So moving to a discussion about insomnia and its relation to hyperarousal, we begin to see a very complex picture. And when we think about insomnia and hyperarousal, and how it relates to the predisposition to developing the disorder of hyperarousal, we see an even more complex picture. So one of the paradigms that researchers, including myself and Henry Ford Hospital, have borrowed from the cardiovascular literature to look at insomniacs is our studies of normotensive subjects. Where an individual's blood pressure reactivity to a laboratory stressor has been shown to be a significant prospective predictor of the development of hypertension and need for medications. This involves a challenge paradigm. And what we want to try to do is look at individuals who we think may be predisposed to developing insomnia, and use a challenge, a stressed challenge to try to elicit some information regarding potential both physiological and cognitive differences, which may predict the long term risk of developing insomnia, just as cardiovascular stress tests including treadmills and so forth, may improve our prediction of cardiovascular disease and mortality. So similar relationships between sleep reactivity, and disease progression, and morbidity may be present in insomnia. So that's sleep reactivity really needs to be studied. One of the things, and the first thing that we did, was to develop a hypothesis. Our specific hypothesis was that premorbid, or prior to developing insomnia, sleep reactivity is a predisposing factor for the future development of chronic insomnia, and this may be from any cause, not just primary insomnia. One of the things we developed was a tool to be able to measure what we believe is an aspect of sleep reactivity. So we ask individuals to report when they experience the following stressful situations, how likely is it for you to have difficulties sleeping? We've termed this test, the Ford Insomnia Response to Stress Test, or the FIRST. And it asks questions such as sleep disturbance occurs before an important meeting the next day. After a stressful experience in the evening, or during the day time. After watching a frightening TV show or after an argument. Before having to speak in public, or before going on vacation the next day. There are certainly positive stressors that can produce sleep disturbance in some vulnerable individuals. And the first thing that we demonstrated was indeed what we have expected was that insomnia do, in fact, have a greater degree of stress related reactivity. Their scores on this FIRST measure are elevated relative to controls. We also wanted to bring these individuals, prior to developing insomnia, into the laboratory for a number of different stressors. The FIRST study looked at habitual sleep in high and low first groups assessed by a two week sleep diary. And as I mentioned, these are not insomniacs in this particular study. Individuals who scored low on the Ford Insomnia Response to Stress Test or sleep reactivity measure actually had sleep within the normal range on sleep efficiency. So the amount of sleep for a given amount of time in bed was really identical to the individuals who scored high on the FIRST. We can see there are no significant differences between the low FIRST group, or low sleep reactivity group, and high sleep reactivity group in terms of their habitual sleep on a diary. They are not insomniacs in terms of sleep efficiency nor are they insomniacs in terms of the amount of time it takes them to fall asleep. Both groups are falling asleep within about 15 to 25 minutes, both the high FIRST group and the low FIRST group. But when we bring them into the laboratory, and as you might imagine, a sleep laboratory can be an extremely stressful place to sleep. What we see, the individuals who reported sleep reactivity, but slept fine habitually, actually had sleep efficiencies that were very, very low. And, in fact, consistent with what one would expect to see in a population of people with insomnia. Whereas, the low FIRST individuals continued to have relatively normal sleep. They were not reactive to this stressor of sleeping in the laboratory in terms of sleep efficiency, but also in terms of the amount of time it takes to fall asleep. High FIRST individuals taking about 25 minutes to fall asleep, whereas, low FIRST individuals taking closer to 10 minutes to fall asleep during this polysomnographic assessment of a sleep laboratory night. What was very interesting to us was that we find the following day, individuals who had high sleep reactivity despite having critically disturbed sleep the night before in terms of very low sleep efficiency and a bit of a longer latency to sleep. They actually had elevations in arousal as measured by the MSLT. So these individuals actually had greater levels of alertness than low FIRST individuals despite having sleep disturbance the prior night. So again, this is somewhat similar to what we see in insomniacs in terms of hyperarousal despite sleep disturbance. So we also looked at other challenges. One of the common sleep disruptive challenges that you could administer is to have individuals consume caffeine prior to bedtime. And in this particular study, we took individuals with low FIRST scores, or low sleep reactivity, and compared them to high FIRST