Sleep and Mood. Podcast with Dr. Jennifer Goldschmied

Guest

In this episode of humanOS Radio, Dan speaks with Jennifer Goldschmied. Jennifer has a Ph.D. in Clinical Psychology from the University of Michigan, and is currently faculty at the University of Pennsylvania. Her research explores how altering aspects of sleep can produce changes in mood and emotional regulation, particularly in those with major depression but also in normal healthy folks.

We know, for instance, that taking naps can boost elements of cognitive performance, even in well-rested people. To better understand how this works, Jennifer and her colleagues recruited 40 subjects, and had them complete a series of challenging computer tasks at the lab. The researchers then randomly assigned them to either take a 60 minute nap or watch a nature documentary for 60 minutes (control). Thereafter, the participants were asked to perform the computer tasks again. Those who had taken the one hour nap spent more time trying to solve the problem, compared to their non-napping counterparts, who seemed to be less able to endure the aggravation associated with the computer task.

These findings suggest that just taking a nap – which is easy and costs nothing – may counteract impulsive behavior and enhance tolerance for frustration. This is something from which most of us could probably benefit, both in work and in other aspects of daily life, and this kind of research has actually motivated some progressive companies to invest in sleep pods. Sometimes, it really is better to work smarter, not harder.

The idea that taking naps would enhance emotional regulation and perseverance probably sounds pretty intuitive to most of you. But here is where things get really interesting. Jennifer’s work has also led her to investigate a long-recognized but poorly understood clinical paradox: Some individuals with depression actually experience mood improvement in response to sleep deprivation.

You read that right – total sleep deprivation has been shown to have antidepressant effects. In fact, an estimated 40-60% of people with major depression may experience significant improvements in symptoms in response to sleep loss. Of course, the benefits dissipate once the patient’s sleep is restored, which is probably one reason why interest in this as a therapy has lagged. But Jennifer and her colleagues are starting to figure out why precisely sleep deprivation seems to improve mood, and which individuals might stand to benefit from sleep manipulation. You can imagine that gaining insight into this strange phenomenon may eventually lead to new treatments for depression and other mental disorders.

To learn more about her fascinating research, and what is on the horizon for this work, check out the interview below!

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Transcript

Jennifer Goldschmied - 00:00: The research started looking more at how sleep deprivation changed positive and negative affect. From the emotion literature, we know that these are distinct emotions that can coexist simultaneously.

Dan Pardi - 00:14: Sleep and mood are tightly linked to one another. Most of us know this all too well from personal experience. If you got poor sleep the night before, you're more likely to be a little more irritable. You might get frustrated more easily by petty obstacles that confront us throughout the day, like traffic on the way to work. Mood is noticeably altered by a bad night's sleep, and usually, not for the better. So the relationship between mood and sleep is pretty complicated, because disruptions in sleep can produce alterations in emotional functioning, but our mood can also alter sleep patterns. If you're angry, or sad, or stressed out, you're likely to have a much harder time falling asleep and staying asleep. Research is only now just starting to fully explore how sleep and emotion interact with one another. Interestingly, in the myths of studying the subject, an interesting clinical paradox has emerged. Certain individuals actually experience mood improvement in response to sleep deprivation. Why is this, and how can we take advantage of this finding?

01:13: To discuss this area of research, I am pleased to have Jennifer Goldschmied on the show. Jennifer has a PhD in clinical psychology from the University of Michigan, and is currently faculty at the University of Pennsylvania. Her research explores how altering aspects of sleep can produce changes in mood and emotion regulation, particularly in individuals with major depression. Jennifer, welcome to humanOS Radio.

Jennifer Goldschmied - 01:36: Thanks so much for having me. It's great to be here.

Dan Pardi - 01:39: Tell us a little bit about your background, and how you became interested in the role of sleep and mood, and emotional processing.

Jennifer Goldschmied - 01:44: Sure. Actually, my interest in sleep started when I was really, really young. I must've read something about dream interpretation, and I was just fascinated. My dad was trying to foster my interest at the time, so he bought me a stack of books about sleep and dreaming, and I read from cover to cover, and I was just hooked. Fast forward to when I was in college at the University of Pennsylvania, I was lucky to secure a job working in a sleep lab, and unbeknownst to me at the time, it was directed by one of the world's leading experts in sleep deprivation and performance, David Dinges. So working there, I was able to see the firsthand effects of sleep deprivation, and I was fascinated by how mood would change in those people.

