I'll actually be talking about some of the impact that insomnia might have upon both clinical variables and upon physiologic and other cognitive variables to be able to address the questions: what about insomnia; why is insomnia impactful; what areas does it impact; and whether or not addressing insomnia could help us avert some of these impairments.

Here's an outline; first of all, I'd like to define insomnia, and since Dr. Ancoli-Israel has done that to some extent, I'll go over it quickly. I'd like to speak about some of the impairments that are associated with insomnia as we see them through 2 separate groups of studies; first, demographic, cross-sectional and longitudinal studies, and second, laboratory studies — experimental studies coming to us from more controlled settings where we can identify the problems and changes a bit more accurately and be able to hopefully make some more tenable conclusions. I'd like to conclude by speculating about some future directions.

In terms of an insomnia definition, the only thing I'd like to stress here is that I'll be making a distinction between primary and secondary insomnia, and I'd like to focus on primary insomnia in trying to understand the impact of insomnia. But the distinction is an important one; if you really want to try to understand what insomnia does, what impairments it causes, you have to try to identify a pure form of insomnia, which is not associated with any other impairments, so you isolate the cause- and-effect relationships. So, we really are interested in primary insomnia when we're trying to understand the impact of insomnia. Of course, the other question is: is there such a thing as primary insomnia, and if so, what causes it?

Dr. Ancoli-Israel has defined primary insomnia, but for those of you who are coming more from a sleep direction rather than from a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) direction, there are many underlying disorders in the International Classification of Sleep Disorders (ICSD) that correspond to primary insomnia. Primary insomnia in the DSM-IV is an umbrella diagnosis, under which many ICSD diagnoses conveniently can fit, such as psychophysiologic insomnia, adjustment sleep disorder, etc. I'll be speaking about these groups of insomnias which we know in DSM-IV as being primary insomnia — insomnia lasting more than a month, associated with functional impairment, and not related to any other primary causes.

Let's talk about some of the demographic studies. Demographic longitudinal cross-sectional studies have shown us a number of impairments associated with insomnia: negative quality of life, increased body pain, poor health (insomniacs are less healthy than other people), increased risk of future psychiatric disorders, decreased job performance, absenteeism (insomniacs don't do so well on the job), increased risk of accidents, and increased health-care costs.

Let me show you some of these data in greater detail. These are data from Zammit looking at telephone survey results of a group of individuals who complain of insomnia vs those without the complaint of insomnia. It's clearly evident that those who have the complaint of insomnia have a higher prevalence of various types of impairments: body pain, and impaired general health, mental health, and physical health; you name it, it's impaired in insomniacs. The question is: is there a cause-and-effect relationship or not? These are folks who complain of insomnia and who have associated impairments; the question is, do they have other underlying illnesses that may be responsible for some of these impairments?

In terms of the daily functioning of insomniacs, looking at individuals in a health maintenance organization (HMO)/primary care type of setting, compared with those without insomnia, the insomniacs have a greater rate of impairment in terms of their role; disability rates are higher, days of limited activity are higher, and days in bed are higher. So insomniacs, during the day, are not doing as much as are other individuals without insomnia.

Occupational performance suffers in insomniacs; we know this from these data from Johnson and Spinweber, from naval recruits. They looked at individuals who came into the Navy who had insomnia, and followed them over the course of 3 to 6 years. The people who had insomnia or slept poorly had a lower rate of promotions, their pay rates were lower, their re-enlistment recommendations were lower, and they had a higher attrition rate. Having insomnia predicted all of these occupational impairments in this group of naval recruits over 3 to 6 years.

In Zammit's study, the insomnia group had a much higher rate of absenteeism on the job compared with those without insomnia.

In another occupational study of insomniacs, studied by Kupperman in an outpatient population, those with a sleep problem had a higher rate of work dissatisfaction, and a lower job performance rate. So having insomnia predicts all sorts of occupational impairments and poor satisfaction rates.

In this household survey done many years ago of individuals with chronic insomnia vs those without, individuals with chronic insomnia had a higher rate of self-reported serious accidents compared with those who did not.

