Contributed by Shawniqua Williams Roberson, M.Eng., M.D., Departments of Neurology and Biomedical Engineering, Vanderbilt University Medical Center, Nashville, TN. Dr. Williams is a graduate of the 2019 NIDUS Bootcamp.
Many of us are familiar with the feeling of not getting enough sleep. Perhaps a storm rattled the windows all night, or the baby couldn’t stop crying. Perhaps there was anticipation about a major event planned for the next day. The less good, quality sleep we achieve, the more bleary-eyed and foggy we feel. Disrupted sleep causes impairments in sustained attention, difficulty with complex executive functions and poor long-term memory.1,2
There are few experiences more disruptive of normal, healthy sleep than that of being a patient in the intensive care unit (ICU). The standard of care in the ICU is such that patients require nursing interventions at least once per hour, 24 hours per day. In most cases the experience also involves being connected to unusual tubes, catheters and restraints through various orifices, natural and unnatural, and listening to incessant beeps, alerts, buzzes and whirring of machines. This is in addition to whatever aches, pains or general discomfort a person may feel in association with his or her illness. It’s hard to imagine anyone getting any amount of sleep under such conditions, so it is no surprise that ICU patients get less good quality sleep.3 Nor is it a shock that these individuals are at higher risk of delirium, an acute state of brain dysfunction characterized by fluctuating levels of alertness, inattention and disordered thinking.4,5
But why is sleep so important to our cognitive function? And how could sleep deprivation precipitate delirium? Electroencephalography (EEG) is a decades-old tool to examine the brain’s patterns of electrical activity – patterns that change predictably with wakefulness, sleep and delirium.6,7 Since specific electrophysiologic patterns mark several of the restorative functions of sleep, these patterns may give insights to the mechanisms by which sleep disruption could lead to acute brain dysfunction in the ICU.
A quick primer on electroencephalography
EEG consists of the recording of time-varying voltage signals from the brain, through electrodes applied to various locations over the scalp. Neurophysiologists visually inspect the EEG signal to evaluate its composition – the relative contributions of voltage oscillations in specific frequency ranges. The most clinically pertinent and easily identified frequency ranges in adult scalp EEG are slow oscillations (less than 1Hz), delta activity (1-4Hz), theta activity (4-7Hz), alpha activity (8-13Hz) and beta activity (13-35Hz). Among healthy adults, the normal waking EEG demonstrates beta activity in the frontal regions and alpha activity in the posterior regions. During drowsiness, theta activity becomes more apparent. During non-rapid eye movement (NREM) sleep, slow oscillations and delta activity dominate the EEG. Sleep spindles, brief sinusoidal oscillations at 12-15Hz in the frontal and central regions, punctuate the EEG in stage II sleep. During rapid eye movement (REM) sleep, beta and theta activity again become more apparent.
The restorative electrophysiology of sleep
The oscillatory patterns recorded on the EEG during sleep are associated with physiologic activities in the brain that support healthy cognitive function. There are two main sleep-related processes in particular that, when disrupted, probably increase risk for delirium: synaptic homeostasis and metabolic waste clearance.
Synaptic homeostasis refers to the process by which the brain reorganizes previously acquired information and optimizes efficiency of information storage. According to the popular synaptic homeostasis hypothesis,8 this efficiency is an important part of ongoing cognitive function, because learning new information requires building and strengthening connections between neurons (called synapses), an energetically expensive endeavor. Synaptic homeostasis during sleep allows more efficient storage of important memories and targeted forgetting of those that are less salient.9 This homeostatic process appears to rely on 3 key subprocesses: 1) replay of memories, 2) re-encoding (or consolidation) of memories deemed important and 3) disengagement (forgetting) of less important memories. Theta oscillations in drowsiness and REM sleep are associated with replay of memories that were acquired during wakefulness.10 Sleep spindles are associated with memory consolidation,11 while delta waves are important for homeostatic forgetting of memories acquired prior to sleep.12
Metabolic waste clearance refers to the processes by which the brain (or any organ, for that matter) eliminates protein fragments and other molecules that are generated as by-products of its normal function. Neurons are among the highest cellular consumers of energy in the body, and produce metabolic waste to a greater extent than other cell types.13 Examples of neuronal metabolic waste products include amyloid beta (A)14 and phosphorylated tau, proteins whose chronic accumulation is associated with Alzheimer’s dementia.15 Evidence suggests we ‘flush out’ such products during sleep by convective exchange of brain fluid in the spaces around our blood vessels (termed the ‘glymphatic system’).16 The rhythmic pulsations of cerebrospinal fluid (CSF) that facilitate this convective exchange are driven by EEG slow oscillations17 during sleep.
