Circadian Rhythm and Human Health

[BSHC]

Circadian Rhythm and Human Health

Joan E. Roberts

Department of Natural Sciences, Room 813
Fordham University, 113 West 60th Street
New York City, NY 10023
jroberts@fordham.edu

Introduction

All life on earth evolved under both a light and dark cycle (Santillo et al., 2006; Musio and Santillo, 2009).

As the sun rises and reaches its peak at noon, the spectrum it emits is smooth throughout the visible spectrum with a high intensity in the blue region [400 - 500 nm].

As the sun sets, blue visible light is preferentially scattered (removed) from sunlight, leaving an emission appearing orange-red [600 - 700 nm].

At night, there is darkness with limited visible light emitted from the stars, with the exception of when there is a full moon. During the full moon, there is five times the amount of visible light emitted from the sky, and significant light emitted in the blue visible range (Ugolini, 2007).

Humans evolved being exposed to different spectra of light in the morning, the late afternoon and evening. So it should not be surprising that human physiology is profoundly affected by the daily and seasonal changes in the visible light spectrum.

Exposure to the appropriate spectrum of light during the day and evening enhances human health and well being, immune response and productivity (Roberts, 2000; Vetch et al., 2004; Cutolo M et al., 2005; Heschong and Roberts, 2009).

However, exposure to light sources that do not match the natural solar spectrum to the time of day or evening, is hazardous to human health (Wilson, 1972; Stevens et al., 2007; Rea et al., 2008; Erren and Reiter, 2008; Arendt, 2010). The reason visible light has such a powerful effect on human health is that light exposure through the eye modifies circadian rhythm (Gaddy et al., 1993; Roberts, 1995; Czeisler et al., 1995).


What is Circadian Rhythm?

Circadian Rhythm is derived from the Latin words circa dies meaning "approximately a day". It may be defined as the changes in human behavior and physiology that occur within a 24 hour period.

The mammalian circadian system is regulated by endogenous clock genes (Reppert and Weaver, 2001; Richter et al., 2004; Berger, 2004; Ueda et al., 2004; Walker and Hogenesch, 2005; Siepka et al., 2007; Belle et al., 2009).

There is a master clock found in the brain in an anterior section of the hypothalamus known as the suprachiasmatic nucleus (SCN) (Reppert and Weaver, 2002).

The SCN synchronizes clock cells in peripheral tissues located in the eye, brain, heart, lung, gastrointestinal tract, liver, kidney and fibroblasts (Roberts et al., 2000; Scher et al., 2002; Dubocovich et al., 2003; Richter et al., 2004; Takahashi et al., 2008).

Clock genes found in lower species of mammals have recently been detected in humans (Su et al., 2002; Ciarleglio et al., 2008).

Without external stimuli, human circadian rhythm has an average period of 24.2 hours (Czeisler et al., 1999). Although there may be some modification of the circadian cycle with food (Mendoza et al., 2010; Mendoza, 2007) and temperature (Van Someren, 2000a),

 the most powerful external stimulus for synchronizing (entraining) circadian rhythm to a 24 hour cyclic is exposure to the light of day and darkness at night.


Light and Dark and Circadian Rhythm

When humans are exposed to a daily dark/light cycle, cyclic production of specific neurohormones and neuropeptides result in changes in sleep and alertness, body temperature and pressure, metabolism, and reproduction (Van Someren, 2000a; Roberts, 2000; Vetch et al., 2004).

Visible light between 460 - 500 nm (Gaddy et al., 1993) received by the human eye (Roberts, 2005, Vetch et al., 2004) is a regulator of the circadian response in humans. The chromophore that receives this circadian light is melanopsin (Provencio et al., 2000; Panda et al, 2002; Rollag et al., 2003; Hannibal et al., 2004; Foster, 2004). Melanopsin is located in the neural retina in the intrinsic photosensitive Retinal Ganglion Cells (ipRGC) (Berson et al., 2002; Berson, 2003). When circadian light impinges on the retina it sends a signal to the SCN in the hypothalamus (Sadan et al., 1984; Takahashi et al., 1984; Klein et al., 1991), leading to a cascade of hormonal changes in the pituitary, pineal, adrenal, and thyroid glands. This is non-visual photoreception. In some forms of blindness the circadian response may be blunted, while in others it remains intact (Czeisler et al., 1995).