02:25: When I went on to get my doctorate in clinical psychology, I knew that I wanted to focus on sleep and emotion more broadly, trying to understand how sleep modulates emotion, because like you mentioned, I think it's natural for us that not getting enough sleep impairs our mood, but we still don't know why or how that occurs. So the natural fit in my career was working with Rosanna Armitage at the University of Michigan, because she was one of the leaders in the area of sleep and depression, and depression is this great model of how sleep and emotion dysregulation interact.

Dan Pardi - 02:57: It's not every day that I have an expert in sleep that has had an interest in the subject since they were a child. It sounds like you're doing work that you were destined to do.

Jennifer Goldschmied - 03:08: I love it. I can't lie. I love doing what I do.

Dan Pardi - 03:11: That's awesome. Explain broadly what research shows regarding the effects of sleep deprivation on emotion?

Jennifer Goldschmied - 03:17: We've really known for a while that sleep deprivation is bad for cognitive functioning. That's the first thing that they focused on. So David Dinges, who I was just mentioning, has been a pioneer in that area, showing that sleep deprivation slows response time, impairs working memory, leads to instability inattention, but the research on the emotional questions, like you mentioned, is much newer, and a lot of what we think about as typical emotional consequences of sleep deprivation is actually much more anecdotal in nature, like increases in irritability for example, since it's difficult to assess irritability objectively, or even sometimes subjectively, since having insight when you're sleep deprived can be difficult.

03:56: Earliest research also conducted by Dinges showed that sleep deprivation generally increased mood disturbance, and they usually did their research using an assessment measure that can be administered at several time points across a day. They use something called the Profile of Mood States. The difficulty with a measure like that though, is that when you look at the actual components that sleep deprivation was shown to affect, like vigor, confusion, fatigue, all those are really more related to sleepiness than mood. Later on, the research started looking more at how sleep deprivation changed positive and negative affect.

04:34: From the emotion literature, we know that these are distinct emotions that can coexist simultaneously, so they're not two different ends of the same continuum. Unfortunately, the research there has been somewhat mixed. A lot of studies do tend to show that sleep deprivation degrades positive mood, instead of increasing negative mood. Beyond then just positive and negative affect, Scott Killgore's group, for example, has done a lot of really cool work in that area, and they've shown that continued wakefulness increases things like subjective sadness and anxiety, but that it also can decrease our ability to regulate emotion, being able to handle a bad thing that happens in the day.

Dan Pardi - 05:19: Regarding Killgore's work, does that mean that your likelihood of an impaired mood increases across the day, or when you go beyond the typical level of wakefulness that a person has within a day, then you start to experience some of those effects that he showed?

Jennifer Goldschmied - 05:33: That's a great question. I'm sure that there are some measures of mood and emotional functioning that do degrade across a normal waking day, but he's shown this with continued wakefulness. Some of his studies look at 56 hours of continued wakefulness, others look at 86 hours of continued wakefulness, and some measures are only affected when you look at really long range sleep deprivation. So for example, impulsivity, he's shown measures of impulsivity are fine at less levels of sleep deprivation like 55 hours, but there seems to be a certain threshold that you pass at a certain point, that now sleep deprivation is starting to affect your mood even more. Yeah.

Dan Pardi - 06:11: It seems like for a lot of cognitive processes, there is some within day variation, but if you got a bad night's sleep last night, you're going to be affected throughout the day. That day would be characterized by that state, but going beyond those levels of typical wakefulness, after that, that's when you start to see some of these features show up in unique and interesting ways. By the way, please remind me to never sign up for a Killgore trial. Thank you.

