2014-02-12-Non-24 Hour Disorder
Seminars@Hadley
Non-24 Hour Disorder: From the Lab to Real Life
Presented by
Dewey McLinn III, Ph.D. – Director, Medical Science Liaisons, Vanda Pharmaceuticals
Moderated by
Larry Muffett
February 12, 2014
Larry Muffett
Welcome to Seminars at Hadley. My name is Larry Muffett. I’m a member of Hadley Seminars team, and I also work in Curricular Affairs here at the school. Today’s seminar topic is Non-24 Hour Disorder: From the Lab to Real Life. Our presenters today are Dewey McLinn III, Ph.D. – Director, Medical Science Liaisons, Vanda Pharmaceuticals, and also joining us today will be Neal Freeling, who lives with this disorder. Today, Dewey and Neal will be sharing their insights with you on all aspects of Non-24 and its impacts on daily life. So now, without any further ado, let me welcome Dewey and Neal and turn the microphone over to them to get us started. So, gentlemen – welcome.
Dewey McLinn
Larry, thank you very much, and good afternoon to everyone. I hope that everyone in the east is warm and safe especially those folks that aren’t really used to this kind of weather in your neighborhoods. So, as Larry said, my name is Dewey McLinn and I’m a neuroscientist and I’ve spent much of my career studying neurobiology and behavior, and I now work for the Medical Affairs group at Vanda Pharmaceuticals.
In the interest of full disclosure, I want to say up front that the company I work for has developed a treatment for one of the disorders I’m going to be talking about today, however, what I really want to focus on today is understanding the biology of the disorder itself. So, of course, the topic of the day is non-24 hour sleep wake disorder, or what we call non-24 for short.
And I’d like to really cover this in sort of three sections today. The first thing I want to do is give an overview of the body’s timing system, or circadian rhythm system and various disorders that can affect it. After that then we’ll look more closely at one of these disorders in particular that frequently occurs in people who are blind which is non-24 and finally we are incredibly fortunate to day to be joined by my friend Neal who is also working with Vanda and is really, you know, he’s generously going to share with us some of his own personal experiences with non-24. So I’m looking forward to that.
So we are going to start today by just really thanking Hadley for the opportunity to be part of this seminar and all of you for joining and for your interest in participating. It looks like there’s forty-seven people on right now. It’s really a great turnout and I appreciate it and I’m looking forward to the discussion and questions today.
I’m not going to spend really much time talking about how crucially important sleep is for our mental and physical wellbeing because I think, you know, we all have personal experience that really gives us insight and there’s been extensive medical literature and research that supports our personal experience of how important sleep is. Instead I really want to just jump right in to understanding how sleep and other daily patterns are regulated by the body.
So in order to really understand how sleep cycles are regulated we first have to understand what a circadian rhythm is. And circadian rhythm is really just, it’s roughly a 24-hour cycle and it’s a cycle in a biological or behavioral process and they happen in plants and animals. The word circadian actually comes from two Latin words. Circa, which means “about” and dias which means “day.” So, really circadian is the twenty-dollar word, it’s a fancy way of saying “about a day.”
We, as a community, really now have a surprising detailed understanding of how these rhythms work on a biological level and there’s a long history of understanding these and research that got us to this point where we are today. The first observations of circadian rhythms surprisingly actually happened in plants, thousands of years ago. The very first people to notice this were, that certain plants, for examples, their flowers, will open and close at the same time every day, so sort of a cycle of opening and closing in this plant behavior. And you know, an unreasonable person could say, well, yeah, that plant’s opening up because the light’s shining on it, right?
So it’s just that that behavior is just some response to the light. Makes sense. But, in the 1700s scientists had an insight and they realized that’s not always the case. If you take a plant and put it in a room that has constant low level of light so there’s no changing light signal across the day, that behavior still exists. That cycle of the plant, opening closing, opening closing, opening closing, still goes on at about twenty-four hours. And then that’s really, a key breakthrough in understanding this. That this kind of behavior isn’t a response to light, but it was really being driven by an internal, biological clock within the plant. The plant has its own timekeeper.
So then over the next few hundred years, you know, we found similar cycles and rhythms that were seen in animals as well and then if we fast forward to the first half of the 1900s we really started making some huge advances. Groups in the US and France have primarily found that if you do the same thing to humans, that the earlier scientists had done to plants, you get the same results. So if you take someone and you put them in an environment without light cues, like a bunker or a cave, they keep showing behaviors in the cycle and that cycle’s around twenty-four hours.
