We know that circadian rhythms regulate our sleep and alertness, blood pressure and heart rate, hormone secretion, and more. Evidence is now associating circadian rhythms with eye growth and refractive error development. Armed with this growing knowledge, researchers hope to determine new approaches to ameliorate refractive errors, like myopia, that commonly develop in children.
Myopia, or short-sightedness, is the most common refractive disorder among children and young adults, and represents the highest incidence of all refractive errors globally. The prevalence of myopia is increasing worldwide. In some regions of Asia, its prevalence reaches 70–80 per cent of young adults, with reports as high as 96 per cent. In Australia, it currently affects around one third of the population, and is expected to steeply increase in the coming years, resulting in about 20 million myopic Australians by 2050.
Circadian rhythms are regulated by a gene translation/transcription feedback process that synchronises biological systems with environmental light
Myopia, especially in its extreme degrees, is a leading cause of visual impairment because of its association with a number of vision threating eye diseases such as retinal tear and detachment, glaucoma and cataract. A large body of clinical research suggests that myopia represents a ‘complex’ disorder with both environmental (such as excessive near work, lesser outdoor light exposure, etc.) and genetic factors contributing to its development and progression. Despite much research, the underlying mechanisms responsible for myopia are unknown. Due to increasing prevalence, high costs associated with optical and surgical correction of myopia, and the disease complications, myopia is recognised as a major and alarming public health problem around the world.
The concept of circadian rhythms in humans is believed to be dated back to the 13th century in Chinese medical texts, and was first recorded on the leaves of the Mimosa pudica plant by a French scientist, Jean-Jacques d’Ortous de Mairan, in 1729. Since then, we have made remarkable progress in understanding the molecular mechanisms and functions of circadian rhythms in the human system. Circadian rhythms are endogenous biological rhythms that oscillate with a period close to 24 hours. These rhythms regulate daily timings of sleep and alertness, blood pressure and heart rate, hormone secretion, and many other cellular and physiological processes in the body, including the eye.
Circadian rhythms are regulated by a gene translation/transcription feedback process that synchronises biological systems with environmental light (or daily light:dark cycle). A specialised set of light sensitive cells in the retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) relay the environmental light information to the suprachiasmatic nuclei (the circadian ‘masterclock’ located in the hypothalamus of the brain).
Our fundamental knowledge of a possible link between circadian dysregulation and myopia has largely emanated from decades of work in various laboratory animals. Previous research shows that disrupting the daily light:dark cycle by altering the duration and/or intensity of light may lead to significant changes in normal eye growth of chickens and primates, possibly due to alterations in circadian rhythms. Clinically, some features of lighting have long been hypothesised to influence refractive errors in human eyes. For instance, a number of recent studies have confirmed the protective effects of outdoor light exposure on both onset and progression of myopia in children. It has been hypothesised that increased exposure to bright light may be the important factor underlying these protective effects of outdoor activity on myopia. However, one might also argue that protective effects of light are mediated by altered circadian rhythms of the eye, the answer to which is not known.
Animal research provides additional evidence that implicates circadian rhythms in refractive error development. Dopamine, an important neurotransmitter found in the retina, regulates the eye’s circadian function, which is imperative to normal physiology and functioning of the eye. Interestingly, retinal dopamine also modulates eye growth, and has been widely studied as a mechanism for myopia. Furthermore, a genetically engineered mouse that lacks melanopsin (the light sensitive pigment in the ipRGC cells that modulates circadian rhythms) exhibits abnormal eye growth and myopia, which further links altered circadian biology to abnormal development of the eye and myopic refractive error.
The other important piece of evidence comes from animal research showing the link between diurnal (or daily) rhythms and refractive error development of laboratory animals. The length of the eye (also known as axial length) is the primary determinant of refractive error; therefore, longer eyes become short-sighted (or myopic) and shorter eyes become farsighted (or hyperopic). The axial length in young animals undergoes diurnal (or circadian) fluctuations throughout the day, with the eye being longest during the day and shortest at night. In chick eyes, experimentally inducing myopia or hyperopia by imposing spectacle lenses over their eyes results in disruption of diurnal rhythms in axial length and significant changes in eye growth, which suggests a strong link between alterations in diurnal fluctuations and refractive error development in animals.