Jennifer Goldschmied - 06:34: Yeah. I think 86 hours of sleep deprivation is quite a feat. He's done some really cool work, specifically looking at impulsivity and reward functioning, which is somewhat related to emotional processing, and there, there's also some really cool work being done. So sleep deprivation, we know preferentially affects the reward system. For example, Matt Walker's lab shows that sleep deprivation increases the number of stimuli individuals rate as positive, rather than neutral. They've shown that there's more activity in reward-related brain areas, in response to positively valence images, and other studies like in rodent models have shown that sleep deprivation increases motivation for both food and substances like cocaine. So sleep deprivation really has this interesting pattern, where you see this outward decrease in mood, so decreases in positive affect, but it's coupled with these increases in motivation for rewards, and it just doesn't make for the greatest combination. Yeah, so that's why we might see some of these outward behaviors that we see during sleep deprivation, like Scott Killgore's shown with this increase in impulsivity that you might not otherwise see.

Dan Pardi - 07:43: I'm very interested to understand what the evolutionary mechanism for that might be. It seems perhaps, the brain is acting in somewhat of a compensatory fashion to increase reward seeking to augment the deficit in mood. I don't know if there's an answer to that.

Jennifer Goldschmied - 07:56: Matt Walker has speculated really nicely about the evolutionary reasons that we have this increase in hedonic approach behaviors. It makes a lot of sense. I like to think in evolutionary terms, so sleep deprivation is just really interesting, because if you think about it, if you're sleep deprived back in the day, that probably meant that there was something wrong. It's still the case, but really interesting area.

Dan Pardi - 08:19: If something's wrong, you might need extra motivation to go and find food. Could that priority be coupled with that behavior for that purpose? My own PhD research was influenced, of course, by Matt's, and hedonic processing around food, so that is something that I had speculated on and considered.

Jennifer Goldschmied - 08:35: It's a really cool area of research. I'm really fascinated by it.

Dan Pardi - 08:39: So a moment ago, we were talking about Killgore's work and how if you go beyond the typical window of wakefulness within a day, then you can see these interesting effects. We did mention within day, and when I think within day sleep and wake, one topic that pops to mind is naps, and in your own work, you've shown that taking a nap can enhance emotional regulation. So tell us about what you found there.

Jennifer Goldschmied - 09:00: Yeah, I'm really interested in our ability to use sleep as an intervention. So this study was designed to see if a nap as short as 60 minutes could affect impulsivity, decision making, mood, emotion regulation, in a positive way. So we recruited 40 subjects who were randomized to a nap or no nap condition, and in the no nap condition, we had our participants watch an episode of Planet Earth, where nothing upsetting or too exciting happened, no animals were harmed in the clip that we picked, and we called it a emotionally neutral nap, no nap condition.

09:36: So before and after the nap, no nap condition, our participants completed questionnaires and a task battery, and the task battery included a task that we adapted to measure what we call frustration tolerance. In the task, participants were asked to copy a figure, and their instructions were to copy the figure without crossing any lines twice, or lifting their pencils from the paper, and you might've seen images like that before. Now, unbeknownst to them, each time they completed the task, before and after the nap, one of the images that they saw was actually unsolvable, and we measured the amount of time they stayed on the task before giving up. And so, what we found was that before the nap, both groups attempted to solve the unsolvable puzzle for about the same amount of time. After the nap, the people who napped spent twice as long trying to solve the puzzle than the people who did not nap, and it was a pretty stunning effect.

10:29: In addition to that, we administered a questionnaire trying to get at what we call state impulsivity. So this idea that impulsivity changes with our circumstances. It's not just we are or are not impulsive by nature, but this can change. And we found a similar story there. So following the nap, those who napped reported feeling less impulsive, where those who did not nap, reported feeling more impulsive. What we concluded was that over the normal course of a waking day, our ability to withstand frustration wanes, but a 60 minute nap, and it even probably could be shorter, because most of our participants didn't fall asleep immediately. So that 60 minute nap could give us a needed boost to tolerate the normal frustrations that happen in life, a little bit better. We thought it was a really cool finding.

Dan Pardi - 11:15: Did these subjects sleep for 60 minutes, or were they given a 60 minute window to get some sleep, and those who did sleep showed this benefit? Do you have an average of the amount of sleep time in that nap period?

Jennifer Goldschmied - 11:30: Yes. Everybody fell asleep. We were really shocked by that, because when I first set out to do this study, I thought, all right, we're going to have a bin of people who don't nap and people who do nap, and then in the nappers, we're going to have people who can't fall asleep and those who do, but everybody ended up falling asleep. It was a little bit surprising, mostly because we recruited undergrads who did not habitually nap, and who were not sleep deprived. So we gave them a sleep diary for the week before, and we screened them pretty strongly, just to make sure that we didn't have anybody that was exhausted, because we didn't want sleep deprivation to play into some of these findings.

