In the last segment, we touched on some theories about the relationship between brain function and sleep and psychiatric disorders. In this segment, we're going to talk about very specific psychiatric disorders, some of the sleep changes that they have, and then develop a little bit of a discussion about the pathophysiology of the disorder based on the sleep changes. We're now going to move into specific alterations of sleep in different psychiatric disorders. There are many psychiatric disorders. The broad categories include the mood disorders, the thought disorders, such as schizophrenia, the anxiety disorders, substance use disorders. We're going to talk about all of these different conditions and the specific sleep problems associated with them, and then try to understand how they reflect alterations in brain function in these different disorders. If you will, this is one way of uncovering a brain-based theory of different psychiatric disorders and how they evolve and emerge. The first psychiatric disorder that we'll talk about is that of depression. Depression is a disorder in which individuals feel sad. They feel blue. They feel hopeless, helpless. So, oftentimes associated with suicidal thinking, thoughts that life is not worth living. And individuals with depression can attempt to take their lives and certainly, don't feel like life is worth living. There is a psychological component to depression, but there's also a physiological component to depression in which it's recognized that the body is simply not functioning the same way in somebody who's depressed as when they're healthy. And one of the physiological disturbances that they have is very characteristic alterations in their sleeping patterns at nighttime. The most common pattern of sleep disturbance in depressed individuals is the insomnia pattern. The insomnia pattern is characterized by difficulty initiating sleep at nighttime or it could be difficulty maintaining sleep throughout the nighttime, also including early morning awakenings, getting up much earlier than they would like to and not being able to return to sleep throughout the daytime. That's the most common presentation of sleep problems in an individual with depression. In contrast, they can also present with hypersomnia or sleeping too much, if you will. In these cases, individuals can sleep at nighttime and have significant difficulty motivating themselves to get out of bed the next day and they just feel sleepy all day long. They have a tendency to just feel sluggish. They don't feel like their brain is really working at a high level. And so, they have a tendency to want to go back to bed during the daytime. That's a less common feature of depression. More commonly, we see the insomnia pattern emerge. These sleep problems can be present before somebody has an episode of depression. They can be especially present during the period of depression. And importantly, even after somebody has recovered from depression, they can continue to have some sleep problems present. This gives a sense that the sleep problems and depression are really reflective of underlying physiological changes in what the individual is doing. And based on our understanding now of the functional neuroanatomy of the different sleep stages, we can start to describe how these changes in sleep are a result of fundamental alterations in the brain structures that are related to emotional behavior, motivation, and the drive to go on, if you will. Many studies have looked at broad characterizations of the EEG sleep patterns in depressed individual. What I mean here is individuals are monitored during sleep with electrophysiological wires that monitor their brain waves and their sleeping patterns. It can tell us when an individual falls asleep, how much time they spend in non-REM sleep, non-rapid eye movement sleep, what is the timing of those sleep stages across the nighttime. So, there are very characteristic patterns of alterations in EEG sleep that have been noted in patients with depression. The most prominent finding is that there are alterations in rapid eye movement sleep in patients with depression. Patients with depression have what's characterized as short REM latency. Meaning, they tend to go into rapid eye movement sleep much quicker than other individuals or healthy individuals. They also have an increase in what's referred to as phasic REM sleep, meaning the number of eye movements that they have in a rapid eye movement sleep period. The first REM period can be much longer in duration. And across the night, the percentage of sleep spent in rapid eye movement sleep can be higher than in healthy individuals. All of these findings in rapid eye movement sleep suggests that there is some pressure for individuals who have depression to enter rapid eye movement sleep and to stay in that sleep for a longer periods of time. The other aspect of non-rapid eye movements sleep. Depressed individuals tend to have reductions in the deeper parts of non-rapid movement sleep. Across the night, their sleep tends to be lighter. They tend not to go into slow-wave sleep, which is stage three and four sleep, to the same degree that healthy individuals will do. And another way of measuring the depth of sleep is by looking at the spectral power of the EEG. The higher the spectral power, the more slow-wave sleep. Depressed patients have been shown to have reductions in spectral power, especially in stage three and four sleep. So the pattern of non-REM sleep that emerges in depression is that they're not able to get into as deep of a sleep as restorative sleep and their sleep tends to be fragmented and lighter across the entire night. They have sleep continuity disturbances that are measured by sleep latency or the time that it takes somebody to fall asleep. This tends to be prolonged in patients with depression. They tend to have increased amounts of wakefulness throughout the nighttime. And they also have a tendency to have early morning awakenings. They would like to get up at maybe seven or eight o'clock in the morning, but their brain automatically wakes them up at three, four o'clock in the morning, and they have a difficult time returning to sleep for the rest of the night. So these then are the characteristic alterations in EEG sleep measures in individuals with depression. These changes have been used as evidence that there are chemical changes in the brains of individuals with depression. One model of depression is that there is an imbalance between the monoaminergic cells of the brain and the cholinergic nerve cells of the brain. The monoaminergic systems include serotonin, norepinephrine, and dopamine. In general, when somebody goes into rapid eye movement sleep, these cells, the monoaminergic cells, cease firing. And when they