Motor vehicle accidents are higher in individuals who complain of having poor sleep quality; this was a retrospective study done in North Carolina. Researchers went to the police records and isolated folks who had had motor vehicle crashes in which the police record indicated that falling asleep at the wheel was a probable cause. How they figured that out is another question. They compared them with individuals who had had car crashes in whom falling asleep at the wheel was not cited as a possible cause, and poor sleep quality certainly does predict the higher prevalence of motor vehicle crashes.

The odds ratio is much higher for those with poor sleep quality in terms of motor vehicle crashes. So, not sleeping well predicts all sorts of bad things when it comes to driving.

These are data looking longitudinally at people with poor sleep and isolating the development of present and future psychiatric disorders. There are now possibly 7 studies showing this.

In this study by Breslau and coworkers looking at individuals who complained of insomnia compared with those without insomnia over the course of 3.5 years, the insomniacs have a much higher incidence of depression, anxiety disorders, and alcohol abuse and drug use. These are new disorders and there's a 4-fold incidence of new depressive disorders compared with noninsomniacs. What also is interesting about this study and the next one is that insomnia was not the only sleep symptom predictive of these future psychiatric impairments; hypersomnia was predictive as well. What's also interesting is that insomnia didn't only predict depression, but it predicted a few other things. So the relationship between insomnia and these other impairments is by no means specific in either direction, either from insomnia to these impairments or from these impairments to insomnia.

Another group of data coming from the National Institutes of Health (NIH) Epidemiologic Catchment Area survey done many years ago and reported by Ford and Kamerow suggests that it's not only the present insomnia that predicts future psychiatric disorders, but it also is the persistence of insomnia that predicts a high rate of future psychiatric disorders. The unresolved insomnia group had a much higher rate of alcohol abuse disorders, major depression, anxiety disorders, etc, compared with those in whom insomnia resolved. Again, in this study, hypersomnia was even a more robust predictor of these future impairments. So insomnia by no means is the only predictor of these future impairments.

In an elegant study spanning the course of 35 to 40 years looking at medical students who had complained of sleep disturbances, the cumulative incidence of major depression was much higher compared with the control group who reported no insomnia.

Interesting observations from these studies are that insomnia and related symptoms are predictors of current and future impairments — medical impairments, psychiatric impairments, occupational impairments, etc. The question is: is there a cause and effect relationship between these impairments? That's where things get a little bit muddy. It's nice to speculate that insomnia caused all of these impairments, but the data don't necessarily lead to that conclusion definitively. For one thing, other potential contributors may have led to some of these impairments; these were not all necessarily primary insomniacs. Some may have had comorbid depression or other comorbid disorders that may have led to the impairments. Finally, even if they didn't have other impairments, it could be that insomnia may represent a symptom of an emerging underlying syndrome. In the depression studies, for example, it could be that insomnia could be the first symptom of an emerging depressive disorder that manifested itself fully many years later. So it predicted depression, but it didn't necessarily cause it. So the cause-and-effect relationship is a relationship with which we still need to do a lot of work.

In order to understand the potential consequences of insomnia and to understand some of these relationships between insomnia and impairments, another group of data come to us from laboratory data. In the laboratory setting, we can isolate primary insomniacs more purely. We also can do experiments that are more controlled in nature, so that the results that we get hopefully have more validity to them. The data with insomniacs come to us from a lot of different laboratory settings and shown are only some of them; I'm not mentioning the behavioral experimental settings, the cognitive settings, or even the psychoanalytic settings where some data have been derived on insomniacs. But let's examine some of these data.

First of all, we have electroencephalogram (EEG) activation data. This examines insomniacs compared with noninsomniacs — these are primary chronic insomniacs. And we're looking, on the left, at delta-power spectra, and on the right, at beta or higher-frequency spectra. It's interesting that insomniacs in their non-rapid eye movement (REM) periods have a lower proportion of delta power and a higher proportion of high-frequency waves, such as alpha and beta waves. So insomniacs have a hyperactivation, if you will, on a cortical level during their non-REM episodes as detected by polysomnographic EEGs. And that's something we'll see as a theme in many of these studies I'll show.

In terms of hyperarousal, hyperactivation, the evidence for it comes to us from a number of different settings. Again, in the EEG polysomnographic setting, this is another group of studies by Perlis looking at primary insomniacs compared with major depressives compared with controls. The primary insomniacs had definitive evidence during their non-REM periods 1, 2, or 3 of higher-power spectra in the 14- to 20-hertz (Hz) range. So insomniacs clearly have hyperactivity from an EEG standpoint.

