Novel Light Intervention to Fight Social Jet Lag in Teens. Podcast with Dr. Jamie Zeitzer

Over the past few decades, sleep duration appears to have been declining for most people living in industrialized countries. But one group for whom this is particularly evident is teenagers. Nearly half of adolescents in the US report insufficient sleep, and suffer from daytime sleepiness on school days. One study of middle school and high-school students found that a whopping 80% slept fewer than 8 hours on school nights, and 33% of the students reported falling asleep in class.

This is not as trivial as it may seem. Teenagers who don’t get enough sleep have poorer academic performance, are more likely to develop psychological problems like depression, are at higher risk of medical issues like obesity and diabetes, and are more likely to be involved in car accidents. The long term implications of insufficient sleep with respect to health, education, and achievement early in life should not be underestimated.

So why is this such a pervasive problem?

One factor that is thought to contribute to this is activity later in the evening – particularly interacting with electronic devices with screens that emit blue light. Technology use around bedtime is highly prevalent, and this is especially true for younger people. More than 90% of adolescents are staring into a glowing screen before bed (and let’s be honest, plenty of adults are doing the exact same thing).

This, of course, means that teenagers wind up staying up late, but are then forced to get up early due to forced school start times. So, an unfortunate confluence of biological, social, and behavioral factors produces an inevitable sleep deficit.

In that case, why not get the teens to go to bed earlier? Well, research has shown that simply educating teens on the merits of getting to sleep sooner is not especially successful. This is likely, in part, because adolescents (as well as some adults) are subject to a natural delay in the timing of their circadian clock.

Behavioral therapy alone is simply not enough to overcome a biological drive to stay awake later and wake up later. We have to find a way to shift that circadian timing earlier.

And that brings me to our guest.

In this episode of humanOS Radio, we welcome Dr. Jamie Zeitzer back to the show. Jamie is an Assistant Professor in the Department of Psychiatry and Behavioral Sciences at Stanford University, as well as at the VA Aging Clinical Research Center at Stanford. He has over 50 publications related to sleep and circadian biology, and he was Dan’s primary mentor at Stanford in his own research.

In our previous interview, we discussed his research on light and timing of biological rhythms. He and his colleagues determined that brief, intermittent flashes of light have a much bigger impact on clock timing than continuous light exposure. This has interesting implications for shift workers, as well as for people who travel across multiple time zones and are subject to jet lag. In theory, you could expose yourself to brief flashes of light while you are asleep and effectively trick your brain into adjusting to a new time zone. Pretty cool.

But could it also be useful for social jet lag – meaning a chronic misalignment between the biological clock and the time when one is forced to be awake and active? In particular, could it be effective for teenagers who have to get up to go to school at a time when their body is driving them to sleep?

To answer that question, Jamie and colleagues conducted a two-phase, randomized controlled clinical trial testing how exposure to brief flashes of light affected sleep onset and total sleep duration in high school students. Here’s what they did:The researchers recruited groups of teenagers who had expressed difficulty going to bed and waking up early. In phase 1 of the trial, 72 participants were randomly assigned to two groups. One group received 4 weeks of light therapy, delivered from a device in the teens’ bedrooms (3-millisecond light flashes every 20 seconds during the final 3 hours of sleep). The other group was administered 4 weeks of sham light therapy (three bright flashes of light per hour, which isn’t enough to affect the body clock) as a placebo. This protocol was largely ineffective – neither sleep timing nor duration were significantly altered in the experimental group.

Zeitzer and his team switched things up a bit for the next phase. In phase 2, the subjects received a slightly different light therapy (3-millisecond light flash every 20 seconds during the final 2 hours of sleep). But in addition, the researchers had the adolescents attend four cognitive-behavioral therapy sessions to try to motivate them to go to bed earlier. Happily, this combination of interventions actually worked! The light therapy plus CBT moved sleep onset 50 minutes earlier, and increased nightly sleep time by an average of 43 minutes. Very impressive.

To learn more about the study and what it means, check out the interview.

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Jamie Zeitzer - 00:00: So just giving them the light, it worked like it intended on the biology, but just changing the biology alone is insufficient to change the behavior of interest.

