The Sobering Science of Sleep

What are the four pillars of health? If you had asked me that question five years ago, I would have responded with the following list:

1. NUTRITION

The research is clear. To minimize one’s risk of metabolic, cardiovascular and neurodegenerative disease, the single best prescription is – in the dangerously concise words of Michael Pollan – to eat real food, mostly plants, and not too much1.

2. EXERCISE

The benefits are endless. Mobility mitigates fall risk2. Weight training reduces metabolic disease risk3. Aerobic exercise improves memory4 and facilitates neurogenesis5. I could go on…

3. STRESS MANAGEMENT

Most people intuitively grasp the damaging effects of chronic stress. The “fight or flight” branch of the autonomic nervous system, which evolved to serve us in circumstances of acute threat, exerts harmful effects on our brain and body when chronically active. These include immune suppression6, cognitive impairment7, and premature aging8. If you want to optimize your lifespan – and more importantly, your healthspan – stress management is critical.

4. SLEEP

Sleep must be important. We spend about one third of our lives sleeping. If it was an expendable adaptation, evolution would have dispensed with it. To lay unconscious, vulnerable to predation for almost half of one’s day is as asinine an evolutionary strategy as one could devise, unless the benefit somehow outweighed the cost. Sleep’s persistence hints at something fundamental about its interaction with our physiology. While this much is clear, precisely why sleep matters is a mystery (in other words, I am uninformed and ignorant).

Fast forward to 2018. If you asked me to rank order these four variables today, my answer would be much different. After reading a fascinating, frightening book called “Why We Sleep” by Dr. Matthew Walker, and digging into the relevant research, I’m now convinced that sleep is, if not more important, at least on equal footing with exercise and nutrition. In this three-part series of posts, I’m going to summarize the body of literature that changed my mind. This first post will focus on a type of sleep called non-rapid eye movement (NREM) sleep. The second will focus on rapid eye movement (dream) sleep. The last post will be a short, tactical list of implementable strategies that you can use to improve your sleep quality.

DECLARATIVE MEMORY

Sleep consolidates memories. When you read a fact in a book, your brain houses it in a region called the hippocampus. Unfortunately, the hippocampus has a finite storage capacity. Your brain overcomes this lack of cognitive real estate by transferring short term memory traces to an area called the neocortex for long term storage. Scientists have long known of the importance of this memory transfer process, but had failed for years to elucidate a satisfactory mechanism. Dr. Matthew Walker, a neuroscientist at UC Berkeley, suspected that sleep was somehow involved. To test his hypothesis, he recruited volunteers for an intense fact-based learning session, after which he divided them into two groups, one which took a ninety minute nap, and one which remained awake. A few hours later, both groups performed another round of learning tasks. The next day, they were tested on the material they had learned in the second bout. If sleep acts as a file transfer mechanism, Walker reasoned, the nap group should register more facts in the second bout, after their hippocampus has been “cleaned out.” This is precisely what occurred. The “nap” group scored 20% higher than the “non-nap” group on the subsequent recall test9. Walker went further, analyzing electrical recordings of each subject’s brain during their post learning nap to search for patterns of interconnectivity. He discovered that the improvement in learning capacity upon waking was tightly linked to the presence of electrical events called sleep spindles, which occur exclusively during stage 2 NREM sleep. Walker observed an electrical loop of such spindles physically travelling from the hippocampus to the cortex (the long term storage vault) during NREM sleep. Walker’s elegantly simple model is shown below.

Saletin, J. M., & Walker, M. P. (2012). Nocturnal mnemonics: sleep and hippocampal memory processing. Frontiers in neurology, 3, 59.

This result confirmed Walker’s suspicion. Sleep does facilitate the transfer of memory substrates from the hippocampus to the cortex. Upon waking, the hippocampus is freshly equipped to absorb newly presented information. Importantly, the sleep spindles which mediated this effect are especially concentrated in the latter hours of one’s sleep. To sleep six rather than eight hours is to deprive yourself of a profoundly restorative piece of cognitive housekeeping. As a student, this finding hits me right where it hurts. It’s hard enough to learn esoteric anatomical terms at the best of times…

NREM sleep not only performs a nightly refresh of our short term memory bank, but it also locks in place memories which have already been transferred to the cortex. In one study, participants learned a set of facts, and then were permitted to sleep for eight hours. The next morning, they performed a recall test. Predictably, participants’ scores turned out to be tightly correlated with the quantity of NREM sleep obtained the previous night. Dr. Walker confirmed this phenomenon using functional magnetic resonance imaging. When he observed the brains of individuals retrieving memories before sleeping, their hippocampus was chiefly active. The next morning, when retrieving the very same memory, the hippocampus was dormant, and the cortex – the long term storage repository – lit up like a Christmas tree.