It’s important, though, that it turns out the cycle that these people have is not exactly twenty-four hours, but in most cases it’s actually slightly longer than twenty-four hours.
So then we fast forward a little more to the late 1900s and then we see we advance the field even farther because people are able to show definitively that it really is the light that’s the most powerful cue in shifting these circadian rhythms a little earlier or a little later to reset this circadian clock. So, even though the natural rhythm, as I mentioned, is slightly longer than twenty-four hours, they can adjust it, or synchronize to the environment by daylight.
Since then, you know, we really have learned even more at an accelerated pace and the last ten years in particular have been very exciting. We found new, you know, pathways, unique kinds of cells that are responsible for this behavior and now we even, believe it or not, understand many of the genes that are responsible for running these internal clocks. So, it’s an exciting time to be studying this kind of thing.
You know, we may ask then, so, where is this clock in a human? And we know that this circadian clock is in a brain region called the hypothalamus. And it’s called the suprachiasmatic nuclear or the SCN, so I’ll just call it the SCN for short. And this SCN is an incredibly small area on the brain. It’s actually only about 20,000 neurons. And we call this area the master body clock because it really controls the internal circadian rhythms that influence the timing of most biological processes in the body. You know, most people are aware and it’s obvious to us that the sleep wake cycle is circadian. We tend to sleep about seven or eight hours a day and that happens once a day and it happens at about the same time.
What most people who don’t study this don’t realize is that, you know, really almost every tissue and organ behavior has some daily cycles. We look at peoples’ mood, at hormone levels like melatonin and cortisol. You can look at peoples’ respiration rate, you can look at someone’s heart rate, what their body temperature is. How they prepare to digest food, their insulin levels, glucose metabolism, even behaviors like alertness and reaction time and you test peoples’ memory and all of these things have the consistent and measurable peak and valley on each day.
So, I mentioned before that you know, the circadian clock runs a little longer than twenty-four hours and then each day light input is detected, actually by special cells in the retina. And those communicate to the SCN, the master body clock, and that light input just provides a small adjustment each day that keeps the clock aligned with the day/night cycle. So, this master body clock then triggers signals throughout the body and all of those other systems that I just mentioned and really synchronizes all of these local clocks throughout the rest of the body to keep everything in line with the typical twenty-four hour day.
So, we know this is the case, as I mentioned before, because you observe someone walking around the normal day. We know that we tend to sleep one eight-hour chunk and then be awake for a long, you know, sixteen-hour chunk and then when we put people in caves or bunkers, you know, we see that they lose that light cue and what happens is they still have about eight hours of consolidated sleep, but the day stretches out a little and extends to about 24.3 hours whenever you remove the light cues.
And this really shows that the intrinsic, natural timing of the cycle is slightly longer than twenty-four hours. And when you take that person and put them back into an environment that has light, then the sleep/wake cycle synchronizes again to the typical, you know, day/night cycle that people try to be aligned to.
The important thing here is to go back to an earlier point is, that I’m using sleep/wake as an example in this case, but it’s also true for the other biological measures that we talked about for circadian rhythms. So if you measure when this person’s, you know, body temperature, this person that has 24.3 hours of a sleep/wake cycle, do you measure their body temperature or their melatonin peak or their cortisol peak or any of these other circadian biological rhythms in that situation, those will also be 24. 3 hours, right, all these things tend to move together.
So, you know, when we know light exposure is needed to synchronize the circadian rhythms, then we can thinking about how these processes can get disrupted, now that we understand how they work. And, generally, this gets disrupted when the two rhythms, the biological and the day/night rhythms become dis-synchronized with each other. We usually kind of put these into two different categories. One is extrinsic disorders, so these are disorders that are caused by something outside of the body and intrinsic disorders, or disorders that are caused by some change within the body, right?
So we’ll talk about extrinsic disorders first. And really, the most common of these two that we think about that everyone’s familiar with, are jet lag and shift work sleep disorder. And we can look at jet lag as an example. So, you know, in someone that has jet lag, their body is correctly trying to maintain the normal twenty-four hour circadian rhythm but then what happens? Well, then they get on an airplane and they go and make the day nineteen hours long. So, now the [natural] sleep and wake cycles, they’re not aligned any longer. And this is not because there’s something wrong with the biology, it’s because of something the person did, right, they shortened the day artificially by flying.