Dan Pardi - 00:10: Average nightly sleep duration has been declining in multiple demographics over the past couple of decades. One group for whom this trend is particularly evident is teenagers. Nearly half of adolescents in the US report insufficient sleep and suffer from daytime sleepiness on school days. Once study of middle-aged school and high school students found that 80% slept fewer than eight hours on school nights, and 33% of the students reported falling asleep during school. This has obvious implications for academic performance as well as health.

00:37: So why is this such a big problem? One obvious factor contributing to this is activity leader in the evening, particularly the use of electronic devices with screens that emit blue light. We all know how patterns of light exposure can influence the timing of our biological rhythms, so people, not just teenagers, wind up staying up late, but are then forced to get up early due to school and work start times. This produces a sleep deficit. But just educating teens on the merits of going to bed earlier hasn't been shown to be especially successful. This is likely in part because adolescents are subject to a normal delay in the timing of their circadian clock.

01:09: Behavioral therapy alone, may not be enough to overcome the biological drive to stay awake later and wake up later. We have to find a way to shift the circadian timing earlier in teenagers. That is why I'm pleased to welcome Dr. Jamie Zeitzer back to the show. Jamie is an assistant professor in the Department of Psychiatry and Behavioral Sciences at Stanford University as well as the veteran affairs aging clinical research center at Stanford. He has over 50 publications related to sleep and circadian biology and was my primary mentor at Stanford in my own research.

01:39: In our previous interview, we discussed his research on light and timing of biological rhythms. He and his colleague determined that brief intermittent flashes of light have a much bigger impact on clock timing than continuous light exposure. This has interesting implications for shift workers and for people who travel across multiple time zones and are subject to jet lag. But could it also be useful for social jet lag, meaning a chronic misalignment between the biological clock and the timing of when one is forced to be awake and active. To that end, Jamie and colleagues conducted a two phase randomized controlled trial testing how exposures to brief flashes of light along with cognitive behavioral therapy affects sleep onset and total sleep duration in ninth through 12th graders.

02:21: Jamie, welcome back to HumanOS Radio.

Jamie Zeitzer - 02:23: Thanks so much, Dan. It's good to be [inaudible 00:02:25] Dr. Dan now.

Dan Pardi - 02:26: Thank you for your L there. So, I'm really interested in this technology. It has the potential to be incredibly practical in helping a variety of different populations. Let's talk about the light flash technology again. Why would flashes of light be more impactful than continuous light? Meaning having a light on continuously in the room, and then when would you want to expose these individuals to that light? Is it just any time during the day or is it certain times of night?

Jamie Zeitzer - 02:50: The light flashes worked better than the continuous light for a couple of reasons. The first is why did the light flashes work at all? And that's because the cells that transmit light information from the retina to circadian clock have a really weird physiology, which is that when you turn the light on, they start fire, and when you turn the light off, they continue to fire. Which is strange. I mean, if you think about it, when you turn the light off in terms of your conscious perception of light, the light's no longer there. It's not like the light's still there, it's off. But these cells respond as if the light were still there.

03:21: So if you give a flash of light and you space them correctly to these scagliola cells that are projecting from the retina, it looks like continuous light to them. So in terms of continuous versus flash, that means that if, for example, we give 10 or 20 seconds in between the flashes, that's 10 or 20 seconds of darkness during which you'll have sensitization of the cells. So they'll basically be more responsive to the light. So if you're giving continuous bright light, most of that effect of the light in terms of circadian timing happens within the first couple of minutes, and there's greatly diminishing returns after that.

03:53: There've been a number of studies that looked at that. So this is kind of an extreme example of this, which is basically saying, well, okay, let's just put all the information, all the light information in the very beginning and separate it out by periods of darkness. It has a definite advantage even if you look beyond the fact that it's more effective. It's got a big advantage in that you can apply it at times when continuous light would say be not called for, like during sleep. During sleep, light still gets through the eyelids, about 10% of light gets through the eyelids depending on the wavelength.

04:23: Blue light, around 4% of that gets through, and around 12% or so of red light gets through. And you're still responsive to light, but if you were in continuous light, that would wake you up. Also, even if it didn't wake you up when you spontaneously awake, and this happens multiple times at night, if there was a big bright light on continuously, that would be kind of annoying when you woke up into that kind of brightness. So by giving these intermittent flashes, it can activate the system in the brain without this awakening response.

