Neuroscience Breakthroughs Since Graduate School - Part 1: Sleep

Behavioral neuroscience discoveries have proceeded at a rapid pace. This series highlights cutting-edge findings and explains their importance for neurofeedback providers and their clients. This initial installment focuses on sleep.

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Sleep Architecture Overview

We can divide sleep into non-REM (NREM) sleep which contains three stages, and rapid eye movement (REM) sleep. Stage 3 sleep (NREM3), termed slow-wave sleep and REM sleep, are arguably the most crucial stages. Following total sleep deprivation, we spend more time in Stage 3 on night one and in REM on night two (Breedlove & Watson, 2020). Graphic retrieved from Healing Touch Diagnostics.

An average night’s sleep contains 4-5 cycles, 90-110 minutes each. Adults spend about 20% of total sleep in REM. Early cycles contain more stage 3 slow wave sleep (SWS), while later cycles contain increasing amounts of REM sleep (Breedlove & Watson, 2020). The hormone hypocretin regulates the order of our sleep stages. Excessive hypocretin is associated with insomnia, whereas deficient hypocretin is observed in narcolepsy (Holm et al., 2022). Graphic of a typical night of young adult sleep © Oxford University Press.

Why Is SWS Important?

SWS performs four functions vital to brain health and performance: growth hormone release, glymphatic system waste removal, replenishing astrocyte glycogen stores, and consolidating memory.

Growth Hormone Release

The body releases most growth hormone (GH; somatotropin) during SWS in the first half of the night. GH promotes bodywide tissue growth and repair by influencing protein metabolism (Breedlove & Watson, 2020). Graphic by Smiley et al. (2019) retrieved from ResearchGate.

At age 60, we spend half the time in stage 3 compared with age 20. Stage 3 sleep disappears by age 90, and its loss may be associated with cognitive impairment. Patients diagnosed with senile dementia spend significantly less time in Stage 3 (Kondratova & Kondratova, 2012). Growth hormone loss due to sleep disruption and the progressive reduction in Stage 3 sleep may cause cognitive deficits. Graphic of elderly sleep © Oxford University Press.

Glymphatic System Waste Removal

The human brain contains a recently-discovered glymphatic system. This astrocyte-controlled lymphatic system removes cellular debris, proteins, and wastes (Xie et al., 2013). The flushing of toxic substances may protect us from neurological disorders like Alzheimer’s (Breedlove & Watson, 2020). Jeff Illiff showed waste removal in mice brains during sleep in his excellent 2014 TED MED Talk, One More Reason to Get a Good Night's Sleep. However, the discovery of the glymphatic system contradicted his view that there are no lymphatic vessels in the brain.

In the diagram below: (1) cerebrospinal fluid (CSF) flows from the subarachnoid space to travel outside pulsing arteries, (2) CSF enters the brain via aquaporins and collects waste, and (3) CSF enters the perivascular space surrounding capillaries and is removed by venous circulation. Graphic adapted by Wostyn and Goddaer (2022).

Stage 3 sleep accelerates the glymphatic system’s clearance of β-amyloid (Holth et al., 2019), which is shown in orange. Graphic © The University of Chicago retrieved from Science Life Education & Research News. Immune cells in the brain play key role in relationship between gut microbes and beta-amyloid.

β-amyloid may initiate a cascade that transforms tau protein into a highly toxic molecule (Zhang et al., 2020), shown in red. Image by Juan Gaertner. Retrieved from News-Medical.Net. Alzheimer's and its helper protein.

Replenishing Astrocyte Glycogen Stores

Astrocytes are star-shaped glial cells that comprise part of the protective blood-brain barrier (BBB). The human brain primarily stores the energy source glycogen in astrocytes (Öz et al., 2007). Astrocyte graphic © Kateryna Kon/Shutterstock.com.

Due to generally reduced metabolic demand compared with waking, stage 3 sleep allows astrocytes to rebuild their energy reserves when demand from neurons is the lowest. Astrocytes release glycogen to neurons during peak activity when we are awake (Bellesi et al., 2018; Schummers et al., 2008).