The absence of circadian blue light in the evening is equally important to the daily oscillation of human hormones (Roberts, 1995, 2000; Eastman and Martin, 1999; Wehr et al., 2001). Different neurohormones and neuropeptides are produced in the presence and absence of circadian light. Circadian light exposure in the morning increases cortisol [stress], serotonin [impulse control], gaba [calm] and dopamine [alertness] levels (Wurtman et al., 1963a, b; Scharrer, 1964; Brainard, 1991; Roberts et al., 1992a; Omura et al., 1993), modifies the synthesis of follicle stimulating hormone (FSH) [reproduction], gastrin releasing peptide (GRP) and neuropeptide Y (NPY) [hunger] (Inouye and Kawamura, 1979; Inouye et al., 1990; Roberts et al., 1992a), and TSH [metabolism] (Hanon et al., 2008). Removal of circadian light exposure at night allows for the production of melatonin [sleep], vasointestinal peptide [lowers blood pressure] and growth hormone [metabolism and repair] (Roberts, 1995) [Tables 1 and 2]. Because of these hormonal changes, the circadian dark/light cycle controls, and modifies the sleep/wake cycle, blood pressure, metabolism, reproduction, and the immune response.

Age-related changes to the human eye may disrupt the circadian response (Roberts, 2001a). Artificial light sources that do not mimic natural lighting for the time of day or season modify proper circadian response. Lack of natural circadian light in the winter leads to the damaging emotional and physiological effects associated with seasonal depression (SAD). These symptoms are defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV), 1994). Travel across multiple time zones also interferes with the normal circadian cycle leading to the symptoms of jet lag (Haimov and Arendt, 1999). Constant change in the circadian cycle due to shift work has the most devastating health effects, increasing risk for cancer, obesity and type 2 diabetes (Baldwin and Barrett, 1998; Levi, 2000; Blask et al., 2005; Erren and Reiter, 2008; Spiegel et al., 2005; Scheer et al., 2009; Arendt, 2010; Stevens et al., 2007). The human immune response also follows a circadian cycle (Levy et al.,1991; Maestroni,1993; Roberts, 1995, 2000; Maestroni and Conti, 1996; Plytycz and Seljelid, 1997; Park and Tokura, 1999). When the natural circadian immune cycle is disrupted, there is an increase risk of autoimmune and infectious diseases (Maestroni, 1993; Conti and Maestroni, 1998; Cutolo et al., 2005).


Improving "Health and Well being" by Controlling Circadian Disruption

In the early 1960's, it was found that external control of the dark/light cycle and/or the administration of melatonin modified the human circadian response (Wurtman, 1963a, b; Aschoff, 1965). By the 1990's, ocular visible light treatment led to effective treatments of circadian mood disorders (Roberts et al., 1992; Arendt, 1999; Van Someren, 2000a; Vetch et al., 2004).

Since 2000, the human "circadian" photoreceptor has been located (Berson, 2003), the circadian photopigment has been identified (Provencio et al., 2000; Panda et al., 2002; Rollag et al., 2003; Hannibal et al., 2004; Foster, 2004), and confirmed with knockout mice, and the action spectrum responsible for circadian regulation (Brainard et al., 2001) (at least for neural melatonin modulation) has been established. It is now possible to define positive and negative physiological effects of natural and artificial light sources and to devise treatment protocols for circadian disorders. However, in order for these treatments for circadian dysfunction to be reproducible and accurate, it is essential that clinical studies follow the basic laws of photobiology.


Laws of Photobiology as Applied to Circadian Treatment

1. The potential therapeutic effect of light on any given human organ depends upon the wavelength transmitted to that organ. Human circadian response is regulated through visible light transmission to the retina. The spectrum and intensity of that light is determined by age and species (Bachem, 1956; Roberts, 2001a). The primate/human eye has unique filtering characteristics that determine in which chamber of the eye a particular wavelength of light will be absorbed (Roberts, 2009). All light below 295 nm is cut off by the human cornea. This means that the shortest, most energetic wavelengths of solar radiation (all UV-C and some UV-B) are filtered out before they reach the human lens. Most UV light is absorbed by the lens, but the exact wavelength range depends upon age. In adults, the lens absorbs the remaining UV-B and all of UV-A (295 - 400 nm), and therefore only visible light reaches the retina. However, the very young human lens transmits a small window of UV-B radiation (320 nm) to the retina, while the elderly lens filters out much of the short blue visible light (400 - 500 nm) (Barker et al., 2001).