These are data from Bonnet and Arand looking again at primary insomniacs and the Profile of Mood States. The insomniacs have a higher rate of confusion scores, tension scores, and also depression scores. It's possible therefore that the hyperactivation and hyperarousal we see on the EEG level may be related to these higher tension and hyperactivity scores.

Looking again at some of Bonnet and Arand's data, insomniacs also, intriguingly, have a hyperalertness on multiple sleep latency testing (MSLT). These are primary chronic insomniacs and the MSLT looks more normal in the insomniacs compared with normal individuals. They're hypernormal, if you will; they're less sleepy than normal people, which is very interesting. So this hyperarousal with insomniacs is clearly seen on multiple sleep latency data as well, where they can't even fall asleep, at least as we define sleep, ie, achieving 1 or more epochs of sleep stage 1 or deeper on MSLT.

These data are interesting; in a recent article that Sateia authored, reviewing MSLT results from 9 different studies, only in 1 study did the MSLT in insomniacs reveal that they were sleepy, in essence. In all of the other studies, the MSLT values were either close to normal or even supernormal.

In another set of early data from Stepanski looking at primary insomniacs in various categories compared with normal individuals, MSLT results indicate that insomniacs have a less sleepy profile on MSLT. If you isolate the individuals who have insomnia without any underlying diagnostic entity, the primary insomniac's profile still looks much like a normal individual's profile. So on the basis of EEG and MSLT, insomniacs are not sleepy during the course of the day. At nighttime, there is high-frequency activity; even during the day, they tend to be hyper. It's intriguing to speculate: is it possible that this hyperarousal at nighttime translates into poor sleep or nonrestorative sleep, which may be related to the symptoms of fatigue on the longitudinal studies and demographic studies I showed earlier?

A second body of experimental laboratory data, again, from Bonnet's lab, reveals hypermetabolism in insomniacs. These are metabolic rates with insomniacs vs controls. Not only are they high at night, but they also are high during the course of the day. So insomniacs have a 24-hour metabolic rate increase, and other laboratories also have shown this result.

These are some additional data showing that metabolic rates increase, not only during the day but also at nighttime.

Cortisol hypersecretion is another observation coming to us from different laboratories. Clearly, there are increasing cortisol values in insomniacs compared with controls only at nighttime, and this does not represent a circadian shift; it's simply a cortisol increase during the course of sleep. Hypothalamic-pituitary-adrenal (HPA) axis abnormalities have been noted in depression; they've been noted in anxiety disorders. It's intriguing to speculate: is this the basis possibly of the increased rates of depression and anxiety disorders that we see in insomniacs?

In another set of data, cortisol secretion concentrations in primary insomniacs at different time points (4 hours before bedtime, after falling asleep, second 4 hours after sleep, and then total sleep period), increased with insomniacs compared with controls.

Other data come to us from the world of the autonomic variables. Looking at heart rate, again from Bonnet and Arand's studies, the interval between heart beats in insomniacs is less, meaning that they have relative tachycardia compared with people who are normal. And autonomic hyperarousal has been linked to various medical disorders such as coronary artery disease and heart disease in general. Is it possible that the increased medical morbidity with insomniacs had some of this autonomic hyperarousal as its basis?

This group of data that has not really led to tremendous future research, an older group of data, shows that there may be some circadian abnormalities in insomniacs. In controls, the maximum core body temperature occurs way before sleep onset and by the time they fall asleep, they're approaching the nadir of their core body temperature, rectal temperature at least. Whereas with insomniacs, sleep onset is occurring very close to that wake zone, ie, the time when core body temperature is still high, implying that circadian temperature dysregulation may be the basis for some of the changes that we see in sleep maintenance and sleep initiation with insomniacs. You wonder what the medical and psychiatric morbidity associated with this might be. Circadian abnormalities have been thought to be the basis of a number of psychiatric disorders, including, potentially, depression. Does this represent a link between insomnia and various affective disorders?

These are data coming from Nofzinger and colleagues looking at glucose metabolism. When we fall asleep, there's a decrease in metabolism in a number of areas of the brain, as depicted in the top portion of this slide of individuals going from wake to non-REM sleep. In individuals with insomnia, that decrease in metabolic rates seems to be less muted.