individuals, or individuals with high sleep reactivity. In response to a three milligrams per kilogram dose of caffeine approximately one hour prior to bed time. And what we see is the low reactivity in individuals did not have much of a response to this relatively low dose of caffeine. But individuals with high FIRST, the high reactivity individuals, had significant sleep disruption in terms of taking about 60 to 70 minutes to fall asleep following caffeine administration relative to no caffeine. Very importantly, what we have established is that there is a vulnerability to acute sleep disturbance that can occur. The acute sleep disturbance being caffeine or sleeping for a night in a sleep laboratory. But I have not yet shown you data to link this type of vulnerability to a potential vulnerability to chronic insomnia over the long-term. So, what are these lengths? And how are they being pursued at the present time? Well, we've just published the study looking at incident insomnia as a function of cognitive intrusion at various levels of sleep reactivity. So, this is an interaction. What I'm about to show you is data from a prospective study done across two years. And it shows that the level of cognitive intrusion that occurs or this cognitive reaction to stressful events is actually elevated and related to an increased probability of developing insomnia across the two year study. But very importantly, individuals who scored higher on the FIRST scale, on the sleep reactivity scale, at a given level of cognitive intrusion, have a much greater probability for developing insomnia in response to that stressor. So this is one of the FIRST prospective studies which has shown a relationship between sleep reactivity and the risk for developing insomnia in response to what we know are exposures to stressful life events that can occur in any individual. What we have shown also is that sleep reactivity acts to increase the risk for depression through its mediation by insomnia. So sleep reactivity is actually an increased risk factor for depression in individuals who develop insomnia from having high sleep reactivity. This mediated effect is a very important effect that we are looking at further in terms of looking at potential underlying pathophysiological mechanisms, which may be common to both insomnia and depression that has to do with an individual's sleep reactivity to stress. We also have looked at data showing that sleep reactivity has a genetic inheritability. In fact, twin studies show that approximately 29% and 43% in females and males respectively of the FIRST scale have a genetic heritability. And so this variance overlapping genetic variance between insomnia and FIRST scores of about 0.54 in females and 0.64 in males. It's very interesting and suggests there may be some heritability of sleep reactivity that we may be able to look for particular genes, which may identify individuals at risk for developing insomnia. And we also show a similar finding in terms of siblings, so there is a familial aggregation where siblings have a high correlation in terms of FIRST course of about 0.61. The big question at the present time in insomnia are, which genes are responsible? And it's unlikely that there is a particular gene, which is specifically associated with an increased risk for insomnia. But there probably are many, many genes, which increase our risk for developing insomnia overtime. These may be, in fact, related to sleep reactivity, some more than others, but there may be genes which relate to other predisposing factors as well. One very recent study, which is a preliminary abstract presented in 2011 suggests there is a relationship between the serotonin transporter polymorphism and sleep reactivity. This certainly is something which needs to be replicated and followed up in future studies in terms of identifying potential underlying specific genetic factors, which predispose individuals to developing insomnia. So in conclusion, we know that, insomnia is a disorder involving nocturnal sleep disturbance. But it is also a disorder, which involves both physiological and cognitive factors. And very importantly, not just nocturnal insomnia symptoms, but also daytime impairments that can lead to very debilitating morbidity in terms of quality of life, accidents, and absenteeism. The cause of insomnia likely involves multiple factors, when we think of the three P model, they're predisposing factors. One of those being sleep-reactivity. Precipitants or broad stressors, which can include both physiological stressors such as medical conditions, but also psycho-social factors such as divorce or loss of a loved one. And perpetuating factors, for example, inappropriate sleep hygiene or behaviors that may actually lead to perpetuating insomnia over many, many, many years. Finally, it is now clear that sleep reactivity is one of the predisposing factors to insomnia. This trait can be quantified, and the trait of sleep reactivity is directly linked to the prospective risk for chronic insomnia. It is a genetic trait, and potentially the serotonin transporter may be involved at some level. I thank you very much for the opportunity to present both the broad area of insomnia and some of the research that I and my colleagues at Henry Ford Hospital have done. Good day.