01/09/2022
What happens when the circadian rhythm goes wrong?
Disorders affecting the sleep-wake cycle have many negative health consequences
2nd August 2018By Dr Nicolette Holt,Dr David Cunnington
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Disturbances of the circadian rhythm are becoming more prevalent in our society.
insomnia
Sleep disorders can arise from intrinsic pathophysiology or can be externally imposed by an individual’s environment.
They can arise due to intrinsic pathology of the circadian system, illness, or the influence of environmental factors such as light exposure and shiftwork during times typically scheduled for sleep.
An estimated 1.9 million Australians were employed in shiftwork arrangements in 2015.1
Understanding and recognition of a circadian rhythm disorder is essential to achieving an accurate diagnosis, especially when a concurrent medical or psychological condition is present.
Circadian dysrhythmia has a multitude of downstream negative health consequences, including metabolic, psychological and cognitive impacts.
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How to Treat — Sleep disorders
What is the circadian rhythm?
The circadian rhythm is the body’s natural timekeeper that modulates most body systems, including the sleep and wake cycle.
Typically, the intrinsic circadian clock runs slightly longer than 24 hours.
It is synchronised across each light-dark period via exogenous stimuli — most potently solar light/dark exposure — in addition to other time-related cues, such as physical activity and meals.2
This synchronisation is known as entrainment.
The principal circadian clock is located in the brain in the suprachiasmatic nuclei of the anterior hypothalamus.
However, each individual human cell contains its own circadian clock, comprising self-sustaining oscillations of about 24 hours, which synchronise within tissues and organs.3
There are three key properties to the circadian rhythm: the length or period of the cycle; the amplitude (strength) of the circadian rhythm; and the phase of the rhythm relative to our external environment (see figure 1).
Figure 1. Properties of the circadian rhythm. Red line shows variation in core body temperature profile with peak occurring just before sleep onset and nadir about an hour prior to awakening.
Note: T period = Tau period; a circadian cycle.
Figure 1
The co-ordination of external environmental cues such as light, activity and meals, together with internal feedback mechanisms, are essential to maintaining the entrainment of the circadian rhythm.
In the absence of these external synchronising signals, the rhythm does not maintain regular entrainment.
In addition to sleep-wake cycle regulation, the circadian rhythm plays an important role in modulating many physiological and metabolic processes.
These include secretion of melatonin and cortisol, rhythms of core body temperature, and appetite.4
What can go wrong?
Circadian rhythm sleep-wake disorders are defined as “alterations of the circadian timekeeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment”.5
Circadian rhythm sleep-wake disorders can arise from intrinsic pathophysiology of the circadian system, or are externally imposed by an individual’s environment.
Box 1 outlines the classification of these disorders.5
Alterations in the intrinsic circadian rhythm phase can result in either advancement or delay of sleep.
The result is a lack of synchrony of the internal rhythm relative to the external environmental light/dark cycle (see figures 2a and 2b).
Overall sleep duration in both delayed and advanced sleep-wake phase disorders are typically normal.
Box 1. Classification of circadian rhythm sleep-wake disorders5
Intrinsic
Delayed sleep-wake phase disorder
Advanced sleep-wake phase disorder
Irregular sleep-wake rhythm disorder
Non-24-hour sleep-wake rhythm disorder
Extrinsic
Shiftwork disorder
Jet lag disorder
Delayed sleep-wake phase disorder
This condition is characterised by a marked delay in preferred sleep-wake timing due to a delayed circadian phase (see figure 2a).
It is the most common form of circadian rhythm sleep-wake disorder.5
The tendency to delay the sleep phase may also be referred to as ‘eveningness-type’ or, colloquially, being a ‘night owl’.
A recent New Zealand study estimated the prevalence of delayed sleep-wake phase disorder to be 1.5% in the general population.6
People with this condition describe difficulty falling asleep and difficulty awakening at the desired social or work schedule.
Adolescents are prone to a delayed sleep-wake phase.
This phenomenon may also be seen in some mental illnesses, including some forms of depression.
Figure 2. Timing of sleep episodes in various circadian rhythm sleep-wake disorders.
2a. Delayed sleep-wake phase disorder. (below)
2A
2b. Advanced sleep-wake phase disorder. (below)
2B
2c. Reduced amplitude circadian rhythm as seen in irregular sleep-wake rhythm disorder. (below)
2C
Non-24-hour sleep-wake rhythm disorder
In extreme cases, rather than maintaining stable phase-delay, sleep onset and awakening times occur progressively later each day.
This can result in a cycle that rotates around the full 24 hours every few weeks, and is called non-24-hour sleep-wake rhythm disorder.
Advanced sleep-wake phase disorder
This condition involves sleep and wake times that occur markedly earlier (see figure 2b). Individuals with this disorder often struggle to stay awake until their preferred bedtime and wake earlier than desired.5
Irregular sleep-wake rhythm disorder
Alterations in the amplitude of the intrinsic circadian rhythm lead to a lack of distinct sleep-wake rhythm, called irregular sleep-wake rhythm disorder (see figure 2c).
Typical symptoms are an inability to sleep at night and excessive sleepiness during the day.5
This condition is more common in people who have withdrawn from environmental cues, and may include patients with psychiatric conditions or chronic medical conditions, including neurodegenerative disorders.