04:50: We've shown this at least in the laboratory and in the field that sometimes people see it on the first night, but usually after that they get used to it and they no longer respond to the light.

Dan Pardi - 04:58: That was always one of my big questions with this, would the light flashes disturb your sleep? But because you're mostly living in darkness, while the light flashes are in the background, you can sleep through that better than you would if the light was simply on.

Jamie Zeitzer - 05:11: There are definitely going to be some people that are going to wake up and it's not going to work. There's definitely people out there who are real sensitive to light, any kind of light that comes in, these are people who are often sleeping with light blocking masks on because any kind of light coming in the room is disruptive to their sleep. These individuals unfortunately just wouldn't work.

Dan Pardi - 05:28: I see. Does the person's individual arousal threshold seem to matter here? You can imagine they could sleep through some of it, but at some point it would cause an arousal and they would have a harder time going back to sleep.

Jamie Zeitzer - 05:38: That's why we're testing how little light do we actually need. So that's some of the stuff that's going in the lab right now is saying, well, instead of giving two hours of light, how about five minutes? How much can we get out of that?

Dan Pardi - 05:49: That is a question that I want to talk more about in depth here in a minute. So to summarize, not only do you have a higher proportion of people that can sleep through the flashes, but it is also more effective than continuous light. So how long did the neurons continue to fire after, was it a three millisecond pulse of light?

Jamie Zeitzer - 06:06: Sure. So, that actually hasn't been tested. What has been tested are longer pulses of light. And there, you can have firing for several minutes.

Dan Pardi - 06:14: Okay, wow.

Jamie Zeitzer - 06:15: So what we had showed previously was that in terms of optimizing between flashes, around nine seconds seems to be optimal. But if you go faster than that, it approaches what you would get out of continuous light, and if you go slower than that and you have diminishing returns, so you get less impact. Around nine seconds in between flashes seems to be optimal.

Dan Pardi - 06:35: I can imagine a product in the future that might be able to tune the strength of the intervention in terms of time of exposure, distance between pulses to somebody's own sensitivity where you could potentially find something that worked really well for you. If you're somebody who can sleep through this then here's the most intense intervention and that's going to cause the greatest shifting. Can you do better in a less intense intervention if you happen to be more sensitive? So, that will be something that you're looking into.

Jamie Zeitzer - 06:58: Yes. That's exactly right.

Dan Pardi - 06:58: Okay. All right, great. So let's talk about this population then, and some of their characteristics of teenagers. Talk to us a little bit about how teenagers want to go to bed later. Is this just because they're misbehaving?

Jamie Zeitzer - 07:10: Yes, of course it is. Teens have kind of two things that are working against them. One is that there's this natural latening during puberty of the biological timing system. The whole thing shifts to a later time. We don't know why it happens, but it happens, and so basically from a biological perspective, they want to go to sleep later and wake up later. Then you couple this with increased social freedoms, and at least in the studies that we've done, we have tried to explore why they're staying up. Is it that they have poor time management skills? Or is it that they're just staying up playing video games or they've got too much homework? What's the driving force, at least from their perspective.

07:47: We found that really varied among teenagers. Different teens had different reasons. The underlying thing really seem to be that this was the time at which they were the adults. The nighttime, their parents were either asleep or no longer parenting. They were in a different part of the house and so the teens really had much more control over their time and their lives, and it's important to them. They're learning about being an adult and kind of how to manage this time. And so they're very reluctant to give that up. And so you have all of these things working and then when they're up, they're usually doing things that are involving light exposure, either through electronics or just having a room light on, which is also driving the system for a later time.

08:27: Many of the things that they're doing, especially if they're using electronic devices, have been gamified to keep them up. I mean, Reid Hastings, the CEO of Netflix once said, and I think this is probably different now, but a few years ago, this is true. He said that his biggest competitor was sleep, and this is true. I think all of these things are working against them and then you have early start times. In California they just passed a law, actually a statewide law, which pushed back school start times for high school students and I hope that's going to help. I don't think it's a solution in terms of solving all of the problems, but I do think that it should help.