Neurons convert glycogen to glucose. Glycolysis and oxidative phosphorylation transform glucose into ATP (Ashrafi & Ryan, 2017). ATP powers vital neuronal functions like the sodium-potassium pumps, which restore a neuron's membrane potential. Graphic © Designua/ Shutterstock.com.

Consolidating Memory

NREM sleep helps to consolidate declarative memories, which are memories we can describe (Nishida & Walker, 2007). In contrast, sleep deprivation helps to create false memories (Marshall et al., 2006). Norepinephrine (NE) levels rise and fall every 30 seconds in the sleeping mouse brain. The peaks (high NE levels) are associated with more than 100 brief awakenings that may aid memory consolidation. The valleys (low NE levels) occur when they are asleep (Kjaerby et al., 2022). Memory consolidation during NREM sleep appears to involve replaying the pattern of

neuronal firing observed when learning a task (Euston et al., 2007).

Each NREM slow wave is a “courier” that moves “packets of information” between anatomical regions (Walker, 2018).

NREM slow waves transfer fragile short-term memories from temporary (hippocampal) to long-term (cortical) storage.

Ripples Contribute to Human Memory Consolidation

We store a memory's sensory elements in specialized areas (e.g., auditory and visual) that are distributed across the cortex. The brain may coordinate these widespread networks during sleep and waking through synchronized 90-Hz oscillations called ripples.

During waking, cortical ripples occur on local high-frequency activity peaks. During sleep, cortical ripples typically occur on the cortical down-to-upstate transition, often with 10- to 16-Hz cortical sleep spindles, and local unit firing patterns consistent with generation by pyramidal-interneuron feedback. We found that cortical ripples group cofiring within the window of spike-timing-dependent plasticity. These findings are consistent with cortical ripples contributing to memory consolidation during NREM in humans (Dickey et al., 2022).

Inferior parietal cortex ripples in the human brain during NREM and waking © PNAS.

NREM-REM Partnership

The consolidation process may also determine which synapses survive and which are pruned away. NREM sleep consolidates new information, and REM sleep integrates it with our experience. NREM sleep removes outdated synapses, while REM sleep strengthens necessary connections. Graphic © Christoph Burgstedt/Shutterstock.com.

Why Is REM Sleep Important?

Rapid eye movements during REM sleep track the dream imagery created by mouse brains (Senzai & Scanziani, 2022). Jagged sawtooth waves (STWs) during REM sleep may synchronize the replay of memories to consolidate them (Frauscher et al., 2020). Graphic © The Atlas of Adult Electroencephalography.

REM sleep revises autobiographical memories to reflect the previous day’s events (Walker, 2018). Below, oligodendrocytes mediate memory formation in the central nervous system (Fields, 2019).

Graphic © Juan Gaertner/Shutterstock.com.

The interaction between NREM and REM sleep remodels neural circuitry based on current priorities to efficiently manage our brain’s limited storage capacity (Walker, 2018).

From Hutchinson and Rathore's (2015) perspective, REM sleep may strengthen and modify emotional memories.

. . . REM sleep represents a unique brain state that allows the emotionally modulated integration and recombination of neocortical memory traces previously consolidated during NREM sleep. In addition, we suggest that REM sleep is involved in the gradual disengagement of successfully consolidated memory traces from the hippocampus—thus mediating the decontextualization of novel memories, allowing generalization, abstraction, etc.

Why Does Sleep Matter?

1. Sleeping less than 6 hours a night is associated with adverse health outcomes and increased mortality (Cappuccio et al., 2010)

2. Insomnia is linked to an increased risk of Alzheimer’s and other neurodegenerative diseases (Sadeghmousavi et al., 2020).

3. Sleep disorders can trigger episodes of disorders like depression and schizophrenia (Khurshid, 2018).

4. Insomnia impairs executive functions like continuous attention and problem-solving, impairing performance (Ballesio et al., 2019). Graphic © TheVisualsYouNeed/Shutterstock.com.