Therefore when conducting a clinical trial involving human response to light, it is essential to report the age of the persons in treatment. The elderly will respond differently to light treatment than the young (Van Someren, 2000b; Yeager et al., 2009; Riemersma-van der Lek et al., 2008; Quinn et al., 1999).


2. A specific wavelength of light must be absorbed by a chromophore (a chemical which absorbs light) to result in a particular biological effect. The light that controls phototopic (day) vision is absorbed by the chromophores in the cones (blue, green or red opsins); while the light that controls night vision is absorbed by the chromophore in the rods (rhodopsin). The chromophore in the intrinsic photosensitive Retinal Ganglion Cells (ipRGC) (melanopsin) (Berson et al., 2002, 2003), (Provencio et al., 2000; Panda et al., 2002; Rollag et al., 2003; Hannibal et al., 2004; Foster, 2004), directs non-visual photoreception and circadian rhythm. The chromophore for non-visual photoreception that triggers a circadian response is melanopsin.


3. To measure the relative effectiveness of an energy source (natural or artificial) to produce a particular biological response, the action spectrum must be determined and the light energy that is emitted in that region must be measured. The action spectrum for light absorbed by the cones has a maximum at 555 nm while that of the rods is 498 nm (Weale, 1951; Berman, 1992). The action spectrum for light absorbed by the ipRGC has a maximum at 480 nm (Brainard et al., 2001). Clinicians working on the circadian, neuroendocrine and therapeutic effects of light in humans have predominantly used photopic illuminance (lux or foot-candles) as their standard light measurement. The use of photopic instrument to measure non-visual photoreception is inappropriate. A spectroradiometeric photometer or a photometer calibrated to 480 nm is the accurate way to determine non-visual phototic effects in humans (Berman, 2008; Rea et al., 2008; Piazena et al., 2006; Pechacek et al., 2008; Sharman and Roberts, 2008) Some light sources (incandescent, fluorescent lamps) have little or no irradiance in the non-visual photoreception region of 480 nm [Figure 1].

Figure 1. Spectral Distribution of Daylight (blue); Incandescent Lamps (red); and Fluorescent Lamps (green)

Therefore when conducting a clinical trial involving human response to light, it is essential to report a detailed description of the spectral properties of the light source and the total irradiance at the action spectra of non-visual photoreception (460-500 nm). Terms such as "Bright Light" and "Dim Light" or continuous light (LL) and continuous dark (DD) are biologically irrelevant.


4. Light is reflective. The direction of the light is important when determining the intensity of ocular light exposure. The amount of light that reaches the human eye depends upon the reflectance of the illuminated surfaces. In the natural environment sand, snow and water offer the greatest light reflectance (Sliney, 2005). In an enclosed environment, the surfaces of the walls, floors and furnishings determine the light intensity that reaches the eye (Pechacek et al., 2008). Furthermore, because of the geometry of the eye, the direction of the illuminance will further determine intensity (Sliney, 2005; Merriam, 1996). Horizontal illuminance received by the eye of a sitting subject (Dollins et al., 1993) will not have the same intensity as light illuminance directly above a patient who is laying on a bed in an intensive care unit (Wilson, 1972).

Therefore when conducting a clinical trial involving the human response to light, it is essential to report the direction of the light, and the total reflective light from all surfaces in the area reaching the eyes of the subject.


5. Timing is essential. There is a distinct change in human physiology depending on the spectrum of light exposure at different times of day. There is a different spectrum of light at dawn (6-9 AM), in the late afternoon (4-9 PM) and in the evening. These natural changes in visible light spectra modify the hormonal and resultant physiological response in humans. Physiological changes due to non-visual light exposure depend on the timing and spectrum of light. For instance, circadian blue light (480 nm) exposure in the evening, "Light at Night", is disruptive to human health (Wilson, 1972; Stevens et al., 2007; Rea et al., 2008; Erren and Reiter, 2008; Arendt, 2010), while exposure to the same source of light in the early morning has a positive effect on human health (Kripke, 1991, 1998; Roberts, 2001b; Vetch et al., 2004; Cutolo et al., 2005; Heschong and Roberts, 2009).

