And now we're going to think a little bit about some of the causes of insomnia. So, I want you to think yourselves about times when you might have had sleep disturbance, what were some of the precipitating factors? And for those of you who've never developed any kind of sleep disturbance and certainly don't have insomnia, what are the factors you think may prevent you from having sleep disturbance which is such a common issue in the general population? Well, there are a number of different pathophysiological models of insomnia. And again, just to remind everyone, we're not talking about a daily sleep disturbance, but we're also not talking about occasional sleep disturbance. We're talking about a disorder. And the pathophysiology of that disorder, really falls into three broad model categories. There are a number of models which stress the cognitive effects which may lead to insomnia and which may exacerbate the disorder, and those are really focusing on some of the thoughts that occur and the cortical systems involved. There are also theories which relate to dysregulated central sleep mechanisms. Most of those sleep mechanisms are located in an area of the brain called the hypothalamus, but there are also a number of models of insomnia which include systems related to stress such as the autonomic nervous system and the HPA axis, and these revolve around something we call hyperarousal. Those hyperarousal systems are typically in the brain stem, but also project up to the cortical areas and really involve a variety of different areas of the brain. Most of these systems are revolving around an area called the locus coeruleus and which is very important in terms of stress responses. And we'll talk a little bit about that in a moment. But certainly, the way we think about insomnia is really in terms of a multifactorial model. This is just a schematic representation. But what you can see here is sleep disturbance in arbitrary units with an insomnia threshold of about 50. And what we see are three components. One very important component, we'll talk about in a bit, is something called a predisposition or vulnerability to developing insomnia. This may be an underlying risk that you have to develop insomnia, even in individuals who are sleeping well and considered good sleepers. It's something which may be manifested over time in response to a precipitating factor, which we see here in yellow. Precipitating factors maybe things like stress and oftentimes, our psychosocial events, stressful events in one's life, but may also be medical disorders which can often precipitate stress and a variety of other precipitating factors. They're also perpetuating factors and this model is sometimes called the 3P model. These maintenance or perpetuating factors can occur in response, behavioral response to sleep disturbance whether that's the stressor or an underlying sleep disturbance which becomes manifested over time in some spontaneous way. But these behavioral responses can be either positive in terms of reducing the amount of sleep disturbance one is exposed to, or they can be exacerbating and actually make someone sleep disturbance worse over time such that when the precipitating factor, the stressor which triggered the insomnia in fact goes away, an individual may continue to experience very chronic and oftentimes severe sleep disturbance. So now we're going to first start out by talking about one of these potential underlying factors of these precipitants and that is, stress. What are the precipitating factors related to stress which may be important to consider in terms of insomnia? And first, a little bit of background, there are number of stress effects which can impact brain function. In animals, those can include unpredictable chronic mild stress which reduces hippocampal neurogenesis, and dampens the hippocampus-dependent negative feedback of the HPA axis. That HPA axis is a critical component of the stress response system and is required for adequate functioning. If the stress becomes chronic, by decreasing inhibitory regulation, it may bias the balance towards a greater excitatory influence into the pair of intraocular nucleus part of the brain, again, which is related to the HPA axis and very central related component can be overactivated. This overactivation may lead to some of the effects we see with regard to hyperarousal and insomnia. But when we think of the actual insomnia precipitating factors, we can measure them in something called life change unit scores. And this is a retrospective study published in 1981 by Healey, which showed a difference between insomniacs and a controlled population in terms of the number of these life change units that occur during the year of onset of their insomnia. What's important to remember is despite the fact that these individuals in this particular study continue to have insomnia two years later, the degree of life change unit scores were reduced almost to the point where controls and insomnia patients had approximately equivalent numbers of life change units. This leads one to hypothesize again, potential perpetuating factors or maintaining of factors which may be present in an insomnia population. People with insomnia may be doing things behaviorally to maintain their disorder over time even when the precipitating factors are no longer present. There are also a number of prospective studies which show stressors and in this case, reports of high family conflict at 7-15 years old are involved in increasing our risk for the eventual development of insomnia. So, for example, in this particular study, if we compare the degree of family conflict across these individuals at 7-15 years, we can see those who have the highest degree or reports of family conflict at 7-15 years of age, are those individuals who are most at risk for developing insomnia. And this is DSM-IV criteria for insomnia at age 20. So, there may be something going on with stress, particularly in these developmental years which may increase our risk, may change something biologically also behaviorally in terms of increasing our risk for developing insomnia. So, back to the multifactorial model, and let's talk a little bit about one of the other components. This is a component that a lot of recent research is being focused on and it's the predisposition component of this three pie model. Again, this is the vulnerability that someone may have for developing insomnia in the future but it's not yet manifested. So, what is this vulnerability? And can we detect the vulnerability to insomnia prior to the onset of the disorder? So, here again we have two individuals, one individual A on the left, as we can see, who has a rather high Pre-Morbid predisposition to developing insomnia, whereas person B on the right panel, has a very low Pre-Morbid vulnerability to insomnia. Also I should point out that neither of the individuals have reached what we think of as the insomnia threshold, so, they're considered pretty good sleepers at the present time. What we want to know at this point is, what underlying pathophysiology is related to the predisposition to developing insomnia. This may lead to potential