Put another way, they have less of a decrease in that metabolic rate. So they, in essence, have a higher metabolic rate, which persists from wakefulness into sleep, again, going along with this hyperactivation/hyperarousal phenomenon that we've been talking about.

Looking at the areas of the brain that show that smaller decrease, they tend to be in the areas of the brain that are possibly responsible for arousal, such as the ascending reticular activating system, the thalamus, etc. So that part of their brain that is supposed to shut down, which also possibly is responsible for wakefulness and arousal, doesn't fully shut down. Again, is it possible that this brain hyperactivity in some way translates into less restorative sleep? In the long run, maybe what's causing these people to remain fatigued and have less energy during the course of the day also may be responsible for what we see on the MSLT; that is, they can't fall asleep even if you put them in quiet bedroom surroundings.

These are data coming to us from the animal world, looking at lesions of the areas of the brain that we think are responsible for the control of deep sleep, such as the ventrolateral preoptic (VLPO) area of the hypothalamus, an area rich in gamma-aminobutyric acid (GABA)ergic fibers. The VLPO, which is GABAergic primarily, is in balance with other areas of the brain (such as the raphe, which is serotonergic and the locus ceruleus, which is norepinephrinergic) that may be responsible for the wakefulness aspect. These two in synchrony represent what's called the sleep/wake switch — when one is active, animals fall asleep; when the other is active, they wake up.

Lesions at the VLPO in a group of animal studies have been shown to be associated with a reduction in total sleep time and a reduction in non-REM sleep. And the reduction in VLPO neurons had been correlated with a percentage reduction in non-REM sleep within a 24-hour period of time. So we're beginning to learn that the genesis of insomnia, at least in animal models, may be related to these deeper structures of the brain, and one day, possibly, we'll begin to learn if these also are areas that are involved in the genesis of insomnia in human beings. By doing so, we may be able to understand better what might be the cause of these insomnias.

This is Sigmund Freud. The reason I put this up was to indicate that there are a number of other theoretical formulations regarding insomnia that I've not discussed, such as the behavioral, the cognitive, the psychoanalytic, etc. By understanding some of these other formulations, we may be able to come even closer to understanding the cause of insomnia, and also understanding the eventual consequence of insomnia. So if you look at insomnia as a psychodynamic problem, a psychoanalytic problem, then the impairment associated with it might be along psychoanalytic realms as well.

Finally, here is a model for insomnia that might help us to understand some of these consequences. We've been talking about hyperarousal, whatever that is; it's not well defined. But at least my own understanding of this is that something, we don't know what it is, is responsible for the cause of this hyperarousability in insomniacs. The manifestations of hyperarousal come to us from a number of different experimental settings along multiple body systems — the HPA axis, sympathetic activation, functional hyperactivity in the brain, EEG arousal — and all of these systems may, in fact, be responsible for producing poor sleep. That is, poor sleep is simply a symptomatic representation of a dysfunction that is a more core dysfunction. Also, these other dysfunctions may be responsible for the daytime impairments that we see on these demographic longitudinal studies, such as medical morbidity, psychiatric morbidity, etc. This is one way at least of understanding how insomnia may lead to consequences.

In conclusion, therefore, insomnia complaints predict the current existence and future emergence of a variety of psychiatric, medical, job-related, and social impairments. But a cause-and-effect relationship has yet to be fully confirmed. Lab studies show there are a number of 24-hour abnormalities on EEG, neuroendocrine, functional, and other measures. Hyperarousal seems to be the central feature, but hyperarousal has not been well defined.

A number of questions for the future include: What's the mechanism by which insomnia predicts these future impairments that I've shown? What are the central processes underlying hyperarousal in insomnia? What produces hyperarousal? Is it a psychodynamic, psychoanalytic conflict? Is it some genetic issue? There are some interesting data reported in animal-model research on insomnia suggesting that there is a hyperarousalability. Maybe hyperarousabilities are a genetically mediated type of phenomenon. What are the consequences of these different arousal manifestations that I showed? Finally, can effective management of insomnia reverse some of these morbidities, such as arousability, depression, medical morbidity, etc?