Interestingly, high-resolution interferometry techniques have corroborated these findings in human eyes as well. My previous research, and findings from other labs, have shown similar patterns of diurnal variation in the axial length of human eyes. Moreover, similar to animals, the introduction of blur with spectacle lenses changes the natural diurnal rhythms of axial length, suggesting that similar diurnal and eye growth mechanisms may be operating in human eyes as well.
Recently, our research team at Flinders University, Adelaide found the effects of visual blur induced by plus and minus lenses to be significantly different, depending on the time of the day. The spectacle lenses were used to artificially simulate ‘near reading’ and ‘relaxed eye’ type blur conditions in healthy, young adults, and the effects of blur were compared when the lenses were applied for two hours in the morning vs. when given in the evening. A ‘relaxed eye’ type blur condition, with plus lenses, caused a greater reduction in axial length when imposed in the evening than it did in the morning. On the contrary, ‘near reading’ type blur, with minus lenses, led to a greater increase in axial length when imposed in the morning than in the evening. It is noteworthy that these axial changes in human eyes are very small (in order of a few microns), and quickly revert back to normal as soon as the lenses are removed. These findings further hint towards a circadian mechanism of eye growth in human eyes.
CIRCADIAN RHYTHMS AND MYOPIA
A small number of recent clinical studies have directly looked into certain aspects of circadian rhythm disruption and myopia. Some have reported poor and delayed sleep in myopes compared to non-myopic individuals. One study found that myopes had higher levels of systemic melatonin (a neurohormone synthesised in the brain that regulates sleep) than non-myopes. Although these studies suggest that disruption in normal circadian function may be associated with myopia, the biological mechanisms underlying these findings are not known.
The advent of artificial lighting in the modern world has markedly affected how biological systems interact with light. The differences in colour, intensity, and spectral properties of artificial lighting affect the environments of all developed societies. The technical evolution of artificial lighting and the use of light emitting electronic devices for reading and entertainment, such as computers and TV screens, has become a recognised concern in several health fields, presumably because artificial lighting disrupts the endogenous circadian clock and hence circadian rhythms.
Besides effects on sleep and mood, circadian disruptions in contemporary societies are increasingly believed to contribute to certain cancers, neurological diseases, obesity, diabetes, etc. However, the impact of circadian disruption in eye health has not been studied extensively. Cumulative evidence from animal and human research supports a strong influence of circadian rhythm disruption in the pathogenesis of myopia. Studying the relationship between circadian dysregulation and myopia is a novel and promising area of future research.
For more details on circadian rhythms and its potential association with myopia, visit onlinelibrary.wiley.com/doi/abs/10.1111/opo.12453
Dr. Ranjay Chakraborty is a Senior Lecturer of Optometry at Flinders University. He graduated in optometry from the Elite School of Optometry, Chennai, India in 2006. After working as an optometrist for three years in India, he joined the PhD program in Vision Science at the Queensland University of Technology. Dr. Chakraborty’s PhD was one of the first investigations to bridge the work on diurnal rhythms and refractive error development in animal models to human eyes, and was awarded an Outstanding Doctoral Thesis Award in 2013 from Queensland University of Technology. Following his PhD, he undertook a postdoctoral fellowship in the Department of Ophthalmology at Emory University in Atlanta, USA, where he examined the contribution of various retinal cell types and pathways in normal eye development and response to visual deprivation myopia in mouse mutants.
Dr. Chakraborty joined Flinders University in February 2017. His areas of research interest are myopia and refractive error development, visual optics and retinal imaging. He uses a range of optical, molecular, and imaging techniques to study various mechanisms underlying the development of refractive errors.