12:07: So everybody fell asleep. Now, to answer your question of do we know how long they slept for? Not exactly. We had EEG, but we were looking specifically at really obvious stages, so REM for example, or slow-wave. So I don't know if our EEG analysis was as fine grained enough for us to do the analysis to see how long everybody slept for, but from behavioral monitoring, every one of our participants in the nap group ended up falling asleep and sleeping for some amount of time.

Dan Pardi - 12:34: A lot of people claim they can't nap during the day, and I bet that's not true, if they were provided the right conditions. I know if I try to take a nap during the day, there is a period where I need to wind down a little bit, where before I drift off, and if I give myself 20 minutes, then that might only occur 15 minutes into the period of time before I maybe nod off. Surprisingly, however, even if I do nod off for just maybe five minutes or so, it is remarkably restorative.

Jennifer Goldschmied - 13:02: Yeah. After the study came out, I got a lot of questions about that, the 20 minute power nap. And we know from the nighttime sleep world, I do a lot of insomnia work with patients, it should take about 15 to 20 minutes to fall asleep. That's a really normal window of time, and if you're falling asleep faster than that, then there might be some sleep deprivation or sleep disorder on board. And so, when people ask me about this 20 minute power nap, I always say, "Well, it's going to take you about 15 minutes to fall asleep. You want to give yourself at least a little bit more time to have an nap."

13:34: Now, you don't probably want to give yourself enough time to get into slow-wave, because then you're going to wake up with some sleep inertia on board, and it's going to be a little bit more difficult to get back into the swing of things. What I usually say is aim for a 45 minute nap. That gives you 15 minutes to fall asleep, 30 minutes where you'll probably stay in stage one and stage two, and then you can wake up feeling a little bit more restored. But of course, not everybody has 45 minutes in the day to be able to take a nap.

Dan Pardi - 14:00: Now that there's more awareness on the importance of sleep, if executives and other people who aren't able to carve out that time will start to create time for an nap as a performance technique, as a way to say, "Okay, well I am going to be working for five, six, seven, eight hours after the nap, and I'm going to get better work done by doing an nap, then omitting it."

Jennifer Goldschmied - 14:18: Absolutely, and I was really happy when the press picked up this study, and what they ran with it, with the headlines is, Tell Your Boss It's Time For a Nap, things like that. Our working hours are getting longer and longer every year, it's putting a lot of stress on folks. They're waking up earlier, they're getting to bed later, so they're not getting more sleep in the evening, but they're working longer hours, and we know that there's a relationship between the number of working hours and productivity. And so, having a nap, even a brief one in the middle of the day, I think can really boost our productivity, and in terms of emotions, I think it just makes us better equipped to handle the small things that happen throughout the day.

Dan Pardi - 14:58: Let's switch gears. You've done work also in people that have depression.

Jennifer Goldschmied - 15:03: Yep.

Dan Pardi - 15:03: How does sleep architecture and other sleep parameters differ in people with major depressive disorder, compared to the non-depressed?

Jennifer Goldschmied - 15:09: Yeah. Sleep in individuals with depression is actually quite different than in healthy individuals. So the classic profile of an unmedicated individual with depression, for example, shows delayed sleep onset latency, or how long it takes to fall asleep, much more fragmented sleep, so you'll see periods of time in the middle of the night where they're awake, which reduces sleep efficiency and total sleep time. Sleep is actually much lighter, so they get less deep slow-wave sleep, and more light stage one sleep. And then there are the REM abnormalities, which is kind of the hallmark of depression. Individuals with depression tend to go into REM much quicker than healthy individuals, so that's REM latency. They have more REM sleep and REM density ,or the number of actual eye movements during REM is also increased.

15:56: Those changes, we call macro-architectural, because you can see them visually on a sleep EEG, but we also know that the underlying frequency pattern of sleep is different in depression, and those we call micro-architectural changes. So there, we'll see an increase in fast frequencies, which some people have suggested could signal of an underlying hyperarousal in depression. Anecdotally then, we also see early morning awakenings. This is when individuals with depression will say, "I wake up one to two hours before my alarm, and then I just can't go back to sleep," but we haven't actually had any robust studies that actually has shown this directly. It's an interesting area that we might want to look at a little bit closer.

