By Christopher Gabor
If you work in the field of delirium, the following scenario may sound familiar to you. You are going about your day as usual, fervently working to prevent delirium and spread awareness, when you are starkly interrupted by a colleague. They appear overly exhausted and tired, and joke, “I think I must be in a delirium!” Little do they know, this is the 17th time you’ve heard this joke. In fact, it may be the “working hard, hardly working" joke cliché of the delirium field. Regardless, you respond with feigned laughter, and give him or her the benefit of the doubt that their sleep deprivation must be what is responsible for such an unoriginal joke. However, as weary of this joke we all may be, perhaps it does call for closer reflection on the relationship between delirium and sleep.
Indeed, delirium appears to be associated with sleep and sleep deprivation in many ways. In fact, some think it may be possible to view their relationship as part of a shared pathophysiological pathway. Delirium contributes to sleep deprivation, and sleep deprivation is known to contribute to delirium, if not precipitates delirium itself. As well, both conditions involve a disruption of the sleep-wake cycle, and often lead to excessive daytime sleepiness, fatigue, irritability, altered psychomotor performance and impaired attention and concentration.
Interestingly, impaired attention is central to both delirium and sleep deprivation. Many of us have experienced the inability to concentrate on our work after a bad night’s sleep, a narrative strongly supported by sleep literature. Similarly, for delirium, the DSM-5 criteria require that inattention is present accompanied by a “reduced ability to direct, focus, sustain and shift attention”. Kirszenblat and Swinderen (2015) propose that sleep and attention are brain states that have co-evolved and regulate one another. They could even be considered two sides of the same coin, so to speak. The authors of this claim point out that on the evolutionary timeline, the daily need for sleep arose at the same time animals became capable of selective attention and more complex learning. As well, attention and sleep both share the property of blocking information flow to allow the suppression of the outside world. Alpha oscillations propagated in certain brain areas are thought to facilitate this on a selective level in the former, while slow wave activity blocks information on a global level in the latter. Lastly, not only is sleep required for maintaining attention during waking hours, but there is some evidence to suggest that attentional load affects sleep need.
Our sleep-wake cycle is influenced by our circadian rhythm. Within the hypothalamus, the suprachiasmatic nucleus (SCN) regulates our circadian rhythm by receiving cues from the outside world about day and night. In one study, albeit with a low sample size, the presence of delirium was associated with altered functional connectivity between the SCN and brain regions involved in attention and awareness. In delirious patients, functional connectivity was decreased between the SCN and the posterior cingulate cortex (PCC) and increased to the anterior cingulate cortex (ACC). The PCC is a component of the default mode network (DMN). The DMN refers to a network of brain areas that is active while your mind wanders and you have a broad level awareness to external and internal stimuli. As well, PCC activity decreases when you fall asleep. On the other hand, the ACC, is involved in the salience network (SN), a network of brain areas that closely monitors and prioritizes stimuli and facilitates a switch from the DMN to more focused attention if needed. Altered functional connectivity of the SCN to these brain regions may, in part, explain reduced wakefulness, awareness and attention in delirium.
Several mechanisms have been hypothesised to explain how delirium interacts with sleep. Melatonin, the “dark” hormone which promotes sleep onset, and its precursor, tryptophan, have been found to be at abnormal levels in patients with delirium. As well, sleep apnea increases the risk of delirium, possibly through hypoxia resulting from oxygen desaturations during apneic phases. Another possibility is that acute systemic inflammation may contribute to delirium. Pro-inflammatory cytokines produced during acute inflammation, such as IL-6 and TNFα are associated with the development of delirium. In response to infection, inflammatory cytokines mediate changes in sleep and contribute to “sickness behaviours” like fatigue, sleep disturbances and poor concentration. Sickness behaviours promote rest and energy conservation, which is thought to be an adaptive response to help your body fight illness. Once the sickness resolves and homeostasis is re-established, behaviours should return to normal. However, if the inflammatory response is poorly regulated cytokines can cause more severe disturbances that can result in an exaggerated sickness behaviour with symptoms similar to those found in delirium. In fact, delirium has been proposed to be a maladaptive equivalent to sickness behaviours. Interestingly, inflammatory cytokines, like IL-1, have been shown to mediate changes in sleep by inhibiting wake promoting neurons, some of which are involved in the Salience Network discussed earlier (e.g. ventral tegmental area).
Dementia is a well-established risk factor for delirium. Disturbances in circadian function are a common feature of many types of dementia, including Alzheimer’s disease (AD). In fact, there is evidence that degeneration of the SCN is at the root of these disturbances in AD. Furthermore, it appears that circadian dysfunction may not only be a result of AD pathogenesis, but also contributes in a causal manner. In fact, impaired circadian rhythms in cognitively normal adults are a signiﬁcant risk factor for the development of AD. Notably, older adults with no dementia who report excessive daytime sleepiness (EDS) have greater β-amyloid (Aβ) accumulation in areas involved in the Default Mode and Salience Network.
Delirium is also an independent risk factor for dementia and may even accelerate cognitive decline in those with pre-existing dementia. That said, current evidence suggests that delirium may not contribute to dementia via conventional dementia pathology including amyloid and tau accumulation. Alternately, delirium itself may cause permanent neuronal damage and lead to dementia through sleep disturbances. Sleep deprivation can precipitate neuronal injury in many ways. In fact, in mice, sleep deprivation can cause mitochondrial oxidative stress in wake promoting neurons and under prolonged conditions, even lead to the death of those neurons. This is an interesting piece of evidence to consider in light of evidence that circadian dysfunction is predictive of AD.
Now forgive me if I wrap up this blog sounding like a basic scientific researcher defending their grant application by offering far-fetched therapeutic and practical applications of their work, but I do believe there is merit in investigating the relationship between delirium, sleep and attention more closely. Perhaps novel therapies that work to restore sleep–wake and circadian function could help prevent and treat delirium. Our current arsenal of pharmacological options are not up to the task. Benzodiazepines interfere with natural sleep and are a major risk for delirium. As well, melatonin’s usefulness in delirium has been mixed, likely because, among other reasons, delirium pathology extends beyond an adjustment of endogenous melatonin levels. If nothing else, a closer examination of delirium and sleep may simply provide additional support for the importance of ensuring good sleep practices in those vulnerable to delirium. Just something to sleep on!
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