Therefore when conducting a clinical trial involving human response to light, it is essential to report both the total spectrum of the light source and the time of day of exposure.

Summary: The basic laws of photobiology must be followed when designing clinical trials involving non-visual photoreception (Portaluppi et al., 2008). Using appropriate lighting protocols and measurements that involve age of recipient, spectrum, intensity, timing and direction will lead to future definitions and treatments for circadian dysfunction that will be reproducible and accurate.


Treatment for Circadian Dysfunction

i. Light Therapy. Light therapy for circadian dysfunction involves exposure to natural daylight and/or light sources that contain sufficient emission in the circadian blue region to trigger non-visual photoreception and subsequent circadian realignment.

ii. Hazards of Light Therapy. No matter which light source is used for "Light Therapy", it is essential to filter any ultraviolet radiation (below 400 nm) emitted from the therapeutic lamp. This will protect the lens from the UV-induction of cataracts (Roberts, 2009), and of autoimmune diseases (Klein et al., 2009a). Fluorescent lamps that are not filtered emit UV radiation (Klein et al., 2009 b). It is also essential to remove very short blue visible light (400 - 440 nm) (Roberts, 2001a) from all therapeutic light sources (Figueiro et al., 2009), as these wavelengths of light present a risk of retinal damage to patients above 40 years old (Roberts, 2001a). There is even greater hazard if light therapy is given in conjunction with a phototoxic prescription or herbal (including St. John's Wort) antidepressant medication (Roberts et al., 1992; Wheatley, 1999; Kasper, 1998; Roberts, 2002; He et al., 2004; Wielgus et al., 2007, Booth and McGwin, 2009) as this can lead to transient or permanent blindness.

iii. "Dark" Therapy. Dark therapy for circadian dysfunction involves removing natural daylight and/or light sources that contain sufficient emission in the circadian blue region to trigger non-visual photoreception and subsequent circadian realignment. One way of removing this blue visible light is through the use of appropriate "sunglasses" (Crowley et al., 2003; Burkhart and Phelps, 2009). Another is to place filters which remove blue circadian light on TV monitors, computers and other blue emitting "gadgets" (Canton and Roberts, 2006; Roberts, 2008). Although the maximal region for the action spectra for non-visual photoreception is between 460 - 500 nm, the full action spectra [Figure 2] is a bell shaped curve that has tail absorbance out to 600 nm. Very intense short red light (590 - 630 nm) has been found to suppress some production of melatonin (Hanifin et al., 2006), but low levels of red light between (600 - 700 nm) may be used as a light source that does not trigger non-visual photoreception (Roberts, 2008).

Figure 2. Action Spectra of Circadian and Photopic Light

A diet high in tryptophan containing foods combined with carbohydrates will increase endogenous melatonin (Wurtman et al., 2003). Supplemental melatonin may also be used to enhance the endogenous sleep hormone, melatonin (Arendt, 2005; Arendt et al., 2008).

iv. Hazards of "Dark" Therapy. The most significant hazard of dark therapy is an undesirable immune response (Zhang et al., 1997; Conti and Maestroni, 1995, 1998; Cutolo et al., 2005; Pandi-Perumal et al., 2008). The human immune response consists of two major pathways: Th1 (T helper 1) [cell mediated immunity] which uses N-Killer (NK) cells and cytotoxic T cells to destroy viruses and cancer, and Th2 (T helper 2) [humoral or antibody-mediated immunity] which enlists B cells to produce specific antibodies to help eradicate bacteria, parasites, and toxins. The Th1 immune response is most active in the evening, at least in part in response to nocturnal production of melatonin, while the Th2 immune response is activated in the morning, in response to the production of cortisol, dopamine and other morning neurotransmitters (Cardinali and Esquifino, 2005). An imbalance of Th1/Th2 immune responses can trigger an autoimmune response. Cutolo et al. (2005) have clearly demonstrated an increase in the symptoms of rheumatoid arthritis with increased morning serum melatonin levels (Sulli et al., 2002; Cutolo et al., 2005). Melatonin is a safe and effective supplement when taken in small quantities (Wurtman et al., 1963a, b; Arendt, 2005) and when the person taking melatonin avoids intense sunlight (Wiechmann et al., 2008). However, precaution should be taken if melatonin is used by those at risk for asthma, as it has been associated with increases in asthma symptoms (Sutherland et al., 2003).