Dan Pardi - 09:00: Right. I can even add in a third variable there. So you have a buy a biological driver, possibly. You've got the fact that then kids have some autonomy in that time to where a lot of their work responsibilities might be taken care of, like homework, and then they're not under the direct influence of their parents who might be asleep, so then they have the chance to select some activities that they're interested in. You have technology that in and of itself is going to engage you, auto play of the next show or some sort of game. The third factor is that if all of your friends are up, you have some pretty serious FOMO, and it's extremely easy to reach out to anybody in your network now through one of many different apps that will involve you in the conversation that's happening.

09:38: That in itself would be a driver, even if their biological sleepiness was pushing you to go to sleep. It'd be hard to miss out on what's happening with your social circle.

Jamie Zeitzer - 09:46: Yeah, that's something that we've seen. We did a study several years ago, actually a high school student did this study with me and she was looking at what was disruptive to sleep in terms of phone utilization. The biggest factor was feeling that you had to be available 24 hours a day. They were waking up in the middle of the night checking their phones multiple times, and they'd wake up and they'd be anxious and they'd stay awake. And really this, more than staying awake late, drove bad sleep, at least from the student's perspective.

Dan Pardi - 10:13: For that age, being social is really one of the primary motivators in your life. That's a tough one.

Jamie Zeitzer - 10:18: I agree.

Dan Pardi - 10:18: 24 hour access.

Jamie Zeitzer - 10:20: I don't know how they do it.

Dan Pardi - 10:21: So you have now a scenario where social and environmental pressures, with some biological drivers create a condition that then lead to sleep loss. Because of the early wake times for school, they can't just sleep in until their biology would dictate. They're missing out on sleep, they have to get up early. What does the National Sleep Foundation recommend as a goal for amount of time that a teenager should be getting sleep? How much time in bed?

Jamie Zeitzer - 10:45: It's eight to nine hours, probably a little more.

Dan Pardi - 10:49: So, if that's what their biology needs to help continue the brain development and also for physical growth, and now they're only getting six hours of sleep opportunity or less, that's going to lead predictably to some poor performance outcomes. Then all sorts of issues. So the goal here is from your study, is there a way to reliably and effectively increase sleep time with your technology?

Jamie Zeitzer - 11:11: Can we basically reduce the biological barriers that are preventing them from going to sleep earlier, to create an environment that would at least be permissive for earlier sleep?

Dan Pardi - 11:21: So the technology would be shifting the window that the teenager would feel sleepiness, they would feel more alert earlier and they would feel sleepier earlier.

Jamie Zeitzer - 11:30: Exactly.

Dan Pardi - 11:32: Tell us about the study. What did it involve and how many people did you have involved?

Jamie Zeitzer - 11:36: The study as we originally designed it, we were going to look at 100 teens, half were going to get light, half were going to get nothing. My background is in physiology and I come from this kind of perspective and it was a very humbling experiment because it was a complete failure. We gave all these teens light, we spent a lot of effort and time and it didn't change your thing. All we did was we pissed them off. Because what happened was we shifted their biological clock earlier so they got tired earlier, but they didn't go to sleep earlier. So just giving them the light, it worked like it intended on the biology, but just changing the biology alone is insufficient to change the behavior of interest.

12:17: They were acting against their own interest in staying awake while they were tired, but that's what they were doing. We redid the experiment and included cognitive behavioral therapy that [Kit Kaplan 00:00:12:31], a really talented postdoc of mine at the time, designed. It mainly focused on some sleep hygiene issues, but the main thing was on motivational interviewing. Finding what the teens found important and showing how getting some extra sleep could benefit them. If athletics are performance, here's why sleep is good for that, or academics or friends, whatever it is.

12:49: How does sleep relate to that so that they would generate their own desire to go to sleep earlier. When we did that without light, they were able to get extra few minutes of sleep per night, but it didn't really help that much. About 10 minutes of extra sleep per night, that was nice, but that really didn't help just doing that alone. When we combined that with the light therapy, then we were getting 45 minutes of extra sleep per night. That to me was an actual amount of sleep that could make a difference.

