesia are even more sensitive to the effects of isoflurane because of sleep deprivation. And we'll talk more about that functional interaction of sleep homeostasis and anesthetic sensitivity later in the talk. So now I'm going to move from the subcortical region to the cortical region, and tell you about an interesting experiment looking at effective cortical connectivity during the waking state and non-REM sleep. So what does effective connectivity mean? Well, you might have heard of functional connectivity. That's when two areas of the brain covary in their activity. But you can have two brain regions that are doing things at the same time, but they're not really influencing one another. So effective connectivity is a measure that looks at causal influence from one brain region to another and vice versa. So it's kind of a surrogate for different brain regions talking to one another. And what you see here, you see a high density EEG cap. And above it is a transcranial magnetic stimulator that's going to deliver a stimulus to the brain. So at the top, you can see the waking state. And at the very top, those red traces just show you the evoked potentials that are spreading after that TMS burst. And below that you see a voltage contour map. And then the third line, you see a picture of the brain with different areas of activation that are lighting up, and importantly, moving around the brain. And you can see that this talking to one another of different brain regions extends to about 280 milliseconds. By contrast, if you go to the lower part of this figure, you see what happens during non-REM sleep. The brain still gets activated and you see a potential, but that activation doesn't really go anywhere, either in space or in time. And the potentials are truncated, in this case, at about 120 milliseconds. Well guess what? The same thing seemed to happen during anesthesia. In this case, unconsciousness induced with medazolam, sometimes known as Versed. You can see that the signal’s still received by the brain, but again, it doesn’t really go anywhere. So both sleep and anesthesia seem to be associated with a loss of cortical effective connectivity. So the brain seems to stop talking amongst the different regions. Now just because we have a shared trait, we were just talking about unconsciousness, it doesn't mean that we always have a shared mechanism. And this is a good example of the difference between sleep and anesthesia. So immobility during anesthesia is mediated primarily by spinal mechanisms. And that was shown in the early 1990s. By contrast, immobility during sleep is mediated primarily by supraspinal mechanisms. So a good example of where you have a shared trait, namely immobility, but without a shared underlying mechanism. So I've talked to you about sleep and anesthesia, sleep being a metaphor for anesthesia, sleep and anesthesia having a shared phenotype that is likely driven by shared underlying mechanisms. But what about shared function?