Extrinsic circadian rhythm sleep-wake disorders
These include jet lag disorder and shiftwork disorder. Jet lag results from a disturbance between environmental light-dark cues and the intrinsic circadian clock when time zones are crossed.
Both the direction of travel and the number of zones crossed impact the severity of jet lag. Generally, westbound travel causes less disturbance than eastbound travel.7
Similarly, shiftworkers experience symptoms of excessive daytime sleepiness or insomnia when working hours encroach on typical periods of sleep.
The extent of disruption to the circadian rhythm is dependent of the type of shiftwork, with night shifts, rotating shifts and early morning shifts typically proving more disruptive.5
Shiftworkers experience more adverse health outcomes, including vascular events, and metabolic consequences such as impaired glucose tolerance and weight gain.8,9
With long-term night shiftwork, there is an increased risk of common primary malignancies.10
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Diagnosing circadian dysrhythmia
The evaluation and diagnosis of a circadian rhythm disorder can be challenging, especially when a concurrent physical or mental illness is present.
A comprehensive clinical and sleep history is essential.
It is important to incorporate assessment of potential comorbid physical, psychiatric and sleep disorders, such as obstructive sleep apnoea, in addition to medication history, sleep-wake schedule and
work profile.
The clinical assessment can be supplemented by a sleep diary.
A range of sleep diaries are available, but for the assessment of circadian rhythm disorders, visual sleep diaries are most helpful as they allow the visual identification of sleep patterns over at least a two-week period.11
An example of a visual sleep diary is available on the American Academy of Sleep Medicine website (see Online resources).
An alternative to a sleep diary is an actigraphy, a device typically worn on the wrist to measure rest and activity via surrogate markers of movement and light exposure.
However, interpretation of an actigraphy requires expert input; hence its use is largely confined to research or specialist settings.
Circadian rhythm biomarkers, such as melatonin profiles or core body temperature, can be used in research settings to establish the circadian phase.
However, these tests are difficult to accurately perform and interpret so are not routinely used in clinical practice.6,7
Case study of delayed sleep-wake phase disorder and phase advancement
Jacob, a 20-year-old university student, has a delayed sleep-wake phase disorder, retiring to bed between midnight and 1.30am.
He struggles to get up in the morning and often falls asleep in the first classes of the day. On weekends, he will often sleep in until 10am.
His sleep quality is otherwise good. He is generally well and does not take any regular medications.
The management strategy with Jacob centred on phase advancement and entrainment of his circadian phase.
Sustained-release melatonin 2mg, taken at 9pm, was recommended and blue light from digital devices restricted after this time.
Bed time and arise time were scheduled 30 minutes earlier every three days. Upon awakening, morning light therapy (outdoor natural sunlight) was scheduled for a minimum of 30 minutes.
The visual sleep diary (below - click to expand) demonstrates the resulting progressive phase advancement.
Sleep diary
Management of circadian rhythm disorders
Appropriate diagnosis is key to management.
Symptoms of circadian rhythm disorder may be mislabelled as other disorders such as insomnia or depression, which require very different treatment approaches.
Once a diagnosis of circadian rhythm disorder has been established, the goal is realignment of the circadian rhythm with the desired sleep-wake period.
The therapeutic intervention is dependent on the specific disorder.
General principles for entrainment of the circadian rhythm include management of synchronising signals to the circadian system such as light, activity and meals.
Patients with delayed phase are managed with morning light exposure and consideration of evening melatonin supplementation to promote sleep onset.
In contrast, those with advanced phase are treated with evening light therapy.
Light
Non-visual (non-rod and non-cone) photoreceptors in the retina are important in the circadian entrainment effects of light, particularly blue wavelength light (450 nm).12
Morning light exposure is a key environmental cue to suppress melatonin, promote alertness and entrain the circadian system.
Outdoor natural daylight contains the required wavelength and intensity of light.
This can be supplemented by artificial lighting if needed, with devices that incorporate LED lights worn close to the eyes or specific therapeutic lights placed on a table.
The exact duration of light required is not clear, but research studies use light exposure for periods of up to 60 minutes.13
Conversely, reducing exposure to blue wavelength light after sundown allows the natural rise in melatonin levels with associated sleepiness to occur.
The effect of light from digital devices and household lighting at night can be reduced via the use of blue blocking glasses or changing the colour temperature of lights and screens to warmer wavelengths.
Activity and meals
Physical activity and meals can also help to synchronise both central and peripheral clocks.
Maintaining regular meal times, at times appropriate to the circadian phase, as well as morning physical activity can augment the effect of light.
Melatonin
A sustained-release formulation of melatonin is available for the treatment of insomnia in people over the age of 55.14
Melatonin can also be helpful in phase-delay to shorten time to sleep onset.13 Morning melatonin can also help promote sleep during daytime hours in shiftworkers.15
Conclusion
Disorders of the circadian rhythm are common and exacerbated by blue light exposure from technological devices and artificial lighting, and the increasing demands from shiftwork and social commitments.
Common symptoms include difficulty getting to sleep or awakening at desired times.
Circadian rhythm disorders should be considered in patients reporting sleep difficulties, particularly those with comorbid mental health problems or chronic illness.
Identifying the contribution of circadian misalignment to sleep symptoms is important to ensure appropriate treatment.