Dan Pardi -13:15: This is so much of what HumanOS is trying to do. If you just simply hand effective technology to people that don't quite understand why they should be using it, the chances of it being successful are low. But if you compare that with self-generated understanding and personalized goals around the benefits of utilizing that technology, then you're fueling the desire to use it and achieve those benefits. It's goal attainment versus call [inaudible 00:00:13:38].

Jamie Zeitzer - 13:39: Right. No, I agree. In terms of behavioral medicine, this is an absolutely crucial thing. In the ideal situation you provide through device or therapy, some sort of permissive environment for them to be successful, but they have to do it. And how do you motivate them, how do you generate that? And I find that to be incredibly important, that component.

Dan Pardi - 13:59: That's a pretty impressive amount of additional sleep. How many people did you have participating in this second study where there was the light flashes plus the CBT?

Jamie Zeitzer - 14:08: That one was smaller. It was a little grant and that one was about 25 people.

Dan Pardi - 14:12: Is there a followup larger study that you would like to conduct?

Jamie Zeitzer - 14:16: We have an application in right now to the NIH to see if they're interested in funding it. The followup is, there's two things. One is, will people do this for a long time? We did this over the span of several weeks, but how about months? If we set this up in September in high school students, will they still be doing this in June? I'm encouraged because of the passive nature of the therapy is that to deliver the light, we used modified bridge beacons. The light that you see on the side of bridges, we had a company in England that modified it to our specifications in terms of the frequency and we just put it in their room, put it on a timer. And so every night it goes off and they don't do anything, which I think is critical for something which is basically going to have to be on every night until they're able to go to college and have later classes.

15:06: That kind of passive nature is critical, because if you take the light away, they'll revert back to their old time. So the question is are they going to do this? Are they going to keep doing this and maintain this kind of later sleep schedule over the course of months as opposed to weeks?

15:20: Second part that we want to know is, so we can improve sleep. What are the longtime behavioral sequelae of this? Do we improve academic performance? Do we change mood? These are two of the critically linked day time sequelae of sleep, especially depression and anxiety in teenagers, also, maybe some risk taking behavior. These are things that we want to see if we change over the long term. Do we see improvements in these?

15:45: When we look at depression, I have to say in these students... Now, we didn't diagnose them with depression. These were validated questionnaires looking at how severe their depressive symptoms were. Around two thirds of them were in significantly clinically depressed range. I feel for these students. They're sleep deprived, they're depressed, they're under a lot of pressure, so it's tough. We get students from a whole bunch of different schools from up and down the peninsula and it seemed to really cut across probably for different reasons, but these problems seem to cut across a variety of sociodemographic variables.

Dan Pardi - 16:18: High achievement in teenage kids is now its own risk factor for things like depression, pressure that you feel, that every test take and every moment of your life, there's no chance of failure or you're going to basically fall out of the pool of people who are attractive for the university that you want to get into. That is a lot of pressure for a young person.

Jamie Zeitzer - 16:36: I think so.

Dan Pardi - 16:37: So, if you can imagine that now creating another condition to drive a young student to curtail their sleep and not attend to their biology, which is a losing longterm strategy, but you can see how the pressures exist for that behavior.

Jamie Zeitzer - 16:49: Yes, definitely. We have an ongoing collaboration with a group in Taiwan who are interested in looking at this, and there you have tremendous pressure to succeed. The students there get even less sleep than they do here. Unlike in the US actually, the parents are less concerned about the lack of sleep. Afterschool, they go to cram school and they're not getting home until 9:00 at night. It's not because they're hanging out with friends.

Dan Pardi - 17:13: I remember when David [Dinn 00:17:14] just came and spoke with the Stanford grand rounds that you organized, he made the comment that one of the first things to go when you extend work times and commute times is sleep and so however frivolous it might seem that somebody is watching, let's say an episode of some show that they like, people will create time for their personal interests, and if their personal time is curtailed significantly, then what ends up suffering is sleep. Teenagers still need a life and autonomy too so if it's literally every waking moment of their day practically is filled with some sort of achievement objective, they still are going to want to have time to go check out whatever they're interested in.

Jamie Zeitzer - 17:45: You need to have a life.