preventative measures or treatments for insomnia which may relate to the underlying pathophysiology of the disorder as opposed to focusing on some of the symptom management that we have available at the present time. So, one of the first place that we looked in terms of understanding insomnia, and in terms of what's available and what's been out there, what are the potential underlying predisposing factors? And one thing we looked at was a study by Nofzinger and colleagues showing again that there's hyper arousal in the brain, there's increased activation particularly in the subcortical limbic areas of the brain. So, is that potentially a predisposing factor? And what other factors may be good candidates for the pathophysiology of insomnia? Well, when you look in the literature, what we see is there's a wealth of data suggesting physiological arousal in insomnia, not only in the brain both asleep and awake, but also in terms of increased 24 hour metabolic rate, increased body temperature, there's also increased alertness as measured by the MSLT, there's also studies which show an elevated sympathetic activity, as well as from heart rate variability measures of high frequency to low frequency ratio, as well as measures of HPA axis functioning such as elevated catecholamines and increased high frequency EEG which is called beta EEG, and that high frequency EEG is seen in insomnia patients even while asleep. These elevations in arousal lead us to think about a number of different areas. So, let's start out with two of the more promising areas, one is the HPA axis and that's activation, and then we'll talk a little bit about sympathetic activity as well. And we can see here that there's an elevation in the stress hormone cortisol across a 24 hour period. And also, in particular, in the evening hours, insomniacs relative to controls. Not only are there elevations in cortisol which is a component of the HPA access, but there's also elevations in norepinephrine, both in terms of its elevation relative to normal controls. But also in terms of the relationship between the elevations in norepinephrine the stress hormone and sympathetic measure in the brain, and elevations in what we call wake time after sleep onset, are those fragmentary awakenings that can occur during the night, the more norepinephrine in the brain, is associated with more sleep disruption during the night. Very importantly, it's not only during the night that we see elevations in arousal in insomnia. Mentioned some of the data regarding 24 hour metabolic rate was elevated. But in the data by Nofzinger and colleagues, we also see elevations in terms of whole brain metabolism which occurs during the waking period. So, we do know that while asleep and this is in during non REM sleep, there's elevations in brain metabolism in insomniacs which may not be very surprising but what is very interesting is the fact that these elevations also occur during the day. So, we're beginning to conceptualize insomnia as a disorder of arousal or hyper arousal which occurs throughout the 24 hour period but it's particularly manifested at night when we're attempting to fall asleep and stay asleep. Here is another example of elevated arousal or hyper arousal in insomnia patients, and we can see this data from Roehrs and colleagues showing that the MSLT or a measure of alertness is elevated in insomniacs relative to normal controls. And in fact, it's of higher level than we would expect for individuals in the general population despite the fact that insomniacs have quite disturbed sleep prior to these particular tests. And again, with some evidence showing a relation to norepinephrine, we see these measures of urinary norepinephrine are elevated in those insomniacs with the highest degree of arousal, the high MSLT group as seen here have greater levels of urinary norepinephrine again during the daytime. So, one of the things to think about is what are these underlying factors of arousal related to specifically particularly in individuals who don't yet have insomnia, but we'll first look at one of the interesting studies done on the impact of stress in insomnia. And in this particular study done by Morin and colleagues, what we see is that it's not a difference in the number of stressful events, that's the biggest difference between insomniacs and controls, but rather it's a difference related to the impact of stressful events which may occur in controls and insomniacs at a relatively similar rate. So, for example, individuals without insomnia may respond to a stressful event with a level close to 2.1 on this particular impact of events scale. Insomniacs however tend to feel the impact of a given event at a greater level. There is some cognitive, potential cognitive components which may relate to this and there's a number of studies ongoing looking at potential effects related to the hyper arousal in terms of cognitive activity that occurs with insomniacs. There's also physiological data to suggest that insomniacs have a greater response to stressors in their environment. This is a laboratory stressor, a laboratory challenge where individuals were asked to immerse their hands into cold water for a number of minutes. And this is called a cold pressor test. And as you might imagine, can elicit a pain response and an elevation in activation physiological and cognitive. In this case, we're looking at heart rate elevations. And what we can see from this particular trial is over the course of the four minutes of this assessment we see elevations in heart rate in insomniacs that are greater than the elevations in normal control individuals. So, people with insomnia have a greater reactivity physiologically to a standardized stressor, in this case the cold pressor. Now back to the information that I gave you a bit earlier on HPA axis elevations and insomniacs relative to controls, particularly in the evening hours, but it's really 24 hour cortisol secretion that was assessed in this particular study. And when we look at a particular time of day when the assessment was done, we can see that it's done half hourly assessments of cortisol throughout this 24 hour period. And we see elevations which occur predominantly during this period of time here. So, let me zoom in on that and there we begin to see a big separation at about 8:00 o'clock at night, a couple hours prior to bed time in this particular study, where insomniacs begin to have elevations in cortisol whereas controls continue to have the normal circadian decline in cortisol levels that we expect to see in preparation for the relaxing environment of the bedroom. So, what may be going on here is a reactivity or response of insomniacs to the bedroom environment which for most individuals is a calming or relaxing situation. So, this hyper arousal or an increased reactivity which it may represent, is a particularly important thing to think about and look at in the context of insomnia. But very importantly, it can be extremely complex to begin to interpret whether hyper arousal occurs prior to the onset of insomnia disorder, or in fact may be a predisposing factor. So, we're going to talk a little bit about that now.