Incidentally, it shouldn’t surprise you to learn that the affected region in most forms of dementia is the hippocampus. This explains what I once found to be a puzzling phenomenon. Individuals with late stage dementia often remember events from their childhood with vivid clarity. The reason for this is simple: those events made it to the cortex before their hippocampus deteriorated.

PROCEDURAL MEMORY

Sleep’s effects are not confined to the realm of fact-based learning. Let’s investigate sleep’s effects on motor learning, the type of memory involved in playing the piano, shooting a free throw, or performing a deadlift. We’ve all been there. You’re learning a new skill. You practice, and practice, and practice, but at a certain point, you hit the metaphorical wall. You just can’t crack the code. Someone wise tells you to sleep on it. You wake up the next day, and it just flows. What drove that unconscious breakthrough? Was it the fact that you took a break, and came back to it? Or was it the fact that you took a break, and slept, and came back to it? Walker examined this question by recruiting a group of volunteers to learn a keyboard number sequence with their non-dominant hand. Half the subjects practiced the sequence in the morning for 12 minutes. They were then tested for speed and accuracy in the evening, after a 12 hour break. The other half of the subjects practiced the sequence in the evening, and were tested for speed and accuracy the following morning, after an equivalent amount of time which included sleep. The group which slept scored 20 percent higher in speed, and 35% higher in accuracy than the group who stayed awake10. To examine the time-dependency of this effect, the “no sleep” group was tested again the next day after a good night’s sleep (far left panel). Remarkably, they accrued the same gains in performance. The far right panel below shows that it was the same magical stage of sleep – stage 2 NREM sleep – which drove skill improvement. It turns out that the old maxim “practice makes perfect” is incomplete. As Walker put it in the title of his paper, “practice with sleep makes perfect.”

Walker, M. P., Brakefield, T., Morgan, A., Hobson, J. A., & Stickgold, R. (2002). Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron, 35(1), 205-211.

DROWSY DRIVING

Let’s switch gears, briefly, from fascinating neuroscience to frightening statistics. For all the attention given to the dangers of drunk driving, scarcely a word is ever said about drowsy driving. And yet, a research team in Australia found that a single night of sleep deprivation impairs cognition and attention as much if not more than being legally drunk11. This means that if you wake up at six a.m. for work, and spend the evening out with friends (but abstain from alcohol) and drive home at eleven p.m., you are as impaired as if your blood alcohol levels were over the legal limit. If you sleep for four rather than 7 hours tonight, and get behind the wheel of a car tomorrow, you are 11.5 times more likely to get in a car crash12. Hopefully that woke you up.

EMOTIONAL INTELLIGENCE

When I’m sleep deprived, I’m an all around horrible human being. I lose the capacity for empathy. I don’t reason particularly well. I feel irrational, volatile, and stressed. Walker’s research team investigated the neurophysiological basis for this common anecdote by scanning the brains of sleep deprived individuals while they viewed emotionally charged images. In comparison to a group that was given a full night’s rest, sleep-deprived individuals responded to stressful stimuli with a 60% increase in activity of a brain region called the amygdala13.

Yoo, S. S., Gujar, N., Hu, P., Jolesz, F. A., & Walker, M. P. (2007). The human emotional brain without sleep—a prefrontal amygdala disconnect. Current Biology, 17(20), R877-R878.

The amygdala is the primary neural locus of fear, anxiety, and rage. How does sleep deprivation turn up the dial on the amygdala? Well, technically, it doesn’t. It actually turns the dial down on the logical, rational “CEO” of the brain, called the prefrontal cortex (PFC), which normally sends inhibitory projections to the amygdala when it overreacts. When you’re well slept, a stressful situation proceeds as follows: the amygdala fires, initiating a frantic stress response, preparing you to fight, flight or freeze. The PFC then logically appraises the stimulus, and if the amygdala’s response was unwarranted, the PFC tells it to quiet down. If you are under-slept, the cortex abdicates its position as emotional thermostat. Threat detection systems kick into high gear, and you shift into a primordial mode of survival, incapable of logically appraising the world around you. If you want the CEO of your brain to show up for work and do its job, making sleep a priority is a good start.