Dan Pardi - 17:47: I do want to circle back to how the technology is implemented. Previously we had spoken about mask technology, so you would have to put on the mask, open the app, set the timing, you would have to willfully engage with it on a nightly basis. This seems like one of the scenarios where you would set it and forget it. Once you configure it, it's going to continue to do its thing until you stop it, and that has a much greater chance of success than even the mask. The mask would be better for some traveling on an airplane, et cetera, but I like this type of intervention, so this could become product that would be something that anybody who wanted to adjust their timing could put this in their room. Either if you're an adult and you're trying to shift your schedule because you're getting up early for a flight or you're a teenager and you have this biological drive to stay up later, you could have that on and it would help.

Jamie Zeitzer - 18:34: I think so. Using a beacon like this has some disadvantages. If you have other people in the room it's not going to work as well. But the passivity of it is important because as you point out, even the simple act of putting something on at night, even if you don't mind wearing something, is still an act that you have to remember to do. You could incorporate it into your nightly routine and make it part of a positive sleep hygiene, but I think that's a lot more effort. You can integrate this with a smartwatch where your Apple watch is now telling this device when it needs to fire in order to resynchronize you.

19:08: So for example, it's a Friday night, you stayed up late and you want to sleep in, so that's fine. But then on Sunday you need to get resynchronized back to your Monday schedule, and it just doesn't automatically. Because again, the less you have to do, the more likely it is that it won't end up in a drawer like so many of the smartwatches.

Dan Pardi - 19:23: What populations do you see as the highest likelihood to benefit? We talked about teenagers, who else?

Jamie Zeitzer - 19:31: Older individuals would definitely benefit. A lot of older individuals, there's nothing wrong with it, but they often go to sleep much earlier than they want to and then they get up earlier than they want to. Again, this is due to a biological shift to an earlier hour in these individuals. From a medical or biological perspective, there's absolutely nothing wrong with that, but they find it socially inconvenient. So this is another population that when you treat them with a standard photo therapy, if you want to go to sleep later, we should give you bright light in the evening. So you have to sit in front of these bright light boxes for several hours in the evening before you go to bed. It's annoying. People don't like doing it.

20:10: This is something that you can have these kind of lights going off while they're going to sleep and it can help to adjust them to the later time.

Dan Pardi - 20:17: Instead of teenagers that have a circadian clock that causes them to stay up later and then want to wake up later, timing of the light would be different for older people that go to sleep earlier and wake up early. Now instead of having the lights go off a couple hours before waking, they'd be gone a few hours after sleep initiation. Over time, they would naturally be able to stay up later and wake up later and that would align better with the social schedule of those around them.

Jamie Zeitzer - 20:40: That's right. So that's one population. As you mentioned earlier, people who are doing jet travel, right now, if we use bright light therapy, the best you can do in the real world is about an hour or two of shift, but with this you can do three hours of shift in one day. Before you get on a plane you can actually shift yourself the night before. So you might not be all the way between here and your new time zone, but it'll get you much of the way there.

Dan Pardi - 21:05: That would be an incredible benefit for those who travel frequently. We have a how to guide for jet lag and in that we ask how many times zones are you crossing, how long will you be there? If you don't have enough time to fully adjust to the new time, then you might simply want to deal with travel fatigue and not have your schedule move. You're going to pay some consequences typically with both poor sleep and poor daytime wakefulness. If you had that ability to bring this beacon with you, you could adjust that window much more quickly.

Jamie Zeitzer - 21:34: Sure. It would change you. Your approach is right on because not everyone goes to a new time zone and spends weeks there, and the question is should you be shifting to the new time zone? Should you be staying on your old time zone? Are you going to just be there and then move on? It's complicated and this is why there are several planes that now have bright light therapy built into their onboard lighting system, which sounds great. You're flying from Los Angeles to Scandinavia and basically the lights come on in Scandinavian times zone sunrise, which is great if you're flying from LA to that part of the world and plan on staying there. It would actually be harmful if you flew into LA the previous day from Hong Kong and now actually that light is going to send you the wrong direction. It's going to send your circadian clock spiraling in the wrong direction, making the jet lag worse.

22:22: The one size fits all definitely doesn't work with this. So that kind of personalized approach that you're discussing is really crucial.

Dan Pardi - 22:29: One simple DIY solution would be to have a light bulb turn on at a certain time if you have the technology to do so and then if you can sleep through that, you will probably adjust faster than you would otherwise.