Insufficient sleep is associated with diverse health and performance problems. Graphic © Harvard Medical School.

How Has the COVID-19 Pandemic Impacted Sleep?

The pandemic has worsened insomnia due to:

1. the disruption of routines, including exercise

2. loss of time anchors (e.g., commuting to work) 3. reduced daylight exposure; increased screen time

4. excessive napping and oversleeping

5. worry and anxiety due to financial and health uncertainty, amplified by COVID fatigue, loss of privacy, and social media

6. social isolation, grief, and depression

7. family/work stress due when entire families shelter in place

8. major increase in screen time, resulting in reduced melatonin release and less sleep pressure

9. stress-related fatigue that robs you of energy and motivation when you wake up

10. increased substance misuse and relapse of substance use disorders

11. relapsing or worsening health problems (SleepFoundation.org, 2020)

Evidence-Based Interventions

Good sleep hygiene is critical for health and successful biofeedback and neurofeedback training. For example, ambient bedroom light can disrupt sleep, lower heart rate variability, and increase insulin resistance.

Sharon Begley and Inna Khazan separately contributed several evidence-based strategies.

1. Sleep in a darkened room.

Why? One night's exposure to bedroom illumination of ~100 lux increased heart rate, decreased heart rate variability, and increased next-morning insulin resistance compared to < 3 lux (Mason et al., 2022). In addition, sleeping with ambient light increases alertness, delays sleep onset, and suppresses melatonin secretion, dysregulating circadian rhythms (Cho et al., 2015). Graphic © Ground Picture/Shutterstock.com.

2. Avoid blue light before bed.

Why? Blue light from an iPad after 9 pm can delay your circadian rhythm by an hour and reduce the restfulness of even 8 hours of sleep (Chang et al., 2015).

In addition, exposure to bright screens 2 hours before bedtime can delay sleep onset. Graphic © Subbotina Anna/Shutterstock.com.

Instead? Swap a paperback for an iPad. (Undergrads might have to Google paperback.) Apple’s Night Shift mode still significantly suppresses melatonin which regulates your circadian rhythm (Nagare et al., 2018).

3. Stop hitting the snooze button.

Why? When you return to sleep and awaken minutes later, you may experience the grogginess of sleep inertia. This can interfere with attention and memory.

Instead? Make your sleep schedule more consistent, allow morning light to awaken you, and adjust your circadian rhythm.

4. Experience daylight.

Why? Daylight is one of the most effective circadian cues. In one small study (Boubekri et al., 2014), workers with windows reported better global sleep quality and fewer disturbances than those without.

How? When your office desk doesn’t provide sunlight, you can walk during your lunch hour to reconnect with this circadian cue. Alternatively, use a full-spectrum lamp.

5. Skip alcohol before bed.

Why? While alcohol may help you get to sleep more quickly, it reduces REM sleep (Ebrahim et al., 2013) and increases nighttime urination. This can cause drowsiness, impaired concentration, and failure to integrate new information. Graphic © Lysenko Andrii/Shutterstock.com.

6. Exercise to lengthen sleep time.

Why? Thirty minutes of afternoon exercise at least three times a week increased elderly participants’ sleep duration by 45-60 minutes after 4 months (Baron et al., 2013). Graphic © Lordn/Shutterstock.com.

Cautions? Don’t exercise 4 hours before bedtime because exercise activates your nervous system and raises core body temperature. Passive stretching and yoga are fine (Khazan, 2019).

7. Put away the clock once in bed.

Why? Looking at the clock while in bed can increase activation and anxiety, disrupting sleep.

Instead? Cover or remove clocks and hide your cell phone.

8. Watch eating and drinking before bed.

Why? Since digestion slows when you sleep, heavy meals 4 hours before bedtime can awaken you. This is critical if you experience heartburn. Drinking fluids before bedtime can increase the frequency of nighttime urination, fragmenting sleep. Instead? Limit food intake to light snacks and stop liquids for 2 hours (alcohol at least 3 hours) before bedtime.