stop firing, there's a disinhibition of brainstem cholinergic cells, and the cholinergic cells then drive rapid eye movement sleep. But one hypothesis in depression recalling that depressed patients have increases in rapid eye movement sleep is that there might be a weakening, if you will, of the monoaminergic systems and a strengthening or a disinhibition of the cholinergic systems, that then drives the expression of rapid eye movement sleep. There's another model of the sleep changes in depression that comes from observations of circadian and homeostatic processes of sleep. Let's review for a second what are those homeostatic and circadian processes. And this comes from the work of Alexander Borbely and colleagues years ago looking at the results of sleep deprivation studies in healthy individuals and circadian timing studies in healthy individuals. The graph here of the sleep-waking cycle shows the two basic processes of sleep. There's process S which is the sleep drive, and the sleep drive increases the longer somebody is awake during the day time. It reaches its peak at the time of somebody getting into bed at night time. So sleep drive is highest when somebody gets into bed. The process of sleep discharges that sleep drive. That's the recovery function of sleep. So sleep drive then throughout the night time while somebody is sleeping returns to the lowest levels of the day. And then as somebody wakes up the next day, there's an increase of sleep drive up until the time of getting into bed the next night. In the background, there is the circadian drive. The circadian drive is more of an arousal drive. And that's present predominantly during wakefulness and is lowest during the sleep period. So, in depression now, we have reductions in slow wave sleep. We have reductions in stage three and fiur sleep, the deeper parts of sleep. So, one possibility is that there is a reduction in this homeostatic process as sleep drive that may result in a reduced slow wave sleep expression and depressed individuals. And if they have reduced expression of slow wave sleep, what takes its place is a shifting of rapid eye movement sleep to earlier in the night. So, there are two possibilities then for the changes in rapid eye movement sleep. One is the absence of slow wave sleep. The other is monoaminergic colinergic imbalance hypothesis that we talked about in the previous slide. There has been a lot of information that we've understood about sleep and depression by looking at the treatment of depression and the effects or the impacts of antidepressant therapy on sleep in depressed individuals. Just to review the general observations in this area, we know that if you treat somebody for depression, that their sleep tends to improve. Tends not to make too much difference what type of treatment that they have. And the two major treatments would be medication management with antidepressants or some type of psychotherapy, cognitive behavioral therapy for example. Just the fact of getting somebody better from their depression is going to lead to an improvement in their sleep at night time. The second observation is that most of the effective antidepressant medications may have a tendency to increase monoaminergic tone. What's meant there is there's a class of medications called the SSRIs such as fluoxetine if you will, one of the most common antidepressant medications. It's known to increase serotonin function in the brain. Serotonin is one of the monoamines. So if you're increasing the monoamines, you are going to suppress the colinergic expression of rapid eye movement sleep. So, most antidepressant medications that work on monoaminergic systems, and the vast majority do, are known to suppress rapid eye movement sleep. This is important because rapid eye movement sleep tends to be increased in depressed individuals. So, something that brings that back down to normal would be thought to be a good thing. Another collection of observations in the treatment of depression is looking at the effects of sleep deprivation on depression and on mood. And it's been well studied and well understood that if you sleep deprive an individual, that has an acute transient antidepressant effect. If you sleep deprive somebody for a night, especially if they're depressed, the next day, they tend to feel a little bit better. Their mood tends to improve. This is a nice feature but it tends not to have long lasting effects. It's a very transient effect that might last for a couple of days. So it's not necessarily the best treatment for the long term management of depression. But these are some of the general observations, if you will, of the effects of antidepressants and sleep. We have learned a lot about the neurobiology of depression by looking at functional brain imaging studies during sleep in depressed individuals. In this study, the functional neuroanatomy of rapid eye movement sleep was looked at in depressed individuals in relationship to healthy individuals. As a background, depressed individuals have increases in rapid eye movement sleep. The top image shows that in healthy individuals, rapid eye movement sleep activates the limbic and paralimbic cortex. This raise the possibility that the REM sleep changes in depressed patients as a result of alterations in limbic and paralimbic circuitry. The bottom image on the right-hand side shows that when depressed patients go into rapid eye movement sleep, there is a super sensitive activation of all the limbic and paralimbic structures, or greater activation of these structures, if you will, in depressed REM sleep than in healthy rapid eye movement sleep. Again, this is evidence, we think, that the REM sleep changes previously observed in depressed individuals reflect alterations in limbic and paralimbic function in depressed individuals. We have also learned a lot about the changes in non-REM sleep or slow wave sleep and depression by looking at functional neuroimaging studies. In these images, we show on the top portion the healthy reductions in metabolic activity in the frontal cortex in non-REM sleep. The lower images are images of depressed individuals taken at exactly the same time. And the primary observation here is that there is less reduction in metabolic activity in the frontal cortex in depressed individuals during non-REM sleep than there is in healthy individuals. If you will, depressed individuals, when they go to sleep at night time, they're not able to rest their brains as much as a healthy individual might. So in this last segment, we have discussed the specific regional changes in rapid eye movement sleep and non-rapid eye movement sleep in depressed individuals. In the next segment, we're going to talk about a different mood disorder, that of bipolar disorder or manic depressive illness.