Treatments of Diseases Associated with Circadian Dysfunction

i. Seasonal Affective Disorder - SAD. It may be surprising that something as simple as light could be an effective treatment for a disease as devastating as depression. And yet clinical trials have confirmed that visible light can alter a deep state of depression (Lewy et al., 1982, 1987, 2007; Rosenthal et al., 1984; Loving et al., 2005; Westrin and Lam, 2007; Lieverse et al., 2008). These changes can and do occur because visible light adjusts the specific chemical make up of the brain that is modified by depression (Brewerton et al., 1995).

Seasonal depression or Seasonal Affective Disorder (SAD) is a depression occurring in the fall, with no apparent outside grief or stress, which is spontaneously reversed or triggers mania in the spring or summer. The symptoms, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) (1994), include sadness, decreased energy and libido, anxiety, increased need for sleep, and strong cravings for carbohydrates. Errors in genes associated with serotonin transmission lead to a high risk for Seasonal Depression (Sher, 2001). Changes in seasons have been linked with changes in serotonin levels, increasing in the summer and decreasing in the winter, and this mimics the pattern of seasonal depression and mania (Brewerton et al., 1995; Praschak-Rieder et al., 2008). The preval‎ence of SAD varies with latitude (i.e., 2% of the population of Florida vs. 10% in New Hampshire). Sub-seasonal depression patients with milder symptoms are even more preval‎ent. While 5% of the population of New York may have seasonal depression, it is estimated that over 15% have sub-seasonal depression (Rosen et al., 1990).

ii. Light Treatment for SAD. Early studies found that seasonal depression could be treated with light therapy consisting of the daily administration of visible light (between 2500 and 10,000 lux) in the very early morning (Lewy et al., 1982, 1987, 1998; Rosenthal et al., 1984; Terman et al., 1990, Badia et al., 1991; Kripke, 1991, 1998; Wirz-Justice, 1993; Swartz, et al., 1996; Eastman et al., 1998). These and other, more recent,studies (Loving et al., 2005; Shirani and St. Louis, 2009) have used a light box with several fluorescent lights adjusted to eye level to administer light therapy. Newer studies have used white (Desan et al., 2007) or blue LEDs (Lockley et al., 2003; Warman et al., 2003; Wright, 2004; Cajochen et al., 2005; Glickman et al., 2006; Strong et al., 2009) which have a far greater intensity in the 460 - 500 nm region than fluorescent lighting [Figure 3]. These lamps efficiently trigger non-visual photoreception (Desan et al., 2007) with less light intensity and exposure time. Natural morning sunlight with its high intensity in the 460 - 500 nm region, also relieves the symptoms of SAD (Kent et al., 2009). The antidepressant response to visible light takes approximately 3-4 days to take effect. Treatment needs to be continued throughout the winter months to avoid withdrawal symptoms.

Figure 3. Spectral Distribution of a White LED

The symptoms of SAD, increased carbohydrate appetite, weight gain and hypersomnia, fit a pattern of serotonin and dopamine depletion (Lam et al., 2001; Neumeister et al, 2001). Furthermore, studies have shown that both serotonin and dopamine are increased as a result of ocular visible light treatment (Rao et al., 1990; Roberts et al.,1992a; Brewerton et al., 1995; Lam et al., 1996; Oren, 1991). These are the same neurotransmitters that are enhanced by more traditional antidepressant medication. It seems likely that disturbances in one or both of these neurotransmitters are involved in the pathophysiology of SAD (Lam and Levitan, 2000). So it is not surprising that light treatment, which increases serotonin and dopamine synthesis, would relieve the symptoms of SAD.