Deliriogenic effects of sleep disruption
When sleep is disrupted, the normal processes facilitating synaptic homeostasis and metabolic waste clearance are not allowed to proceed. Disruptions in synaptic homeostasis may lead to impaired retention of old information and impaired integration of new information, resulting in cognitive slowing and disorganized thinking. Decreased clearance of metabolic waste products may result in buildup of toxins and molecules that could disrupt normal brain cell signaling by altering the brain’s electrochemical milieu. A classic example of toxic buildup affecting cerebral processes is that of hepatic encephalopathy: buildup of ammonia leads to altered synthesis of glutamine, a neurotransmitter precursor molecule. The resulting biochemical changes in the brain precipitate a syndrome of altered mental status, abnormal movements and fluctuating levels of consciousness.18 In the case of hepatic encephalopathy, ammonia buildup is due to impaired hepatic clearance via the urea cycle. Yet it is conceivable that ammonia and other molecules may accumulate in the absence of hepatic failure if the brain goes several days without the slow oscillations that drive its normal waste clearance processes.
In this way, sleep deprivation over several days during critical illness could result in altered mental status and fluctuating level of consciousness due to impaired waste clearance, and to cognitive slowing with disorganized thinking due to impaired synaptic homeostasis. These clinical manifestations (altered mental status, fluctuating level of consciousness, cognitive slowing and disorganized thinking) are characteristic of delirium. Inattention, a cardinal sign of delirium, may be a result of the above
combination of symptoms, or may be due to the preferential effect of sleep disruption on prefrontal areas of the brain that mediate executive functions such as planning and attention.
Delirium and sleep disruption – a bidirectional relationship?
Delirium itself is associated with characteristic EEG patterns: an increase in theta and delta activity, a decrease in alpha activity and loss of the spatial organization of oscillations typically present during normal wakefulness or sleep. This may be due to a lack of coordinated slow oscillations that normally modulate cerebral function during sleep. In a convenience sample of 12 patients recovering from orthopedic surgery, severity of delirium was associated with shorter total sleep time the night after surgery, increased delta activity during the subsequent day, and decreased delta activity on the second night.19 The bidirectional relationship between delirium and sleep deprivation may induce a self-propelling cycle, with worsening impairments in memory, cognition and metabolic waste clearance that escalate over time.
Summary and Conclusion
The cognitive benefits of sleep are most obvious when normal sleep is disrupted, and nowhere is this more the case than in the intensive care unit. EEG is an important tool for understanding the physiologic processes underlying sleep and the bidirectional relationship between sleep disruption and delirium. Unique EEG patterns are associated with brain functions mediating synaptic homeostasis and metabolic waste clearance, and their disruption may explain the impairments in cognition, attention and alertness commonly seen in delirium. These theoretical links, if confirmed experimentally, may provide mechanistic insight to one of the many exposures leading to delirium in the ICU.
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- Elliott R, McKinley S, Cistulli P, Fien M. Characterisation of sleep in intensive care using 24-hour polysomnography: an observational study. Crit Care. 2013;17(2):R46.
- Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y. Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007;33(1):66-73.
- Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA : the journal of the American Medical Association. 2001;286(21):2703-2710.
- Krishnan V, Chang BS, Schomer DL. Normal EEG in Wakefulness and Sleep: Adults and Elderly. In: Schomer DL, Lopes da Silva FH, eds. Niedermeyer’s Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. 7 ed.: Oxford University Press; 2017.
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- Tononi G, Cirelli C. Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration. Neuron. 2014;81(1):12-34.
- Poe GR. Sleep Is for Forgetting. J Neurosci. 2017;37(3):464-473.
- Theodoni P, Rovira B, Wang Y, Roxin A. Theta-modulation drives the emergence of connectivity patterns underlying replay in a network model of place cells. eLife. 2018;7:1-33.
- Fernandez LMJ, Lüthi A. Sleep spindles: Mechanisms and functions. Physiological Reviews. 2020;100(2):805-868.
- Kim J, Gulati T, Ganguly K. Competing Roles of Slow Oscillations and Delta Waves in Memory Consolidation versus Forgetting. Cell. 2019;179(2):514-526.e513.
- Berndt N, Holzhutter HG. The high energy demand of neuronal cells caused by passive leak currents is not a waste of energy. Cell Biochem Biophys. 2013;67(2):527-535.
- Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258(5079):126-129.
- Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577-1590.
- Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra111.
- Fultz NE, Bonmassar G, Setsompop K, et al. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science. 2019;366(6465):628-631.
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- Evans JL, Nadler JW, Preud’homme XA, et al. Pilot prospective study of post-surgery sleep and EEG predictors of post-operative delirium. Clinical Neurophysiology. 2017;128(8):1421-1425.