Dan Pardi - 16:38: Yeah. Sleep restriction has been shown to affect people with depression, in this unusual and sort of fairly surprising way. So compared to counterparts without depression, what is different?

Jennifer Goldschmied - 16:48: This is actually one of my favorite concepts in sleep research, and one that drove me to study sleep and depression in the first place. In about 50% of individuals, sleep deprivation results in a really rapid antidepressant response. Towards the morning hours, during sleep deprivation, you'll see this really robust improvement in mood, and it's eye-opening. I mean, you'll see them just kind of perk up, they'll be bright-eyed. It's really interesting.

Dan Pardi - 17:15: Upon awaking, their mood or the severity of their depressive symptoms is improved, if they've been sleep restricted.

Jennifer Goldschmied - 17:22: Yeah. So throughout sleep deprivation, you'll notice that their mood starts improving. And we've known this since about the '70s, and initially, there was a ton of effort to kind of characterize it and understand it better with researchers, and they looked at total sleep deprivation versus selective REM deprivation, early and late partial sleep deprivation. And in 2017, our group actually published a meta-analysis looking at all of the results, so about 66 studies, and concluded that sleep deprivation, in many forms, results in this rapid mood improvement in 50% of people. So we know that if you have eight people with depression, four of them are going to get better when you restrict their sleep and watch them under these conditions of sleep deprivation.

Dan Pardi - 18:06: Is it a permanent solution?

Jennifer Goldschmied - 18:09: Well, that's the [inaudible 00:18:10].

Dan Pardi - 18:10: Yeah.

Jennifer Goldschmied - 18:11: The mood improvements last until sleep occurs, and it doesn't have to be a full night of sleep. Naps or even periods of a microsleep, so that happens during prolonged periods of sleep deprivation, have been shown to result in relapse. I don't really look at sleep deprivation like an alternative for an intervention, but I'm really interested in understanding the mechanism of why it works, so we can develop new interventions or targets for novel interventions. I think that's how many people are looking at it, although I know some people are trying to use sleep deprivation as an intervention, but just to kind of get it started, and then using chronotherapeutics to continue the effects.

Dan Pardi - 18:48: What do you think are some of the underlying mechanisms?

Jennifer Goldschmied - 18:50: Ah, that's a terrific question, and the answer is that we still just don't know, and that's probably I think why some of the interest in this area waned. It was so hot for so long. When it was first discovered, we didn't have the methods to be able to understand it fully, and now we're finally getting some better methods, and I think some of the interest is coming back. For example, my colleague, Phil [inaudible 00:00:19:12], right now, has a funded study from NIH that's investigating potential mechanisms, so he's using neuroimaging. The study is almost complete, so we actually might start to have answers soon, but right now, we just still don't know. And older studies, we're interested in trying to tease it apart, but they were looking at early versus late partial sleep deprivation, and they were trying to understand what component of sleep was responsible.

19:39: For example, slow-wave sleep tends to predominate at the beginning of the night, and REM occurs later in the night. If you do selective deprivation, where you either do early or late partial sleep deprivation, it's one way to look at the contributions. Those studies tend to show that late partial sleep deprivation is just as effective as total sleep deprivation, but not early sleep deprivation. A lot of the researchers using that started to speculate that it's the REM deprivation that contributes to the antidepressant effects, but it's really difficult to look at that directly, because if you do just a selective REM deprivation experiment, you actually just decrease total sleep time, because to reduce REM, you need to wake someone up.

20:20: I'm also a little hesitant about the early partial sleep deprivation studies, only because slow-wave activity is a really robust homeostatic drive. It's possible if you deprive someone early in the night, that slow-wave activity will just occur later in the night. Personally, I'm more interested in slow-wave sleep, it plays a larger role in depression, and potentially, the antidepressant effects of sleep deprivation, and we can examine the contributions of slow-wave activity in ways that you can't with other stages of sleep. Slow-wave is probably our better target.

Dan Pardi - 20:52: Is there a way then to not entirely remove slow-wave sleep, but reduce it without decreasing total sleep time?