iii. Jet Lag. Crossing several time zones significantly affects circadian rhythm. With this change comes a dramatic imbalance of not only neurotransmitters but endocrine hormones (thyroid hormone, insulin), which can lead to drastic changes in mood and concentration. This syndrome is commonly called jet lag (Hirshfield, 1996). There is evidence that jet lag produces temporal lobe atrophy (amnesia) and spatial cognitive deficits (location errors and disorientation) (Cho, 2001). Typically problems occur when the circadian period is phase shifted (lengthened or shortened) as it is in a trip from west to east (i.e., New York to Paris) or east to west (i.e., Paris to New York).

iv. Jet Lag Therapy. The judicious use of light (therapy and/or sunlight) at the appropriate time can quickly rebalance erratic circadian rhythm and speed recovery from jet lag. (Boulos et al., 1995; Wever, 1985; Dollins et al., 1994; Revell et al., 2006; Canton and Roberts, 2006; Paul et al., 2009). Jet lag treatment is especially effective when used in conjunction with exogenous melatonin (Arendt, 1997; Arendt et al.,1999; Revell et al., 2006). Melatonin, the body's natural endogenous sleep aid, is a tryptophan metabolite synthesized from serotonin by N-acetyl transferase (NAT) in the dark (Moore and Klein, 1974). In the presence of visible light, NAT is inhibited and melatonin production is shut down. Under normal circadian conditions, there is a small peak of melatonin production every afternoon at about 4 pm, and a much larger peak that occurs later in the evening between approximately 10 pm and 3 am. This pathway can be modified by a combination of light and exogenous melatonin treatment.

Internal melatonin can be enhanced by taking melatonin pills (0.5 mg is sufficient to fill all melatonin receptors associated with circadian imbalance) (Zhdanova et al., 1995), or by increasing its natural production by changes in the diet (Wurtman et al., 2003). Consuming foods that contain protein high in tryptophan, i.e., milk, especially together with sweets (increased insulin helps transport tryptophan across the blood-brain barrier), will naturally increase melatonin production and produce drowsiness. In contrast, high-protein food, such as meat that is rich in tyrosine and low in carbohydrates, can increase excitatory neurotransmitters and enhance wakefulness (Wurtman et al., 2003; Canton and Roberts, 2006).

In summary, by judicious exposure to daylight or circadian blue light and with careful timing of meals and intake of a low dose of melatonin, it is possible to resynchronize circadian rhythms and reduce symptoms of jet lag. (Brown, 1994; Arendt, 1997; Arendt et al., 1999; Eastman et al., 2005; Roberts, 2001b; Revell et al., 2006; Wurtman et al., 2003).

v. Shift Work. Jet lag, while unpleasant, is usually an infrequent occurrence. Shift work, which requires employees to constantly change their waking and sleeping hours, is a much more common occurrence. Over 20% of industrial workers and 30 % of health care providers engage in shift work (Arendt, 2010). Constant changes in work shift lead to a loss of alertness, productivity and increase in accidents. Night work and alternating patterns of shift work are the most injurious to human health, and can lead to chronic and even lethal diseases (Straif et al., 2007; Arendt, 2010).

Reports from Europe (International Agency for Research on Cancer) (IARC 2006) and the United States (Stevens et al., 2007) have noted that shift-work that involves circadian disruption is a risk factor for cancer, especially breast (Hansen, 2001; Stevens et al., 1992, Stevens, 2006; Blask et al., 2005, 2002; Blask, 2009), and prostate cancer (Baldwin and Barrett, 1998; Kubo et al., 2006). Exposure to visible light at night deregulates the circadian gene, Per2, which is involved in human breast and endometrial cancer development (Chen, 2005).

Visible light at night, whether from nighttime shift work or inadvertent light trespass, suppresses the natural production of melatonin, decreasing its natural killer-cell antitumor activity (Irwin et al., 1996). Disruption of the natural circadian immune cycle also changes the T-helper1/T-helper 2 cytokine balance, reducing cellular immune defense and surveillance leading to increased risk of infectious disease (Dimitrov et al., 2004, 2007) and autoimmune diseases (Conti and Maestroni 1995, 1998; Zhang et al., 1997; Cutolo et al., 2005; Pandi-Perumal et al., 2008).