9. Don’t nap.

Why? Stanford sleep researcher Donn Posner compares napping to eating snacks before dinner. Naps make us less drowsy since they decrease sleep pressure. However, naps are less disruptive for habitual nappers (Hirschlag, 2020).

Summary

Sleep is critical for health and optimal performance. Clients whose sleep architecture and duration satisfy their individual needs often achieve better executive functioning and self-regulation.

The discovery of the glymphatic system and its role in waste clearance during SWS was one of the most important discoveries in the neuroscience of sleep. This breakthrough revealed that the lymphatic system encompasses the brain and clears most wastes during SWS. Sleep disorders that reduce SWS risk the buildup of proteins that may promote neurodegenerative diseases like Alzheimer's. The finding that growth hormone is released during SWS, which steadily declines with aging until it disappears by age 90, provides another explanation for reduced brain repair and neurodegeneration.

The eight evidence-based recommendations provide a foundation for good sleep hygiene. Suppose clients continue to experience insomnia after implementing these suggestions. In that case, they might consult their physician for a home sleep study that could justify an in-clinic study at an accredited sleep laboratory.

Glossary

astrocytes: star-shaped glial cells that communicate with and support neurons and help determine whether synapses will form.

β-amyloid: the main constituent of amyloid plaques found in Alzheimer's patients.

glucose: a simple sugar that is the body's main energy source.

glycogen: the stored form of glucose comprised of many connected glucose molecules.

glymphatic system: an astrocyte-controlled lymphatic system that removes cellular debris, proteins, and wastes from the brain.

growth hormone (GH, somatotropin): an anterior pituitary tropic hormone released during SWS that regulates cell and tissue growth.

hypnogram: a diagram that summarizes the stages of sleep recorded in the sleep laboratory.

hypocretin (orexin): a peptide hormone that regulates the transition between sleep stages.

insomnia: a condition marked by trouble falling asleep or staying asleep.

insulin resistance: impaired insulin utilization resulting in elevated blood glucose.

melatonin: a hormone that helps regulate circadian rhythms, produced in a predictable

daily rhythm by the pineal gland.

non-REM (NREM) sleep: sleep stages without rapid eye movements, divided into stages 1, 2, and 3 sleep.

oligodendrocytes: glial cells that insulate adjacent axons within the brain and spinal cord of the central nervous system.

rapid eye movement (REM) sleep: also called paradoxical sleep. A sleep stage characterized by small-amplitude, fast EEG waves, no postural tension, and rapid eye movements.

ripples: synchronized high-frequency (90-Hz) cortical oscillations that coordinate widespread cortical networks during sleep and waking to bind sensory elements and consolidate memory.

sawtooth waves (STW): bursts of slow oscillations in the scalp EEG.

sleep architecture: the pattern made when sleep stages are charted on a hypnogram.

sleep cycle: a period of slow-wave sleep followed by a period of REM sleep that typically lasts 90-110 minutes.

sleep deprivation: the partial or total prevention of sleep.

sleep hygiene: habits, like stopping caffeine in the afternoon, that promote healthy sleep.

sleep recovery: the process of sleeping more than is normal after a period of sleep deprivation as though in compensation.

stage 1 sleep: also called NREM1. The initial stage of NREM sleep, which is characterized by small-amplitude EEG waves of irregular frequency, slow heart rate, and reduced muscle tension.

stage 2 sleep: also called NREM2. A stage of NREM sleep that is defined by bursts of EEG waves called sleep spindles.

stage 3 sleep: also called NREM3. A stage of NREM sleep that is defined by the presence of large-amplitude, very slow waves (delta waves).

tau protein: a protein that helps stabilize axon microtubules but can produce toxic neurofibrillary tangles when modified.

theta rhythm: 4-8-Hz rhythms generated a cholinergic septohippocampal system that receives input from the ascending reticular formation and a noncholinergic system that originates in the entorhinal cortex, which corresponds to Brodmann areas 28 and 34 at the caudal region of the temporal lobe.

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2. loss of time anchors (e.g., commuting to work)