Jennifer Goldschmied - 20:58: Yeah. Our group has actually been using it as a really elegant paradigm. It was initially described by Dirk [Yon 00:21:05] Dyke's group in the late '80s, and it selectively disrupts slow-wave activity, and it doesn't decrease total sleep time. What they do in the paradigm is they use auditory stimulation. Whenever two slow waves are detected, tones are played, and they're not phase-locked to any particular component of the slow-wave, but serves to reduce the level of slow-wave activity we have, but it does not decrease total sleep time, because the tones are loud enough to knock them out of slow-wave, but it's not loud enough to wake them. We can decrease it without waking the participant, and we do it in a really tailored way to the individual. And using that paradigm, both our group and Ruth Benca's group from UW Madison showed that slow-wave disruption was associated with mood improvements in individuals with depression. To me, that lends even more support to this idea that perhaps the mechanism of sleep deprivation's antidepressant effects might be the suppression of slow-wave activity.

Dan Pardi - 21:58: We tend to think of getting more slow-wave sleep as generally a good idea to try to promote. There's conditions that suffer from the lack of slow-wave sleep, so we're trying to figure out ways to augment it, but in this population, it seems to be problematic or at least correlated with the intensity of depressive symptoms, and lightening it in a way that doesn't totally disrupt sleep time, could be a therapeutic area. Do the patients, do they suffer from next day consequences like sleepiness?

Jennifer Goldschmied - 22:28: In general, people with depression, most of the time report symptoms of insomnia. So just feeling like they can't settle down, they can't reduce their thinking. If they want to take a nap, they say they can't. There's also a subtype of people with depression that have hypersomnia. They feel tired all the time. In terms of using slow-wave disruption, when we've done this paradigm, we don't actually get many people reporting increased sleepiness, although we would expect some of that. After our study, we made sure to say, "Try not to drive," we had people come and pick them up. It's something that we would expect, because slow-wave is known to be recuperative sleep. So if we're disrupting slow-wave, we might expect some symptoms of sleepiness, but we don't have enough data right now to know what the consequences would be one way or the other.

Dan Pardi - 23:15: Have you been able to find anything else about slow-wave disruption that is interesting?

Jennifer Goldschmied - 23:20: Once we knew that slow-wave disruption improved mood, we were interested in understanding how slow-wave functions differently in depressed and healthy individuals, right? Because obviously, it's doing something. One of the current hypotheses about slow-wave is that it's a marker of our need for sleep, which decreases over the sleep period. It's been shown that EEG theta activity can be considered kind of a homologous waking marker of sleeping. With continued wakefulness, it increases, and after sleep, it decreases. But David Plante, also at Wisconsin, has shown that in individuals with depression, waking theta does not decrease following sleep.

23:59: We were interested in what would happen to waking theta if we did this slow-wave disruption paradigm, and what we found was that there was absolutely no modulation of theta across baseline sleep in depression. But following slow-wave disruption, we saw a significant decrease, and then in healthy individuals, although the fluctuations didn't reach statistical significance, because we had a pretty low sample, there was some evidence of a basic pattern of increasing [inaudible 00:24:25] across waking, decreasing following sleep, but when we did the slow-wave deprivation, there was no modulation. Our takeaway from that study was that it did seem like intact slow-wave activity was necessary for the modulation of theta activity in healthy individuals, but that slow-wave seemed to play a completely different role in depression, and that there's evidence that slow-wave in that population can be maladaptive. We're not the first to make that speculation, that slow-wave activity in depression might not be a good thing.

Dan Pardi - 24:57: I'm recalling a study from Paul Franken on theta-dominated wakefulness and narcolepsy, and how there was an interesting connection there. Without going into details about it, it seems depending on the condition, determines whether or not these different brain wave activities are something that we want to try to operationalize around getting more of or less of. It's hard to say, "Well, if you have this amount of this stage, then that means you get this much benefit." It does seem context dependent.

Jennifer Goldschmied - 25:22: Absolutely. If you ask me, slow-wave is so important, right?

Dan Pardi - 25:26: Yeah.