In addition to an increased risk of cancer and autoimmune disorders, shift workers have higher risk of cardiovascular disease (Knutsson and Boggild, 2000) and metabolic disorders including Type 2 diabetes (Spiegel et al., 2005; Van Cauter et al., 2008; Hanon, et al., 2008) and obesity (Di Lorenzo et al., 2003), and fertility dysfunction (Bisanti et al., 1996).

Besides physical dysfunction, there are mental and emotional problems associated with shift work, including depression (Sookoian et al., 2007), anxiety (Neckelmann et al., 2007), and psychosis (Mariani and Hart, 2005). Learning and memory are also impeded by shift work and sleep deprivation (Harrison and Horne, 2000; Vandewalle et al., 2009).

vi. Shift Work Therapy. Treatment for the physical and emotional problems associated with shift work is complex. It involves varied lighting regimens, with enhanced circadian blue light in the evening to increase alertness, blue blocking glasses in the morning to prevent circadian stimulation, and enhanced daytime darkness and/or melatonin to aid in restorative deep (delta) sleep (Eastman et al., 1999; Smith et al., 2009). These strategies have recently been reviewed (Arendt, 2010; Stevens et al., 2007). As with jet lag, diet (tyrosine containing foods for alertness and tryptophan containing foods for sleep), may aid in rebalancing shift work circadian disruption (Wurtman et al., 2003; Canton and Roberts, 2006).


vii. Sleep Disruption. Human sleep is complex and is controlled by both endogenous homeostatic and circadian hormone secretion (Cardinali and Pandi-Perumal, 2005). It can be categorized into three components: Non-sleep (wakefulness); REM (rapid-eye-movement) sleep (the brain, eyes, and body muscles are active-dreaming); and Slow-wave sleep, which is further classified as either theta (light sleep or drowsiness) or delta (deep sleep). The level of alertness or sleepiness may be quantitatively measured by noting the changes in the electroencephalographic (EEG) power spectrum. In general the lower the number (Hz) the slower the brain pattern and vice versa [Table 3].

The endogenous homeostatic control of sleep is related to how long someone has been awake and the subsequent depth of their sleep. Circadian rhythm determines the onset of sleep and the relative duration of REM and Slow-Wave sleep (NonREM or NREM sleep) (Gillettte and Abbott, 2005). Circadian modification of sleep is influenced by age, with onset delayed in adolescents (Tarokh and Carskadon, 2010) and a reduction in Slow-Wave sleep in the elderly (Cajochen et al., 2006).

Sleep comes in cycles beginning with Slow-Wave sleep and ending with REM or dream sleep. Each cycle of sleep induces a different neuroendocrine change, which affects all aspects of human physiology (Carcinali and Esquifio, 2005). Delta sleep is the deepest sleep, and is restorative. During this cycle there is a decrease in stress related hormones, lowering of blood pressure and heart and respiration rate, and an increase in growth hormone. REM sleep is a state of brain activation that increases heart rate and blood pressure and induces irregular respiration. Although REM sleep and total duration of sleep are relatively stable with increasing age, the duration of Slow-Wave, in general and delta sleep in particular, decreases with each decade of life (Dijk and Duffy, 1999). Although 15% of night sleep is delta sleep, only 5% of daytime (naptime) sleep is delta sleep. The inability to get sufficient delta sleep in the daytime may explain some of the health hazards associated with shift work (Arendt, 2010).

Sleep research has benefitted from recent discoveries of the chemical, physiological and biophysical contributions of visible light control to human circadian response (Provencio et al., 2000; Berson et al., 2002, 2003; Brainard et al., 2001). As sleep research has become an interdisciplinary study, integrating neuroscience, endocrinology, circadian rhythm, photobiology, and sleep physiology, a more precise understanding of the molecular mechanisms involved in human sleep and wakefulness have begun to be defined. [Cardinali and Pandi-Perumal, 2005; Pandi-Perumal et al., 2008). This knowledge of the neuroendocrinology of sleep, and the dark/light control of the human circadian response has been directly applied to treat sleep disorders (Dowling et al., 2008; Riemersma-van der Lek et al., 2008; Waff et al., 2010; Werken et al., 2010).