It’s disruptive to people that have jet lag. Many of you have probably experienced it. You know how bad it is. Tend to be awake all night, fall asleep, maybe in public during the day. It’s inconvenient, but, you know, it resolves after a few days. The body eventually uses light and the other time cues available and those are all working properly so it synchronizes back to a new twenty-four hour day.
So that’s the extrinsic disorders. Then se think about the intrinsic disorders and these occur the other way around, right. So this is when there’s something wrong with the circadian system itself. And it can happen in a number of different ways. One example is what we called delayed sleep based disorder. And so this is particularly common in adolescents so if you’ve been around adolescents at all you are familiar with this. Person with delayed sleep based, has a twenty-four hour circadian rhythm. But it happens at an hour in the day that’s later than is desirable. So they have a regular twenty-four hour clock, but it’s shifted so that everything happens a few hours later than typical, so maybe instead of wanting to go to sleep at 10:00 p.m. and wake up at 6:00 a.m., they may want to sleep at 2:00 a.m. and wake up at 10:00 a.m. That’s an example of intrinsic disorder.
And the other one that we’re going to be talking about more, of course, is non-24 hours disorder, when there’s a loss of transmission on these light/dark signals to the brain that are necessary to entrain or to synchronize the circadian rhythm.
So, as we go into that, I just want to address one question which is why does it matter if someone had a circadian rhythm disorder? Or if these rhythms aren’t aligned with the day/night cycle. You know, we focus on talking about sleep, and we focus on that for a few reasons. We know that sleep is important to how we feel and we know that chronic loss of sleep can lead to other health issues as well. And as individuals, you know, we’re also very aware when our sleep gets disrupted. We can all relate to it, we all notice it. For example, we talked about jet lag. We all know how terrible we feel when we have jet lag for a few days.
But, remember, that nearly every body system that we talked about has these daily rhythms. And all of those are potentially affected by chronic circadian disruption. In fact, for these various circadian disorders, along with sleep loss, it’s been documented that they can lead to increased gastrointestinal disorders, including ulcers. They’ve been associated with higher risks of obesity, and Type II Diabetes. Menstrual/reproductive irregularities, things like increased risk of cardiovascular disease and that includes, you know, hyper tension or high blood pressure. And that even an increased risk of certain cancers. I was surprised when I first started looking at circadian rhythms that the World Health Organization actually lists shift work as a possible carcinogen. So, these are, you know, disorders that are serious and need to be taken seriously and thought about.
So I think I’m going to pause here for a moment before we go into talking about non-24 specifically and ask Larry if there are any questions that I should address now or we’ll move to talking about non-24.
Larry Muffett
Well, we can turn loose of the microphone here and see if there’s some questions. There’s not a lot in the text box right now, but we’ll release the microphone and if you have a questions this is a quick opportunity to jump in. Otherwise we’re going to go ahead and start the next section.
XXX
Yeah. I have a question. A lot of times when I’m on my computer I can get really involved with something and especially if it’s a problem and it takes a long time for me to fix, then after I get off the computer, like, and then I go to bed, it take, I get some sleep eventually, but it takes a long time for me to wind down so that I can get the proper sleep. And I’m wondering is this part of non-24?
Dewey McLinn
That’s an interesting comment, you know, so, I’m talking a lot about light and the effects of light on sleep today. And light is the most powerful input that can affect this clock. But there are other things that also affect it, and social interactions certainly can affect it. Your, how your body treats food and prepares for eating is affected by this, but also vice versa. Having meals or having exercise late at night or irregular times of the day or social interactions like that certainly can affect sleep as well.
XXX
I would like to ask about sleep disorder and Alzheimer’s. I have observed and I was talking with the activity director in the retirement facility in which I live about some of this very thing and she was interested to know if there was, what, the Alzheimer’s patient goes through, especially we’ve noticed in our facility that they tend to roam a lot at night. They’re up and they’re walking and, you know, going here and there. Whereas in the daytime they want to sleep. And I’m wondering if you can talk about this, how this all works.
Dewey McLinn
Yeah. Thanks for the question. It’s an incredibly challenging problem with Alzheimer’s disease. You often refer to it as sun downing, this tendency for patients with dementia to become very active in the evenings and there are some evidence that they have circadian disruption, not non-24, but other kinds of circadian disruption that may be comorbid with dementia and it’s – I don’t think the mechanisms underlying it are well understood. But it’s definitely well-recognized that its’ common in patients with dementia to have this effect of becoming very, very active in the evenings and it’s of course challenging for caregivers and for people working in care facilities.