Jennifer Goldschmied - 25:27: It's just this recuperative, restorative sleep, but for some reason, in depression, it just plays a different role, and it's going to be super important for us to keep working on understanding what slow-wave is doing, the mechanism of it, in both healthy people and depressed people. We take for granted that clinical populations can be different. A lot of people said, "Let's just increase the amount of slow-wave we have across the board," and that just might not be true for people with depression, or other clinical groups.

Dan Pardi - 25:56: Any ideas about why disruption in slow-wave sleep might improve mood?

Jennifer Goldschmied - 26:00: Great question. I just don't think I'm going to provide a satisfying response.

Dan Pardi - 26:04: Well, that's okay. Yeah.

Jennifer Goldschmied - 26:05: The way I've been thinking about this is akin to exercise. If you work out, let's say, by lifting weights, and you do so with poor form, you can really end up hurting yourself. The literature has shown that in a subset of folks with depression, slow-wave activity regulation is not functioning appropriately. It might, in that case, be better to have less of it. That's the conceptual answer, but we've speculated about mechanisms, and we did this in a recently published review paper, and we tried to integrate some of the most recent relevant theories into one model.

26:39: In it, we discussed the synaptic homeostasis hypothesis, a really elegant theory by Tononi and Cirelli at UW Madison. And there, they talk about slow-wave activity during sleep as facilitating the resetting of our neurons. We also discuss Christoph Nissen's group's model of the antidepressant effects of sleep deprivation. In their paper, they suggest individuals with depression have deficient levels of synaptic strength. That is, the change in neurons that support memory and learning, but what also needs to be reset during sleep. We put these two ideas together, and when we did that, we speculated that slow-wave activity actually might be what is maintaining the deficient levels of synaptic strength in depression, and that if we disrupt slow-wave, we'd allow the deficient synaptic strength to build to normal levels. Now, it's totally a working hypothesis. I've been fortunate to receive funding from the National Institute of Mental Health to examine it more closely. I'm going to say maybe in four years, I'll have a more satisfying answer for you,

Dan Pardi - 27:43: So you could imagine disruption in sleep, particularly slow-wave sleep could be a temporary mechanism to get the brain into a better place, where it's manifesting healthier physiology, that would then translate into improvements in mood?

Jennifer Goldschmied - 27:57: Exactly.

Dan Pardi - 27:58: Really interested to see your work on that going forward.

Jennifer Goldschmied - 28:01: Thanks.

Dan Pardi - 28:01: There's also some evidence about antidepressant medications altering sleep architecture. Is it possible that this is one of the mechanisms through which antidepressants improve mood?

Jennifer Goldschmied - 28:09: Yeah, it's absolutely true that traditional antidepressants affect sleep. Of course, there's some variability in how, depending on the medication class and type. Also, results vary by study, so for example, the effects of antidepressants on slow-wave sleep are really variable. Some studies show that it increases, some decreases, and some show that there are no differences. But I think by and large, most antidepressants affect REM sleep, either by delaying the onset of REM, decreasing the relative amount of REM, or both. For example, SSRIs, or selective serotonin reuptake inhibitors, we believe work by increasing the availability of serotonin in the brain. We also know that SSRIs impact REM, but whether or not it's the antidepressant effects occur because of the effects on REM, we just don't know that yet.

28:59: Interestingly, and I get this question a lot, our slow-wave disruption paradigm did reduce the amount of REM. With the reduction in slow-wave, we also saw a reduction in REM, but the reduction in REM was not associated with the improvements in mood. So I still don't actually believe that it's a REM-mediated effect, but it's definitely a possibility. There are slow-wave researchers, and there are REM researchers. I'm a slow-wave researcher, and I have to veer into the REM world for a little bit to explore it, because it's definitely a possibility.

29:27: But there's a new antidepressant on the market, esketamine, and it's shifting the conversation, which is really nice. Our traditional models of depression were based on the monoamine theory that depression is due to deficiencies in one neurotransmitter or another, so serotonin, for example, or dopamine, and that the traditional antidepressants were effective, because they increase the availability of those neurotransmitters, but we know now that those theories are probably far too simplistic. And so, esketamine is an NMDA receptor antagonist, which works completely differently from those classic antidepressants. Research has shown that esketamine may actually exert its effects by increasing throughput via a completely different receptor, or the AMPA receptor, by the neurotransmitter glutamate. Those new theories of depression are actually starting to focus much more on neuroplasticity, and I think it's just a really exciting time for depression research, because we haven't had such a fundamental shift in the way we've been thinking about things for a long time.