viii. Sleep Disorder Treatments. Appropriate circadian blue light (480 nm) (Brainard et al., 2001) in the morning and avoidance of circadian blue light in the evening (Vetch et al., 2004), emitted from lamps (Doljansky et al., 2005), TV and computer monitors and "gadgets", has a powerful effect on improving circadian input of sleep. A cooler room temperature (Van Someren, 2000c), evening diet containing food such as milk, that is enhanced with the precursor of melatonin, tryptophan (Wurtman et al., 2003), and daytime physical activity (which increases the production of melatonin in the evening) (Knight et al., 2005), have been found to lead to better sleep patterns. Taking these simple steps is often sufficient to overcome most mild sleep disorders.

Additional procedures may be necessary to overcome the sleep disturbances that accompany old age and dementia. The elderly are particularly susceptible to sleep disturbances (Cajochen et al., 2006) due in part to the changes in the transparency of their lens to circadian light (Roberts, 2009). Alzheimer's disease is known to damage the cholinergic pathways and the circadian pacemaker in the suprachiasmatic nucleus which can also contribute to sleep disruption. Dementia is often associated with difficulty in falling asleep (sleep latency), and frequent nighttime awakenings. There is also a decrease in slow-wave sleep, rapid eye movement sleep, and total sleep time, and an increase in daytime napping.

Cyclic agitation episodes (sundowning), nightmares or hallucinations, sleep attacks, and nocturnal behavioral outbursts are often associated with specific dementia syndromes (McCurry and Ancoli-Israel, 2003). Modifying the exposure to circadian blue light in the late afternoon and evening (Van Someren, 2000; Dowling et al., 2008; Riemersma-van der Lek et al. 2008; Werken et al., 2010) in conjunction with exogenous melatonin have been found to enhance nighttime sleep in the elderly. Waff et al. (2010) modified the lighting in the rooms of elderly and Alzheimer's nuns to increase daylight in the morning, and replaced white light with red light in the rooms and hallways in the evening. This resulted in increased undisturbed nighttime sleep, with a concomitant decrease in blood pressure for both the elderly and the Alzheimer patients.

Loss of sleep can disrupt more than cognitive functions, it enhances the risk for diseases such as cancer and hypertension (Stevens et al., 2007). Metabolic changes associated with sleep deprivation increase the risk of Type 2 diabetes and obesity (Van Cauter et al., 1992, 2008; Spiegel et al., 1999; Staels et al., 2006). The human immune response is circadian (Levi et al., 1991; Levi and Schibler, 2007). Exposure to circadian light in the evening modifies immune function (Everson, 1993; Maestroni, 1993; Maestroni and Conti, 1996; Nelson, 2004).

Sleep deprivation suppresses natural killer-cell activity and changes the T-helper 1/T-helper 2 cytokine balance, reducing cellular immune defense and surveillance (Roberts, 2000; Dimitrov et al., 2004, 2007). Sleep deprivation and circadian disfunction deregulate circadian genes involved in cancer-related pathways (Gery and Koeffler, 2007; Fu and Lee, 2003; Fu et al., 2002; Viola et al., 2007; Belle et al., 2009; Smith et al., 2008). Inactivation of the circadian Period gene, Per1-3, promotes tumor development in mice, and in human breast, prostate and endometrial tumors (Chu et al., 2005; Chen et al., 2008).

Sleep disorders are often chronic conditions. Therefore, it may be prudent to treat sleep disorders with the non-pharmacological methods that have been proven to be both safe and effective.

CONCLUSION
Sufficient basic science has been published to establish proper lighting protocols to rebalance circadian rhythm. These include considering the age of recipient, spectrum, intensity, timing and direction of therapeutic light. Treatment of circadian dysfunction is essential to the health, productivity and well being. Future definitions and effective treatments for circadian dysfunction (including intensive care psychosis, insomnia, and hazardous shift work associated diseases of cancer, obesity and Type 2 diabetes) will only be possible when light treatments follow the laws of photobiology. In that way they will be reproducible and accurate. Correct use of evidenced based lighting design in homes, schools, offices, assisted living facilities and hospitals will prevent circadian disruption, maintain a healthy environment for all, and help preserve human dignity in old age.