Jamie Zeitzer - 22:41: For the most part, the circadian system is most sensitive to light when you're asleep. Getting that light during sleep, that's why that's of critical importance. It's not only most sensitive to light in terms of how much shifts can get, but it's also sensitive because if you're exposed to hours of darkness, you've sensitized your system and so it's going to be even more responsive to light. You've got several things working there. If you couple the nighttime therapy with the daytime therapy, you can definitely help out a lot and as you said, even if it's just a standard bulb that you can program to turn on at a certain time, you're just simulating a sunrise and earlier time, or you're extending sunset to a later hour and all these things will get communicated to the clock and can be helpful.

Dan Pardi - 23:21: Might be interesting is having a very high kelvin bulb that's very blue light. Just blue in a way can seem darker to the visual system. So if you have that on automatically at a certain time, that could be an interesting solution to protect sleep, but also have the circadian shifting effects that you desire.

Jamie Zeitzer - 23:39: As I mentioned, blue light isn't as effective at penetrating the eyelids, but it is more effective photon for photon. And as you say, your conscious perception of light is much lower.

Dan Pardi - 23:49: Did you happen to measure melatonin in any of the studies looking at shifting? Do you actually suppress melatonin release during the period of time where the subject is still sleeping the light pulses are occurring? Even majority of that time is still under darkness.

Jamie Zeitzer - 24:04: Sure. We have looked at melatonin and we don't see any effect on melatonin at all. Melatonin doesn't suppress the flashes. When you look at alertness, alertness isn't impacted by the flashes. We're not sure about the explanation completely, but there are different ganglion cells that project to different parts of the brain that control these different processes, and so the phase shifting isn't always the same as suppression of melatonin, which isn't always the same as alertness or change in cardiovascular function. So there seems to be some independence of the impact of light on these, probably due to the anatomical connections between the retina and these different parts of the brain.

Dan Pardi - 24:39: That's fascinating. It seems like you can really gain the system here without inducing a bunch of other externalities that you would not want to induce.

Jamie Zeitzer - 24:46: That's what we're trying to do.

Dan Pardi - 24:48: Do you have another study that is enrolling now or you're waiting for that grant from the NIH?

Jamie Zeitzer - 24:53: We're waiting for that one for the NIH. We're doing other studies right now. We're doing light flash studies, but we're trying to develop the parameters of those studies right now in terms of what are the parameters of light and how do they contribute to these flashes? We have two publications under review right now. Lauren is looking at how long the flashes have to be. We see that even a pulse that's a couple of microseconds long has as much capacity as flashes that are a couple of seconds long, so millions of more photons, same effect. And we also looked at the intensity of the light, and light intensities at which we're seeing the effects are actually much lower than with continuous light making us think that this might actually be a rod or a [inaudible 00:25:35] mediated effect as opposed to a melanopsin mediator effect.

25:39: So, that's the stuff we're working on in the lab under highly controlled circumstances. Can we work out the parameters and then can we test those parameters in a field setting to see, well, in theory it works. How about in actuality? What are the roadblocks that exist to implementing this as an actual therapeutic?

Dan Pardi - 25:56: What percentage of people were able to sleep with the light flashes on?

Jamie Zeitzer - 26:00: It's a very high percentage, but it's a biased percentage because anyone who is sensitive to light during sleep wouldn't have signed up for the study. If you know that you're sensitive to light, you're not going to volunteer for this kind of study. We had over 98% compliance and people were fine with the light, but that's a biased number.

Dan Pardi - 26:18: Was it an explicit exclusion criteria or the people that signed up were enriched for knowing their own sensitivity to light?

Jamie Zeitzer - 26:24: I think they were just enriched. It was not a specific exclusion criteria. We talked about getting light during sleep. People who were worried about it weren't going to sign up.

Dan Pardi - 26:33: Well, Jamie, thanks again for coming back on. I'm really interested in tracking the tech here because there's very clear utility for a lot of populations in today's world. You're doing great work on this and we appreciate your time.

Jamie Zeitzer - 26:44: Thank you. Well, I appreciate being on Dan, and getting chance to talk to you. It's always a pleasure and it's great seeing how this stuff actually can work.