Dan Pardi - 30:24: Esketamine seems to have very rapid, sometimes complete remission of depression. It just lasts for a week or so. That relief could be beneficial, but what does it tell us about what's happening? That mechanism of altering neuroplasticity, you could liken that back to how we're trying to intervene by manipulating sleep for the positive benefit as well.

Jennifer Goldschmied - 30:43: Absolutely, and I think that's where my interest lies now, in terms of the effects of slow-wave activity on neuroplasticity. The synaptic homeostasis hypothesis speculates that sleep is affecting neuroplasticity, and it can be in a very similar way to esketamine. And so, when you think about the fact that both sleep deprivation and esketamine have these really rapid antidepressant effects, they may be working through the same mechanism, then that's really cool. I think esketamine is great in terms of having this rapid antidepressant effects, but like sleep deprivation, it's not super long lasting. I'm interested in it from this perspective of what can it tell us about depression? Is depression more of a disorder of neuroplasticity? And if that's the case, then we need to shift gears into looking at different ideas than what we've been looking at for the last 20 to 30 years.

Dan Pardi - 31:33: The other really interesting line of work that's taking place in depression is with psychedelics. Robin Carhart-Harris has done some very interesting work looking at the way that our brain changes under the influence of different levels of these types of compounds that stimulate this psychoactive state, and how the improvements that you see in people that have had intractable types of depression are really unparalleled. And so, I'm glad that we're now looking at these compounds that have been out of the reach of researchers for a long time because of their regulatory status, and how we're now using them both to understand better ways to apply therapy, and also the way that they're working tells us about other techniques that we could utilize to get at the same effect through different strategies.

Jennifer Goldschmied - 32:18: It's such an exciting time with all of these different ideas. The depression literature got stale for a little while. I know that that was the case in the depression and sleep world. People stopped looking at it once they couldn't figure out the sleep deprivation stuff, and I think now it's time to revive what we're looking at, and try again to understand depression a little bit better.

Dan Pardi - 32:42: Major depression now affects the most people around the world, in terms of a chronic disability. The need is growing, and so we need to continue this work in this area.

Jennifer Goldschmied - 32:47: Absolutely.

Dan Pardi - 32:48: What are some of the next questions that you are going to be investigating?

Jennifer Goldschmied - 32:52: This grant that we're starting really soon is exciting, because we're looking at this idea of slow-wave disruption, and we're planning to get really nice sized samples, so we can ask lots of questions. One of the things that we know is that there are sex differences in how sleep changes in depression. So I've been talking kind of really broadly, but in terms of the slow-wave changes, we know that men are actually a little bit more vulnerable than women to having distinct changes in slow-wave activity. I'm excited to be able to examine those sex differences a little bit more closely.

33:24: Also in this project, what we're really trying to do is understand synaptic strengths, and we can't really do that very well in humans. So a lot of the amazing work that Tononi and Cirelli have been doing, have been focused in rodent models, just because we have so many amazing methods that we can use in rodents that you just can't use in humans. This project is focused on using a few different multimodal assessments to try to get at synaptic strength, to understand if they're all moving in the same direction, because that'll give us our best guess, if we're onto the right conclusions, in terms of how slow-wave activity affects plasticity. So we're going to be using TMS for example, to measure cortical excitability. We're going to be doing that waking EEG paradigm again. We're also going to be measuring brain-derived neurotrophic factor, so BDNF. Hopefully, if we use all of these noninvasive methods that you can use in humans and they all move in the same direction, we'll be able to get a little bit further than we have so far.

Dan Pardi - 34:24: Jennifer, thank you for coming onto the show and talking to me about this really exciting area. Sleep and mood has been a subject peripheral to the work that I've done, but you're a real expert on the subject, and I think you are going to be one of the forces driving a better understanding and better therapies for people who are suffering in this way. And also very interesting to understand our relationship in people that don't have depression, and how sleep and mood interact. So thank you for your time and coming onto the show.

Jennifer Goldschmied - 34:54: Well, thanks so much. It's been really fun. Thank you for having me.