JMS Pearce
Hull, England

 

I first started to enquire about circadian rhythms when wondering what it was that caused the periodicity of migraines in relationship to such diverse factors as emotions, tiredness, relaxation, hormonal changes, bright lights, and noise.¹ The periodic threshold appeared susceptible to hypothalamic function, which in turn was modulated by seasonal patterns and diurnal biological clocks.²

Circadian rhythms are driven by an internal “biological clock” found in all living organisms. Although physicians have long been aware of innate variation and fluctuation in physiological and clinical phenomena, the word circadian (Latin circa, about + dies, day) is of surprisingly recent origin. A German physician, Franz Halberg, first reported “Circadian rhythms in human plasma testosterone and other hormones” in 1956.³ He stated: “Circadian might be applied to all ‘24 hour’ rhythms, whether or not their periods are different from 24 hours, longer or shorter, by a few minutes or hours.” A graduate of Münster University, Halberg moved to Minnesota, where he established the first American chronobiology laboratory.

One might argue teleologically that the circadian system must [sic] have evolved to help plants and animals to adapt to environmental changes in light, temperature, and available food. Since they govern the temporal regulation of physiology to maintain homeostasis, without them, many vital functions would fail.

Twenty-four-hour circadian rhythms develop gradually during the first four months of life. Central circadian activity of the suprachiasmatic nucleus (SCN) begins when light stimulates the ganglion cells of the retina. The SCN is composed of about 20,000 neurons whose activity is coupled and they oscillate in synchrony. Efferent projections innervate both the pineal gland producing melatonin, and peripheral cells via autonomic preganglionic neurons. The major efferent neurotransmitters are hypothalamic arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), and neuropeptide Y, which play a role in the regulation of circadian rhythms. Melatonin is also produced in high concentrations by chromaffin cells of the intestinal mucosa and affects gut motility, pain, and inflammatory mechanisms.

Misalignment of the light–dark cycle and feeding time can uncouple central (SCN) and peripheral clocks with harmful effects, for example on insulin resistance, body mass, and cellular aging. The central clock regulates food intake and energy expenditure; the peripheral clock in the gut regulates glucose absorption. Peripheral clocks in muscle, adipose tissue, and liver regulate local insulin sensitivity, and in the pancreas, insulin secretion is regulated. Innate and adaptive immune mechanisms to pathogens depend on circadian variations.⁴

Although the central SCN clock orchestrates circadian rhythms of behavior and physiology, peripheral molecular circadian oscillations are driven by genetic feedback loops in cells. Genetic studies in the fruit fly, mammals, rodents, and humans show a biological process that has been maintained over evolutionary time. It operates through regular cycles, or oscillatory signaling and repression of core clock genes, which potentially regulate the expression of nearly half the genome.⁵

Environmental factors—zeitgebers (time givers)—influence physiological circadian rhythms. Peripheral cellular clocks synchronize (entrain) the organism’s internal biological clock (SCN) with the external environment. They operate by auto regulatory feedback loops and are synchronized by environmental cues such as light and feeding. They affect sleep-wake cycles, alertness, cognition, blood pressure, neutrophils, T and B lymphocyte trafficking, and hormone secretion. They govern self-sustained rhythms of about twenty-four hours.

 

Disorders of circadian rhythm

The dominance of the central circadian pacemaker SCN is illustrated by the Inuit who live in the Arctic Circle where there is little darkness in summer and little light in winter. If the sleep-waking cycle were primarily controlled by peripheral zeitgebers, they would sleep most of the day in winter and hardly at all in summer. However, they maintain a regular pattern of sleeping and waking throughout the year.

In jet lag, traveling through different time zones, the SCN causes a mismatch between the body’s natural sleep-wake cycle and the sleep-wake cycle of the new location. The SCN regulates melatonin secretion from the pineal gland that starts at dusk, peaks in the middle of the night, and thus modulates circadian rhythms, which are temporarily disrupted by jet lag. If melatonin is taken near the bedtime at the destination, it can be effective. Similarly, disturbed sleep and daytime alertness and efficiency are periodically hampered in workers with variably timed shiftwork.

Those who suffer from the rare familial advanced sleep phase disorder are “morning larks” with a four-hour advance of the sleep, temperature, and melatonin rhythms, attributed to missense mutations of human Period 2 (hPER2), a gene crucial for resetting the central clock in response to circadian light clocks.⁶

Irregular sleep-wake rhythm disorder is another circadian rhythm disorder characterized by multiple episodes of sleep within a twenty-four-hour period. Patients have difficulty either falling or staying asleep and are somnolent in daytime. It is associated with cognitive impairment in children and with neuro-degenerative illnesses.

Circadian sleep patterns change with normal aging, but are more severe in patients with neurodegenerative diseases and in their presymptomatic stages. In Alzheimer’s disease there is increased sleep latency, increased nocturnal awakenings, and daytime sleepiness. Parkinson’s disease patients may suffer from insomnia, daytime sleepiness, and restless legs.⁷

Additionally, there are therapeutic implications, since certain medications and vaccines may be more effective if given at selected times of day.⁴

Clinically, in those with disordered circadian rhythms, there is an increased incidence of ischemic heart disease,⁸ strokes,⁹ and gastrointestinal disorders. People who have a genetic disruption of normal circadian rhythms of the hormone leptin are prone to obesity. Some studies have suggested that disruption of circadian rhythms, either through genetic mutations or environmental factors, may contribute to the development of cancer. Abnormal circadian variation has been shown in both migraine and cluster headaches, in seasonal affective disorder, and in irritable bowel syndrome. Some success with melatonin has been reported in their treatment.

 

References

1. Pearce JMS. Headache. J Neurology, Neurosurgery & Psychiatry 1994;57:134-143.
2. Rao NS, Pearce JMS. Hypothalamic–Pituitary–Adrenal axis studies in migraine with special reference to insulin sensitivity. Brain 1971; 94 Part 2: 289-98.
3. Halberg, F, Nelson, LD, Johnson EA. Circadian rhythms in human plasma testosterone and other hormones. Science 1956;123(3209): 844-845.
4. Rijo-Ferreira F, Takahashi JS. Genomics of circadian rhythms in health and disease. Genome Med. 2019 Dec 17;11(1): 82.
5. Braun R, et al. Universal method for robust detection of circadian state from gene expression. Proceedings of the National Academy of Sciences 2018;115(39), E9247-E9256.
6. Toh KL, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science. 2001;291:1040–3.
7. Hunt J, et al. Sleep and circadian rhythms in Parkinson’s disease and preclinical models. Mol Neurodegeneration 2022;17: 1-21.
8. Reiter R, et al. Circadian dependence of infarct size and left ventricular function after ST elevation myocardial infarction. Circ Res 2012;110:105–10.
9. Reidler P, et al. Circadian rhythm of ischaemic core progression in human stroke. J Neurology, Neurosurgery & Psychiatry 2023;94:70-73.

 

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JMS PEARCE is a retired neurologist and author with a particular interest in the history of medicine.

 

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