ALZHEIMER’S DISEASE

Alzheimer’s Disease (AD) is a debilitating form of dementia, which afflicts 40 million people worldwide. It is characterized by the accumulation of a pair of toxic proteins in the brain called beta-amyloid and tau, which kill brain cells. Though the causes of AD are wide-ranging, recent research suggests that sleep deprivation plays a causal role in its development. If you took high school Biology, you may vaguely remember something called the “lymphatic system,” which transports waste products surrounding our body’s cells into general circulation for degradation by the liver. In 2013, Dr. Maiken Nedergaard, one of the world’s experts on the Blood-Brain-Barrier, published a paper called “Garbage Truck of the Brain14” in which she introduced a functionally analogous system in the brain. She called it the “glymphatic” system because it is orchestrated in large part by glial cells. Neurons are highly metabolically active, constantly producing toxic byproducts which accumulate in interstitial fluid. Two such byproducts are amyloid beta and tau, the proteins associated with Alzheimer’s. The glymphatic system works tirelessly to drain this toxic soup of interstitial fluid, replacing it with fresh, nutrient-rich cerebrospinalfluid (mechanism shown below).

Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., … & Takano, T. (2013). Sleep drives metabolite clearance from the adult brain. science, 342(6156), 373-377.

Though this was a landmark finding in its own right, Nedergaard’s most important discovery concerns the link between the glymphatic system and sleep. During the pulsing rhythm of NREM sleep, the glymphatic system’s fluid transfer rate increases twentyfold15! Given the striking correlations between sleep loss and AD, this provides a compelling causal link between the two phenomena. How precisely does sleep accelerate this critical process? During NREM sleep, the glial cells (specifically called astrocytes, a subtype of glia) shrink in size up by up to 60%, increasing the space around neurons to facilitate more efficient toxin flushing.

Obviously, poor sleep is only one of many predictors of Alzheimer’s Disease. AD is undoubtedly caused by a constellation of complex, interconnected factors, and it would be careless to attribute any individual’s case of AD to sleep deprivation alone. Nonetheless, the mechanistic account described above gives me ample motivation to optimize my sleep habits as early as possible.

If you found this line of research half as fascinating as I did, this post was worth writing. The next instalment in this series will focus on what I think is an even more interesting story: dream sleep. Stay tuned, and in the meantime, sleep well.

References

1. Pollan, M. (2013). Food rules: An eater’s manual. Penguin Group USA.

2. Pata, R. W., Lord, K., & Lamb, J. (2014). The effect of Pilates based exercise on mobility, postural stability, and balance in order to decrease fall risk in older adults. Journal of bodywork and movement therapies, 18(3), 361-367.

3. Vinet, A., Obert, P., Dutheil, F., Diagne, L., Chapier, R., Lesourd, B., … & Walther, G. (2015). Impact of a lifestyle program on vascular insulin resistance in metabolic syndrome subjects: the RESOLVE study. The Journal of Clinical Endocrinology & Metabolism, 100(2), 442-450.

4. Ten Brinke, L. F., Bolandzadeh, N., Nagamatsu, L. S., Hsu, C. L., Davis, J. C., Miran-Khan, K., & Liu-Ambrose, T. (2015). Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial. Br J Sports Med, 49(4), 248-254.

5. Knowles, J. (2017). Evaluation of the effects of aerobic exercise interventions on levels of brain derived neurotropic factor (BDNF) in adults with major depression (Doctoral dissertation, Queen Margaret University).

6. Dhabhar, F. S. (2014). Effects of stress on immune function: the good, the bad, and the beautiful. Immunologic research, 58(2-3), 193-210.

7. Arnsten, A. F. (2015). Stress weakens prefrontal networks: molecular insults to higher cognition. Nature neuroscience, 18(10), 1376.

8. Zannas, A. S., Arloth, J., Carrillo-Roa, T., Iurato, S., Röh, S., Ressler, K. J., … & Menke, A. (2015). Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome biology, 16(1), 266.

9. Saletin, J. M., & Walker, M. P. (2012). Nocturnal mnemonics: sleep and hippocampal memory processing. Frontiers in neurology, 3, 59.

10. Walker, M. P., Brakefield, T., Morgan, A., Hobson, J. A., & Stickgold, R. (2002). Practice with sleep makes perfect: sleep-dependent motor skill learning. Neuron, 35(1), 205-211.

11. Williamson, A. M., & Feyer, A. M. (2000). Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication. Occupational and environmental medicine, 57(10), 649-655.

12. http://aaafoundation.org/acute-sleep-deprivation-risk-motor-vehicle-crash-involvement

13. Yoo, S. S., Gujar, N., Hu, P., Jolesz, F. A., & Walker, M. P. (2007). The human emotional brain without sleep—a prefrontal amygdala disconnect. Current Biology, 17(20), R877-R878.

14. Nedergaard, M. (2013). Garbage truck of the brain. Science, 340(6140), 1529-1530.

15. Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., … & Takano, T. (2013). Sleep drives metabolite clearance from the adult brain. science, 342(6156), 373-377.